Hidradenitis Suppurativa

'REGOR"%*EMEC*EAN2EVUZ*AMES*,EYDEN%DS
(IDRADENITIS3UPPURATIVA
'REGOR"%*EMEC*EAN2EVUZ*AMES*,EYDEN %DS
Hidradenitis
Suppurativa
7ITH&IGURESAND4ABLES

Gregor B. E. Jemec, MD, DMedSc
University of Copenhagen
Roskilde Hospital
Department of Dermatology
Kgevej 713
4000 Roskilde, Denmark
Jean Revuz, MD, DMedSc

CHU Henri Mondor
Service Dermatologie
Avenue Marechal de Lattre de Tassigny 51
94010 Crteil CX, France
James J. Leyden, MD
University Hospital of Pennsylvania
Department of Dermatology
Spruce Street 3400
19104 Philadelphia, USA
Library of Congress Control Number: 2006928941
ISBN-10 3-540-33100-X Springer Berlin Heidelberg New York

ISBN-13 978-3-540-33100-1 Springer Berlin Heidelberg New York
This work is subject to copyright. All rights are reserved, whether the whole or part of the
material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproductiononmicrofilmor inanyotherway, andstorage indata
banks. Duplication of this publication or parts thereof is permitted only under the provisions
of the German Copyright Law of September 9, 1965, in its current version, and permissions for
use must always be obtained from Springer. Violations are liable for prosecution
under the German Copyright Law.
Springer is a part of Springer Science + Business Media

springer.com
Springer-Verlag Berlin Heidelberg 2006

Printed in Germany
The use of general descriptive names, registered names, trademarks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt
from the relevant protective laws and regulations and therefore free for general use.
Product liability: The publishers cannot guarantee the accuracy of any information about
dosage and application contained in this book. In every individual case the user must check
such information by consulting the relevant literature.
Editor: Marion Philipp, Heidelberg

Desk Editor: Ellen Blasig, Heidelberg
Cover design: Frido Steinen-Broo, eStudio Calamar, Spain
Reproduction and typesetting: AM-Productions GmbH, Wiesloch
Production: LE-TEX Jelonek, Schmidt & Vckler GbR, Leipzig
Printed on acid-free paper 27/3100 YL 5 4 3 2 1 0

dedicated to
Borut
#ONTENTS 6))
Preface
This is the first and most comprehensive book perts to give their opinion and interpretation of
dedicated to the understanding and treatment the disease, and left our own point of view to the
of hidradenitis suppurativa. The most recent chapters summarizing pathogenesis and thera-
monograph on this disease was Dr Benedeks py. At points you may therefore find discussions
supplement to Acta Dermatovenerologica in of e.g. apocrine glands with which the editors
1957 (1)! The long interval has not been justified may disagree, but rather than suppress informa-
by a benign nature or quiet disposition of the tion we have sought to stimulate and inspire an
disease. This is a common and debilitating dis- an open dialogue. The book is intended for both
ease that significantly reduces the quality of life concrete factual information, as well as inspira-
for patients. In spite of this it has not achieved a tion for further studies of aetiology, pathogen-
deserved level notoriety and scientific interest, esis and therapy.
but remains an obscure an ill-understood men- We would like to thank our colleagues for
ace to the patients. generously sharing their insight and knowledge.
There may be several reasons for this neglect. We would also like to thank Ms Ellen Nissen for
One reason may be that it is has been described providing expert translation from French, the
as a heart sink disease, both for patients and anonymous patients for sharing their stories
physicians alike. Patients often find it a debili- and our publisher for a smooth and efficient
tating and embarrassing disease with a high de- cooperation.
gree of morbidity; and at the same time treating
physicians generally find it a difficult disease to Gregor B.E. Jemec
treat. Patients therefore hide their disease and Roskilde, Denmark
chose to suffer in silence rather than to seek
help. Physicians similarly often adopt a reduc- Jean Revuz
tionist approach rather than seeking insight in Paris, France
the face of the clinical challenge. Finally, it may
be that it is only now that a sufficient college of James Leyden
experts have gathered. Philadelphia, USA
It is therefore our hope that this book will be
of benefit to the many patients; and of inspira- Summer 2006
tion and insight to the many different specialists
treating the disease. We have adopted an open, 1. Benedek T. Hidradenitis suppurativa. Its etiology,
exploratory approach to the topic, rather than a pathogenesis and specific vaccine therapy. Acta Derm
normative one. We have invited recognised ex- Venerol (Stockholm) 1957; 37(Suppl. 37): 347.
Contents
Chapter 1 3.3.2 Atypical Localizations

Hidradenitis Suppurativa Introduction Other Zones May Be Involved . . . . 17
Albert Kligman 3.3.3 Distribution of Lesions . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . 3 3.4 Evolution of the Disease
and its Severity . . . . . . . . . . . . . 19
Chapter 2 3.4.1 Age at Onset and Resolution . . . . . 19
Verneuil and Verneuils Disease: 3.5 Clinical Course . . . . . . . . . . . . 19
an Historical Overview 3.5.1 Intermittent/Benign Course
Grard Tilles of the Disease . . . . . . . . . . . . . 20
3.5.2 Intermediate Course of the Disease . 20
2.1 Biographical Landmarks 3.5.3 Continuous Disease:
of a Surgeon-Venereologist . . . . . . 4 Moderate, Severe. . . . . . . . . . . . 20
2.2 LHidradnite Phlegmoneuse 3.6 Severity Indexes . . . . . . . . . . . . 21
(Verneuils Disease), 3.6.1 Hurleys Clinical Staging [2] . . . . . 21
Primary Observations . . . . . . . . 5 3.6.2 Sartorius [9] . . . . . . . . . . . . . . 21
2.3 Further Observations 3.7 Diagnosis . . . . . . . . . . . . . . . . 22
and Discussions in Europe 3.7.1 Diagnostic Criteria . . . . . . . . . . 22
and Overseas . . . . . . . . . . . . . . 6 3.7.2 Delay in Diagnosis . . . . . . . . . . 22
2.4 Hidrosadenitis and Acne Conglobata: 3.7.3 Differential Diagnoses . . . . . . . . 23
Controversial Views . . . . . . . . . . 8 References . . . . . . . . . . . . . . . 23
2.5 Acne Inversa, the Last Meta-
morphosis of Verneuils Disease? . . 9 Chapter 4
References . . . . . . . . . . . . . . . 9 Pathology of Hidradenitis Suppurativa
Alison Layton
Chapter 3
Clinical Presentation 4.1 Introduction . . . . . . . . . . . . . . 25
Florence Poli, Gregor B.E. Jemec, 4.2 Glandular Elements of the Skin . . . 26
Jean Revuz 4.2.1 Sebaceous Glands
and the Pilosebaceous Unit . . . . . 26
3.1 Introduction . . . . . . . . . . . . . . 11 4.2.2 Apocrine Glands . . . . . . . . . . . 27
3.2 Individual Lesions . . . . . . . . . . . 12 4.2.3 Eccrine Glands . . . . . . . . . . . . . 27
3.2.1 Primary (Early) Lesions. . . . . . . . 12 4.2.4 Apoeccrine Glands . . . . . . . . . . 27
3.2.2 Secondary Lesions . . . . . . . . . . . 13 4.3 Histological Appearance of HS . . . 27
3.2.3 Tertiary Lesions . . . . . . . . . . . . 14 4.3.1 Early Lesions . . . . . . . . . . . . . 27
3.2.3.1 Comedones . . . . . . . . . . . . . . . 15 4.3.2 Established Hidradenitis
3.2.4 Other Lesions . . . . . . . . . . . . . 15 Suppurativa . . . . . . . . . . . . . . 28
3.3 Topography . . . . . . . . . . . . . . . 16 4.4 Immunohistochemistry
3.3.1 Involved Areas . . . . . . . . . . . . 16 of Hidradenitis Suppurativa . . . . . 30
3.3.1.1 Two Main Zones . . . . . . . . . . . 16 4.5 Cytokeratin Expression in HS . . . . 30
3.3.1.2 The Two Less Frequently
Involved Zones . . . . . . . . . . . . 17
8 #ONTENTS
4.6 Comparison with Other Disorders . 31 Chapter 7

4.6.1 FoxFordyce Disease . . . . . . . . . 31 Hidradenitis Suppurativa
4.6.2 Acne . . . . . . . . . . . . . . . . . . . 31 and Crohns Disease
4.6.3 Follicular Occlusion Triad . . . . . . 31 Philippe Seksik, Jean-Franois Contou,
4.6.4 Pilonidal Sinus . . . . . . . . . . . . . 31 Anne Cosnes and Jacques Cosnes
4.6.5 Crohns Disease . . . . . . . . . . . . 32 7.1 Definition and Course
4.7 Conclusions . . . . . . . . . . . . . . 32 of Crohns Disease . . . . . . . . . . . 50
Acknowledgements . . . . . . . . . . 33 7.1.1 Pathophysiology . . . . . . . . . . . . 50
References . . . . . . . . . . . . . . . 33 7.1.1.1 Genetic Factors . . . . . . . . . . . . 51
7.1.1.2 Enteric Microflora . . . . . . . . . . 51
Chapter 5 7.1.1.3 Immune-Mediated Tissue Injury . . 51
Imaging 7.2 Pathology . . . . . . . . . . . . . . . . 51
Ximena Wortsman, Gregor B.E. Jemec 7.3 Clinical Aspects . . . . . . . . . . . . 52
5.1 Introduction . . . . . . . . . . . . . . 34 7.3.1 Disease Location . . . . . . . . . . . 52
5.2 Ultrasound . . . . . . . . . . . . . . . 34 7.3.2 Clinical Presentation . . . . . . . . . 52
5.3 Magnetic Resonance Imaging (MRI) 36 7.4 Therapeutic Aspects and Prognosis 52
5.4 X-Ray Examination . . . . . . . . . . 36 7.5 Cutaneous Crohns Disease. . . . . . 52
5.5 Discussion . . . . . . . . . . . . . . . 36 7.5.1 Clinical Presentation
References . . . . . . . . . . . . . . . 37 of Cutaneous Lesions . . . . . . . . . 53
7.5.2 Therapeutic Aspects and Prognosis . 53
Chapter 6 7.6 Crohns Disease
Associated Diseases: and Hidradenitis Suppurativa . . . . 53
Causality or Complications? 7.6.1 Differential Diagnosis . . . . . . . . 53
Aude S. Nassif and Gregor B.E. Jemec 7.7 Co-Existence of HS and CD . . . . . 55
6.1 Introduction . . . . . . . . . . . . . . 38 7.8 Treatment of Perianal Co-existent
6.2 Cutaneous Diseases (Excluding CD and HS . . . . . . . . . . . . . . . 55
Squamous Cell Carcinomas) . . . . . 39 References . . . . . . . . . . . . . . . 55
6.2.1 Follicular Occlusion Diseases . . . . 39
6.2.1.1 Acne Conglobata . . . . . . . . . . . 40 Chapter 8
6.2.1.2 Dissecting Folliculitis of the Scalp . 40 Epidemiology
6.2.1.3 Pilonidal Sinus . . . . . . . . . . . . . 41 Luigi Naldi
6.2.2 Pigmentation Disorders 8.1 Introduction . . . . . . . . . . . . . . 58
of the Skin Folds: DowlingDegos 8.2 Descriptive Epidemiology . . . . . . 58
and Kitamuras Diseases . . . . . . . 41 8.3 Analytic Epidemiology . . . . . . . . 60
6.3 Rheumatological Disorders . . . . . 42 8.4 Clinical Epidemiology:
6.3.1 Clinical Picture . . . . . . . . . . . . 42 Natural History and Prognosis . . . 62
6.3.2 Radiographic Features . . . . . . . . 42 8.5 Perspectives . . . . . . . . . . . . . . 63
6.3.3 Treatment. . . . . . . . . . . . . . . . 42 References . . . . . . . . . . . . . . . 64
6.3.4 Mechanisms . . . . . . . . . . . . . . 43
6.4 Associated Cancers . . . . . . . . . . 43 Chapter 9
6.4.1 Non-Skin Cancers . . . . . . . . . . . 43 Nosology and Classification
6.4.2 Squamous Cell Carcinoma . . . . . . 44 Jean Revuz, Gregor B.E. Jemec
6.4.2.1 Incidence and Prevalence . . . . . . 44 and James Leyden
6.4.2.2 Clinical Picture . . . . . . . . . . . . 44 9.1 Introduction . . . . . . . . . . . . . . 65
6.4.2.3 Differential Diagnosis . . . . . . . . 45 9.2 Morphology . . . . . . . . . . . . . . 66
6.4.2.4 Treatment . . . . . . . . . . . . . . . 45 9.2.1 Anatomy . . . . . . . . . . . . . . . . 66
6.4.2.5 Prognosis . . . . . . . . . . . . . . . . 45 9.2.2 Clinical Features . . . . . . . . . . . 66
6.5 Other Co-Occurrences . . . . . . . . 45 9.3 Etiology; Pathogenesis . . . . . . . . 67
6.6 Conclusion . . . . . . . . . . . . . . . 46 9.3.1 Infection . . . . . . . . . . . . . . . . 67
References . . . . . . . . . . . . . . . 46 9.3.2 Inflammation . . . . . . . . . . . . . 68
#ONTENTS 8)
9.3.3 Hormones . . . . . . . . . . . . . . . 68 Chapter 12

9.3.4 Treatments . . . . . . . . . . . . . . . 68 Endocrinology
9.4 Conclusion . . . . . . . . . . . . . . . 69 Michel Faure, Evelyne Drapier-Faure
12.1 Introduction . . . . . . . . . . . . . . 95
Chapter 10 12.2 Hyperandrogenism and the Skin . . 95
Genetics of Hidradenitis Suppurativa 12.2.1 Androgenization . . . . . . . . . . . 95
Jan von der Werth, Pam Wood, 12.2.2 Androgen Metabolism . . . . . . . . 96
Alan D. Irvine, W.H. Irwin McLean 12.2.3 Causes of Hyperandrogenism . . . . 96
10.1 Clinical Genetics 12.3 Lack of Association between HS
of Hidradenitis Suppurativa . . . . . 70 and Endocrinopathies. . . . . . . . . 97
10.2 Genodermatoses . . . . . . . . . . . . 74 12.4 HS and Biological Hyper-
10.3 Methods for Identifying androgenism . . . . . . . . . . . . . . 97
Disease Genes . . . . . . . . . . . . . 74 12.5 End-Organ Androgen Sensitivity? . 98
10.4 Genetic Markers . . . . . . . . . . . . 75 References . . . . . . . . . . . . . . . 98
10.5 Positional Cloning of Dominantly
Inherited Disease Genes . . . . . . . 75 Chapter 13
10.6 Genome-Wide Linkage Analysis Immunity
in Familial HS . . . . . . . . . . . . . 77 Istvn Nagy, Lajos Kemny
10.7 Linkage of Hidradenitis Suppurativa 13.1 Introduction . . . . . . . . . . . . . 100
to 6q25.2 . . . . . . . . . . . . . . . . 78 13.2 Ancient and Modern:
10.8 Identification of a Second HS Locus Innate and Acquired Immunity . . 101
to Chromosome 19 . . . . . . . . . . 79 13.3 TLR/IL-1R Superfamily and their
10.9 Candidate Genes Analysed Signaling Pathways in the Skin . . 102
in Linked HS Kindreds . . . . . . . . 79 13.4 Members of the TLR Family
10.9.1 Oestrogen receptor-A and HS . . . . 79 Expressed by Keratinocytes . . . . 102
10.9.2 ZNF91 and HS . . . . . . . . . . . . . 79 13.5 IL-1 Receptors in the Skin . . . . . 104
10.9.3 TIZ Association with HS . . . . . . . 80 13.6 Signaling Pathways via TLR/IL-1R 104
10.9.4 Potential Contribution 13.6.1 MyD88-Dependent Signaling
of the VIP Gene to HS . . . . . . . . 80 Pathway . . . . . . . . . . . . . . . . 104
10.10 Additional Candidate Gene-Protein 13.6.2 MyD88-Independent Signaling
Systems in HS . . . . . . . . . . . . . 81 Pathway . . . . . . . . . . . . . . . . 105
10.10.1 Interleukin 1-A . . . . . . . . . . . . 81 13.7 Keratinocyte-Derived Effector
10.10.2 TNF Signalling and HS . . . . . . . . 81 Molecules in the Innate Immune
10.11 Discussion . . . . . . . . . . . . . . . 81 System of the Skin . . . . . . . . . . 105
10.12 Conclusions . . . . . . . . . . . . . . 82 13.8 Antimicrobial Peptides . . . . . . . 105
References . . . . . . . . . . . . . . . 83 13.9 B-Defensins . . . . . . . . . . . . . 106
13.10 Cathelicidins . . . . . . . . . . . . . 106
Chapter 11 13.11 RNase7 . . . . . . . . . . . . . . . . 107
Bacteriology 13.12 Antileukoprotease (ALP) . . . . . . 107
of Hidradenitis Suppurativa 13.13 Pro-Inflammatory Chemokines . . 107
Cristina Oprica, Carl Erik Nord 13.14 Pro-Inflammatory Cytokines . . . 108
11.1 Normal Microflora of the Skin . . . 86 13.15 TLR Recognition and the
11.2 Bacteria Found in HS Lesions . . . . 87 Commensal Microbiota of the Skin 109
11.3 General Factors About Bacterial 13.16 Skin Infections and Innate Immune
Involvement in HS Pathogenicity . . 90 Responses of the Epidermis . . . . 110
11.4 The Role of Antibiotics 13.17 Hidradenitis Suppurativa
in the Treatment of HS . . . . . . . . 91 and the Skin Immune System . . . 110
11.5 Possible Consequences for Bacterial 13.18 Conclusions . . . . . . . . . . . . . 112
Ecology due to Antibiotic Treatment References . . . . . . . . . . . . . . 112
in HS . . . . . . . . . . . . . . . . . . 92
References . . . . . . . . . . . . . . . 92
8)) #ONTENTS
Chapter 14 16.3.2 Spironolactone . . . . . . . . . . . . 126

Quality of Life in Hidradenitis 16.4 Finasteride . . . . . . . . . . . . . . 126
Suppurativa References . . . . . . . . . . . . . . 127
Pierre Wolkenstein
14.1 Introduction . . . . . . . . . . . . . 116 Chapter 17
14.2 Concept and Measure Oral Retinoids
of Quality of Life . . . . . . . . . . 116 for Hidradenitis Suppurativa
14.2.1 Why Try to Measure Quality Jurr Boer
of Life? . . . . . . . . . . . . . . . . 116 17.1 Introduction . . . . . . . . . . . . . 128
14.2.2 Reporting the Viewpoint of Patients: 17.2 Isotretinoin . . . . . . . . . . . . . 128
Methods of Measurement 17.2.1 Mechanism of Action [1, 2] . . . . . 128
of Quality of Life . . . . . . . . . . 117 17.2.2 Clinical Experience . . . . . . . . . 129
14.2.3 Reporting the Viewpoint 17.2.2.1 Isotretinoin Monotherapy for HS . 129
of Physicians: Uniform Outcome 17.2.3 Isotretinoin Therapy in Patients
Variables . . . . . . . . . . . . . . . 117 with Acne and Coexistent HS . . . 129
14.2.4 Practical Approach Reconciling 17.2.4 Isotretinoin in the Pre-
the Viewpoints of Patients and Postoperative Phase . . . . . . 131
and Physicians . . . . . . . . . . . . 117 17.2.5 Isotretinoin in Combination
14.3 Impact of HS upon Quality of Life 117 Treatment of HS . . . . . . . . . . . 131
14.3.1 Altered Self-Reported Health: 17.2.6 Side-Effects . . . . . . . . . . . . . . 131
Qualitative Approach . . . . . . . . 117 17.3 Etretinate and Acitretin. . . . . . . 132
14.3.2 Measure of Quality of Life: 17.3.1 Mechanism of Action . . . . . . . . 132
Quantitative Approach . . . . . . . 118 17.3.2 Clinical Experience: Etretinate
14.4 Impaired Quality of Life: and Acitretin for HS . . . . . . . . . 132
What Conclusion? . . . . . . . . . . 118 17.3.3 Side-Effects . . . . . . . . . . . . . . 134
14.4.1 Conclusion for Patients . . . . . . . 118 References . . . . . . . . . . . . . . 134
14.4.2 Conclusion for Physicians . . . . . 119
References . . . . . . . . . . . . . . 119 Chapter 18
Immunosuppressive Therapy
Chapter 15 in Hidradenitis Suppurativa
Antibiotic Therapy Hanne Nybk, Gregor B.E. Jemec
James Leyden, Jean Revuz 18.1 Introduction . . . . . . . . . . . . . 136
15.1 Introduction . . . . . . . . . . . . . 120 18.2 What Can We Achieve
15.2 Clinical Experience . . . . . . . . . 121 With Therapy? . . . . . . . . . . . . 137
15.3 Therapy . . . . . . . . . . . . . . . . 121 18.3 Immunosuppressive Therapies . . 137
References . . . . . . . . . . . . . . 123 18.3.1 Prednisolone
and Other Corticosteroids . . . . . 138
Chapter 16 18.3.2 Ciclosporin . . . . . . . . . . . . . . 138
Antiandrogens 18.3.3 Dapsone . . . . . . . . . . . . . . . 138
Evelyne Drapier-Faure, Michel Faure 18.3.4 Methotrexate . . . . . . . . . . . . . 138
16.1 Introduction . . . . . . . . . . . . . 124 18.4 Hidradenitis Suppurativa
16.2 Antiandrogens as a Side-Effect of Immuno-
and Antiandrogen Therapies . . . 124 suppressive Drugs . . . . . . . . . . 139
16.2.1 Cyproterone Acetate . . . . . . . . 125 18.5 Practical Use of Immuno-
16.2.2 Spironolactone . . . . . . . . . . . . 125 suppressive Therapy . . . . . . . . . 139
16.2.3 Finasteride . . . . . . . . . . . . . . 125 References . . . . . . . . . . . . . . 140
16.2.4 Antiandrogenic Progestins . . . . . 125
16.2.5 Oral Contraceptives . . . . . . . . . 125
16.3 Antiandrogens in HS . . . . . . . . 126
16.3.1 Cyproterone Acetate . . . . . . . . 126
#ONTENTS 8)))
Chapter 19 21.4.2 Fusidic Acid . . . . . . . . . . . . . 157

Zinc and Other Experimental 21.5 Intralesional Therapy . . . . . . . . 157
Medical Treatments 21.6 The Use of Local Therapy . . . . . 158
Brigitte Dreno, Anabelle Brocard 21.7 Publication Bias . . . . . . . . . . . 158
19.1 Introduction . . . . . . . . . . . . . 141 References . . . . . . . . . . . . . . 159
19.2 Zinc Salts . . . . . . . . . . . . . . . 141
19.2.1 Mechanisms of Action: Chapter 22
Modulation of the Proliferation Surgery
and Differentiation of Keratino- Jan Lapins, Lennart Emtestam
cytes and Cell Apoptosis . . . . . . 141 22.1 Introduction . . . . . . . . . . . . . 161
19.2.2 Anti-Inflammatory Activity . . . . 142 22.2 Methods of Closure . . . . . . . . . 164
19.2.3 Activity Against 5A-Reductase . . 142 22.3 Anatomical Regions Involved . . . 165
19.2.4 Healing . . . . . . . . . . . . . . . . 142 22.3.1 Axillary HS . . . . . . . . . . . . . 165
19.3 Zinc Salts in Verneuils Disease . . 142 22.3.2 Inguinal Disease . . . . . . . . . . . 165
19.4 Other Experimental Drugs . . . . 143 22.3.3 Gluteal-Perianal-Perineal Disease 165
References . . . . . . . . . . . . . . 144 22.4 Excision Margins . . . . . . . . . . 166
22.5 Complications . . . . . . . . . . . . 166
Chapter 20 22.5.1 Recurrent Disease After Surgery . 167
Biologics For Hidradenitis Suppurativa 22.6 Carbon Dioxide Laser Surgery
(Verneuils Disease in the Era in HS . . . . . . . . . . . . . . . . . 167
of Biologics) 22.6.1 Anesthesia . . . . . . . . . . . . . . 168
Sharon E. Jacob, Francisco A. Kerdel 22.6.2 Postoperative Wound Care . . . . . 168
20.1 Introduction . . . . . . . . . . . . . 145 22.6.3 Practical Hints and Comments . . 168
20.2 Background . . . . . . . . . . . . . 145 22.6.3.1 The Carbon Dioxide
20.2.1 Crohns Disease and Hidradenitis Laser Technique . . . . . . . . . . . 168
Suppurativa Co-Occurrence: 22.6.3.2The Use of Scanners . . . . . . . . . 169
A Rationale for Anti-TNF Therapy 147 22.6.3.3 How Radical Should
20.3 Anti-TNF Drugs in HS . . . . . . . 147 the Therapy Be? . . . . . . . . . . . 170
20.4 Future Prospects . . . . . . . . . . . 148 22.6.3.4 Concluding Remarks . . . . . . . . 171
References . . . . . . . . . . . . . . 149 References . . . . . . . . . . . . . . 171
Chapter 21 Chapter 23
Topical Treatment Radiation Therapy
Karin Sartorius, Jurr Boer, Renato G. Panizzon
Gregor B.E. Jemec 23.1 Introduction . . . . . . . . . . . . . 174
21.1 Introduction . . . . . . . . . . . . . 150 23.2 Treatment Regimens . . . . . . . . 175
21.2 Antibiotics . . . . . . . . . . . . . . 151 23.3 Case Series Reports . . . . . . . . . 175
21.2.1 Topical Clindamycin . . . . . . . . 152 23.4 Conclusion . . . . . . . . . . . . . . 175
21.3 Keratolytics . . . . . . . . . . . . . . 152 References . . . . . . . . . . . . . . 175
21.3.1 Resorcinol as a Keratolytic Agent
in Hidradenitis Suppurativa . . . . 152 Chapter 24
21.3.1.1 Indications . . . . . . . . . . . . . . 154 Experimental Physical Therapies
21.3.1.2 Mechanism of Action . . . . . . . . 154 Gregor B.E. Jemec
21.3.1.3 Side-Effects of Resorcinol . . . . . 155 24.1 Introduction . . . . . . . . . . . . . 177
21.3.1.4 Treatment Schedule 24.2 Photodynamic Therapy . . . . . . . 177
with Resorcinol Creams . . . . . . 156 24.3 Depilation . . . . . . . . . . . . . . 179
21.3.1.5 Clinical Experience . . . . . . . . . 156 24.4 Cryosurgery . . . . . . . . . . . . . 179
21.4 Topical Anti-Inflammatory 24.5 Discussion . . . . . . . . . . . . . . 180
Therapy . . . . . . . . . . . . . . . . 157 24.6 Practical Guidelines for Testing
21.4.1 Azelaic Acid . . . . . . . . . . . . . 157 New Physical Therapies . . . . . . 180
References . . . . . . . . . . . . . . 181
8)6 #ONTENTS
Chapter 25 Chapter 27
Treatment An Uncommon Valor
Gregor B.E. Jemec, Jean Revuz Sylvia Shawcross
25.1 Introduction . . . . . . . . . . . . . 183 27.1 Kevin . . . . . . . . . . . . . . . . . 194
25.2 Staging the Disease . . . . . . . . . 183 27.2 Deborah . . . . . . . . . . . . . . . 195
25.3 Treatment of Hidradenitis 27.3 Elizabeth . . . . . . . . . . . . . . . 195
Suppurativa Hurley Stage I . . . . . 184 27.4 Melony . . . . . . . . . . . . . . . . 195
25.4 Treatment of Hidradenitis 27.5 Kerrie . . . . . . . . . . . . . . . . . 196
Suppurativa Hurley Stage II . . . . 184 27.6 John . . . . . . . . . . . . . . . . . . 197
25.5 Treatment of Hidradenitis 27.7 Caroline . . . . . . . . . . . . . . . 197
Suppurativa Hurley Stage III . . . . 185 27.8 Arnold . . . . . . . . . . . . . . . . 197
25.6 Hidradenitis Suppurativa 27.9 Mabel . . . . . . . . . . . . . . . . . 198
with Cysts . . . . . . . . . . . . . . 185 27.10 Nassim . . . . . . . . . . . . . . . . 199
25.7 Experimental Therapies . . . . . . 186 27.11 Mira . . . . . . . . . . . . . . . . . . 199
25.8 General Requirements 27.12 Mindy . . . . . . . . . . . . . . . . . 200
for Treatment . . . . . . . . . . . . 186
Subject Index . . . . . . . . . . . . . . . . 201
Chapter 26
Hidradenitis Suppurativa
Patients Frequently Asked Questions
Jean Revuz
26.1 General Questions . . . . . . . . . . 187
26.2 Heredity . . . . . . . . . . . . . . . 188
26.3 Pregnancy . . . . . . . . . . . . . . 188
26.4 Treatment. . . . . . . . . . . . . . . 189
26.5 Practical Questions . . . . . . . . . 189
26.6 Hints For Daily Life . . . . . . . . . 190
26.7 Relations To Other Factors . . . . . 190
26.8 Psychological Aspects . . . . . . . . 191
26.9 Children and Adolescents . . . . . 192
26.10 Social Security . . . . . . . . . . . . 192
List of Contributors
*URR"OER %VELYNE$RAPIER &AURE

(E-Mail: [email protected]) (E-mail: [email protected])
Deventer Hospital Department of Gynaecology
Department of Dermatology Hpital Edouard Herriot
Postbox 5001 3 place dArsonval
7400 GC Deventer 69437 Lyon 03
The Netherlands France
!NABELLE"ROCARD "RIGITTE$RENO
(E-Mail: [email protected]) (E-mail: [email protected])
Clinique Dermatologique Clinique Dermatologique
Hotel Dieu Hotel Dieu
Place Alexis Ricordeau Place Alexis Ricordeau
44093 Nantes 01 44093 Nantes 01
France France
*EAN &RANOIS#ONTOU ,ENNART%MTESTAM

(E-mail: jean-francois.contou (E-mail: [email protected])
@sat.ap-hop-paris.fr) Department of Dermatology
Service de Gastroentrologie et Nutrition Karolinska University Hospital Huddinge
Hpital St-Antoine SE-141 86
Paris Stockholm
France Sweden
!NNE#OSNES -ICHEL&AURE
(E-mail: [email protected]) (E-mail: [email protected])
Service de Dermatologie Department of Dermatology
Hpital Henri Mondor Hpital Edouard Herriot
51 av du Mal de Lattre-de Tassigny 3 place dArsonval
94010 Crteil 69437 Lyon 03 France
France
!LAN$)RVINE
*ACQUES#OSNES (E-mail: [email protected])
(E-mail: [email protected]) Department of Paediatric Dermatology
Service de Gastroentrologie et Nutrition Our Ladys Hospital for Sick Children Crumlin
Hpital St-Antoine Dublin 12
Paris Ireland
France
XVI
86) #ONTENTS
List of Contributors
3HARON%*ACOB *AN,APINS
Department of Dermatology Department of Dermatology
and Cutaneous Surgery Karolinska University Hospital
University of Miami Huddinge
1600 NW 10th Ave SE-141 86 Stockholm
Room 2023A RMSB (R250) Sweden
Miami Florida 33136
USA !LISON,AYTON
(E-mail: ALISON.LAYTON
'REGOR"%*EMEC @hhc-tr.northy.nhs.uk)
(E-mail: [email protected]) Department of Dermatology
Dept of Dermatology Harrogate District Hospital
University of Copenhagen Roskilde Hospital Lancaster Park Road
Kgevej 713 Harrogate HG2 7SX
Roskilde DK-4000 U.K.
Denmark
*AMES,EYDEN
,AJOS+EMNY (E-mail: [email protected])
(E-mail: [email protected]) Hospital of the University of Pennsylvania
Department of Dermatology Department of Dermatology
Dermatological Research Group of the 3600 Spruce Street
Hungarian Academy of Sciences Philadelphia PA 19104
University of Szeged USA
Kornyi fasor 6
6720 Szeged 7()RWIN-C,EAN
Hungary (E-mail: [email protected])
Human Genetics Unit Division
&RANCISCO!+ERDEL of Pathology and Neuroscience
(E-mail: dermatology.department Ninewells Hospital and Medical School
@hcahealthcare.com) University of Dundee
Department of Dermatology Dundee DD1 9SY
Cedars Medical Center UK
University of Miami
1400 NW 12th Avenue 6 South )STVN.AGY
Miami FL 33136 (E-mail: [email protected])
USA Department of Dermatology and Allergology
University of Szeged
!LBERT+LIGMAN Kornyi fasor 6.
(E-mail: [email protected]) 6720 Szeged
Department of Dermatology Hungary
University of Pennsylvania
226 Clinical Research Building ,UIGI.ALDI
415 Curie Boulevard (E-mail: [email protected])
Philadelphia PA 19104 Centro Studi GISED
USA U.O. Dermatologia Ospedali Riuniti
L.go Barozzi 1
24128 Bergamo
Italy
List of Contributors 86))
!UDE3.ASSIF *EAN2EVUZ
Centre mdical de lInstitut Pasteur Service de Dermatologie
211 rue de Vaugirard Hpital Henri Mondor
75724 Paris 15 51 av du Mal de Lattre-de Tassigny
France 94010 Crteil
France
#ARL%RIK.ORD
(E-mail: [email protected]) +ARIN3ARTORIUS
Department of Clinical Bacteriology (E-mail: [email protected])
Karolinska Universitary Hospital Department of Dermatology
Huddinge Karolinska University Hospital
SE-141 86 Stockholm Huddinge
Sweden SE-141 86 Stockholm
Sweden
(ANNE.YBK
(E-mail: [email protected]) 0HILIPPE3EKSIK
Dept of Dermatology (E-mail: [email protected])
University of Copenhagen Roskilde Hospital Service de Gastroentrologie et Nutrition
Kgevej 713 Hpital St-Antoine
Roskilde DK-4000 Paris
Denmark France
#RISTINA/PRICA 3YLVIA3HAWCROSS
Department of Clinical Bacteriology 872 Highway 105
and Department of Dermatology Chelsea
Karolinska Universitary Hospital Quebec
Huddinge Canada
SE-141 86 Stockholm J9B 1P3
Sweden
'ERARD4ILLES
2ENATO'0ANIZZON (E-mail: [email protected])
(E-mail: [email protected]) Muse de lhpital Saint-Louis
Department of Dermatology 1 av Claude-Vellefaux
University Hospital CHUV 75475 Paris, Cedex 10
Rue du Bugnon 46 France
1011 Lausanne
Switzerland *ANVONDER7ERTH
(E-mail: [email protected])
&LORENCE0OLI Department of Dermatology
(E-mail: [email protected]) Conquest Hospital
Service de Dermatologie St Leonards-on-Sea
Hpital Henri Mondor UK
51 av du Mal de Lattre-de Tassigny
94010 Crteil
France
86))) List of Contributors
0IERRE7OLKENSTEIN 8IMENA7ORTSMAN
Service de Dermatologie Servicio de Imagenologa
Hpital Henri Mondor Clnica Hospital del Profesor
51 av du Mal de Lattre-de Tassigny Santiago
94010 Crteil Chile
France
0AM7OOD
(E-mail: [email protected])
Human Genetics Unit Division of Pathology
and Neuroscience
Ninewells Hospital and Medical School
University of Dundee
Dundee DD1 9SY
UK
Chapter 1
Hidradenitis Suppurativa Introduction

Albert Kligman
1
#ONTENTS sweat glands [1]. This concept held sway over

more than a century, during which numerous
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 reports were in concordance. It was not till 1939
that Brunsting identified the apocrine, rather
than the eccrine sweat glands as the specific tar-
get of the disease, although he did not quarrel
with the prevailing idea that the primary event
was inflammation of the apocrine glands [2]. In
At long last, hidradenitis suppurativa, a disease a later paper in 1952 [3] he presciently recog-
first described a century and a half ago and one nized that hidradenitis suppurativa had some
of the most devastating among the thousands of similarities to acne vulgaris regarding clinical
dermatologic entities, has finally received rec- manifestations. The latter idea was further
ognition by a text dedicated solely to this horri- fleshed out in 1951 by Kierland, also of the fa-
ble disorder. mous Mayo Clinic, who perceived that hidrad-
This publication reminds us that this disease, enitis suppurativa was not solely restricted to
neglected for most of its history, would merit localization of the apocrine glands. He saw a re-
classification by taxonomists as a nomen dubi- lationship between acne conglobata and dissect-
um et confusum, about which there has been ing cellulites of the scalp, which sometimes
no consensus regarding etiology, pathogenesis, occurred concomitantly [4]. Later workers con-
histopathology, bacteriology, genetics, etc. firmed Kierlands concept that hidradenitis
Major dermatologic texts the world over give suppurativa was an umbrella term encompass-
rudimentary, incomplete, misleading, even fal- ing a variety of clinical expressions.
lacious and contradictory accounts of this baf- It was Shelley and Cahns report in 1955 that
fling, multifarious, polymorphic disorder. gave scientific credence to the belief that in-
The historicity of hidradenitis suppurativa, flammation of the apocrine glands was the pri-
which has been described under a variety of lati- mary pathogenic event [5]. They sought to vali-
nized names, is in itself a fascinating, convolut- date the concept by inducing the disease
ed story, demonstrating once again that the only experimentally, historically a successful strate-
path to enlightenment and the resolution of gy embodied in Kochs postulates. They plucked
controversies is through serious basic investiga- the axillary hairs of 12 male volunteers and im-
tions. It is worth recounting too how patent fal- mediately covered the area with an occlusive
lacies can be perpetuated by the pronounce- adhesive tape impregnated with belladonna, the
ments of influential clinical figures, schooled in latter presumably to suppress secretory activity.
the descriptive morphology of dermatologic In 3 of the 12 volunteers, they histologically
diseases. All this has thankfully changed owing demonstrated hyperkeratotic plugging and dila-
to investigations by authoritative contributors tation of only one apocrine sweat duct in each
to this volume. specimen, associated with a severe inflamma-
The disease was named by Verneuil, a French tory infiltrate engulfing and destroying the
surgeon, who in 1864 held that the primary gland. Notably there was no involvement of
event in pathogenesis was inflammation of the the surrounding eccrine, apocrine or sebaceous
2 Albert Klingman
glands. They concluded that hidradenitis sup- more than a half-dozen reports on the histopa-
1 purativa represented an infection of the ob- thology, bacteriology, and clinical aspects of the
structed apocrine duct by the resident micro- diverse manifestations of this polymorphic dis-
flora of the axilla in the absence of known ease [1214]. In fact, all of the contributors to
pathogens. Their findings were so commanding this volume have worked in the field, with cred-
and persuasive that a host of reports for many ible bona fides. Jemec compared 60 consecutive
years afterwards by many different observers biopsy samples of hidradenitis suppurativa pa-
thoroughly endorsed the concept, which was tients with 30 normals, the first large controlled
thereby elevated to the status of a dogma. study, which failed to verify the ancient con-
Interestingly, no attention was paid to an cept.
early blunt dissenting opinion in 1957 by Tiber Some redeeming remarks are in order re-
Benedek, a Chicago dermatologist, who opined garding the Philadelphia triad, Pillsbury, Shelly
that the experiments from the famous Depart- and Kligman, who perhaps deserve honorable
ment of Dermatology of the University of Penn- mention for elaborating on Kierlands percep-
sylvania School of Medicine in Philadelphia tive observations that hidradenitis suppurativa
were poorly conceived and that the results was more than a disease of apocrine glands but
bore no resemblance to the native disease either belonged to a family of related conditions [3].
bacteriologically or histopathologically, noting They presented a unifying concept which led
also that there was no evidence that the disease them to coin the term the follicular occlusion
had been reproduced clinically [6]. Additionally triad, relating acne conglobata, hidradenitis
Xu and Cooks substantial histologic studies 30 suppurativa and dissecting cellulitis of the scalp
years later completely failed to demonstrate ke- into one nosologic grouping. This notion has
ratinous plugging of the apocrine ducts at any now achieved universal acceptance. Plewig and
stage [7]. Curiously, the prevailing dogma was Kligman added another component, the piloni-
not weakened in any way by the sharp criti- dal sinus, comprising what is now called the fol-
cisms. licular occlusion tetrad [15]. Finally, it was left to
On the contrary, in 1956, Pillsbury, Shelley, Plewig and Steger to coin the term acne inversa
and Kligman of the University of Pennsylvania to acknowledge that hidradenitis suppurativa,
School of Medicine in Philadelphia proclaimed while part of the occlusion tetrad, was a clinical
in their popular 1956 text, Dermatology that entity, emphasizing its localization to the axilla,
hidradenitis suppurativa is a severe, chronic, anogenital area, and the buttocks [16]. By con-
recurrent suppurative infection of the apocrine trast, acne vulgaris favors the face and trunk.
sweat glands, resulting from poral closure and So, hidradenitis logically became the inverse
secondary bacterial infection [8]. It was not un- form of acne vulgaris. The first comprehensive
til decades later that a steady stream of reports account of acne inversa may be found in the
in the world literature failed to verify the Phila- third edition of Acne and Rosacea by Plewig and
delphia doctrine that obstructive hyperkeratotic Kligman in 1993. The most elaborate account of
plugging of the apocrine duct was the initiating acne inverse is given by Jansen and Plewig [17].
pathogenic event, or that infection was a com- For the last and final word on acne inversa,
mon complication [911]. The Philadelphia con- the interested scholar should read Plewigs elab-
cept has not withstood the test of time and is no orate treatise entitled Acne inversa, acne keloi-
longer tenable, as described by later investiga- dalis nuchae, abszedierende follikulitis der kop-
tors. James Leyden, a younger member of the fhaut [18]. He goes to great pains to emphasize
Philadelphia group, one of the co-authors of this that acne vulgaris originates in sebaceous folli-
volume, has joined the chorus of dissenters cles while acne inversa invokes terminal hair-
against the views of his eminent predecessors, bearing follicles.
to which the name of Kligman has perforce been Attention is called to a fascinating paper by
added! Sellheyer and Krahl with the provocative title
Another of the authors, G.B.E. Jemec, is Hidradenitis suppurativa is acne inversa! An
clearly a leading authority who has published appeal to finally abandon a misnomer in which
Hidradenitis Suppurativa Introduction Chapter 1 3
they trace out the convoluted history of how 5. Shelley WB, Cahn MM (1955) The pathogenesis of
concepts of the disease generated conflicting hidradenitis suppurativa in man. Arch Dermatol
notions of its nature, culminating at last in a 71:562565
6. Benedek T (1957) Hidradenitis suppurativa. Its eti-
consensus [19].
ology, pathogenesis and specific vaccine therapy.
Sellheyer and Krahl are not speaking as his- Acta Dermatovenereol 37:147
torians sitting on the sidelines. They report on 7. Xu CCW, Cook MG (1990) Hidradenitis suppura-
what is probably the most extensive histopatho- tiva: a disease of follicular epithelium, rather than
logic study ever undertaken. They took 176 bi- apocrine glands. Br J Dermatol 122:763769
opsy specimens of acne inversa, depicting the 8. Pillsbury DM, Shelley WB, Kligman AM (1956)
evolution of the disease from its earliest stages Bacterial infections of the skin. In: Dermatology,
1st edn. Saunders, Philadelphia, pp 459498
to its end-stage fibrotic disfigurements, accom-
9. Edlich RF, Silloway KA, Rodeheaver GT et al (1986)
panied by abundant high-quality illustrations. Epidemiology, pathology and treatment of axillary
It is a certainty that knowledge about this hidradenitis suppurativa. J Emerg Med 4:369378
mysterious, intriguing entity has greatly in- 10. Heller DB, Haefner HK, Hameed M et al (2001) Vul-
creased, with few remaining controversies [20]. var hidradenitis suppurativa. Immunohistochemi-
Nonetheless, it is abundantly clear that many cal evaluation of apocrine and eccrine involvement.
important questions remain to be addressed. J Reprod Med 47:695700
Tools for obtaining answers already exist in the 11. Attanoos RL, Appleton, MAC, Douglas-Jones AG
(1995) The pathogenesis of hidradenitis suppu-
modern arsenal of techniques such as molecular rativa: a closer look at apocrine and appo-eccrine
biology, bioengineering, imaging, pharmacoge- glands. Br J Dermatol 133:254
nomics, genetics, biochemistry, and still others. 12. Jemec, GBE, Faber M, Gutshik E et al (1996) The
The most daunting of the many questions which bacteriology of hidradenitis suppurativa. Derma-
await enlightenment relate to recognizing the tology 193:203206
earliest manifestations, which may be mimicked 13. Jemec GBE, Hansen U (1996) Histology of hidrade-
by unrelated disorders, so as to bring to bear nitis suppurativa. J Am Acad Dermatol 34:994999
14. Jemec GBE, Heidenheim M, Wielson NA (1996)
treatments which prevent progression to the
The prevalence of hidradenitis suppurativa and its
chronic, disabling end-stage, for which there is potential precursor lesions. J Am Acad Dermatol
no therapeutic option other than extensive sur- 35:191
gery. 15. Plewig G, Kligman AM (1993) Acne inversa. In:
One has reason to hope that this authorita- Plewig G, Kligman AM (eds) Acne and rosacea,
tive volume will not only stimulate greater in- 2nd edn, Springer, Berlin Heidelberg New York,
terest in this disease, enlarging the cadre of in- pp 284289
vestigators, but more importantly to generate 16. Plewig G, Steger M (1989) Acne inversa (alias acne
triad, acne tetrad or hidradenitis suppurativa). In:
the funds necessary to underwrite the research Marks R, Plewig G (eds) Acne and related disorders.
that will usher in a new era that will garner for Martin Dunitz, London, pp 345357
acne inversa the same level of support accorded 17. Janssen T, Plewig G (1998) Acne inversa. Int J
to other chronic dermatoses. Dermatol 37:96100
18. Plewig G (2004) Acne inversa, ackne keloidalis
nuchae, abszedierende follikulitis der kopfhaut. Ein
References ver bindendus kozzept. In: Plewig G, Prine J (eds)
Fortschritte der praktischen dermatologie und
venerologie. Springer, Berlin Heidelberg New York,
1. Verneuil A (1864) De Lhidrosadenite phlegmoneuse
p 192
et des abces sudoripares. Arch Gen Med 2:537557
19. Sellheyer K, Krahl D (2005) Hidradenitis suppura-
2. Brunsting HA (1939) Hidradenitis suppurativa:
tiva is acne inversa! An appeal to finally abandon a
abscess of the apocrine seat glands. Arch Dermatol
misnomer. Int J Dermatol 44:535
Syphilol 39:108120
20. Jemec GBE, Thomsen BM, Hansen U (1997) The
3. Brunsting HA (1952) Hidradenitis and other vari-
homogeneity of hidradenitis suppurativa lesions.
ants of acne. Arch Dermatol Syphilol 65:303315
A histological study of intra-individual variation.
4. Kierland RR (1951) Unusual pyodermas (hidradeni-
APMIS 105:378383
tis suppurativa, acne conglobata, dissecting celluli-
tis of the scalp). Minn Med 34:319341
Chapter 2
Verneuil and Verneuils Disease:

an Historical Overview 2
Grard Tilles
Key points 2.1 Biographical Landmarks

of a Surgeon-Venereologist
Q Hidradenitis suppurativa is a clinically
well described entity Aristide Auguste Stanislas Verneuil (Fig. 2.1)
was born in Paris on 29 November, 1823. He was
Q The classification has been a continu- appointed Interne des Hpitaux de Paris in
ous source of debate for more than 1843, graduated as a Doctor in Medicine in 1852
100 years (thesis: the movements of the heart) and became
Professeur Agrg at the Paris Faculty of Medi-
Q The lack of sweat gland involvement cine in 1853 (thesis: the anatomy and physiology
has been described in early studies of the venous system).
As Surgeon of the Paris Hospitals from 1856,
he was officially in charge of the teaching of ve-
nereal diseases from 1863. Non syphilitic vene-
real diseases and primary syphilis were at this
#ONTENTS time managed essentially by surgeons (for ex-
ample, Ricord in Le Midi Hospital) whereas
2.1 Biographical Landmarks
dermatologists notably in Saint Louis were
of a Surgeon-Venereologist . . . . . . . . . . . . . . . . . 4
more involved in the management of secondary
2.2 LHidradnite Phlegmoneuse and tertiary forms of syphilis.
(Verneuils Disease), Primary Observations . . 5
In fact dermatology and syphilology were
2.3 Further Observations and Discussions first regarded only as complementary special-
in Europe and Overseas . . . . . . . . . . . . . . . . . . . . 6 ties. Cazenave head of Saint Louis Hospital
2.4 Hidrosadenitis and Acne Conglobata: was in charge of teaching skin diseases from
Controversial Views . . . . . . . . . . . . . . . . . . . . . . . 8 1841 until 1843, succeeded by Hardy from
2.5 Acne Inversa, the Last Metamorphosis 1862 [1]. The political events that followed
of Verneuils Disease? . . . . . . . . . . . . . . . . . . . . . . 9 the Franco-Prussian 1870s war encouraged the
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Faculty of Medicine to accept the creation of
Chairs of medical specialties. In this trend, the
first Chair encompassing cutaneous and syphi-
litic diseases at the Paris Faculty of Medicine
was founded in 1879 and attributed to Alfred
As a surgeon Verneuil remains closely connect- Fournier.
ed to the history of dermatology. In fact he de- After successive appointments as the head of
scribed the cutaneous disease subject of this Lourcine Hospital (for syphilitic women), Le
book and was the first official teacher of syphilis Midi Hospital (for syphilitic men) (1865), Hpi-
and venereal diseases at the Paris Faculty of tal Lariboisire (1865), La Piti (1872) and Htel-
Medicine at a time when skin diseases were still Dieu (1889), and Professor of Clinical Surgery
taught separately. (18721889) in La Piti hospital, Verneuil head-
Verneuil and Verneuils Disease Chapter 2 5
irritations of the sebaceous follicles, by the ab-

sence of cleanliness () this kind of inflamma-
tion which evolution is usually slow can be
sometimes quite painful. Its usual ending is
suppuration; healing is exceptional. Velpeau
described a different clinical aspect named
phlegmon rysiplateux, similar to the previous
one but always quite painful. Patients are some-
times afflicted with indurations and tumors
that may remain the whole life through.
Velpeau regretted the ignorance of the au-
thors regarding the awful consequences of these
inflammations of the axillae which frequency is
probably underestimated, while nothing is more
common.
Then, from 1854 until 1865 Aristide Verneuil
published a series of articles on skin tumors [5].
Observing the absence of any study on this top-
ic, Verneuil indicated he would deal with those
sudoral tumors that may have a surgical inter-
est. Although Velpeau mentioned the origin of
the abscesses in the sebaceous follicles, Verneuil
taught that Velpeaus tumors had their origin in
Fig. 2.1. Aristide Auguste Stanislas Verneuil (1823 the sweat glands.
1895). Coll Photothque de lAcadmie Nationale de Verneuil admitted he had never observed any
Mdecine patient with such an acute inflammation of the
sudoral glands. In fact, the only occasion he had
to observe it was on the cadaver of a young pa-
ed the first Chair of Surgery at Htel-Dieu Hos- tient who died from cachexia. In this observa-
pital (18891892). tion entitled inflammations de la rgion sacre
President of the Socit de Chirurgie in et fessire, abcs multiples circonscrits et sous
1869 and Charter member of the Congress of cutans sigeant probablement dans les glandes
Surgery, he was elected as President in 1888. He sudoripares, Verneuil indicated in an extreme-
was also a member of the Acadmie de Mde- ly precise way that the buttocks area was scat-
cine (1869), Member of the Acadmie des Sci- tered with a great number of little escarrs sepa-
ences (1887), and Commander of the Legion of rated from the others () moreover a great
Honour. Verneuil died from a bronchopneumo- number of pustules, the size of a pinhead, with-
nia on Tuesday 11 June, 1895. His funeral took out any sign of inflammation were disseminat-
place on 14 June in a Paris suburb, Maisons- ed; these pustules were filled by a liquid lifting
Lafitte [2, 3]. the epidermis without breaking it. After remov-
ing the epidermis, the cleaning of the pustule
made perceptible a tiny red hole in which one
2.2 LHidradnite Phlegmoneuse could introduce a bristle of a boar or a very thin
(Verneuils Disease), stylet; then one entered a channel of one fifth to
Primary Observations one third millimeter crossing the dermis and
leading to a subdermal cavity larger than the
Two French surgeons fathered the description of subepidermal one and filled with the same
hidrosadenitis. In 1833, Velpeau (17951867) liquid.
described a phlegmon tubriforme [4] of the Observing these cavities both linked by a
axilla, frequently induced by rubbings and thin channel across the dermis, Verneuil as-
6 Grard Tilles
sumed necrosis of the sudoral glands, the pus [10]. However, the translators of Kaposis text-
being excreted by the sudoral duct and accumu- book into French, Besnier and Doyon, although
lating under the epidermis. admiring the master of Vienna, did not confirm
Verneuil localized the abscesses in the sweat the Austrian opinion. Although they admit the
2 gland through clinical and micro anatomical uncertainties on the histopathological aspects
observations only. Therefore, he added prudent- of the sweat glands, Besnier and Doyon insisted
ly I make this observation with reservation for on the true existence of the dermal abscesses in
it is chiefly the curious distribution of these col- the axillary area, which, according to them, rep-
lections that made me adopt the interpretation resent the most perfect type of the hidrosadeni-
which I give here. It is therefore a point to be tis described by Verneuil.
restudied and to be demonstrated in a more sat- In London, Erasmus Wilson [11], a leading
isfactory manner. However he indicated to light in British dermatology, summarized Ver-
have no more doubt on the existence of a new neuils description and indicated that the tu-
variety of skin tumors consisting of the hyper- mors, differ from boils in their deep origin, in
trophy of sweat glands. Nevertheless, he added, the absence of elevation and pointing and also
I have nothing to say on the aetiology of this in the absence of core. Wilson considered the
disease: the causes of these glandular cysts, the affection as caused by external irritation of the
symptoms, the evolution cannot be inferred skin from neglect of cleanliness, friction, and
from such a small number of observations. sweating. At the same time, Radcliffe Crocker
In 1864 Verneuil named this disease hidro- described hidradenitis briefly as a type of fu-
sadnite phlegmoneuse [6]. A few decades later runculosis that begins in the sweat coil [12].
when complementary cases were published, Probably the first histopathological study of
Dubreuilh (Bordeaux, France) considered the hidrosadenitis was published in 1889 by Giovan-
word hidradenitis as improper and hydrosade- nini, who demonstrated the existence of an in-
nitis as barbarism [7]. flammatory process borne in the sudoral glands
that led to their complete destruction [13].
However, despite this publication which
2.3 Further Observations seemed to demonstrate the origin of hidrosade-
and Discussions in Europe nitis, the existence of the disease described by
and Overseas Verneuil was highly questioned until the 1890s.
In fact most authors denied it as a separate en-
The disease described by Verneuil first received tity.
very little attention from dermatologists except From the 1890s on the disease seemed to
from Bazin (Paris) who coined a syphilid under come into a new era of existence.
the name hydradnite syphilitique [8]. Bazin In Paris, Barthlmy authored a comprehen-
was actually convinced that this type of syphilid sive study on the subject. He regarded hidrade-
had its seat in the sweat glands. Therefore, he nitis as a part of the folliculitis that could be
regarded the disease described by Verneuil as of generalized or localized in the axillary, labia
possible syphilitic origin and pointed out that major or perianal areas. In Barthlmys article,
there is no need to make any differential diag- hidradenitis described by Verneuil disappears
nosis between gommous syphilid and hidra- and is encompassed in a new nosological frame-
denitis suppurativa. work that includes acnitis and folliclis, terms
In Vienna, Hebra denied the existence of su- coined by the author to designate follicular and
doral tumors considering that, up to the pres- perifollicular inflammation of unknown origin
ent time, the sudoriparous glands have not been [14].
shown to be subject of any structural affections At the same time Pollitzer and Dubreuilh [7]
[9]. A few years later, Kaposi, Hebras successor, (Bordeaux) independently described what they
did not admit the disease as a distinct affection believed to be abscesses of the sweat glands.
either: talking about hidradenitis that does not In the North American medical literature,
exist as a separate affection seems superfluous the disease described by Verneuil was not men-
tioned until Pollitzer (New York) [15] pointed presented in the axilla inflamed swelling, dis-
out the fact that the disease was in danger of charged sinuses, and scars. The condition had
being dropped from our dermatological nosol- started 6 months beforehand. Corson regarded
ogy and even in Paris the affection was so for- this case as a typical picture of involvement of
gotten that in a recent conspicuous example it sweat glands by pyogenic organisms. Knowles
was not diagnosed, alluding to the cases ob- underlined the fact that these cases occurred
served by Barthlmy (Paris) in Saint-Louis mostly in women. During the discussion, the
Hospital. Pollitzer regarded the observations participants considered this observation to be
made by Barthlmy as descriptions that coin- the counterpart of the picture presented previ-
cided in every detail with Verneuils first obser- ously, with similar lesions in both axillae. This
vations. case was first thought to be bilateral tuberculo-
Pollitzer who regarded Verneuils descrip- sis but inoculations failed to support this hy-
tion as the admirable style of the French clini- pothesis. Finally the observation was considered
cian added that the lesions could occur most to be an infection due to some type of acid-fast
commonly in the axilla, anus, nipple, scrotum, organism probably involving the sweat glands.
and labia majora. He insisted on the inflamma- In 1933 Lane, authoring a rsum of foreign
tion of the sweat glands (hidradenitis) as being literature, observed that the disease is not un-
the most characteristic pathological feature, common and it presents a definite clinical pic-
the complete destruction of the affected gland ture but it is apparently not very well known
(destruens). probably because it is hardly mentioned in most
Dubreuilh indicated that the lesions had their works on surgery in the English language and it
origin in the sweat coil and emphasized the fact is not mentioned or is only briefly described in
that even the authors who considered hidrade- many textbooks on dermatology [20].
nitis as a disease of the pilosebaceous follicle did Brunsting, presenting complementary de-
not dare to deny any responsibility to the sudo- scriptions of hidradenitis at the annual session
ral glands. Dubreuilh rejected the terms folliclis of the American Medical Association [21], re-
and acnitis and preferred to keep hidrosadeni- gretted that dermatology textbooks paid so little
tis, which, he said, attested to a pathological re- attention to the disease. He described its clinical
ality. appearance, insisted on the fact that the disease
In 1902, Trk (Budapest) had the impres- is characterized by its localization on cutaneous
sion that the pathological process is located surfaces in which the apocrine type of sweat
chiefly in that layer of the skin which encloses glands are situated, and emphasized the impor-
the glomeruli of the sweat gland [16]. tance of a surgical treatment in the early forms
In fact the description of the apocrine sweat of the disorder.
glands in 1921 [17] established the relationship A few years later, Brunsting, reviewing the
between this type of sweat gland and the pecu- subject at the 71st Annual Meeting of the Amer-
liar localization of the disease. ican Dermatological Association, indicated that
In the 1920s several papers were published in hidradenitis, acne conglobata and dissecting
the North American medical literature that em- cellulitis of the scalp should be considered as
phasized the existence of hidradenitis and its regional counterparts in which the acne pro-
connection to the sweat glands. cess is manifested in its variants and in its more
On 27 September 1928, Cole and Driver pre- fulminating forms [22]. He emphasized the
sented at the Cleveland Dermatological Society fact that these diseases have so much in com-
the case of a negro boy aged 3 who showed a mon that a description of one disorder well fits
peculiar folded and thickened axillary skin with another: the presence of comedones is common
small suppurating lesions in various stages. No in the three diseases and in fact he endeavored
discussion followed [18]. to underline the common clinical and etiologi-
A few years later, on 20 December 1935, Cor- cal factors of the disorders, namely the acne
son presented at the Philadelphia Dermatologi- process. However, many attendees of the meet-
cal Society [19] the case of a woman aged 22 who ing denied Brunstings attempt to group acne
8 Grard Tilles
conglobata, dissecting cellulitis of the scalp and could not still envision to file perianal and
hidradenitis. perimamelonal abcesses among the idrosadni-
In fact for the North American School tis [sic] [26]. However, for him more consistent
of Dermatology, Verneuils hidradenitis truly probabilities existed for the sudoral origin of the
2 existed as a disease of the apocrine sudoral axillary abscesses, despite the absence of any
glands. histopathological evidence. In fact he regarded
Shelley and Cahns experimental work [23] tuberous abscesses of the axillaries as a subcuta-
supported this view. The authors applied a per- neous boil (furuncle).
forated belladonna adhesive tape to one axilla of In 1949, Degos et al. (Paris) presented a case
12 adults between 20 and 40 years old. In every of acne conglobata abnormally localized to the
subject, apocrine anhidrosis developed in taped axillaries, perianal area, and inter- and sub-
areas. Three of the twelve subjects developed mammary region, sparing the scalp and the
clinical hidradenitis suppurativa, presenting back of the neck [27, 28]. For the authors, the
deep, small, and tender nodules located at the observation gave credence to the follicular ori-
tape site. The biopsy specimens revealed kerati- gin of the so-called hidradenitis.
nous plugging of the apocrine sweat ducts, dila- In fact, Degos insisted on the difficulty or
tation of the duct, and severe inflammation lim- impossibility of establishing a definite distinc-
ited to a single apocrine sweat gland unit. The tion between acne conglobata and Verneuil dis-
authors also noticed that adjacent glands were ease. In this respect, Moline (Paris) underlined
entirely normal with respect to the hair follicles, the fact that the close relations between sweat
the sebaceous glands, and deeper eccrine glands. glands and pilosebaceous follicles and the con-
They concluded from this study that the nod- sequences of the infectious process made a rig-
ules clinically observed were simply an inflam- orous distinction between acne conglobata and
matory change which had singled out the apo- hidrosadenitis quite difficult. A common un-
crine glands and that hidradenitis suppurativa derstanding of both diseases may be consid-
appeared to be a bacterial infection of an ob- ered [29].
structed apocrine sweat gland. Confirming the French point of view, Debay
(Paris) [30], concluding his work on perineal
suppurations, considered that the same clinical
2.4 Hidrosadenitis and Acne feature can result from three distinct processes:
Conglobata: Controversial Views acne conglobata, Verneuils disease [aetiology
adopted by the Anglo-Saxon authors; no valid
In the twentieth century the French School of differential criterion exists between Verneuils
Dermatology centered the nosological discus- disease and heterotypical forms of acne conglo-
sion on the connections between acne conglobata) ()] and the dysembryoplasia whose clini-
bata (described in 1901 by Spitzer under the cal features are almost identical to those of acne
name of dermatitis folliculitis et perifolliculitis conglobata and Verneuils disease.
conglobata) [24] and hidrosadenitis. Mouly (Paris) [31] tried to reconcile the
In 1904, Audry (Toulouse), authoring the French and American views, drawing attention
chapter on sweat glands in the prestigious Pra- to the fact that French authors essentially knew
tique Dermatologique, pointed out the fact that the axillary features of the disease, whereas the
reading the authors who dealt with this ques- Anglo-Saxon authors described the perineal
tion gave an impression of a complete darkness, features extensively. He insisted also on the fact
distinct diseases being described under a com- that hidrosadenitis was commonly designated
mon name. Audry indicated he had never under the name of Verneuil in the English-
found any convincing evidence of the initial speaking medical literature. He incited his
origin in the sweat glands [25]. French colleagues to acknowledge Verneuils
Thirty-five years later in the subsequent mas- primary work and to definitively coin the dis-
terpiece of the French School of Dermatology ease maladie de Verneuil.
(Nouvelle Pratique Dermatologique) Audry
4. Velpeau ALA. Aisselle, phlegmons, abcs. In Dic-

2.5 Acne Inversa, tionnaire de Mdecine ou rpertoire gnral des
the Last Metamorphosis sciences mdicales, 2nd edn, Vol. II. Bchet, Paris,
of Verneuils Disease? 1833, pp 91101.
5. Verneuil A. Etude sur les tumeurs de la peau: de
quelques maladies des glandes sudoripares. Arch
In 1956, Pillsbury, Shelley, and Kligman brought Gen Med 1854, Vol. II, Vth Series, Vol. 4, pp 447
together acne conglobata, hidradenitis suppura- 468, 693705; de lhidrosadnite phlegmoneuse
tiva, and dissecting cellulitis of the scalp [32] et des abcs sudoripares, ibid., 1864, 114:537557;
under the name follicular occlusion triad [33], 115:327337; 1865, pp 437453.
whose common feature was a tendency to fol- 6. Verneuil A. De lhidrosadnite phlegmoneuse et des
abcs sudoripares. Arch Gen Med 1864, 115:327
licular hyperkeratinization leading to the reten-
337.
tion of keratin products with secondary bacte- 7. Dubreuilh W. Hidrosadnites suppuratives dis-
rial infection. smines. Arch Med Exp Ana Path 1893, 5:63101.
In 1975, Plewig and Kligman [34] added pilo- 8. Bazin PAE. Leons thoriques et cliniques sur la
nidal sinus to the triad and proposed the term syphilis et les syphilides. Adrien Delahaye, Paris,
acne tetrad, pointing out the absence of apo- 1866, p 364.
crine involvement in hidradenitis suppurativa. 9. Hebra F. Trait des maladies de la peau compre-
More recently, Plewig and Steger proposed des- nant les exanthmes aigus, traduit et annot par le
docteur Doyon. Masson, Paris, 1869, p 71.
ignating entities previously named acne triad or 10. Kaposi M. Leons sur les maladies de la peau tradu-
tetrad as acne inversa [35]. ites et annotes par Ernest Besnier et Adrien Doyon.
The fundamental change in acne inversa is Masson, Paris, 1881, Vol. I, p 207.
the hyperkeratosis of the infundibulum as in 11. Wilson E. On diseases of the skin. A system of cu-
acne vulgaris [36]. The authors denied that ec- taneous medicine. John Churchill, London, 1867,
crine or apocrine sweat glands are involved in pp 808809.
the pathogenesis of acne inversa. The involve- 12. Radcliffe CH. Diseases of the skin. HK Lewis, Lon-
don, 1888, p 231.
ment of sweat glands was regarded as secondary
13. Giovannini S. Un caso dhidrosadenite. Giorn Ital
only. More recently, studies have shown that Mal Vene e dellle Pelle, 1889, pp 302305.
acne inversa is a defect of the terminal follicular 14. Bathlmy T. De lacnitis ou dune varit spciale
epithelium. According to these authors [36], the de folliculites et prifolliculites dissmines et g-
association of acne inversa with many disorders nraliss. Ann Dermatol Syphil 1891, Vol. II, p 1.
in which poral occlusion is prominent gives 15. Pollitzer S. Hydradenitis destruens suppurativa.
credit to the follicular origin of acne inversa. J Cutan Genito Urinary Dis 1892, X, pp 924.
They insisted that it was necessary to abandon 16. Trk L. Hidrosadenitis phlegmonosa s. suppu-
rativa. In: Mracek F. (ed) Handbuch der Haut-
the term hidradenitis suppurativa [37]. krankheiten. Hlder, Vienna, 1902, Vol. 1, p 438.
As for Verneuil, the original eponym of this 17. Schiefferdecker P. Uber morphologische Sektre-
long and confused history, he seems aban- tionserscheinungen in der ekkrinen Hautdrusen
doned. des Menschen. Arch Dermatol Syphil 1912, 132,
p 130.
18. Cole HN, Driver JR. Multiple abscesses of the
References axillary sweat glands. Arch Dermatol Syphil 1929,
19:310.
19. Corson EF, Knowles FC. Hidradenitis suppurativa.
1. Chauffard EM. Rapport sur la rorganisation des
Arch Dermatal Syphil 1936, 34:346.
cours cliniques complmentaires. Gaz Hebdomad
20. Lane JE. Hidrosadenitis axillaries of Verneuil. Arch
Med Chirurg, 1875, 48:753757.
Dermatol Syphil 1933, 28(5):609614.
2. Dcs de M. Verneuil. Bull Acad Med, 18 juin
21. Brunsting HA. Hidradenitis suppurativa: abscess
1895, pp 627629.
of the apocrine sweat glands. Arch Dermatol Syphil
3. Huguet F. Les professeurs de la Facult de Mdecine
1939, 39:108120.
de Paris, dictionnaire biographique 17941939. In-
22. Brunsting HA. Hidradenitis and other variants of
stitut Nationale de Recherche Pdagogique, Paris,
acn. Arch Dermatol Syphil 1952, 65:303315.
1991, pp 495496.
10 Grard Tilles
23. Shelley WB, Cahn MM. The pathogenesis of 31. Mouly R. Hidrosadnites inguino prino fessires.
hidradenitis suppurativa in man. Arch Dermatol Bull Soc Fran Dermatol 1959, 66:184190.
Syphil 1955, 72:562565. 32. Hoffman E. Perifolliculitis capitis abscedens et
24. Spitzer L. Dermatitis folliculitis et perifollicultis suffodiens: case presentation. Dermatol Zeitschrift
2 conglobata. Dermatolog Z 1901, 10:8. (Berlin) 1908, 15:122123.
25. Audry C. Glandes sudoripares. In: Besnier E, Brocq 33. Pillsbury DM, Shelley WB, Kligman AM. Bacterial
L, Jacquet L (eds) La pratique dermatologique. infections of the skin. In: Dermatology. Saunders,
Paris, Masson, 1904, pp 402432. Philadelphia, 1956, pp 482484.
26. Audry C. Idrosadnites. In Darier F-J, Sabouraud R, 34. Plewig G, Kligman AM. Acne, morphogenesis and
Gougerot H et al. Nouvelle pratique dermatologique, treatment. Springer, Berlin Heidelberg New York,
Vol. VII. Masson, Paris, 1936, pp 257261. 1975, pp 192193.
27. Degos R, Garnier G, Niel JL. Acn conglobata 35. Plewig G, Steger M. Acne inversa (alias acne triad,
localisation htrotypique et avec infiltration pro- acne tetrad or hidradenitis suppurativa). In: Marks
fondes, pri anales, pseudo tuberculeuses. Bull Soc R, Plewig G (eds) Acne and related disorders.
Franc Dermatol Syphil 1949, pp 346347; 489490. Dunitz, London, 1989, pp 354347.
28. Degos R, Garnier G, Caron J. Acn conglobata trs 36. Jansen T, Plewig G. Acne inversa. Int J Dermatol
amliore par lauromycine. Bull Soc Fran Derma- 1998, 37:96100.
tol Syphil 1949, pp 489490. 37. Jansen T, Plewig G. Whats new in acne inversa
29. Moline J. Formes htrotopiques de lacn conglo- (alias hidradenitis suppurativa)? J Eur Acad Der-
bata ou maladie de Verneuil? Thse pour le doctorat matol Venereol 2000, 14:342343.
en Mdecine. Paris, 1960.
30. Debay M. Les suppurations prino fessires chro-
niques non spcifiques. Thse pour le doctorat en
Mdecine. Paris, 1962, dirige par R Degos.
Chapter 3
Clinical Presentation
Florence Poli, Gregor B.E. Jemec, Jean Revuz
3
3.3 Topography. . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Key points 3.3.1 Involved Areas . . . . . . . . . . . . . . . . . . . . . . . . 16
3.3.1.1 Two Main Zones . . . . . . . . . . . . . . . . . . . . . . . 17
Q Hidradenitis suppurativa (HS) 3.3.1.2 The Two Less Frequently
or Verneuils disease is a chronic, Involved Zones . . . . . . . . . . . . . . . . . . . . . . . . . 17
recurrent inflammatory, painful 3.3.2 Atypical Localizations
disease of apocrine-gland-bearing skin Other Zones May Be Involved . . . . . . . . . . . 18
3.3.3 Distribution of Lesions . . . . . . . . . . . . . . . . . 18
Q HS is an overlooked disease that affects 3.4 Evolution of the Disease and its Severity . . 18
a significant number of patients 3.4.1 Age at Onset and Resolution. . . . . . . . . . . . . 18
3.5 Clinical Course . . . . . . . . . . . . . . . . . . . . . . . . 19
Q Women are more frequently involved: 3.5.1 Intermittent/Benign Course
M/F = 1/3 of the Disease . . . . . . . . . . . . . . . . . . . . . . . . . .20
3.5.2 Intermediate Course of the Disease . . . . . .20
Q HS develops in the second or third 3.5.3 Continuous Disease: Moderate, Severe . . .20
decade of life 3.6 Severity Indexes . . . . . . . . . . . . . . . . . . . . . . . . 21
3.6.1 Hurleys Clinical Staging [2] . . . . . . . . . . . . . 21
Q Typical lesions are deep-seated nodules, 3.6.2 Sartorius [9] . . . . . . . . . . . . . . . . . . . . . . . . . . .22
sinus tract and hypertrophic fibrous 3.7 Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22
scars 3.7.1 Diagnostic Criteria . . . . . . . . . . . . . . . . . . . . .23
3.7.2 Delay in Diagnosis . . . . . . . . . . . . . . . . . . . . .23
3.7.3 Differential Diagnoses . . . . . . . . . . . . . . . . . .23
Q The two main areas involved are axillae
and inguino-femoral zones References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24
Q There is an extreme variety

in the severity of the disease 3.1 Introduction
Q Quality of life is severely impaired Hidradenitis suppurativa (HS) is a distinctive
chronic disease primarily located to inverse
areas of the skin, e.g. axillae and groin. These ar-
eas generally may also be said to be apocrine-
gland-bearing skin, although the apocrine
#ONTENTS glands are not primarily involved in the disease.
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
In the early stages the disease is an inflammato-
ry and pustular follicular disease, but subse-
3.2 Individual Lesions. . . . . . . . . . . . . . . . . . . . . . 12 quently it becomes predominantly suppurative
3.2.1 Primary (Early) Lesions . . . . . . . . . . . . . . . . . 12
3.2.2 Secondary Lesions. . . . . . . . . . . . . . . . . . . . . . 13
and scarring. In addition to the objective clinical
3.2.3 Tertiary Lesions . . . . . . . . . . . . . . . . . . . . . . . . 14 manifestations of the disease, the inflammatory
3.2.3.1 Comedones . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 changes and suppuration cause immediate pain,
3.2.4 Other Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . 15 soreness and discomfort to the patients. In spite
12 Florence Poli, Gregor B.E. Jemec, Jean Revuz
of the distinctness of HS it is commonly misdi- 3.2 Individual Lesions

agnosed and frequently poorly managed, which
adds to the burden of this disabling chronic dis- 3.2.1 Primary (Early) Lesions
ease, which severely impairs the quality of life.
Epidemiological and clinical observations Insidious onset with pruritus, erythema and
may be of help, as corroborating evidence, in hyperhidrosis has been reported, but such pro-
3 establishing the diagnosis of HS. Generally, HS dromes are most likely rare or not noticeable to
develops almost always after puberty, usually in the patients. Most frequently, the first lesion is a
the second or third decade of life. It is not an un- solitary painful, deep-seated nodule (0.52 cm
common disease with a prevalence rate of 1% [8]. in diameter), in an area of inverse or apocrine-
Women are more frequently affected than men; gland-bearing skin such as e.g. the axilla (see
the sex ratio is 3:1 [1, 7, 8]. This has led to specu- Fig. 3.1a, b). This lesion is round and deep with-
lation about the aetiological role of endocrine out any pointing or central necrosis such as
and behavioural factors, although none of these occurs in a furunculosis (it forms a blind boil).
have hitherto been found to be convincing on It may resolve spontaneously within several
closer examination. Epidemiological studies days a mean of 7 days is described [12] or
however suggest that tobacco may play an aetio- persist as a non-tender, silent nodule with
logical or more likely a pathogenic role in the subsequent recurrences of inflammatory epi-
disease, as 84% of patients are current smokers sodes over weeks or even months without any
[1]. Another frequently suspected aetiological/ evidence of suppuration.
pathogenic factor is obesity. Being overweight is Usually the lesion will progress to form an
not uncommon but not a unifying characteristic abscess which may open superficially to the
of the patients either: among the 164 patients of a surface yielding purulent and/or sero-sangui-
personal series [1] 20% were overweight and 20% nous drainage. This abscess may fail to open
obese (body mass index, BMI, >30 kg/m2). The spontaneously and becomes extremely pain-
median BMI was, however, 23.6 kg/m2, which ful, leading to a surgical drainage (see Fig. 3.2).
may be considered normal. Similarly, another Drainage typically offers temporary relief, but
earlier series found no significant deviation from the disease has a strong tendency to reoccur at
ideal body weight in a series of 76 patients as a exactly the same place. The diagnosis is fre-
whole [6]. It is most likely that these factors play quently missed at this stage.
a role as pathogenic elements in the progression
of the disease and in the severity of the disease
rather than as actual aetiological factors.
Fig. 3.1 a, b. a Early

nodule; this lesion is not
a typical deep-seated
nodule, which is more
palpable than visible;
it is a more superficial
nodule. b Early lesion,
inflammation accessible
to antibiotic therapy
Clinical Presentation Chapter 3 13
Fig. 3.2. Incision of an abscess yielding pus

Fig. 3.3. Inguinal hidradenitis suppurativa (HS): nodule,
closed sinus, comedones; severity: Hurleys I in a quiet
period
3.2.2 Secondary Lesions
Chronicity and recurrences are the hallmark of

HS. Recurrence at the same site, appearance
of new lesions in adjacent skin and coalescence
of existing lesions by extension will result in
secondary lesions. Fibrosis is another hallmark
of the secondary lesions. Fibrosis affects the
surrounding skin, and the secondary lesions are
therefore thought to perpetuate the disease.
Histologically the secondary lesions are charac-
terized by the appearance of sinus tracts. Clini-
cally these are persistent for months, or even
years, and regularly cause problems to the pa-
tient. Fig. 3.4. More severe case of inguinal HS with nodules,
This kind of lesion may seem to resolve, only fistulas, hypertrophic scarring. Severity: Hurleys IIIII
to start draining again after several months of
rest (see Fig. 3.3). Their potential for resolu-
tion is not known, and to the patients they often
appear as permanent problems. The sinus tracts
are not always palpable, and may only become
apparent when an intralesional injection is
made and the injected substance appears at a
distance from the site of injection.
The draining sinus has a linear or angular
shape. At first it is single, then multiple sinus
tracts usually appear, with permanent discharge.
There is frequently foul odour from Gram-neg-
ative colonization (see Fig. 3.4). Because of the
chronic inflammation and disruption of the si-
nus tracts multiple pyogenic granulomas may
appear, adding another recognizable feature to Fig. 3.5. Pyogenic granulomas sprouting from HS si-
the secondary lesions of HS (see Fig. 3.5). nuses
3.2.3 Tertiary Lesions
The final stage of the disease (Hurley stage III,

see below) is characteristic and most often rec-
ognized. The chronic inflammation and pain
are accompanied by a very peculiar and specific
3 form of hypertrophic fibrous scarring leading
to indurated plaques in which the inflammatory
nodules and sinus remains active (see Figs. 3.6,
3.7a, b). This process may involve the entire zone
of apocrine-gland-bearing skin to form a sub-
cutaneous honeycomb-like structure on clinical
examination. In more lax, flexural skin (e.g. ax-
illae), this bridged scarring results in thick
linear, rope-like bands (see Fig. 3.6), sometimes
as big as a finger, which are highly characteristic
and specific for this disease. When it is severe,
such scarring may decrease the mobility of Fig. 3.6. Rope-like hypertrophic scar
Fig. 3.7. Severe inflamed

HS; severity: Hurleys III
Fig. 3.8. Severe axillary involvement with limitation of Fig. 3.9. Pubic lymphoedema in HS
arm mobility
a limb, particularly abduction of the arm (see 3.2.4 Other Lesions

Fig. 3.8) or even produce a lymphatic obstruc-
tion with oedema (see Fig. 3.9). It is however of A number of other lesions may be seen in pa-
note that lymph node enlargement and/or in- tients with HS. Some of these lesions are clearly
flammation is generally absent, except in cases follicular and may therefore obscure HS lesions
of acute superinfection with lymphangitis. and cause a delay in the diagnosis. Common
small follicular papules and pustules are
frequent in area in both early and late HS (see
3.2.3.1 Comedones Fig. 3.11) and may occur isolated in a region not
involved by HS [1, 2]. The general prevalence of
Closed comedones (white heads) are never minor pustular follicular lesions of the skin in
present in areas of HS. Open comedones (black not known, but such transient lesions are esti-
heads) are also absent in early disease but may mated to be very common. In HS patients such
appear in long-lasting HS, usually as double- lesions are not uncommon on the buttocks, but
ended comedones. These may be taken to reflect they do not constitute a diagnostic clue for HS
the distortion and degradation of the dermal ar- (see Fig. 3.12). Other common findings are the
chitecture caused by the extensive inflamma- circular depressed superficial scars also some-
tion and scarring of the disease. They are par- times observed on the buttocks of patients.
ticularly conspicuous in burnt out lesions, These are most likely secondary to the unspe-
presumably when no longer obscured by the ac- cific elements, and are not a clue for the diagno-
tive disease (see Fig. 3.10). As in acne conglobata sis of HS.
these are tertiary lesions i.e. tombstone come- In a subgroup of patients, however, cysts oc-
dones. They are present in 50% of patients [8]. cur as a prominent associated finding. These
Their prevalence does not appear to be affected cysts are either white, round 1- to 2-cm smooth
by either concurrent acne or a previous history elastic cysts grouped in flexural areas, or large
of significant acne [1].
Fig. 3.10. Comedones, black heads in burnt-out lesions Fig. 3.11. Folliculitis close to HS
3.3.1.1 Two Main Zones
The axillary and the inguino-crural zones are

the two main areas involved in HS [1, 2, 7]. The
diagnosis is often most obvious in the axillary
region. Involvement of axillae may extend to
3 the lateral part of the chest (see Fig. 3.14) and
sometimes achieve connection with lesions on
the breast, where they may be misdiagnosed as a
breast abscess. Rope-like hypertrophic scarring
is particularly prominent in advanced axillary
lesions.
Fig. 3.12. Buttock folliculitis in a patient with axillary Inguino-crural or groin involvement is more
typical lesions of HS frequent than axillary involvement and is espe-
cially frequent in women: the inner thighs (fre-
quently), the mons pubis (see Fig. 3.15) and the
labia major may be involved. Groin involvement
is less frequent in men, and scrotal localization
is unusual. Differential diagnoses should there-
fore be particularly strongly considered for
scrotal lesions.
Fig. 3.13. Epidermal (epithelial) cyst
(35 cm) epidermal cysts, which can also be ob-

served on the trunk or face of patients with HS
(see Fig. 3.13). Clinically, these cysts appear to
be associated with primary elements of HS and
offer a positive clue to the possible efficacy of Fig. 3.14. Lateral thoracic extension of axillary involve-
retinoids in the treatment. Other lesions such as ment
acne or pilonidal cyst are covered in Chap. 6.
3.3 Topography
3.3.1 Involved Areas
The typical distribution of HS lesions closely

corresponds to the anatomical localization of
apocrine sweat glands: armpits and the groin.
Lesions also occur in a line connecting these
two regions passing by the breast and extending
to the anal zone. Fig. 3.15. Pubic and inner thigh involvement
In some patients the inguino-genital local- ola. These lesions have the same characteristics
ization may extend to involve the perineal and as HS lesions elsewhere and are, as a rule, easily
perianal area, but in most patients these are differentiated from acne lesions. It is a clinical
clearly separate lesions. Thus, it is important to diagnostic aid that comedones are not present
distinguish between anterior and posterior lo- in HS.
calizations as their differential diagnosis, prog- In contrast, the perineal and perianal zones
nosis and treatment are different. are mainly involved in male patients (see Fig.
3.17). When this zone is the only one involved,
HS has to be differentiated from several condi-
3.3.1.2 The Two Less Frequently tions especially pilonidal sinus and Crohns dis-
Involved Zones ease, see Chaps. 6, 7.
The breast may be involved in women, particu-

larly the sub-mammary folds, sometimes the 3.3.2 Atypical Localizations Other
inter-mammary fold (see Fig. 3.16) and the are- Zones May Be Involved
The buttocks are one of the most frequent of

these atypical localizations especially in men.
The clinical aspect is sometimes very peculiar:
the deep-seated abscesses and sinus are closely
associated in a unique lesion slowly extending at
the periphery over a period of years (see Fig.
3.18). The lesions may be very large, solitary and
very deep. Such single macro lesions may be
mistaken for regular abscesses of the muscle or
even bone-derived lesions. Lesions of the but-
tock therefore are easily differentiated from su-
perficial follicular inflammation.
Numerous other localizations have been re-
ported: the nape of neck, the waist (correspond-
ing to the waist band), peri-umbilical lesions,
the external auditory meatus, retro-auricular
Fig. 3.16. Inter-mammary HS
Fig. 3.17. Perianal and buttock involvement Fig. 3.18. A unique buttock lesion slowly extending
peripherally over a period of years
folds and the eyelids. Some of these reports stem

from the finding of inflamed apocrine glands,
and therefore reflect the mistaken supposition
that HS is an apocrine gland disease. These
lesions are usually not typical of HS, and their
relationship to HS is often at best tenuous. Fur-
3 thermore, they are infrequent and there is al-
ways doubt about whether they are part of the
general disease HS. From a disease management
point of view it is often more fruitful if they are
considered as being diseases possibly associated
with HS, rather than as part of HS itself.
Fig. 3.20. Areas involved in 43 men [1]
3.3.3 Distribution of Lesions
The frequency of each localization is different Table 3.1. Areas of involvement in men and women [1]
in men and women [1, 4]. Axillary involvement HS patients Female Male p
has no gender predilection whereas genito-fem- (n=164, 121 female,
oral lesions are significantly more common in 43 male)
women. In contrast perianal and perineal as
well as buttock lesions are significantly more Axillae 70 (58%) 30 (70%) NS
common in men (see Figs. 3.19, 3.20; Table 3.1). Mammary 31 (26%) 2 (5%) 0.006
One or several sites may be involved in the and inter-mammary
same patient, and activity in the sites may vary Inguino-femoral 111 (92%) 32 (74%) 0.007
as well. New regions may be involved at the Perianal and perineal 40 (33%) 24 (56%) 0.01
same time as the disease burns out in regions Buttocks 30 (25%) 21 (50%) 0.006
previously affected. One site may be quiescent,
while another experiences a flare. In general,
lesions are roughly symmetrical, indicating a
systemic disease rather than local infection. 3.4 Evolution of the Disease
and its Severity
3.4.1 Age at Onset and Resolution
HS develops after puberty, usually in the second

or third decade. In a personal series of 164 pa-
tients mean age at onset was 22.8 years with ex-
tremes of 10 and 57 years (see Fig. 3.21). This
finding was similar to those of other series
[4, 12]. Genetic factors may affect the onset of
disease. Patients with a familial history of HS
tend to experience an earlier onset (mean age 20
versus 23 years), although positive bias through
over-reporting may occur in families where HS
Fig. 3.19. Areas involved in 121 women [1] is a communal rather than a personal problem.
The age at onset and age distribution of the
cases appear to suggest co-occurrence with hor-
monal factors, see Chap. 12. Prepubertal cases
are rare. In general they are not linked to an
Fig. 3.21. Age at onset in

men (n=43) and women
(n=121)
severe disease as evaluated by the Sartorius in-

dex [1].
The development of new lesions generally
tends to slow down after 50 years, with less in-
flammation and suppuration but sometimes
with severe sequelae with extensive fibrosis and
tissue destruction (see Fig. 3.22). It may be spec-
ulated that low-grade disease resolves with age,
while more severe disease persists or progresses.
3.5 Clinical Course

Fig. 3.22. Sequelae of severe HS
Chronicity is one of the main features of HS. In a
early menarche, although cases have been pub- questionnaire survey of 110 patients Von der
lished in which the two co-occur. Similarly, Werth and Williams reported that in their pop-
there is a tendency for the disease to burn out ulation mean age 40 years the average dura-
after menopause in women. Patients with con- tion of the disease had been 18.8 years and 98/110
tinuously active disease after the age of 50 still had active disease [12]. This is indeed a
(mostly men), however, regularly appear, and heart sink condition for the patient. Further-
for some the disease may even have started at more, there is an extreme variation in the sever-
that age. ity of HS. In a personal series of 164 patients [1],
For most patients the worst years are the first 76% were in Hurleys stage I, 20% in stage II and
10 or 15 years after onset [12]. The chance of 4% in stage III. Most of the patients were there-
cure after localized excisions also appears to in- fore early or mild cases where diagnosis remains
crease with increasing age of the patient, sug- the most difficult. Premenstrual flare is com-
gesting that the underlying pathogenic mecha- monly observed, and may aid the diagnosis of
nisms abate at an older age [5]. In one series HS. Patient physiology and behaviour may influ-
older patients (>40 years) and a patient with a ence the severity of the disease. The BMI does
tardy diagnosis however had significantly more not appear to be an independent risk factor for
disease onset, but may influence the course of modes of disease evolution. The disease may be
the disease. Overweight and obese patients have restricted to a single region e.g. axillary or
significantly more severe disease, as evaluated expand to all possible areas. The disease severity
by the Sartorius index [1]. The smoking of may also vary. It may be active in all areas or
tobacco may, in contrast, be a risk factor for the only in one or two areas; and in each involved
development of HS. In terms of disease severity, area the degree of involvement may vary. It may
3 current smokers appear to have slightly more se- be massive with no normal skin left or the dis-
vere disease, but the difference does not reach ease may be represented by only one or two nod-
statistical significance. These factors are of clini- ules or draining sinuses. In a given region, each
cal importance to the management of patients. new attack may be a revival of an old lesion or
The disease is highly intrusive in the lives of alternatively the appearance of new nodules and
patients. Von der Werth and Williams reported abscesses each time.
that 62% of patients acknowledged the presence If one is to classify the severity of intermedi-
of permanently painful boils that failed to sub- ate disease further the number of areas involved,
side [12]. In our own series 30% of the 164 pa- the extent of lesions in each area, and the num-
tients experienced pain more than 15 days a ber of days with pain and/or suppuration are the
month [1]. It is obvious that the pain, suppura- main factors in the assessment.
tion and repercussions for the patients social
and sex life are responsible for this diseases
severe impact on quality of life [11, 13]. 3.5.3 Continuous Disease:
General practitioners and most specialists Moderate, Severe
are more familiar with the dramatic aspect of
severe disease and remember this picture, thus In more severe cases there are no days off for the
possibly overlooking the less severe cases that patient: pain and suppuration are permanent
are intermittent, benign or of medium severity. features of their lives and the disease is relent-
This failure to recognize mild forms of HS lessly progressive in one or several areas. In-
explains why the prevalence of HS is generally flammatory nodules rupture externally giving
underestimated. rise to chronic sinuses with intermittent or per-
manent discharge of a mixture of blood, serous
exudate and pus. Who among the patients pro-
3.5.1 Intermittent/Benign Course gresses to this stage of the disease cannot cur-
of the Disease rently be predicted with any certainty. Neither
clinical examination nor other tests offer reli-
In these forms the disease may manifest itself as able predictive data.
episodes of one nodule or abscess followed by a In the extremely severe, untreated cases, one
period of remission which may last for several or several affected sites are covered by a mixture
months; during this interval the clinical aspect of permanently draining sinus and severe scar-
is normal or one non-tender nodule may persist. ring with oedema and limitation of mobility.
The finding of such single nodules on palpation The sinuses can dissect deep into the underly-
of the affected region aids the diagnosis signifi- ing tissues and go much further than can be es-
cantly. The severity at this stage is best evaluated timated clinically. Cases have been reported
by the number of episode per year and the dura- where an apparent breast abscess proved to be
tion of each episode. the extension of axillary HS. Ulceration may
also occur and burrowing abscesses may perfo-
rate neighbouring structures such as muscles or
3.5.2 Intermediate Course fascia, leading to various fistulas in the genital
of the Disease and perianal region. Fistula formation may in-
volve the rectum, urethra and vagina, and has to
A large variation in clinical picture can be ob- be differentiated from fistulas arising within
served, depending on the several different these organs.
In this stage of the disease long-lasting sup-

puration has previously led some patients to Q Stage II:
complications such as anaemia, hypoprotein- Recurrent abscesses with tract formation
emia and amyloidosis. This kind of wasting and cicatrization. Single or multiple,
syndrome is generally not seen today; however, widely separated lesions.
other complications may occur. Carcinoma may Q Stage III:
occur, particularly on the buttocks. These can- Diffuse or near-diffuse involvement, or
cers appear to have a particularly bad prognosis, multiple interconnected tracts and
possibly because of the local immunodeficiency abscesses across entire area.
caused by the long-lasting inflammation and
scarring. Except for the common paraclinical Stage I can usually be managed with drugs and
signs of inflammation, such as elevated sedi- stage II patients may benefit from both limited
mentation rate, low serum iron and elevation of excisions for recalcitrant lesions and drug ther-
alpha-2 and gamma globulin, the patients are apy. Patients in stage III are unlikely to benefit
however usually in good general health and from medical therapy, and should be offered
without biological repercussions, even in cases wide surgery.
of long-lasting severe disease.
The process usually burns out with more or
less fibrous sequelae, but the ending of the in- 3.6.2 Sartorius [9]
flammatory process is unpredictable. Frequent-
ly menopause brings relief in women, but the The need for uniform outcome variables when
association is not constant, and the end may reporting treatment effects has led to a proposi-
come after or before the menopause. For men it tion of a score by Sartorius and co-workers. This
is similarly unpredictable. classification allows for better dynamic moni-
toring of disease severity in individual patients,
and therefore forms a complimentary system to
3.6 Severity Indexes the Hurley classification.
Due to the large spectrum of clinical severity, to 1. Anatomical region involved (axilla, groin,
the severe repercussions on quality of life and to gluteal or other region or infra-mammary
the variety of treatments available, a reliable region left or right: 3 points per region
method for evaluating disease severity is need- involved).
ed. Ideally it should take into account the num- 2. Number and scores of lesions (abscesses,
ber, type and size of lesions, evolution, pain and nodules, fistulas, scars; points for lesions
repercussions for quality of life. Such a compre- of all regions involved: abscesses/nodules
hensive instrument does not yet exist, but two 2, fistulas 4, scars 1, others 1).
attempts have been proposed to classify patients 3. The longest distance between two relevant
according to severity. lesions, i.e. nodules and fistulas in each
region, or size if only one lesion (<5 cm, 2;
<10 cm, 4; >10 cm, 8).
3.6.1 Hurleys Clinical Staging [2] 4. Are all lesions clearly separated by normal
skin? In each region(yes 0/no 6).
This is historically the first classification sug-
gested and is still useful for the classification of A total score or a score by region can be calcu-
patients in overall groups. lated. This score has been assessed retrospec-
tively and should be assessed prospectively in
Q Stage I: future therapeutics studies.
Abscess formation, single or multiple The Sartorius score lacks a subjective evalua-
without sinus tracts and cicatrization. tion of the patient, i.e. what is the burden of dis-
ease for the individual patient? How much pain
is caused by the disease? And how is the quality Table 3.2. Questions which aid the diagnosis of hidrad-
of life affected? Pain can be assessed on a visual enitis suppurativa
analog scale (VAS), and the quality of life may Questions where a positive answer supports
be assessed using a validated questionnaire such the diagnosis of HS:
as the Dermatology Life Quality Index (DLQI) 1. Does anyone in your family suffer from
or Skindex. In a study of quality of life in 60 pa- the same symptoms?
3 tients a good correlation was observed between
2. Do your boils recur at the same spot every time?
the Sartorius score and the Skindex score for
quality of life, offering support for the validity 3. Do you smoke tobacco?
of the proposed scores [13]. 4. Do you experience a premenstrual flare
An evolutivity score integrating objective of your boils regularly?
and subjective evaluation of the disease to be Questions where the negative answer supports
used for the management of medical treatments, the diagnosis of HS:
however, has yet to be constructed. 5. Do you get random boils on your skin,
i.e. on the thighs or abdomen as well?
6. Has the treatment offered by your doctor helped?
3.7 Diagnosis
7. Do you suffer from infections elsewhere?
The diagnosis is primarily clinical. No diagnos- 8. Do you get a fever when your boils appear?
tic paraclinical tests are currently available and
a biopsy is rarely required to exclude an alterna-
tive diagnosis. Frequently, and especially in be-
nign cases, the diagnosis has to be established 3.7.2 Delay in Diagnosis
primarily on patient history, i.e. more on the
questioning of the patient than on objective data The varying sites involved and the non-specific
gathered by examination. In atypical cases e.g. nature of early lesions mean that patients with
buttock involvement alone the chronicity of HS are referred to many different specialists,
the inflammatory and suppurative process is a including general surgeons, gynaecologists,
cornerstone of the diagnosis. In 30% of patients, plastic surgeons, dermatologists, infectious
a positive familial history of HS is found thus medicine specialists, immunologists, gastroen-
helping to establish the diagnosis. This occurs terologists, proctologists and urologists. This
especially among female patients [4]. occurs mainly because lesions are most often
considered to be common abscesses requiring
treatment with short courses of antibiotics and
3.7.1 Diagnostic Criteria lancing, which is an ineffectual form of therapy
that must be strongly discouraged.
Establishing the diagnosis relies on three main Unfortunately, the disease is not well known
features: to many general practitioners and other non-
dermatology specialists. This may cause delay
Q Typical lesions, i.e. deep-seated nodules in the diagnosis and treatment, and consequent-
(blind boils) and/or fibrosis ly in passing information to the patients. In our
Q Typical localizations, i.e. armpit and personal series of 164 patients the mean delay
groin in diagnosis was 7 years with an extreme of
Q Relapses and chronicity 42 years [1]. Failure to recognize HS, failure to
give a correct diagnosis and advice on how to
Typical lesions can be seen depicted in this manage this chronic disease are therefore com-
chapter. Questions to ask when taking a patient mon and add to patients severe distress and im-
history which may aid the diagnosis are given in pairment of quality of life.
Table 3.2.
3.7.3 Differential Diagnoses (also called sebocystomatosis). Steatocystoma

multiplex may be differentiated from HS by the
To the untrained eye the main impression of an finding of innumerable cysts evenly distributed
acute lesion is the inflammatory, focal process. over the entire skin, and not only limited to in-
The most frequent mistake is therefore a failure verse areas. Its association with HS is not well
to recognize what appears as a common ab- documented.
scess as a manifestation of HS. Carbuncles, fu- Late lesions in the ano-perineal location are
runculosis, lymphadenitis, infected Bartholins to be distinguished from other chronic scarring
gland, and the infected epidermal cyst are there- inflammations such as tuberculosis, actinomy-
fore to be differentiated from early lesions [3]. cosis, cat-scratch disease and lymphogranuloma
Carbuncles and furunculosis and other venereum. For this region an important and
staphylococcal skin infections are often asym- difficult differential diagnosis is anal Crohns
metrical in distribution and by their nature disease (see Chap. 7).
they involve random areas of the skin. Upon ex- In general, the differential diagnoses must
amination pathogens are commonly found. be considered, but rarely form true diagnostic
Treatment is generally rapidly rewarding when dilemmas for the experienced clinician. The co-
topical and systemic antibiotics are used simul- existence of a number of other diseases which
taneously. In addition to identifying the offend- naturally occur when a disease is as common as
ing pathogens in the lesions, carriers or other HS may, on the other hand, present as signifi-
sources of infection can often be properly iden- cant confounders in the diagnostic process, and
tified and treated. Paraclinically, these patients subsequent nosology of the disease. The co-ex-
also show signs of infection, such as elevated isting diseases are discussed in greater detail in
erythrocyte sedimentation rates, granulocyto- Chap. 6.
sis, etc.
When inflammation is not caused by micro-
organisms alone, the situation is much more References
similar to HS, and extra care has to be taken in
establishing the correct diagnosis. Epidermoid 1. Faye O, Bastuji-Garin S, Poli F, Revuz J. Hidradenitis
(or epithelial) cysts, mistakenly called sebaceous suppurativa: a clinical study of 164 patients (manu-
cysts, can be present in HS patients; they may script in preparation)
2. Hurley HJ. Axillary hyperhidrosis, apocrine brom-
exist independently from HS and when in an hidrosis, hidradenitis suppurativa, and familial be-
axillary or inter-mammary localization with nign pemphigus: surgical approach. In: Roenigk RK,
occasional inflammation are frequently consid- Roenigk HH, editors. Dermatologic surgery. Marcel
ered erroneously as HS. The cysts are however Dekker, New York, 1989, pp 729739
most often single and therefore lack the basic 3. Janssen T, Altemeyer P, Plewig G. Acne inversa (alias
symmetry of HS. Furthermore, a primary ele- hidradenitis suppurativa) J Eur Acad Dermatol Ve-
ment may be recognized. The true epidermoid nereol 2001; 15:532540.
4. Jemec GB. The symptomatology of hidradenitis sup-
cyst is a superficial firm elastic dome-shaped
purativa in women. Br J Dermatol 1988; 119(3):345
nodule mobile over the deeper structures. Clini- 350.
cally there may be a central punctum but even 5. Jemec GBE. The effect of localised surgical excisions
in the absence of this, there is often a history in hidradenitis suppurativa. J Am Acad Derm 1988;
of occasional expression of the semi-solid 19: 11031107.
keratinous, foul-smelling and greasy content. 6. Jemec GBE. Body weight in hidradenitis suppurativa.
Ultrasound examination often reveals a canal In: Marks R, Plewig G, editors. Acne and related dis-
corresponding to the central punctum. The orders. Dunitz, London, 1989, pp. 375376.
7. Jemec GB. Hidradenitis suppurativa. J Cutan Med
identification of the epidermal sack is of course Surg 2003; 7(1): 4756.
also possible after incision. 8. Jemec GBE, Heidenheim M, Nielsen NH. The preva-
True sebaceous cysts form a smooth elastic lence of hidradenitis suppurativa and its potential
swelling; they have an oily content. They may be precursor lesions. J Am Acad Dermatol 1996; 35:
solitary or be part of a steatocystoma multiplex 191194.
9. Sartorius K, Lapins J, Emtestam L, Jemec GB. Sug- 12. von der Werth JM, Williams HC. The natural histo-
gestions for uniform outcome variables when re- ry of hidradenitis suppurativa. J Eur Acad Dermatol
porting treatment effects in hidradenitis suppura- Venereol 2000; 14(5): 389392.
tiva. Br J Dermatol 2003; 149(1): 211213. 13. Wolkenstein P, Loundou A, Barrau K, Auquier P,
10. Slade DE, Powell BW, Mortimer PS. Hidradenitis Revuz J. Quality of life impairement in hidradenitis
suppurativa: pathogenesis and management. Br J suppurativa: a study of 61 cases (submitted)
Plast Surg 2003; 56(5): 451461.
3 11. von der Werth JM, Jemec GB. Morbidity in patients
with hidradenitis suppurativa. Br J Dermatol 2001;
144(4): 809813.
Chapter 4
Pathology of Hidradenitis Suppurativa

Alison Layton
4
4.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Key points
Acknowledgements . . . . . . . . . . . . . . . . . . . . 33
Q HS is a follicular disease References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Q Apocrine gland involvement appears

to be secondary to follicular events 4.1 Introduction
Q A lymphocytic infiltrate predominates There has been significant debate around the
in early lesions pathological features of hidradenitis suppurati-
va (HS) over the years. This debate focuses on
Q Keratin expression suggests that sinus whether the primary event relates to an inflam-
tracts are fragile matory process of the apocrine duct or whether
follicular occlusion is integral to the initiating
Q Keratin expression suggests that the process.
outer root sheet may be involved HS was first described as a distinct clinical
in HS lesions entity in 1839 by Velpeau [1]. In 1854 Verneuil
suggested that the inflammatory changes which
affected skin of the axillae, sub-mammary/
mammary regions (Fig. 4.1) and perianal areas
#ONTENTS were linked directly to a disease of the sweat
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .25 glands [2]. In 1922 a direct association was made
between HS and the apocrine glands [3]. As a
4.2 Glandular Elements of the Skin . . . . . . . . . .26
4.2.1 Sebaceous Glands
result of the anatomical distribution and the
and the Pilosebaceous Unit . . . . . . . . . . . . .26 inflammatory changes noted, the term apo-
4.2.2 Apocrine Glands . . . . . . . . . . . . . . . . . . . . . . . 27 crinitis was used as a synonym for HS. This
4.2.3 Eccrine Glands . . . . . . . . . . . . . . . . . . . . . . . . 27 terminology was supported when Brunsting
4.2.4 Apoeccrine Glands . . . . . . . . . . . . . . . . . . . . . 27 demonstrated the presence of distended apo-
4.3 Histological Appearance of HS . . . . . . . . . . 27 crine glands containing polymorph neutrophils
4.3.1 Early Lesions . . . . . . . . . . . . . . . . . . . . . 27 in the subcutis sections from 16 cases of estab-
4.3.2 Established Hidradenitis Suppurativa . . 28 lished HS. He concluded that the disease was an
4.4 Immunohistochemistry infection that entered the hair follicle duct and
of Hidradenitis Suppurativa . . . . . . . . . . . .30 expressed its full inflammatory effect within
4.5 Cytokeratin Expression in HS . . . . . . . . . . .30 apocrine glands, with further progression oc-
curring via the subcutaneous lymphatic chan-
4.6 Comparison with Other Disorders . . . . . . . 31
4.6.1 FoxFordyce Disease . . . . . . . . . . . . . . . . . . . 31
nels [4]. This explanation of pathogenesis was
4.6.2 Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 considered the explanation for the increased
4.6.3 Follicular Occlusion Triad . . . . . . . . . . . . . . 31 frequency of HS in African Americans, who
4.6.4 Pilonidal Sinus . . . . . . . . . . . . . . . . . . . . . . . . 31 have more apocrine glands per unit area of
4.6.5 Crohns Disease . . . . . . . . . . . . . . . . . . . . . . . . 32 skin.
26 Alison Layton
was evident in all of the specimens regardless of

disease duration, which ranged from 1 month to
18 years. In contrast, control specimens from
axillary and inguinal regions did not demon-
strate any follicular occlusion [7]. In the same
study, active folliculitis was associated with
apocrinitis and apocrine destruction whereas
apoeccrine glands, which drain directly onto
the epidermal surface, remained intact and
4 showed no evidence of inflammation. This work
provided clear evidence that follicular occlusion
by keratinous material, with subsequent active
folliculitis and secondary destruction of the
skin adnexae and subcutis, occurs as an integral
step in the pathogenesis of HS.
A further study examining early lesions has
confirmed that keratin plugging of follicles and
sinuses and inflammation around the hair fol-
licle are frequent features in HS [8]. Clinical
support for follicular occlusion includes typical,
large, multiple and grouped comedones evident
Fig. 4.1. Chronic hidradenitis suppurativa of the axilla in HS in apocrine sites [9, 10].
Hence, it is now believed that HS conforms
to a disorder of terminal follicular epithelium
However, in 1955 Shelley and Cahn applied within apocrine-gland-bearing skin but that
belladonna-impregnated occlusive tape to de- apocrine involvement does not appear to be a
pilated axillary skin in 12 healthy male volun- primary event in the majority of cases [11].
teers. They produced typical lesions of HS in 3
out of the 12 cases at the sites of application of
the adhesive tape. The histological inflamma- 4.2 Glandular Elements of the Skin
tion was confined to the apocrine glands [5].
This work introduced the concept that the initi- The cutaneous glands in humans include holo-
ating event in HS relates to follicular occlusion crine or sebaceous glands and merocrine or
followed by involvement of the apocrine gland. sweat glands. Merocrine glands are subdivided
In 1990, Yu and Cook retrospectively examined into apocrine and eccrine glands.
axillary skin from 12 patients with established
HS [6]. Of the 12 cases, 10 showed squamous-
epithelium-lined cysts or sinuses in the dermis 4.2.1 Sebaceous Glands
all containing keratin and half contained hair and the Pilosebaceous Unit
shafts, suggesting they were derived from hair
follicles. Only 4 of the cases had apocrine in- The sebaceous glands are an integral part of the
flammation and when apparent this was evident pilosebaceous unit and are found over the entire
around eccrine glands, hair follicles and epithe- body surface with the exception of the palms
lium-lined structures. This work suggested that and soles. The gland itself is made up of several
follicular occlusion was a more constant diag- lobules, which are separated by vascular con-
nostic feature than inflammation around the nective tissue. These lobules all empty into a
apocrine glands. short duct which then empties into the upper
A further retrospective pathological study of part of a hair follicle at the level of the infun-
118 skin specimens from 110 patients suffering dibulum. More than one sebaceous duct may
from HS demonstrated that follicular occlusion drain into the upper part of the hair follicle.
Pathology of Hidradenitis Suppurativa Chapter 4 27
4.2.3 Eccrine Glands
Eccrine glands are derived from a specialized

down-growth of the epidermis in utero. They
represent small tubular structures that drain di-
rectly onto the skin surface. They exhibit ther-
moregulatory control when the body is exposed
to a warm environment or during heavy exer-
cise. They are found in all sites of the skin ex-
cluding mucous membranes. The sites of maxi-
mum concentration are the palms, soles, axillae
and forehead.
4.2.4 Apoeccrine Glands
These represent axillary glands in adults and

combine morphological features of both eccrine
Fig. 4.2. Diagrammatic representation of the piloseba- and apocrine glands. A straight intradermal
ceous unit
duct opens directly onto the skin surface. The
deep secretory component conforms to a dilated
The hair follicle, the hair, the sebaceous gland apocrine segment whilst proximally the epithe-
and arrectores pilorum muscle and (in certain lium is compatible with an eccrine derivation.
regions) the apocrine glands make up the pilo-
sebaceous unit (Fig. 4.2).
4.3 Histological Appearance of HS
4.2.2 Apocrine Glands 4.3.1 Early Lesions (Fig. 4.3 ad)
Apocrine glands are found predominantly in Follicular hyperkeratosis with plugging and
the axillary and anogenital regions, although dilatation of the hair follicle is seen as an early
they are also found in the ear canal (ceruminal event in HS. The follicular epithelium may pro-
glands) and eyelids (Molls glands). They are liferate or may be destroyed. Inflammation is
derived from epidermis and develop as an out- frequently not apparent in early lesions but peri-
growth of follicular epithelium. They represent folliculitis will ensue and the inflammatory in-
compound sweat glands with a secretory coil filtrate embraces neutrophils, lymphocytes and
that extends deep through the dermis into sub- histiocytes. Early lesions may show acute in-
cutaneous tissue and drains via a long straight flammation involving the apocrine gland and
secretory duct, usually into a hair follicle. The duct but this is not always apparent and would
function of apocrine glands in humans is not appear to be a rare primary event [7]. In a study
altogether clear but in other mammals they are of 36 patients apocrinitis was present in only 5%
responsible for sexual attraction, and scent pro- [11].
duction is responsible for axillary and inguinal Rupture of the follicle spills its contents, in-
odour. They become functionally active and cluding keratin and bacteria, into the surround-
larger at puberty. The secretion is opalescent ing dermis [12].
and malodorous.
28 Alison Layton
Fig. 4.3 ad. Early lesions in hidradenitis suppurativa. a Acute HS lower power. b Follicular plugging. c Folliculitis
dense collection of neutrophils around hair follicle. d Acute folliculitis in HS
4.3.2 Established Hidradenitis histiocytes and giant cells that may be related to
Suppurativa (Fig. 4.4 ae) keratin fragments. Granulation tissue with in-
flammatory cells and occasional foreign body
Biopsy samples from established HS lesions giant cells is present in 25% of biopsy specimens
show sinus tracts with marked suppuration and [13]. Apocrine glands are generally absent in the
frank abscess formation. The sinuses are lined affected area but may appear quite normal in
by stratified epithelium and are surrounded by adjacent tissue. Extensive fibrosis is frequently
fibrosis and inflammation. The squamous epi- seen as a late result in the disease course [14].
thelium extends from the associated follicular Hence it would appear that the involvement
epithelium. The inflamed sinus tracts frequent- of the apocrine as well as eccrine glands repre-
ly contain desquamated keratin and hair shafts sents a secondary phenomenon in HS and re-
within the dense fibrosis [6]. Within the adja- sults from the inflammatory problem in deep
cent connective tissue there is frequently a dense structures.
chronic inflammatory infiltrate, which contains
Fig. 4.4 ae. Histological changes in established HS.

a Chronic folliculitis dense lymphocytic infiltrate
around hair follicle. b (i) Acute and chronic inflam-
matory cells around apocrine glands low power.
(ii) Acute and chronic inflammatory cells around
apocrine glands high power. c Pus in follicle.
d Sinus tract formation. e Scarring around hair
follicle
30 Alison Layton
4.4 Immunohistochemistry These changes mirror those found in experi-

of Hidradenitis Suppurativa mentally induced early acne lesions [16] where a
high ratio of T4 to T8 cells was found at 24 h.
Immunohistochemical evaluation of apocrine Further work looking at time-coursed biopsy
and eccrine involvement in HS has been per- samples in acne also confirmed these findings
formed retrospectively on sections of HS from [17].
vulval skin. Markers of apocrine differentiation These identical results in early HS and acne
(GCDFP-15, CD15, lysozyme) and eccrine lesions suggest there may be a common mecha-
differentiation (GCDFP-15, S-100, CA-19.9, nism with a type-IV delayed hypersensitivity
4 HMB45) were used. response to an as yet unidentified antigen.
In total 13 cases were examined; the majority
of glands identified in the samples from vulval
skin were eccrine. Apocrine glands were either 4.5 Cytokeratin Expression in HS
not seen or were present away from the area of
active inflammation in 10 of the 13 cases. In 2 Cytokeratin (CK) is an important marker for
cases the inflammatory process had apparently evaluating the origin and state of differentiation
destroyed all glands. Follicular obstruction was of epithelial cells. CK17 (found in normal in-
evident in 11 of the 13 cases. The inflammatory fundibulum, Fig. 4.6) has been shown to be ab-
component varied, being severe in some cases to sent from infundibular-like keratinized epithe-
minimal in burnt-out disease. When present, lium from HS lesions. This suggests fragility of
inflammation of glands was only evident in the draining sinus epithelial, which may allow
association with poral occlusion, suggesting this rupture to occur more easily, thus resulting in a
was a secondary phenomenon. Fibrosis appeared subcutaneous abscess. Keratin expression in
to correlate with more chronic disease [15]. non-infundibular keratinized and non-keratin-
In a study looking at acute lesions of HS, im- ized epithelium of HS lesions has been shown to
munohistochemical examination showed a pat- be similar to that observed in the outer root
tern of lymphocytic predominance suggestive sheath in normal hair follicles [18]. Hence drain-
of a cell-mediated response characterized by ing sinus epithelium in HS may possess charac-
CD4 helper cells (Fig. 4.5) expressing HLA-DR teristics of undifferentiation and hyperprolifer-
positivity in keeping with an activated state ation.
(personal communication, Dr Julian Barth).
The T-helper-to-suppressor ratio was high in
the acute HS lesions and in keeping with a cell-
mediated response.
Fig. 4.6. Normal pilosebaceous unit, CK17 was present

in suprabasal layers of the infundibulum (original mag-
Fig. 4.5. CD4 cells around the follicular duct nification =100)
Fig. 4.7. Dissecting folliculitis of the scalp
4.6 Comparison 4.6.3 Follicular Occlusion Triad

with Other Disorders
In 1956, Pillsbury, Shelley and Kligman coined
4.6.1 FoxFordyce Disease the term follicular occlusion triad for the com-
mon association of acne conglobata, HS and
FoxFordyce disease has the same anatomical dissecting folliculitis of the scalp. They pro-
distribution, as well as age and sex incidence as posed that the pathological event unique to each
HS. This condition is more convincingly associ- disease was follicular hyperkeratinization [19].
ated with an inflammatory process of the apo- All three diseases, HS, acne conglobata and
crine duct. Of interest there have been descrip- dissecting folliculitis, represent chronic, recur-
tions of some cases of FoxFordyce disease rent deep-seated folliculitis resulting in abscess-
progressing to HS. es followed by sinus tract formation and scar-
ring. In an actively inflamed lesion the sinus
contains hairs surrounded by neutrophils, gran-
4.6.2 Acne ulation and scar tissue (Fig. 4.7). In an end-stage
lesion there is scarring with patchy inflamma-
The pathogenesis of acne embraces increased tion, which may track down a healed sinus at the
sebum production, follicular hyperkeratosis, site of a destroyed hair follicle.
colonization with propionibacteria and inflam- The key histological features of all these con-
matory changes. The sebaceous duct hyperkera- ditions are:
tinization is mediated by the production of in-
terleukin-1 alpha (IL1-A) and tumour necrosis 1. Poral occlusion of the pilosebaceous units
factor alpha (TNF-A) by keratinocytes and T- within intertriginous skin sites, especially
lymphocytes. The result is hyperproliferation of the axillary area and anogenital regions
keratinocytes, reduced apoptosis and conse- 2. Secondary inflammation of apocrine
quent hypergranulosis. As a result the sebaceous glands
follicle becomes blocked with densely packed 3. Inflamed nodules and sterile abscesses,
keratin and so evolves the comedo. Early come- which are followed by sinus tracts,
dones show a dilated hair follicle associated with fistulae and hypertrophic scars.
infundibular hyperkeratosis. Later due to rup-
ture an acute dermal inflammatory response
ensues. This can be complicated by a foreign 4.6.4 Pilonidal Sinus
body granulomatous reaction. In severe cases
abscesses frequently present and cysts and si- In 1975 pilonidal sinus (PS) was reported to be-
nuses form. Dermal scarring frequently results long to the category of follicular occlusion dis-
in these cases. eases so creating the follicular tetrad [20]. His-
topathological findings in PS show follicular
32 Alison Layton
Fig. 4.8. Pilonidal sinus Fig. 4.10. Crohns disease with epithelioid granulomas
entiated [21]. Infundibular-like epithelium con-

tained CK1, CK10 and CK14, similar to normal
infundibulum, but CK17 was absent (Fig. 4.9).
4.6.5 Crohns Disease
Differentiating HS from Crohns disease merits

attention. At times these diseases can be clini-
cally indistinguishable and authors have em-
phasized that although foreign body granulo-
mas are a common finding in HS, the presence
of discrete epithelioid granulomas in the dermis
away from the site of active inflammation is un-
usual and should alert the pathologist to the
possibility of systemic granulomatous disease
such as Crohns or sarcoidosis [22]. Several
Fig. 4.9. Pilonidal sinus CK17 was absent in type A
epithelium (original magnification =100)
authors have reported the co-morbidity of HS
and Crohns [23] (see Fig. 4.10).
hyperkeratosis of the infundibulum with plug-

ging and dilatation of the follicle (Fig. 4.8). Su- 4.7 Conclusions
perficially the sinus is often lined with stratified
squamous epithelium but towards the deeper
reaches the wall consists of granulation and scar W
tissue. The early inflammatory event is perifol- The histological spectrum of HS is broad. The
liculitis with neutrophils, lymphocytes and his- disease appears to be predominantly follicu-
tiocytes leading to rupture of follicular epithe- lar and apocrine glands appear to be primarily
lium. involved in only a minority of histological
In a recent study using immunohistochemis- specimens. Although inflammation does not
try with six antikeratin antibodies it has been appear to originate within the apocrine
demonstrated that CK expression in PS is simi- glands, the exclusive finding of the disease
lar to that in HS, suggesting that the epithelium within apocrine-gland-bearing skin indicates
may be fragile, hyperproliferative and undiffer-
7. Attanoos RL, Appleton MAC, Douglas-Jones AG.

an apocrine effect. This diversity of pathologi- The pathogenesis of hidradenitis suppurativa: a
cal presentation may well explain the thera- closer look at apocrine and apoeccrine glands. Br J
peutic challenge that this condition poses. Dermatol 1995; 133:254258
8. Boer J, Weltevreden EF. Hidradenitis suppurativa
or acne inversa: a clinicopathological study of early
lesions. Br J Dermatol 1996; 135:721725
Acknowledgements 9. Brunsting HA. Hidradenitis and other variants of
acne. Arch Dermatol Syphilol 1952; 65:303315
I would like to acknowledge the following peo- 10. Mortimer PS. Hidradenitis suppuritiva diagnostic
ple: criteria. In: Marks R, Plewig G (eds) Acne and Re-
lated Disorders. Martin Dunitz, London, 1989, pp
Professor I Kurokawa, Department of Der-
359360
matology, Hyogo Prefectural Hospital, Japan, 11. Jemec GBE, Hansen U. Histology of hidradenitis
for providing me with and permitting me to in- suppurativa. J Am Acad Dermatol 1996; 34:994
clude information and slides on the immuno- 999
histochemistry of HS and PS. 12. Mortimer PS, Lunniss PJ. Hidradenitis suppurativa.
Dr Anne Gledhill, Department of Pathology, J R Soc Med 2000; 93:420422
Harrogate and District Foundation Trust, UK 13. Weedon D. Skin Pathology. Churchill Livingstone,
and Dr S Edwards Department of Pathology, Edinburgh, 1999, p 390
14. Fitzpatrick JE. Inflammatory reactions of the sweat
Leeds Teaching Hospital, UK, for providing his- unit. In: Farmer ER, Hood EF (eds) Pathology of
tological sections of HS and related diseases. the Skin. Appleton and Lange, Norwalk, 1990, pp
Dr Julian Barth, Department of Chemical 461462
Pathology, Leeds Teaching Hospital, UK, for 15. Heller DS, Haefner HK, Hameed M. J Reprod Med
providing valuable advice and information on 2002; 47(9):695689
HS. 16. Norris JFB, Cunliffe WJ. A histological and im-
Dr Anthony Yung, Department of Dermatol- munohistochemical study of early acne lesions. Br
J Dermatol 1988; 118:651659
ogy, Leeds Teaching Hospital, UK
17. Layton AM, Morris C, Cunliffe WJ, Ingham E. Im-
mmunohistochemical investigation inflammation
in lesions of acne. Clin Exp Dermatol 1998; 7:191
References 197
18. Kurokawa I, Nishijima S, Kusumoto K. Immuno-
1. Velpeau A. Dictionnaire de Medicine, un Repertoire histochemical study of cytokeratins in hidradeni-
General des Sciences Medicales Sous La Rapport tis suppurativa (acne inversa). J Int Med Res 2002;
Theorique et Pratique. Aiselle, Bechet, 1839 30:131136
2. Verneuil A. Etudes sur les tumours de la peau et 19. Pillsbury DM, Shelley WB, Kligman AM. Derma-
quelques maladies des glandes sudoripares. Arch tology. Saunders, Philadelphia, 1956, p 481
Gen Med 1854; 4:447468 20. Plewig G, Steger M. Acne inversa (alias acne triad,
3. Schiefferdecker B. Die Hautdrusen des Menschen, acne tetrad or hidradenitis suppurativa). In: Marks
und der Saugetierre, ihre Histologische und rassena- R, Plewig G (eds) Acne and Related Disorders. Mar-
natomische Bedeutung Sowie die Muscularis Sexu- tin Dunitz, London, 1988, pp 345357
alis. Schweizerbart, Stuttgart, 1922 21. Kurokawa I, Nishijima S, Suzuki K. Cytokeratin
4. Brunsting HA. Hidradenitis suppurativa; abscess of expression in pilonidal sinus. Br J Dermatol 2002;
apocrine sweat glands a study of clinical and path- 146:409413
ological features with a report of 22 cases and a re- 22. Attanoos RI, Appleton MA, Hughes LE. Granulo-
view of the literature. Arch Dermatol Syphilol 1939; matous HS and cutaneous Crohns disease. Histo-
39:108120 pathology 1993; 23:111115
5. Shelly WB, Cahn MM. The pathogenesis of hidrad- 23. Church JM, Fazio VW, Lavery IC. The differen-
enitis suppurativa in man. Arch Dermatol 1955; 72: tial diagnosis and comorbidity of HS and perianal
562565 Crohns disease-a further support to this associa-
6. Yu CCW, Cook MG. Hidradenitis suppurativa: a dis- tion. Int J Colorectal Dis 1993; 8:117119
ease of follicular epithelium, rather than apocrine
glands. Br J Dermatol 1990; 122:763769
Chapter 5
Imaging
Ximena Wortsman, Gregor B.E. Jemec
5
5 Key points axillae, the ano-genital region or under the

breasts, they may penetrate far from the skin,
Q Hidradenitis lesions extend into and may reach distant sites. If this is not prop-
the deeper tissue erly identified before treatment the presence of
such lesions may adversely affect the outcome
Q Imaging may facilitate the assessment of, for example, surgery. Similarly, appropriate
of disease severity and treatment visualization of the extent of all lesions may help
in the planning of surgery; finally, non-invasive
Q Imaging may aid differential diagnosis visualization of lesions may be used to monitor
the effect of, for example, medical therapy. Im-
aging of this debilitating skin disease may there-
fore have broad positive consequences for the
patients. Two methods have been used for the
#ONTENTS study of HS: high-frequency ultrasound and
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .34
MR scanning.
5.2 Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . .34
5.3 Magnetic Resonance Imaging (MRI) . . . . .36 5.2 Ultrasound
5.4 X-Ray Examination . . . . . . . . . . . . . . . . . . . . 35
5.5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
Ultrasound imaging is determined by the tis-
sues physical properties. These physical pro-
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 perties delay the propagation of sound waves.
The sound propagation velocity is usually set at
1540 m/s, although it varies slightly in different
5.1 Introduction tissues; for example in the skin it has been shown
to be 1580 m/s. The sound is emitted from a
Hidradenitis suppurativa (HS) is a chronic, re- transducer, which also serves as a piezoelectric
current and often devastating disease with long- receiver of the reflected echoes, transforming
term evolution and severe psychological impact the discrete pressure of an echo into an electric
on patients. For practical management of pa- current. The current is then transformed into a
tients as well as for pathogenetic research, skin surrogate black/white image which can be used
imaging at a lesser magnification than used for for tissue analysis by a trained ultrasonogra-
histopathology may also be of interest. In vivo pher.
imaging in the millimetre range allows visual- Ultrasound equipment is widely available
ization of the hair follicle structure as well as the in many hospitals, and therefore offers an excel-
identification of associated inflammation and lent opportunity for monitoring the subcuta-
the spread of the disease into deeper tissues. neous spread of HS. More pathogenetic in-
This may be of considerable benefit to patients. vestigations are however also possible. Using
When abscess and sinus tracts develop in the high-frequency ultrasound machines, with fre-
Imaging Chapter 5 35
Fig. 5.2. Dermal fluid collection in a patient with exten-

sive hidradenitis lesions
Fig. 5.1. Dermal focal hypoechoic nodular lesion. Hi-
dradenitis patient with subclinical lesion in the axillary tion of skin, and presented as easily detected,
zone not suspected by the clinician characteristic patterns.1)
Ultrasound morphological changes of HS
quencies of 1520 MHz, detailed visualization can be classified as follows:
of hair follicle structure is possible. It has been
shown that hair follicles of predisposed regions Q Dermal fluid collections (indicating
in HS patients differ from those of healthy con- inflammation)
trols [1, 2]. The patients appear to have hair fol- Q Dermal increase of thickness (secondary
licles with a larger hypoechoic or echolucent to inflammation)
diameter at the deeper end, which may reflect Q Dermal decrease of echogenicity (oedema)
either an actual distortion of the follicle lumen Q Dermal increase of echogenicity (fibrosis
or ongoing, subclinical inflammation. In addi- or long-term inflammatory changes)
tion to such observations, studies of HS compli- showing hair follicle enlargement
cations or spread of disease are also possible. Q Dermal hypoechoic focal nodular lesions
To illustrate this point we have studied 5 pa- (subclinical)
tients (4 women and 1 man) with HS and 13
healthy control subjects using Philips 5000 and In particular the existence of dermal hypoecho-
Philips IU 22 Real Time and High Resolution ic nodular lesions (see Figs. 5.1, 5.2) is important
Ultrasound Machines with 15- and 17-MHz fre- in the management of the disease.
quency linear probes. Images were acquired by a
radiologist skilled in the ultrasound examina- 1) Data on file
36 Ximena Wortsman, Gregor B.E. Jemec
5.3 Magnetic Resonance 5.5 Discussion

Imaging (MRI)
The use of imaging techniques is not widely de-
Magnetic resonance imaging is dependent on veloped in dermatology, most likely because the
the alignment of hydrogen nuclei (protons) in skin is immediately available for inspection and
water in a magnetic field. The MR signals that clinical examination. Imaging techniques, how-
provide the diagnostic information are pro- ever, do have a role to play in the examination of
duced within the patients tissue in response to skin diseases, in particular in diseases that may
radiofrequency pulses, generated by a transmit- spread to deeper tissues. HS is an excellent ex-
ter coil built into the construction of the mag- ample of such a disease.
net. Between the electromagnetic radiofrequen- Different techniques are available (see Table
5 cy pulses, the nuclei relax and realign releasing 5.1) and each method has different advantages,
energy which is recorded and used for imaging although traditional x-ray examination appears
of the tissue. This imaging technique provides to be less useful than the more modern meth-
good spatial resolution as well as a good ability ods. The use of either high-frequency ultra-
to distinguish between tissues, and is being ex- sound or MRI may be helpful, and the two differ
tensively used in other areas of medicine. mainly in that high-frequency ultrasound is
In HS, MRI has shown lesions with increased more readily available and that ultrasound is ca-
skin thickness, induration of subcutaneous tis- pable of distinguishing the involvement of su-
sues and abscess-like lesions [3]. The skin perficial skin layers, meaning that ultrasound
changes are not reported as distinguishable may be able to detect early changes, even sub-
from other those of other disorders, e.g. erysip- clinical ones, of the disease leading to earlier
elas or cellulitis. It may however be useful in the diagnosis and treatment.
identification of fistulas and deeper sinus tracts Ultrasound may be of particular use in the
and abscesses [4]. Similarly, MRI may give management of HS. The fluid collections found
information about the presence of alternative by ultrasound examination are mostly bigger in
causes of fistulation to the skin, for example, size and depth than the clinical lesions, and the
and as such help to identify patients who need changes in echogenicity and thickness of the
different treatment. skin layers are also more extensive when com-
Currently there are no commercially avail- pared to the clinical lesions. In addition, ultra-
able coils specifically for skin imaging, and sound will often identify nodular hypoechoic
although these are being developed experimen- (inflammatory) lesions in the skin that are not
tally, this method appears most helpful when perceptible to the clinician. In this way the ul-
studying deeper or extensive involvement. trasound examination may give valuable infor-
mation about the size and severity of the disease
in a given patient.
5.4 X-Ray Examination The ultrasound examination is also capable
of determining the real magnitude of the dis-
Traditional x-ray examination may occasionally
be useful if combined with contrast media. Nad-
Table 5.1. Imaging of HS. If high-frequency ultrasounda
gir and co-workers [5] thus were able to identify
is used excellent imaging is possible of primary lesions
perirectal sinus tracts and fistulas caused by HS and sinus tracts as well, whereas more widely available ul-
using a traditional barium enema technique. trasound equipment is less well adapted to skin imaging
The use of radiography for the identification of
skin lesions or abscesses does not appear fruit- Ultrasounda MRI X-ray
ful in view of the other techniques available. Primary lesions ++(+) +
Sinus tracts / ++(+) ++ +
fistulas
Abscesses +++ +++ ?+
Imaging Chapter 5 37
ease and measures the extent and sometimes location, near to the bowel or ano-genital area.
volume of the fluid collections. Monitoring this In this case laboratory tests and chest radio-
disease with ultrasound can therefore show, in graphs could be helpful.
an objective way, treatment effects and thereby Contrast media ultrasound and molecular
help guide subsequent steps in medication or imaging using MRI may be a future tool for ear-
surgery. In some cases the fluid collections can ly identification of inflammatory activity in the
also be punctured and drained under ultra- skin in asymptomatic or mild cases, since the
sound guidance. goal of the imaging methods is to make an ear-
Finally ultrasound may add to our under- lier diagnosis and improve treatment.
standing of this disease process. Enlargement of
the hair follicles is often seen in areas of the in-
volved zones that are not generally scarred or References
oedematous, suggesting that it may be an early
event in the development of the disease. These 1. Jemec GBE, Gniadecka M. Ultrasound examination
observations are in good accordance with earli- of hair follicles in hidradenitis. Arch Dermatol 1997;
er studies. 133: 967972.
2. Holm EA, Wortsman X, Gniadecka M, Wulf HC,
Imaging may also be used in cases where Jemec GBE. Real time spatial compound imaging
other complications are suspected, and may of skin and skin lesions. Skin Res Technol 2004; 10:
help to distinguish internal disease such as 2331.
Crohns disease from HS. Crohns disease tracts 3. Kelly AM, Cronin P. MRI features of hidradenitis
are different from HS fistulas because they tend suppurativa and review of the literature. AJR Am J
to connect with the bowel or anorectal area. In Roentgenol 2005; 185: 12011204.
HS the tracts are mostly superficial in location. 4. Cuenod CA, de Parades V, Siauve N, Marteau P,
Grataloup C, Hernigou A, Berger A, Cugnenc PH,
In patients where Crohns disease is suspected a
Frija G. MR imaging of ano-perineal suppurations.
computed tomography examination may help J Radiol 2003; 84: 516528.
to determine inflammatory changes to the bow- 5. Nagdir R, Rubesin SE, Levine MS. Perirectal sinus
el. Tuberculosis can also produce sinus tracts tracks and fistulas caused by hidradenitis suppura-
and fistulas and they also tend to be deeper in tiva. AJR Am J Roentgenol 2001; 177(2): 476477.
Chapter 6
Associated Diseases:
Causality or Complications? 6
Aude S. Nassif and Gregor B.E. Jemec
6.5 Other Co-Occurrences . . . . . . . . . . . . . . . . .45

Key points
6.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . .46
Q A number of diseases have been References . . . . . . . . . . . . . . . . . . . . . . . . . . . .46
6 described to co-occur with hidradenitis
suppurativa
6.1 Introduction
Q Evidence of a true causal relationship
between hidradenitis suppurativa Some patients are less lucky than others and
and these diseases is weak have several diseases at the same time. When
this occurs the diseases can be seen as complete-
Q Skin cancer can occur as a rare compli- ly separate, or as a reflection of a deeper com-
cation in hidradenitis suppurativa mon aetiology or core pathogenic process. How-
of long standing ever, keeping in mind Adamss statement that
co-occurrence does not imply association [1],
we have attempted in this chapter to cover all
the diseases associated with hidradenitis suppu-
#ONTENTS rativa (HS) except for Crohns disease. It is our
hope that by exploring the described associa-
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .38
tions it will be possible to suggest avenues of
6.2 Cutaneous Diseases future research into the aetiology and patho-
(Excluding Squamous Cell Carcinomas) . . 39 genesis of HS. The observations can lead to a
6.2.1 Follicular Occlusion Diseases . . . . . . . . . . . 39
6.2.1.1 Acne Conglobata . . . . . . . . . . . . . . . . . . . . . . .40
segregation of the readership into aggregators
6.2.1.2 Dissecting Folliculitis of the Scalp . . . . . . .40 and dividers. Aggregators tend to aggregate
6.2.1.3 Pilonidal Sinus . . . . . . . . . . . . . . . . . . . . . . . . 41 similar diagnoses into one, whereas dividers
6.2.2 Pigmentation Disorders split closely related diseases into subgroups. Ei-
of the Skin Folds: DowlingDegos ther approach may be appropriate, providing it
and Kitamuras Diseases . . . . . . . . . . . . . . . . 41 is argued from a rational perspective; the argu-
6.3 Rheumatological Disorders . . . . . . . . . . . . .42 ment cannot only be theoretical or practical, but
6.3.1 Clinical Picture . . . . . . . . . . . . . . . . . . . . . . . .42 must take the clinical reality into consideration
6.3.2 Radiographic Features . . . . . . . . . . . . . . . . . .42 in all its complexity.
6.3.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42 We have first described cutaneous diseases
6.3.4 Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . .43
including follicular occlusion diseases and pig-
6.4 Associated Cancers . . . . . . . . . . . . . . . . . . . .43 mentation disorders of the skin folds (Dowl-
6.4.1 Non-Skin Cancers . . . . . . . . . . . . . . . . . . . . .43 ingDegos and Kitamuras diseases), then rheu-
6.4.2 Squamous Cell Carcinoma . . . . . . . . . . . . . .44
6.4.2.1 Incidence and Prevalence . . . . . . . . . . . . . . .44
matologic diseases, neutrophilic diseases and
6.4.2.2 Clinical Picture . . . . . . . . . . . . . . . . . . . . . . . .44 finally cancers (cutaneous and others). By de-
6.4.2.3 Differential Diagnosis . . . . . . . . . . . . . . . . . .45 scribing the plethora of diseases in which a pos-
6.4.2.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45 sible causal association has been contemplated,
6.4.2.5 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45 it is our hope to stimulate the creative curiosity
Associated Diseases: Causality or Complications? Chapter 6 39
of the reader, to investigate the possible aetiolo- Table 6.1. Follicular occlusion diseases
gy and pathogenesis of this disease.
Hidradenitis suppurativa
Acne vulgaris (AV)
6.2 Cutaneous Diseases (Excluding Acne conglobata (AC)
Squamous Cell Carcinomas) Dissecting cellulitis of the scalp
or perifolliculitis capitis abscedens et suffodiens
6.2.1 Follicular Occlusion Diseases Pilonidal cyst
The term follicular occlusion disease refers to a

possible common pathogenic mechanism of oc-
clusion of sebaceous or apocrine glands, and siderably between AV and HS, while the other
diseases included in this term are listed in Table diseases are both much more rare and less in-
6.1. An association of these disorders has been vestigated. HS is more common in older persons
described in several patients, suggesting that a and women, while AV is more common in
causal relationship may be found rather than younger men. Similarly, Propionibacterium
mere co-occurrence. It has therefore been sug- acnes and seborrhoea, which are central factors
gested that the association of HS, acne conglo- in the development of acne, do not appear to be
bata (AC) and dissecting folliculitis of the scalp prominent in HS. In relation to the pilonidal
should be named follicular occlusion triad. Acne cyst, the abundance of hairs found in these cysts
tetrad includes pilonidal cyst in addition to the and their solitary and restricted distribution are
three aforementioned components. The actual obvious differences not only between HS and
evidence in favour of such aggregation is how- pilonidal cysts, but also between pilonidal cysts
ever predominantly morphological. and various forms of acne.
Epidemiological studies raise doubt about The diseases included in the acne triad/tet-
the general value of these observations (see rad have many similarities, but also profound
Chap. 8). They have failed to support it and clin- differences. Our current understanding of the
ical experience also suggests that these diseases pathogenesis of these diseases, their topographi-
are not generally associated with HS. Acne vul- cal distribution and their clinical responses to
garis (AV) appears to be uncommon in HS pa- treatment (see Table 6.2) all point towards dif-
tients, and while patients may display AC, clini- ferences, while the epidemiology points towards
cal experience suggests that the two diseases are significant differences. Therefore, occasional
separate as they react very differently to therapy. association may well be due to co-occurrence
The epidemiology of these diseases is also dif- rather than a truly common pathogenic mecha-
ferent. The age and sex distribution differ con- nism or a gene linkage.
Table 6.2. Treatment options in follicular occlusive diseases. (? Unknown utility, not useful, +a useful in selected
cases, + useful, ++ somewhat useful, +++ very useful)
Surgery Retinoids Tetracyclines Immunosuppression
and macrolide antibiotics
Hidradenitis suppurativa +++ +a ++ ++
a
Acne vulgaris + +++ +++ +a
Acne conglobata + +++ ++ +
Pilonidal cyst +++ ? ?
40 Aude S. Nassif and Gregor B.E. Jemec
6.2.1.1 Acne Conglobata 6.2.1.2 Dissecting Folliculitis of the Scalp
Acne conglobata (AC) is a disease attributed to A synonym for this entity is perifolliculitis capi-
an occlusion of sebaceous glands by a process of tis abscedens et suffodiens. This disease shows
keratinization. This occlusion can be responsi- considerable geographical variation and most
ble for secondary sebaceous inflammation. often appears to affect Afro-Caribbean male pa-
Clinically, the patient presents with comedones, tients. It usually starts during early adulthood.
cysts, abscesses and draining sinus tracts, main- It has been described in women and girls [20] as
ly located on the trunk and buttocks, but the well, and familial occurrence has also been doc-
face, neck and extremities may also be involved. umented [21]. An association with acne is re-
In the literature, several cases of so-called AC ported in 30% of cases [22]. The disease is how-
may very well in fact be HS, such as in Whipps ever uncommon and only a few cases have been
two familial cases of fatal squamous cell carci- reported in the literature making it difficult to
noma, in which a 56-year-old woman had suf- establish reliable arguments for an association
6 fered from widespread abscesses predominant- [20].
ly affecting the buttocks, AXILLAE and back Clinically, dissecting folliculitis of the scalp
[3]. The question of an association between AC is characterized by peri-follicular pustules, nod-
and HS arises. In contrast to HS, AC is predom- ules, abscesses and sinus that progressively
inant in men [2]. It is however also highly in- evolve into scarring alopecia. The clinical pic-
flammatory, starting in early adult life with an ture is often complicated by a keloid tendency
important tendency to scarring, which in AC is [4, 9, 15, 23]. The course of the disease is chronic
sometimes keloidal. Oral isotretinoin represents and relapsing. Squamous cell carcinoma may
a major therapeutic improvement in the treat- arise in chronic relapsing lesions and has a rec-
ment of this once disfiguring disease. The drug ognized metastasizing potential. Death from
is considerably more effective in clinical use metastatic carcinoma has been described in one
than earlier drugs such as tetracyclines, but patient [9].
treatment requires high dosages of up to 2 mg/kg Treatment is generally not rewarding. Anti-
per day for months [2]. Immunosuppressive biotics are commonly prescribed, and combina-
therapy is also indicated when highly inflamed tion therapy using rifampicin and clindamycin
lesions are present. Malignant transformation has been advocated [24]. Tetracyclines in acne
into squamous cell carcinomas has been repor- doses are usually not effective, whereas some
ted, similar to other long-standing inflamma- relief may be gained from anti-staphylococcal
tory states of the skin such as ulcers [3]. medicines such as dicloxacillin in long-term
Evidence for a possible causal association is therapy (authors personal experience). Isotreti-
however not strong, and epidemiological stud- noin is occasionally (rarely) helpful at a dosage
ies have failed to support a fixed relationship to between 0.67 and 1.0 mg/kg per day when pre-
cancer. Besides publications mentioning case scribed for several months [2529]. Topical
reports of AC [415], it has been stated that it is isotretinoin has also been reported to be effi-
quite common to find a medical history signifi- cient [22]. Alternatives include zinc [30], sys-
cant for acne vulgaris requiring isotretinoin in temic or intralesional corticosteroids, surgical
HS patients [16]. The level of evidence is there- excision and skin grafting [29]. X-ray therapy is
fore at case-story level or lower. Unfortunately, no longer recommended because of its carcino-
even though isotretinoin can provide long-last- genic risk. Both CO2 laser [31] and 800-nm la-
ing remissions and possibly even cure AC, its sers [32] have been used in a severe case of dis-
efficiency against HS is usually minimal. Re- secting cellulitis of the scalp. More recently,
ports have suggested the efficacy of etretinate or long-pulse non-Q-switched ruby laser has been
acitretin on both HS and AC, but systematic reported as efficient in three patients [33].
evidence is lacking [13, 1719]. However, even in In contrast to acne, the tendency for scarring
these published cases a relapse of HS occurred and the recalcitrant nature of this disease bear
between 4 months and a year after stopping ret- clear similarities to HS. In the absence of actual
inoid treatment (see Chap. 17). genetic classification, the absence of specific
epidemiological data and the relative rarity of DDD was first described by Dowling and
the two diseases, however, make actual assess- Freudenthal in 1938 [35], then by Degos and Os-
ment difficult. sipowski in 1954 [36]. It is characterized by a
reticulate pigmentation of the flexures with
prominent comedo-like lesions and pitted scars
6.2.1.3 Pilonidal Sinus [3756]. The disease runs in families, it has a ge-
netic autosomal dominant transmission [42, 44]
Many HS patients mention previous surgery for but it may be more prominent in women. DDD,
supposed pilonidal sinus, with a tendency to re- usually localized in axillae, neck and groin, may
cur several times. Clinically it is very difficult to occur during childhood or early adulthood and
be sure that these pilonidal sinuses are not in may extend progressively. Also noteworthy are
fact localized HS. It is particularly difficult to the pitted acneiform scars around the mouth
distinguish the two if histopathology has not present in most of the patients described in the
been performed and if the patient keeps having literature.
abscesses in the gluteal cleft. The differential di- Pathology shows thin branching pigmented
agnosis is further complicated by the fact that epidermal strand-like proliferations arising
pilonidal sinus is most often treated by sur- from the lower border of the epidermis and the
geons, whereas HS is treated by dermatologists; walls of the follicles. The principal differential
and the diagnostic criteria and specification diagnosis is acanthosis nigricans but the pres-
may therefore differ by tradition and training. ence of comedo-like structures and the pathol-
The clinical picture is identical to a flare of ogy can make the difference. Only two thera-
HS, except for the strict localization to the glu- peutic options have been proposed: topical
teal cleft [10, 34]. Histologically the identifica- adapalene [55] and Erbium YAG laser [56].
tion of a substantial accumulation of terminal Kitamuras reticulate acropigmentation (KRA)
hair characterizes the pilonidal sinus. In con- is another rare genodermatosis. This reticulate,
trast, terminal hair is not very frequently ob- slightly depressed pigmentation affects the ex-
served in of HS lesions, and when it occurs it tensor surfaces of hands and feet, occurs during
usually just shows only as small fragments. His- childhood, and it is often associated with mili-
tology is however not regularly done on these um-sized keratotic papules or simple breaks in
lesions, and it is therefore not easy to find an the epidermal ridge pattern on palms and fin-
estimate of the true frequency of the possible gers. A few families have been described in
association between HS and pilonidal sinus. In whom some members show features of KRA
addition to the histological differences and top- and some patients have features of both DDD
ographical limitations, the solitary nature of and KRA diseases [36, 38, 39, 4245]. Crovato
pilonidal sinuses also contrasts with the multi- and other authors have therefore suggested that
focal nature of HS. these disorders of pigmentation are two differ-
Mechanical strain has been implied as part of ent clinical expressions of the same nosological
the pathogenesis of both diseases, but no con- entity.
clusive experimental evidence has been present- Some patients are reported as having only
ed yet. DDD or only KRA while others have an asso-
ciation of HS and a pigmentation disorder. In
most of these observations, patients pigmenta-
6.2.2 Pigmentation Disorders tion phenotype is not reported and one could
of the Skin Folds: Dowling wonder whether this abnormality is not more
Degos and Kitamuras Diseases common in people with a dark skin colour. This
pigmentation may be the result of post-inflam-
DowlingDegos disease (DDD) or dark dot dis- matory pigmentation after bacterial infections
ease and Kitamuras reticulate acropigmenta- or after the frequent inflammation of the folds
tion are both rare pigmentation genodermatoses as seen in HS. The specificity of these signs
that have been described in association with would therefore appear to be poor. The associa-
HS. tion is not well supported by epidemiological
studies either. It is fair to ask questions such as: Table 6.3. Rheumatological manifestations of HS
How often in our everyday practice do we
Axial arthritis with predilection for the sacroiliac
see hyperpigmentation in axillary and other joints and lumbar spine. Some cases may present as
folds? and How often do we report it?. The ankylosing spondylitis
answers are most likely Very often for the first Peripheral arthritis of large joints, usually an oligo-
question and Never for the second one for arthritis, less commonly a polyarthritis. Peripheral
most dermatologists. Data are therefore lacking joint involvement consists of symmetrical or asym-
to establish the likelihood of a causal relation- metrical erosive arthritis of the hands, wrists,
ship between these rare diseases and HS. The knees and ankles and periosteal reaction involves the
likelihood of a causal relationship is neverthe- phalanges and tibia
less estimated to be low. Enthesopathy, which is inflammation at the site of
ligaments and fasciae insertion over the bone. The
most common localizations are the so-called sausage
6.3 Rheumatological Disorders digits (dactylitis), heel pain (plantar fasciitis) and
6 swelling of the Achilles tendon
Inflammatory dermatoses such as psoriasis have
well-known rheumatological associations and
often lead to collaboration between dermatolo-
gists and rheumatologists for the benefit of ization. In the axial skeleton, sacroiliitis (unilat-
the patient. Similarly pustular diseases have eral or bilateral) syndesmophytes, squaring of
well recognized rheumatological aspects, e.g. vertebrae, erosions and sclerosis of vertebrae
SAPHO syndrome, where SAPHO stands for may all be observed. Some patients even had
the combination of synovitis, acne, pustulosis, asymptomatic roentgenographic changes com-
hyperostosis and osteitis. The association be- patible with sacroiliitis [12].
tween HS and rheumatological disorders has
been less well studied, although a better under-
standing of it may add significant information 6.3.3 Treatment
about the pathogenesis of HS.
There seems to be a general agreement in the lit-
erature that stabilizing HS is probably helpful
6.3.1 Clinical Picture for stabilizing rheumatological manifestations
co-occurring with the disease, and in some
Most reported cases describing rheumatological patients treatment with antibiotics or surgery
complications/associations with HS involve for HS or both has resulted in a dramatic im-
black subjects [4, 11, 12, 15, 58, 60, 6265, 67]. provement in rheumatological symptoms [57,
Three different types of manifestations can be 62, 63]. These observations strongly suggest the
observed (see Table 6.3). These patients are HLA interdependence of the two diseases and argue
B27 negative, and aspirate from the involved against simple co-occurrence.
joints, when they are performed, are always Maximum control of cutaneous HS is
sterile. Rheumatoid factor and anti-nuclear an- therefore recommended in all patients with as-
tibodies are also uniformly absent [62]. sociated rheumatological disease. For the rheu-
matological complaints, different treatment
modalities have been proposed, starting with
6.3.2 Radiographic Features simple anti-inflammatory drugs, giving some
relief, sometimes intra-articular corticosteroid
Erosions are common, involving the joints of injection [7], or systemic steroids for resistant
hands and feet and medial malleoli; other ab- cases [4, 11]. One isolated case of efficiency of
normalities include periarticular osteoporosis, isotretinoin (1 mg/kg per day) has been repor-
loss of cartilage in wrists, periosteal new bone ted, again supporting the causative role of skin
formation, hyperostosis and diffuse demineral- changes [15]. d-Penicillamine alleviated peri-
pheral arthritis symptoms in one patient from rates was negative in all the patients who under-
Rosners series [11] but it had no effect on the went this test. The following mechanisms have
axial involvement. Sulfasalazine allowed dis- been proposed:
continuation of systemic steroids in one patient
[4]. More recently, one case of HS associated Q A bacterial fragment could share a
with Crohns disease and spondyloarthropathy common antigenic structure with
responded to anti-tumour necrosis factor (TNF) cartilage or bone and induce an immuno-
therapy [65]. logically inappropriate response against
the joint
Q Some bacterial cell-wall fragments
6.3.4 Mechanisms coming from HS lesions may get into the
bloodstream, become complexed to
Numerous non-specific rheumatological abnor- antibodies and then happen to deposit in
malities have been described in co-occurrence synovial tissue, where they could activate
with HS, involving the axial and peripheral complement and produce an inflamma-
skeleton, but the majority of HS patients do not tory but sterile arthritis
show any rheumatological signs. Although con- Q HS may expose cutaneous antigens to
vincing cases have been presented, arguing for the immune system and thereby cause
the interdependence of skin and joint disease in auto-immune reactions. This way,
HS, we are more inclined to think that these a rupture in tolerance towards antigens
manifestations may be an indirect consequence that may become unmasked because
of HS on genetically predisposed individuals, of the inflammatory process involved
i.e. patients have a rheumatological susceptibil- in HS is another possible mechanism.
ity rather than a true common pathogenic
mechanism.
It is interesting to note that arthritis is almost 6.4 Associated Cancers
always reported after the beginning of HS, and
only occurs when the disease has lasted for sev- 6.4.1 Non-Skin Cancers
eral years. One explanation could be that im-
munological mechanisms against the different Growth of sinus tracts is a histological hallmark
auto-antigens present in the chronic HS lesions of HS. Histologically the sinus tracts often
provoke rheumatological symptoms. For exam- appear as pseudo-neoplastic changes, and the
ple, circulating immune complex deposits might co-occurrence of actual cancer is therefore not
be responsible for the joint involvement, which only of clinical interest, but of potentially patho-
is a well-known mechanism in reactive rheuma- genic relevance as well, and may reflect an over-
tological diseases. Some publications support all trend for HS patients. To our knowledge,
this hypothesis because of the presence of circu- there is only one epidemiological study, from
lating immune complexes or cryoglobulinemia Sweden, addressing this matter [68]. This regis-
[7, 11, 12, 58, 59, 60, 61]. However, investigations try-based study concerned the relative incidence
in these patients have not been systematic and of cancer in patients treated for HS in the period
similar in all reported cases. Some authors do from 1965 until 1997. In total 2119 patients were
not mention looking for immune complexes, included. The overall risk of any cancer was
while others do not find them even though they increased by 50% (standardized incidence rate
looked for them. Immune complex deposition 95%, confidence interval 1.11.8) among this
cannot therefore explain all the cases. Hellmann cohort of patients hospitalized for HS, based on
gives some interesting hypothesises [56] to ex- the finding of 73 cases of cancer in HS patients
plain these rheumatological manifestations. and comparing the figure to the expected inci-
First, is an infectious localization of a germ dence in the general Swedish population. The
coming from HS lesions through haematoge- average age at diagnosis of cancer was 51.2 years
nous spread. However, culture of synovial aspi- for women and 55 years for men. There was a
significantly increased relative risk not only for scribed in women [5, 53, 54, 74, 85, 88, 91, 92].
non-melanoma skin cancer but also for buccal This may however partly be explained by re-
cancer and primary liver cancer. Whether this porting bias. For instance, vulval squamous cell
increased relative risk was correlated with alco- carcinomas may well be under-reported in as-
holism and/or smoking could not be ascertained sociation with HS, as this diagnosis was explic-
in this study. The data suggest a co-occurrence itly excluded from Moras series of squamous
of HS and cancer but these observations await cell carcinoma in a black population. Predispos-
confirmation in other HS populations. If con- ing factors are rarely searched for in the litera-
firmed it may give direction to further aetio- ture. The occurrence of non-skin cancers sug-
logical and pathogenic research in HS. gests that general carcinogens such as tobacco
may play a role. Some authors have suggested
that skin cancers predominate in the perineal
6.4.2 Squamous Cell Carcinoma region [52, 82], which raises the possibility of
co-carcinogenic factors such as human papillo-
6 Many chronic suppurative lesions such as ma virus (HPV) [52, 87, 88] and/or past radio-
chronic osteomyelitis and chronic leg ulcers are therapy [72, 88]. The presence of these factors
well known for their potential for malignant and other known carcinogen exposure should
transformation into squamous cell carcinoma reinforce vigilance and encourage physicians to
[69, 70]. The resultant tumours are known as perform a biopsy in any case of suspicious HS
Marjolins ulcers, named after Marjolins first lesions.
description in 1826 [87]. Such tumours have
been described in HS.
6.4.2.2 Clinical Picture
6.4.2.1 Incidence and Prevalence The clinical picture is rather stereotypical. Le-
sions occur almost exclusively in the perineal
It is very difficult to find reliable figures about area, but one case of axillary cancer in HS has
the incidence or prevalence of squamous cell been reported [94]. In almost all cases, squa-
carcinoma in HS patients since there are very mous cell carcinoma arises in an individual
few publications describing follow-up of HS pa- with a long-lasting HS, usually between 10 and
tients. Mostly isolated didactic cases are de- 30 years of duration, but extremes of 3 years [78,
scribed, which increase clinical vigilance but do 92] and 50 years [85] have been reported. Le-
not provide predictive data. The risk of squa- sions start insidiously with usual sinus tracts
mous cell carcinoma in HS has been estimated and oozing, but the recent onset of increased
at between 1.7% and 3.2% [52]. Case reports pain and discharge, as well as the presence of
however also allow the reader to form a clinical firm infiltrated subcutaneous nodules and/or
picture of a given problem when they are suffi- extensive and ulcerated granulation tissue
ciently numerous. In fact, there may be as many should alert the physician, especially if the dis-
as 100 [87, 92] cases of squamous cell carcinoma ease has lasted for many years and keeps wors-
arising from HS reported so far in the literature: ening. The tumour may rapidly enlarge and is
these include cases arising from so-called acne usually resistant to any treatment including sur-
conglobata of the buttocks/perineum or post- gery except for wide excision. The diagnosis of
sacral skin [5, 5254, 7093] and cases of malig- squamous cell carcinoma is sometimes a sur-
nant degeneration occurring in patients with prise during excision for HS and discovery of an
long-standing pilonidal disease, with a mean indurated area [78] or a histological surprise
duration of 23 years [92]. Both these diagnostic [88, 92], requiring a wide re-excision.
groups may potentially be confused with HS. Patients may present with metastatic lymph
Reviewing the published cases there seems to nodes. Three cases with associated paraneoplas-
be a clear predominance in men, since only eight tic hypercalcaemia have been published [75, 77,
cases of squamous cell carcinoma have been de- 83] and, in one of these, the presenting symp-
toms could be attributed to a paraneoplastic 6.4.2.5 Prognosis

parathyroid-hormone-like protein [83]. Other
paraneoplastic symptoms may occur and one The absence of large, well-defined cohorts pre-
case has been published describing a paraneo- cludes precise assessment of survival figures.
plastic neuropathy in association with HS-re- The reported follow-up varies between 18 days
lated squamous cell carcinoma [89]. and 4 years. In the early publications, diagnosis
was usually very late and a rate of 50% death was
seen [82]. In more recent literature this appears
6.4.2.3 Differential Diagnosis to have improved significantly, most likely be-
cause of the general quality improvements in
Clinically, the following diagnosis may be health care and education. Undoubtedly the
considered: anal fistula, lymphogranuloma ve- dermatological community is now more aware
nereum, granuloma inguinale, Crohns disease, of this potential complication, and progress in
tuberculosis cutis, Nocardia infection, actino- survival rates has been made, due to earlier di-
mycosis, tularaemia, chronic pyoderma gan- agnosis and more skilled surgical interventions
grenosum and erysipelas. with wide excisions.
Biopsy should be performed to exclude ma-
lignancy. In fact, diagnosis relies on biopsy,
which should be repeated in cases of suspicion, 6.5 Other Co-Occurrences
even if the first biopsy samples are reassuring,
because the histological differential diagnosis These other co-occurrences may be pure coinci-
with pseudoepitheliomatous hyperplasia may dences, but they may also give us clues to a bet-
be very difficult [88, 91]. The clinical picture ter understanding of the mechanisms of this
should always guide the physician; for instance, disease. HS is occasionally seen as a side-effect
a very fast and extensive recurrence after sur- to other treatments (see Table 6.4). HS has been
gery indicates a high suspicion of malignant described in several cases in association with
disease. lithium therapy, where it appears to have simi-
larities to other poral occlusive diseases, as well
as to immunosuppressive therapy used follow-
6.4.2.4 Treatment ing kidney transplantation.
HS has also been described as a side-effect of
The only curative treatment is wide excision rapamycin therapy, with a 12% frequency in a
with re-excision if margins are too close. Sur- cohort of 80 kidney transplants. This immuno-
geons insist on the necessity of assessment of suppressive drug hints either that immune
margins because the tumour often spreads more mechanisms may be involved in HS, or that sim-
widely than its external appearance would sug- ple infections may be promoted by the drug and
gest [85]. Wounds heal surprisingly well in the misinterpreted as HS by non-dermatologists.
perineal area. It has been suggested that early The diagnostic accuracy of the reported cases
reconstruction may hide a recurrence, and sec- however allows confusion with differential
ondary healing by granulation without colosto- diagnosis.
my has therefore been advocated [85].
Squamous cell carcinoma is a relatively che-
moresistant tumour [76, 77, 85]. Radiotherapy is Table 6.4. Drugs where hidradenitis has been implied as
a side-effect
usually ineffective because of the extent and
volume of tissue to be irradiated [72, 76, 85]. So Rapamycin [95]
both treatments should be considered only as Lithium [9699]
palliative treatments.
9. Curry SS, Gaither DH, King LE Jr. Squamous cell

6.6 Conclusion carcinoma arising in dissecting perifolliculitis of
the scalp. A case report and review of secondary
squamous cell carcinomas. J Am Acad Dermatol
W 1981;4:673678
A number of diseases have been described as 10. Zisova L, Sakakushev B. Acne tetrad in a family. Fo-
co-occurring with HS. The association may of- lia Med (Plovdiv) 1994;36:5157
ten occur by chance taking into account the 11. Rosner IA, Richter DE, Huettner TL, Kuffner GH,
Wisnieski JJ, Burg CG. Spondyloarthropathy asso-
prevalence of HS in the general population.
ciated with hidradenitis suppurativa and acne con-
The serendipitous observation of co-occur- globata. Ann Intern Med 1982;97:520525
rence may however also reflect a causal rela- 12. Rosner IA, Burg CG, Wisnieski JJ, Schacter BZ,
tionship between the diseases, and thereby Richter DE. The clinical spectrum of the arthropa-
lead to a better aetiological or pathogenic un- thy associated with hidradenitis suppurativa and
derstanding of both diseases. Taking all the acne conglobata. J Rheumatol 1993;20:684687
suggested associations into account a very 13. Chow ET, Mortimer PS. Successful treatment of
6 heterogeneous picture emerges, which does hidradenitis suppurativa and retroauricular acne
with etretinate. Br J Dermatol 1992;126:415
not allow hard conclusions to be made. This
14. Scheman AJ. Nodulocystic acne and hidradenitis
review of the literature strongly underlines suppurativa treated with acitretin: a case report.
the continued need for systematic observa- Cutis 2002;69:287288
tions in larger numbers of patients. The estab- 15. Libow LF, Friar DA. Arthropathy associated with
lishment of patient cohorts of sufficient size cystic acne, hidradenitis suppurativa, and perifol-
to allow longitudinal studies is therefore en- liculitis capitis abscedens et suffodiens: treatment
couraged. with isotretinoin. Cutis 1999;64:8790
16. Hurley HJ. In: Fitzpatricks dermatology in general
medicine, 3rd edn. McGraw Hill, New York, 1987,
pp 712717
References 17. Vahlquist A, Griffiths W. Retinoid therapy in HS a
report of a case. Retinoids Today Tomorrow Issue
1. Adams BB. Co-occurrence does not imply associa- 1990;18:2830
tion. Int J Dermatol 2004;43:699700 18. Hogan DJ, Light MJ. Successful treatment of hi-
2. Strauss JS. In: Fitzpatricks dermatology in general dradenitis suppurativa with acitretin. J Am Acad
medicine, 3rd edn, Vol. 1. McGraw Hill, New York, Dermatol 1988;19:355356
1987, pp 678679 19. Stewart WD. The retinoids: a significant advance in
3. Camisa C. Squamous cell carcinoma arising in acne dermatology. Medical Education Services, Canada,
conglobata. Cutis 1984;33:185187, 190 1984, p 51
4. Thein M, Hogarth MB, Acland K. Seronegative ar- 20. Scheinfeld NS. A case of dissecting cellulitis and a
thritis associated with the follicular occlusion triad. review of the literature. Dermatol Online J 2003;9:8
Clin Exp Dermatol 2004;29:550552 21. Bjellerup M, Wallengren J. Familial perifolliculi-
5. Dufresne RG Jr, Ratz JL, Bergfeld WF, Roenigk RK. tis capitis abscedens et suffodiens in two brothers
Squamous cell carcinoma arising from the follicular successfully treated with isotretinoin. J Am Acad
occlusion triad. J Am Acad Dermatol 1996;35:475 Dermatol 1990;23:752753
477 22. Karpouzis A, Giatromanolaki A, Sivridis E, Kousk-
6. Goldsmith PC, Dowd PM. Successful therapy of the oukis C. Perifolliculitis capitis abscedens et suffo-
follicular occlusion triad in a young woman with diens successfully controlled with topical isotreti-
high dose oral antiandrogens and minocycline. J R noin. Eur J Dermatol 2003;13:192195
Soc Med 1993;86:729730 23. Montgomery JR, White TW, Martin BL, Turner
7. Olafsson S, Khan MA. Musculoskeletal features ML, Holland SM. A novel connexin 26 gene muta-
of acne, hidradenitis suppurativa, and dissecting tion associated with features of the keratitis-ichthy-
cellulitis of the scalp. Rheum Dis Clin North Am osis-deafness syndrome and the follicular occlusion
1992;18:215224 triad. J Am Acad Dermatol 2004;51:377382
8. Boyd AS, Zemtsov A. A case of pyoderma veg- 24. Powell JJ, Dawber RP, Gatter K. Folliculitis de-
etans and the follicular occlusion triad. J Dermatol calvans including tufted folliculitis: clinical, his-
1992;19:6163 tological and therapeutic findings. Br J Dermatol
1999;140:328333
25. Schewach-Millet M, Ziv R, Shapira D. Perifollicu- 41. Balus L, Fazio M, Amantea A, Menaguale G. [Dowl-
litis capitis abscedens et suffodiens treated with ing-Degos disease and Verneuil disease.] Ann Der-
isotretinoin (13-cis-retinoic acid). J Am Acad Der- matol Venereol 1993;120:705708
matol 1986;15:12911292 42. Brown WG. Reticulate pigmented anomaly of the
26. Koca R, Altinyazar HC, Ozen OI, Tekin NS. Dis- flexures. Case reports and genetic investigation.
secting cellulitis in a white male: response to Arch Dermatol 1982;118:490493
isotretinoin. Int J Dermatol 2002;41:509513 43. Crovato F, Rebora A. Reticulate pigmented anom-
27. Taylor AE. Dissecting cellulitis of the scalp: re- aly of the flexures associating reticulate acropig-
sponse to isotretinoin. Lancet 1987;2(8552):225 mentation: one single entity. J Am Acad Dermatol
28. Scerri L, Williams HC, Allen BR. Dissecting cellu- 1986;14:359361
litis of the scalp: response to isotretinoin. Br J Der- 44. Crovato F, Nazzari G, Rebora A. Dowling-Degos
matol 1996;134:11051108 disease (reticulate pigmented anomaly of the flex-
29. Bachynsky T, Antonyshyn OM, Ross JB. Dissect- ures) is an autosomal dominant condition. Br J Der-
ing folliculitis of the scalp. A case report of com- matol 1983;108:473476
bined treatment using tissue expansion, radical 45. Rebora A, Crovato F. The spectrum of Dowling-
excision, and isotretinoin. J Dermatol Surg Oncol Degos disease. Br J Dermatol 1984;110:627630
1992;18:877880 46. Crovato F, Desirello G, Rebora A. Is Dowling-Degos
30. Kobayashi H, Aiba S, Tagami H. Successful treat- disease the same disease as Kitamuras reticulate
ment of dissecting cellulitis and acne conglobata acropigmentation? Br J Dermatol 1983;109:105110
with oral zinc. Br J Dermatol 1999;141:11371138 47. Grosshans E, Bouffioux B, Toufik-Bellahcene M.
31. Glass LF, Berman B, Laub D. Treatment of peri- Arguments for the follicular origin of Verneuils
folliculitis capitis abscedens et suffodiens with disease (chronic suppurative hidradenitis). Ann
the carbon dioxide laser. J Dermatol Surg Oncol Dermatol Venereol 1991;118:207209
1989;15:673676 48. Wilson Jones E, Grice K. Reticular pigmented anom-
32. Boyd AS, Binhlam JQ. Use of an 800-nm pulsed-di- aly of the flexures. Arch Dermatol 1978;114:1150
ode laser in the treatment of recalcitrant dissecting 1157
cellulitis of the scalp. Arch Dermatol 2002;138:1291 49. Jones EW, Grice K. Reticulate pigmented anomaly
1293 of the flexures. Dowling Degos disease, a new geno-
33. Chui CT, Berger TG, Price VH, Zachary CB. Re- dermatosis. Arch Dermatol 1978;114:11501157
calcitrant scarring follicular disorders treated by 50. Bedlow AJ, Mortimer PS. Dowling-Degos disease
laser-assisted hair removal: a preliminary report. associated with hidradenitis suppurativa. Clin Exp
Dermatol Surg 1999;25:3437 Dermatol 1996;21:305306
34. Gertsch P, Mosimann R. [Verneuils disease in the 51. Fenske NA, Groover CE, Lober CW, Espinoza CG.
differential diagnosis of suppuration of the ano-per- Dowling-Degos disease, hidradenitis suppurativa,
ineo-buttock region.] Helv Chir Acta 1980;47:477 and multiple keratoacanthomas. A disorder that
481 may be caused by a single underlying defect in pilo-
35. Dowling G, Freudenthal W. Acanthosis nigricans. sebaceous epithelial proliferation. J Am Acad Der-
Br J Dermatol 1938;50:467471 matol 1991;24:888892
36. Degos R, Ossipowski B. Dermatose pigmentaire r- 52. Li M, Hunt MJ, Commens CA. Hidradenitis suppu-
ticule des plis. Ann Dermatol Syphilol 1954;81:147 rativa, Dowling Degos disease and perianal squa-
151 mous cell carcinoma. Aust J Dermatol 1997;38:209
37. Berth-Jones J, Graham-Brown RA. A family with 211
Dowling Degos disease showing features of Kita- 53. Weber LA, Kantor GR, Bergfeld WF. Reticulate pig-
muras reticulate acropigmentation. Br J Dermatol mented anomaly of the flexures (Dowling-Degos
1989;120:463466 disease): a case report associated with hidradenitis
38. Loo WJ, Rytina E, Todd PM. Hidradenitis suppura- suppurativa and squamous cell carcinoma. Cutis
tiva, Dowling-Degos and multiple epidermal cysts: 1990;45:446450
a new follicular occlusion triad. Clin Exp Dermatol 54. Tuthill RJ. Dowling-Degos disease associated with
2004;29:622624 hidradenitis suppurativa and squamous cell carci-
39. Cox NH, Long E. Dowling-Degos disease and noma. J Cut Pathol 1990;l7:322
Kitamuras reticulate acropigmentation: support 55. Altomare G, Capella GL, Fracchiolla C, Frigerio
for the concept of a single disease. Br J Dermatol E. Effectiveness of topical adapalene in Dowling-
1991;125:169171 Degos disease. Dermatology 1999;198:176177
40. Ostlere L, Holden CA. Dowling-Degos disease asso- 56. Wenzel G, Petrow W, Tappe K, Gerdsen R, Uerlich
ciated with Kitamuras reticulate acropigmentation. WP, Bieber T. Treatment of Dowling-Degos disease
Clin Exp Dermatol 1994;19:492495 with Er:YAG-laser: results after 2.5 years. Dermatol
Surg 2003;29:11611162
57. Hellmann DB. Spondylarthropathy with hidrad- 73. Humphrey LJ, Playforth H, Leavell UW Jr. Squa-
enitis suppurativa. J Am Med Assoc 1992;267:2363 mous cell carcinoma arising in hidradenitis suppu-
2365 rativum. Arch Dermatol 1969;100:5962
58. Tallo R, Quinet R, Waxman J. Reactive arthritis due 74. Gordon SW. Squamous cell carcinoma arising in hi-
to hidradenitis suppurativa mimicking osteomyeli- dradenitis suppurativa: case report. Plast Reconstr
tis. South Med J 1991;84:11471149 Surg 1977;60:800802
59. Kenik J, Hurley J. Arthritis occurring with hidrad- 75. Alexander SJ. Squamous cell carcinoma in chronic
enitis suppurativa. J Rheumatol 1985;12:183184 hidradenitis suppurativa: a case report. Cancer
60. Vasey FB, Fenske NA, Clement GB, Bridgeford PH, 1979;43:745748
Germain BF, Espinoza LR. Immunological studies 76. Black SB, Woods JE. Squamous cell carcinoma
of the arthritis of acne conglobata and hidradenitis complicating hidradenitis suppurativa. J Surg On-
suppurativa. Clin Exp Rheumatol 1984;2:309311 col 1982;19:2526
61. Bennett RE, Wilke WS, Murphy DP. Spondyloar- 77. Sparks MK, Kuhlman DS, Prieto A, Callen JP. Hy-
thropathy and hidradenitis suppurativa. Ann In- percalcemia in association with cutaneous squa-
tern Med 1983;98:112 mous cell carcinoma. Occurrence as a late compli-
62. Shenefelt PD. Pyoderma gangrenosum associated cation of hidradenitis suppurativa. Arch Dermatol
6 with cystic acne and hidradenitis suppurativa con- 1985;121:243246
trolled by adding minocycline and sulfasalazine to 78. Zachary LS, Robson MC, Rachmaninoff N. Squa-
the treatment regimen. Cutis 1996;57:315319 mous cell carcinoma occurring in hidradenitis sup-
63. Bhalla R, Sequeira W. Arthritis associated with purativa. Ann Plast Surg 1987;18:7173
hidradenitis suppurativa. Ann Rheum Dis 1994; 79. Chicarill ZN. Follicular occlusion triad: hidradeni-
53:6466 tis suppurativa, acne conglobata, and dissecting cel-
64. Grassi W, Offidani AM, Blasetti P, Simonetti O, lulitis of the scalp. Ann Plast Surg 1987;18:230237
Cervini C. HLA-B27 negative ankylosing spondy- 80. Anstey AV, Wilkinson JD, Lord P. Squamous cell
litis and hidradenitis suppurativa: report of a case. carcinoma complicating hidradenitis suppurativa.
Clin Rheumatol 1988;7:278283 Br J Dermatol 1990;123:527531
65. Roussomoustakaki M, Dimoulios P, Chatzicos- 81. Williams ST, Busby RC, De Muth RJ, Nelson H.
tas C, Kritikos HD, Romanos J, Panayiotides JG, Perineal hidradenitis suppurativa: presentation of
Kouroumalis EA. Hidradenitis suppurativa associ- two unusual complications and a review. Ann Plast
ated with Crohns disease and spondyloarthropa- Surg 1991;26:456462
thy: response to anti-TNF therapy. J Gastroenterol 82. Mendonca H, Rebelo C, Fernandes A, Lino A, Gar-
2003;38:10001004 cia e Silva L. Squamous cell carcinoma arising in
66. Hamoir XL, Francois RJ, Van den Haute V, Van hidradenitis suppurativa. J Dermatol Surg Oncol
Campenhoudt M. Arthritis and hidradenitis sup- 1991t;17:830832
purativa diagnosed in a 48-year-old man. Skeletal 83. Welsh DA, Powers JS. Elevated parathyroid hor-
Radiol 1999;28:453456 mone-related protein and hypercalcemia in a pa-
67. Leitch DN, Holland CD, Langtry JA. Hidradenitis tient with cutaneous squamous cell carcinoma
suppurativa and monoarthritis of the hip. Clin Exp complicating hidradenitis suppurativa. South Med
Dermatol 1997;22:206207 J 1993;86:14031404
68. Lapins J, Ye W, Nyren O, Emtestam L. Incidence of 84. Perez-Diaz D, Calvo-Serrano M, Martinez-Hijosa
cancer among patients with hidradenitis suppura- E, Fuenmayor-Valera L, Munoz-Jimenez F, Turega-
tiva. Arch Dermatol 2001;137:730734 no-Fuentes F, Del Valle E. Squamous cell carcinoma
69. Kaplan RP. Cancer complicating chronic ulcerative complicating perianal hidradenitis suppurativa. Int
scarifying mucocutaneous disorders. Adv Derma- J Colorectal Dis 1995;10:225228
tol 1987;2:1946 85. Shukla VK, Hughes LE. A case of squamous cell
70. Mora RG, Perniciaro C. Cancer of the skin in blacks. carcinoma complicating hidradenitis suppurativa.
I. A review of 163 black patients with cutaneous Eur J Surg Oncol 1995;21:106109
squamous cell carcinoma. J Am Acad Dermatol 86. Lin MT, Breiner M, Fredricks S. Marjolins ulcer oc-
1981;5:535543 curring in hidradenitis suppurativa. Plast Reconstr
71. Anderson MJ Jr, Dockerty MB. Perianal hidradeni- Surg 1999;103:15411543
tis suppurativa; a clinical and pathologic study. Dis 87. Cosman BC, OGrady TC, Pekarske S. Verrucous
Colon Rectum 1958;1:2331 carcinoma arising in hidradenitis suppurativa. Int
72. Donsky HJ, Mendelson CG. Squamous cell carcino- J Colorectal Dis 2000;15:342346
ma as a complication of hidradenitis suppurativa. 88. Short KA, Kalu G, Mortimer PS, Higgins EM.
Arch Dermatol 1964;90:488491 Vulval squamous cell carcinoma arising in chron-
ic hidradenitis suppurativa. Clin Exp Dermatol
2005;30:481483
89. Rosenzweig LB, Brett AS, Lefaivre JF, Vandersteen- 95. Mahe E, Morelon E, Lechaton S, Sang KH, Man-
hoven JJ. Hidradenitis suppurativa complicated by souri R, Ducasse MF, Mamzer-Bruneel MF, de Prost
squamous cell carcinoma and paraneoplastic neu- Y, Kreis H, Bodemer C. Cutaneous adverse events
ropathy. Am J Med Sci 2005;329:150152 in renal transplant recipients receiving sirolimus-
90. Altunay IK, Gokdemir G, Kurt A, Kayaoglu S. Hi- based therapy. Transplantation 2005;79:476482
dradenitis suppurativa and squamous cell carcino- 96. Stamm T, Lubach D. [Undesirable side effects on
ma. Dermatol Surg 2002;28:8890 the skin caused by lithium therapy case report
91. Manolitsas T, Biankin S, Jaworski R, Wain G. Vulval and references (authors transl).] Psychiatr Prax
squamous cell carcinoma arising in chronic hidrad- 1981;8:152154
enitis suppurativa. Gynecol Oncol 1999;75:285288 97. Gupta AK, Knowles SR, Gupta MA, Jaunkalns R,
92. Gur E, Neligan PC, Shafir R, Reznick R, Cohen M, Shear NH. Lithium therapy associated with hidrad-
Shpitzer T. Squamous cell carcinoma in perineal enitis suppurativa: case report and a review of the
inflammatory disease. Ann Plast Surg 1997;38:653 dermatologic side effects of lithium. J Am Acad
657 Dermatol 1995;32:382386
93. Malaguarnera M, Pontillo T, Pistone G, Succi L. 98. Marinella MA. Lithium therapy associated with
Squamous-cell cancer in Verneuils disease (hidrad- hidradenitis suppurativa. Acta Dermatol Venereol
enitis suppurativa). Lancet 1996;348(9039):1449 1997;77:483
94. Whipp MJ, Harrington CI, Dundas S. Fatal squa- 99. Aithal V, Appaih P. Lithium induced hidradenitis
mous cell carcinoma associated with acne con- suppurativa and acne conglobata. Indian J Derma-
globata in a father and daughter. Br J Dermatol. tol Venereol Leprol 2004;70:307309
1987;117:389-92.
Chapter 7
Hidradenitis Suppurativa
and Crohns Disease 7
Philippe Seksik, Jean-Franois Contou, Anne Cosnes and Jacques Cosnes
7.6 Crohns Disease

Key points and Hidradenitis Suppurativa . . . . . . . . . . . 53
7.6.1 Differential Diagnosis . . . . . . . . . . . . . . . . . . 53
Q An association between hidradenitis
suppurativa (HS) and Crohns disease 7.7 Co-Existence of HS and CD . . . . . . . . . . . . . 55
(CD) appears to be well established 7.8 Treatment of Perianal Co-existent CD
and HS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
7 Q Recognizing HS in a patient with CD, References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
or vice versa, has no immediate major
therapeutic implications but may lead
to the choice of a more aggressive Crohns disease (CD) is a chronic granuloma-
medical strategy tous inflammatory bowel disease that may in-
volve the anus and the perianal region. About
Q One can expect that a genetic link 50% of patients with CD develop perianal le-
between the two diseases will be sions during the course of their disease. In some
demonstrated and may lead to the of these patients, perianal cutaneous lesions
development of specific targeted may mimic those of HS. Moreover, the occur-
therapies rence of both HS and CD in the same individual
has been reported in quite a large number of
cases. This paper reviews the main pathophysi-
ological and clinical aspects of CD, describes
the perianal lesions of CD, comparing them to
#ONTENTS those of HS, and discusses the links between the
7.1 Definition and Course
two diseases.
of Crohns Disease . . . . . . . . . . . . . . . . . . . . .50
7.1.1 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . .50
7.1.1.1 Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . 51 7.1 Definition and Course
7.1.1.2 Enteric Microflora . . . . . . . . . . . . . . . . . . . . . 51 of Crohns Disease
7.1.1.3 Immune-Mediated Tissue Injury . . . . . . . . 51
7.2 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 7.1.1 Pathophysiology
7.3 Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . 52
7.3.1 Disease Location . . . . . . . . . . . . . . . . . . . . . . . 52 The cause of CD remains unknown. Recent ad-
7.3.2 Clinical Presentation . . . . . . . . . . . . . . . . . . . 52 vances in the pathogenesis of CD involve inter-
7.4 Therapeutic Aspects and Prognosis . . . . . . 52 actions of three elements: genetic factors, enteric
microflora and immune-mediated tissue injury.
7.5 Cutaneous Crohns Disease . . . . . . . . . . . . . 52
7.5.1 Clinical Presentation
Furthermore cigarette smoking has been de-
of Cutaneous Lesions . . . . . . . . . . . . . . . . . . . 53 scribed as the main risk factor for relapse and
7.5.2 Therapeutic Aspects and Prognosis . . . . . . 53 poor evolution of the disease [1].
Hidradenitis Suppurativa and Crohns Disease Chapter 7 51
7.1.1.1 Genetic Factors 6. The influence of antibiotics and probiot-

ics in experimental animals and in some
CD appears to have a genetic tendency, with clinical situations (postoperative relapse
multiple susceptibility genes. The first suscepti- of CD) [10].
bility locus for CD, which was found in replica-
tive studies worldwide [2, 3], is on the pericen-
tromeric region of chromosome 16 (IBD1 locus).
Mutations of the NOD2 gene in this region have 7.1.1.3 Immune-Mediated Tissue Injury
been conclusively associated with CD. Homo-
zygosity and compound heterozogosity increase Hostmicrobial interactions involve commen-
the relative risk of developing CD by 20- to sal species that reside permanently within the
40-fold compared to non-NOD2-mutated sub- gastrointestinal tract and this adaptation active-
jects. Nods proteins are thought to be cytosolic ly contributes to immunological tolerance and
receptors for pathogenic bacterial signals. Nod2 homoeostasis within the healthy gut. Molecular
recognizes muramyl dipeptide (MDP) [4], a mechanisms of this prokaryote/eukaryote cross-
conserved structure in bacterial peptidoglycan. talk involve different bacterial signals and pat-
Nod2 is expressed in monocytes and activates tern recognition receptors (PPRs) such as toll-
nuclear factor kappa B (NF-KB), which is a key like receptors (TLRs) and NODs [11]. The
transcriptional factor involved in the initiation bacterial stimuli represent a cluster of various
of the inflammatory response [5]. Since NOD2 signals called pathogen-associated molecular
variants seem to account for less than 20% of patterns (PAMPs) such as lipopolysaccharide
CD, other candidate susceptibility genes need to (LPS), peptidoglycans and bacterial nucleic ac-
be investigated. ids (CpG DNA). TLR are key regulators of the
innate immune response, and different changes
in selective epithelial expression of TLRs have
7.1.1.2 Enteric Microflora been reported to occur in CD [12]. In CD tissue
damage arises from excessive TH1 cytokine re-
The absence of evidence for transmission of sponses or a failure to turn off such responses
either CD or ulcerative colitis argues against a after pathogenic infection in genetically suscep-
transmissible infectious etiology. However, tible individuals. Additionally, cytokines act on
there are several pieces of indirect evidence that local microvasculature, upregulate adhesion
commensal microflora contribute to the patho- molecules and facilitate the recruitment of neu-
genesis of CD, such as: trophils and phagocytes, which contribute to
the amplification of the inflammatory response
1. The failure of induction of colitis in and further tissue damage. In healthy individu-
germ-free animals [6] als, activated mucosal T cells are controlled
2. The occurrence of inflammatory bowel through regulatory T cells and apoptosis path-
disease (IBD) lesions in areas of greatest ways, both of which seem to be defective in pa-
bacterial exposure tients with CD [13].
3. The induction of relapse in ileal CD
by the fecal stream [7]
4. The difference of fecal and mucosal flora 7.2 Pathology
composition between patients with CD
and healthy subjects [8] The elementary intestinal lesion consists of fo-
5. The loss of tolerance to the compo- cal infiltration of mononuclear cells, eosino-
nents of endogenous flora in patients phils, and polymorphonuclear cells in the lami-
with CD [9] na propria, small vessels, and epithelium [7].
Lesions tend to become chronic and deeper, in-
volving in some places all the width of the intes-
tinal wall. Important characteristics are the
52 P. Seksik, J.-F. Contou, A. Cosnes et al.
patchy distribution of the lesions, the epitheli- 7.4 Therapeutic Aspects

oid granulomas which are observed in up to and Prognosis
60% of patients, and the formation of strictures
and fistulas. Flare-up episodes are usually treated with ami-
nosalicylates or prednisolone, according to their
clinical severity. When steroid therapy fails
7.3 Clinical Aspects (10%30% of patients), the anti-tumor necrosis
factor-alpha antibody infliximab 5 mg/kg is
CD is usually diagnosed during the third de- usually active.
cade of life, but is not exceptional in childhood Maintenance treatment prescribed with the
and after 60 years. goal of preventing flare-ups uses aminosalicy-
lates and, in more severe forms, immunosup-
pressive drugs (azathioprine or methotrexate).
7.3.1 Disease Location Immunosuppressants are very effective as main-
tenance treatment, achieving and maintaining
CD may involve any part of the digestive tract, remission, sparing steroids, leading in some
7 but is located most commonly to the ileum and/ cases to mucosal healing, and improving quality
or the colon [14]. Most frequently, the disease of life [15]. Accordingly, there is a clear tendency
location remains the same, namely ileocolonic, over time to initiate immunosuppressants ear-
ileal, or colonic, throughout the course of the lier and in a larger proportion of patients [16].
disease, although some patients (fewer than Nowadays about two-thirds of patients receive
10%20%) may develop new lesions in another immunosuppressants. Repeated perfusions of
part of the intestine. infliximab may be used in the few patients
who are non-responders to classical immuno-
suppressants. Surgery is reserved for stenotic
7.3.2 Clinical Presentation and extra-parietal complications, or intractable
forms after a well-conducted medical manage-
Symptoms depend on disease location (colonic ment. The cumulative risk of intestinal surgery
lesions being more expressive) and anatomical is 82% after 20 years.
severity. Patients usually present with diarrhea, CD is an all-life chronic disease with no ten-
mucous and blood discharges, abdominal pain, dency to burn out over time. However, most pa-
and weight loss. Other features of flares are tients are able to have an almost normal life.
fatigue, fever, articular, cutaneous and ocular Mortality is slightly increased when compared
manifestations, and biological inflammatory to the general population [17].
response (elevated C-reactive protein and eryth-
rocyte sedimentation rate, ESR). In some cases,
the disease is latent until the development of a 7.5 Cutaneous Crohns Disease
complication, a stricture causing an intestinal
obstruction or a perforation (peritonitis, or At the time of diagnosis of intestinal CD, ex-
more commonly internal fistula with abscess amination of the anus shows anal or perianal
formation). The course of CD is poorly predict- lesions in about one-quarter of patients. Later
able. Most patients have flares separated by re- on, up to half of patients eventually develop
mission phases of variable duration; others perianal lesions. Those lesions are more fre-
(about 10%15%) have a chronic active disease. quent when CD involves the distal part of the
The disease has a protracted benign course in colon and rectum, but may be associated with
fewer than 15% of patients. ileal disease without colonic involvement, and
also may precede for years the development of
intestinal lesions. Recent data identified a new
variant gene OCTN (organic cation transporter)
associated with perianal and fistulizing CD.
This gene is located on the locus of IBD-5.
7.5.1 Clinical Presentation exacerbations without abscess formation), but

of Cutaneous Lesions not as a maintenance therapy. Surgical inter-
vention is required for drainage of an abscess,
The primary lesions of CD are confined largely non-cutting seton drainage of complex fistulas
to the endoanal skin, the transitional epithelium with deep pus collection [22, 23], and dilatation
of the anal canal, and the contiguous 12 cm of of a symptomatic anal stenosis.
rectal mucosa. The primary lesion is a painless, The effect of immunosuppressants is not as
midline fissure of the anal canal, which usually favorable as it is on the intestinal disease. In
remains symptomless and benign. Edematous children, purine analogs have been shown to
skin tags arise from the distal margin of super- improve perianal tenderness and induration in
ficial fissures. They may be voluminous, with most patients and to achieve fistula closure in
no tendency to decrease. A second and more some [24]. In adults, although purine analogs
destructive lesion is a penetrating ulcer which may induce the closure of perianal fistulas [25],
gives rise to fistulas [18]. Fistulous tracts may be only one-third of patients with perianal lesions
low, superficial, or high, long and tortuous, de- clearly improve. Patients aged 40 years or more,
pending on the location of their primary open- with recent perianal lesions, and without fistula
ing in relation to the anal canal. They may form are the best responders [26].
cavities and lead to abscess formation. They may The management of perianal fistulizing dis-
extend to the anal sphincter and have an impact ease resistant to standard treatment has greatly
on continence. Finally, anal lesions may lead to improved with the introduction of infliximab
stricture formation [19]. Over one-quarter of [27]. The complete arrest of the drainage of fis-
patients with CD will present with or develop tulas is obtained in 46% of patients 10 weeks af-
perianal fistula. ter the administration of 510 mg/kg of inflix-
Aggressive ulceration is an uncommon form imab at weeks 0, 2 and 6 and lasts on average for
that extends rapidly beyond the perianal skin to 12 weeks. However, fistula closure is often in-
involve the perineum and often the vulva [18]. It complete or superficial, fistulous tracts can per-
is usually associated with cavitating endoanal sist despite closure of the external opening, and
ulcers. Involvement of skin distant to the gas- relapses are common. This may lead to a re-
trointestinal tract (metastatic CD) is uncom- sumption of infliximab and to its being admin-
mon, but CD affecting penile and scrotal skin istered on a chronic basis (510 mg/kg every
has been described. 2 months), with a tendency to a loss of efficacy
Perianal lesions should be carefully assessed with time. In cases of incontinence or when the
and classified (ulceration, fistula, stricture) by lesions are severely disabling, proctectomy may
physical examination. However examination become necessary (10%38% of patients).
under anesthesia and modern imaging tech-
niques (endoanal sonography, magnetic reso-
nance imaging) improve the detection and 7.6 Crohns Disease
characterization of fistulas and abscesses, and and Hidradenitis Suppurativa
are necessary before defining a therapeutic
strategy. 7.6.1 Differential Diagnosis
In a patient with perianal disease, the differen-

7.5.2 Therapeutic Aspects tial diagnosis between CD and HS is usually
and Prognosis easy, as in HS other disease sites (axillae, groin)
have been involved and anal examination does
The overall strategy facing perianal CD is con- not demonstrate endoanal lesions or primary
servative [20, 21]. The control of sepsis is the ulcerations with fistula formation. Fistulas to
first objective. Antibiotics (metronidazole, cip- the anal canal may occur in HS, however they
rofloxacin, and clofazimine) are used for self- do not extend more than the extreme location of
limited complications (small abscesses, acute the apocrine glands [28, 29]. In contrast, in CD
Fig. 7.1. The elementary lesions of perianal Crohns dis- Fig. 7.2. A CD fissure merging on the perianal skin
ease (CD, posterior fissure, skin tags, and fistulas)
Fig. 7.3. A suppurative form of perianal CD with mul- Fig. 7.4. HS lesions in a patient with operated perianal
tiple fistulas CD
anal lesions may be absent or have healed. The

aspect of the perianal lesions also differs. In CD
the lesions are more ulcerative, scars are retrac-
tile, and the skin is involved only around the
anus (Figs. 7.17.3), whereas in HS, there are cu-
taneous scarring, comedones, skin bridges and
sinuses (Figs. 7.4, 7.5). From a pathological point
of view, lesions may be very similar. Attanoos et
al. [30] specifically looked at the granuloma in
101 HS patients. They found that although for-
eign-body-type granulomas are a common fea-
ture of HS (25%), the presence of discrete epi-
thelioid granulomas in the dermis away from
the site of active inflammation is unusual and Fig. 7.5. HS lesions in a patient with CD
should alert one to the possibility of granuloma-
tous disease such as CD [30].
7.7 Co-Existence of HS and CD lead to colonoscopy, as the presence of gastroin-

testinal endoscopic lesions and granulomas on
A clinical association between HS and CD has biopsy establishes the diagnosis of CD. Con-
been described in some cases reports [3133] versely, there is a need for a systematic search
and in one case series [34]. Gower-Rousseau et for acne, folliculitis, and HS skin lesions in CD
al. reported the occurrence of HS in two first- patients, particularly when a steroid treatment
degree relatives of patients with CD [35]. This is planned.
finding suggests a common genetic susceptibil-
ity for the two diseases. In the study by Church
et al. [34], CD lesions were found in 24 out of 61 7.8 Treatment of Perianal
patients with HS. In our series of 2926 patients Co-existent CD and HS
with CD, 18 (0.6%) have such an association.
This figure should be considered as minimal, as The use of steroids should probably be discour-
a systematic search for HS was not made. Of aged in the acute phases because of their poor
note, the proportion of active smokers was 78% efficacy and the risk of septic complications.
in our patients with both diseases. Clinical Immunosuppressants need to be evaluated once
characteristics of patients with HS and CD in sepsis has been completely controlled. Inflix-
the two latter studies are given in Table 7.1. CD imab has been proven to be efficient in the treat-
patients with HS differ from other CD patients ment of cutaneous CD manifestations such as
by a higher frequency of colonic and perianal pyoderma gangrenosum [36]. This led some
involvement, an increased need for immuno- authors to use infliximab in patients with both
suppressants, and, more importantly, a very un- HS and CD [3742]. Infliximab was introduced
usual need for proctectomy and definitive ileos- when conventional medical treatment and sur-
tomy. Finally, the evolution of the two diseases gical drainage failed. Various infliximab regi-
is not parallel, with possible exacerbations of HS mens of one to three perfusions have been re-
while the intestinal disease is burning out. ported with prolonged efficacy. Improvement
From a practical point of view, the occur- was noted in both the perineal CD course and
rence of digestive symptoms or unexplained axillary or perineal HS lesions. These observa-
biological abnormalities (anemia, hypoferri- tions reinforce the link between the two diseases
tinemia, elevated C-reactive protein) in one pa- and suggest a shared inflammation pathway.
tient with HS should alert the physician and
Table 7.1. Characteristics of Crohns disease (CD) in two References

series of CD associated with hidradenitis suppurativa
(HS) 1. Cosnes J. Tobacco and IBD: relevance in the under-
standing of disease mechanisms and clinical practice.
Cleveland St. Antoine Best Pract Res Clin Gastroenterol 2004;18:48196.
Clinic 2. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard
JP, Belaiche J, Almer S, Tysk C, OMorain CA, Gas-
Males/females 11/13 7/11
sull M, Binder V, Finkel Y, Cortot A, Modigliani R,
Median age at diagno- Laurent-Puig P, Gower-Rousseau C, Macry J, Colom-
sis of CD (years) 39 (1875) 26 (1150) bel JF, Sahbatou M, Thomas G. Association of NOD2
CD location (small leucine-rich repeat variants with susceptibility to
bowel/colon/both) 2/20/3 3/11/4 Crohns disease. Nature 2001;411:599603.
3. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen
Perianal CD 24 (100%) 16 (88%)
FF, Ramos R, Britton H, Moran T, Karaliuskas R,
Excisional surgery Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirsch-
for CD 21 (88%) 9 (50%) ner BS, Hanauer SB, Nunez G, Cho JH. A frameshift
Proctectomy 17 (71%) 8 (44%) mutation in NOD2 associated with susceptibility to
Crohns disease. Nature 2001;411:6036.
Immunosuppressants Not 13 (72%)
indicated
4. Girardin SE, Boneca IG, Viala J, Chamaillard M, 17. Jess T, Winther KV, Munkholm P, Langholz E,
Labigne A, Thomas G, Philpott DJ, Sansonetti PJ. Binder V. Mortality and causes of death in Crohns
Nod2 is a general sensor of peptidoglycan through disease: follow-up of a population-based cohort in
muramyl dipeptide (MDP) detection. J Biol Chem Copenhagen County, Denmark. Gastroenterology
2003;278:886972. 2002;122:180814.
5. Mahida YR, Johal S. NF-kappa B may determine 18. Hughes LE. Clinical classification of perianal
whether epithelial cellmicrobial interactions in Crohns disease. Dis Colon Rectum 1992;35:928
the intestine are hostile or friendly. Clin Exp Im- 32.
munol 2001;123:3479. 19. Linares L, Moreira LF, Andrews H, Allan RN, Al-
6. Elson CO, Cong Y, Brandwein S, Weaver CT, exander-Williams J, Keighley MR. Natural history
McCabe RP, Mahler M, Sundberg JP, Leiter EH. Ex- and treatment of anorectal strictures complicating
perimental models to study molecular mechanisms Crohns disease. Br J Surg 1988;75:6535.
underlying intestinal inflammation. Ann N Y Acad 20. Faucheron JL, Saint-Marc O, Guibert L, Parc R.
Sci 1998;859:8595. Long-term seton drainage for high anal fistulas in
7. DHaens GR, Geboes K, Peeters M, Baert F, Pen- Crohns disease a sphincter-saving operation? Dis
ninckx F, Rutgeerts P. Early lesions of recurrent Colon Rectum 1996;39:20811.
Crohns disease caused by infusion of intestinal 21. Scott NA, Nair A, Hughes LE. Anovaginal and rec-
contents in excluded ileum. Gastroenterology tovaginal fistula in patients with Crohns disease. Br
7 1998;114:2627.
8. Marteau P, Lepage P, Mangin I, Suau A, Dore J,
J Surg 1992;79:137980.
22. Joseph M, Hewett PJ, Hill H. The use of setons in the
Pochart P, Seksik P. Review article: gut flora and management of complex enterocutaneous fistulae of
inflammatory bowel disease. Aliment Pharmacol the abdominal wall. Aust N Z J Surg 1994;64:628
Ther 2004;20 Suppl 4:1823. 9.
9. Duchmann R, May E, Heike M, Knolle P, Neurath 23. Williams JG, MacLeod CA, Rothenberger DA,
M, Meyer zum Buschenfelde KH. T cell specificity Goldberg SM. Seton treatment of high anal fistulae.
and cross reactivity towards enterobacteria, bacte- Br J Surg 1991;78:115961.
roides, bifidobacterium, and antigens from resident 24. Jeshion WC, Larsen KL, Jawad AF, Piccoli DA,
intestinal flora in humans. Gut 1999;44:81218. Verma R, Maller ES, Baldassano RN. Azathioprine
10. Marteau P, Seksik P, Lepage P, Dore J. Cellular and and 6-mercaptopurine for the treatment of perianal
physiological effects of probiotics and prebiotics. Crohns disease in children. J Clin Gastroenterol
Mini Rev Med Chem 2004;4:88996. 2000;30:2948.
11. Akira S, Hemmi H. TLR Signalling and the func- 25. Korelitz BI, Present DH. Favorable effect of 6-mer-
tion of dendritic cells. Chem Immunol Allergy captopurine on fistulae of Crohns disease. Dig Dis
2005;86:12035. Sci 1985;30:5864.
12. Cario E, Podolsky DK. Differential alteration in 26. Lecomte T, Contou JF, Beaugerie L, Carbonnel F,
intestinal epithelial cell expression of toll-like re- Cattan S, Gendre JP, Cosnes J. Predictive factors
ceptor 3 (TLR3) and TLR4 in inflammatory bowel of response of perianal Crohns disease to azathio-
disease. Infect Immun 2000;68:701017. prine or 6-mercaptopurine. Dis Colon Rectum
13. Shanahan F. The host-microbe interface within the 2003;46:146975.
gut. Best Pract Res Clin Gastroenterol 2002;16:915 27. Present DH, Rutgeerts P, Targan S, Hanauer SB,
31. Mayer L, van Hogezand RA, Podolsky DK, Sands
14. Gasche C, Scholmerich J, Brynskov J, DHaens G, BE, Braakman T, DeWoody KL, Schaible TF, van
Hanauer SB, Irvine EJ, Jewell DP, Rachmilewitz D, Deventer SJ. Infliximab for the treatment of fistu-
Sachar DB, Sandborn WJ, Sutherland LR. A sim- las in patients with Crohns disease. N Engl J Med
ple classification of Crohns disease: report of the 1999;340:1398405.
Working Party for the World Congresses of Gas- 28. Brown SC, Kazzazi N, Lord PH. Surgical treatment
troenterology, Vienna 1998. Inflamm Bowel Dis of perineal hidradenitis suppurativa with special
2000;6:815. reference to recognition of the perianal form. Br J
15. Rutgeerts PJ. Conventional treatment of Crohns Surg 1986;73:97880.
disease: objectives and outcomes. Inflamm Bowel 29. Culp CE. Chronic hidradenitis suppurativa of the
Dis 2001;7 Suppl 1:S2S8. anal canal. A surgical skin disease. Dis Colon Rec-
16. Cosnes J, Nion-Larmurier I, Beaugerie L, Afchain tum 1983;26:66976.
P, Tiret E, Gendre JP. Impact of the increasing use 30. Attanoos RL, Appleton MA, Hughes LE, Ansell ID,
of immunosuppressants in Crohns disease on the Douglas-Jones AG, Williams GT. Granulomatous
need for intestinal surgery. Gut 2005;54:23741. hidradenitis suppurativa and cutaneous Crohns
disease. Histopathology 1993;23:11115.
31. Burrows NP, Jones RR. Crohns disease in associa- 37. Martinez F, Nos P, Benlloch S, Ponce J. Hidrad-
tion with hidradenitis suppurativa. Br J Dermatol enitis suppurativa and Crohns disease: response
1992;126:523. to treatment with infliximab. Inflamm Bowel Dis
32. Ostlere LS, Langtry JA, Mortimer PS, Staughton 2001;7:3236.
RC. Hidradenitis suppurativa in Crohns disease. Br 38. Katsanos KH, Christodoulou DK, Tsianos EV. Ax-
J Dermatol 1991;125:3846. illary hidradenitis suppurativa successfully treated
33. Roy MK, Appleton MA, Delicata RJ, Sharma AK, with infliximab in a Crohns disease patient. Am J
Williams GT, Carey PD. Probable association be- Gastroenterol 2002;97:21556.
tween hidradenitis suppurativa and Crohns dis- 39. Bocchini SF, Habr-Gama A, Kiss DR, Imperiale AR,
ease: significance of epithelioid granuloma. Br J Araujo SE. Gluteal and perianal hidradenitis sup-
Surg 1997;84:3756. purativa: surgical treatment by wide excision. Dis
34. Church JM, Fazio VW, Lavery IC, Oakley JR, Mil- Colon Rectum 2003;46:9449.
som JW. The differential diagnosis and comorbidity 40. Roussomoustakaki M, Dimoulios P, Chatzicos-
of hidradenitis suppurativa and perianal Crohns tas C, Kritikos HD, Romanos J, Panayiotides JG,
disease. Int J Colorectal Dis 1993;8:11719. Kouroumalis EA. Hidradenitis suppurativa associ-
35. Gower-Rousseau C, Maunoury V, Colombel JF, ated with Crohns disease and spondyloarthropa-
Coulom P, Piette F, Cortot A, Paris JC. Hidradeni- thy: response to anti-TNF therapy. J Gastroenterol
tis suppurativa and Crohns disease in two fami- 2003;38:10004.
lies: a significant association? Am J Gastroenterol 41. Gupta AK, Skinner AR. A review of the use of inf-
1992;87:928. liximab to manage cutaneous dermatoses. J Cutan
36. Sheldon DG, Sawchuk LL, Kozarek RA, Thirlby RC. Med Surg 2004;8:7789.
Twenty cases of peristomal pyoderma gangreno- 42. Rosi YL, Lowe L, Kang S. Treatment of hidrad-
sum: diagnostic implications and management. enitis suppurativa with infliximab in a patient with
Arch Surg 2000;135:5648; discussion 5689. Crohns disease. J Dermatolog Treat 2005;16:5861.
Chapter 8
Epidemiology
Luigi Naldi
8
Key points 8.1 Introduction

Q Hidradenitis suppurativa (HS) is a The ultimate aim of epidemiologic research is to
relatively common skin disease find means to prevent disease onset (primary
affecting about 1% of the general prevention) and to restore health once a disease
population in some European countries has been developed (secondary prevention). Ad-
ditional purposes are to evaluate and optimize
Q Both genetic and environmental factors healthcare. It is not surprising that the main
8 have been proposed for causation. clinical areas covered by epidemiologic research
In particular, smoking is a well estab- are those associated with a high mortality rate
lished potentially avoidable cause in the population as a whole, such as tumors,
and those involving a major disability problem,
Q An association with non-melanoma for example chronic inflammatory diseases. I
skin cancer needs further clarification believe that hidradenitis suppurativa (HS) be-
since it may suggest common risk longs to this second group. However, the disease
factors to the diseases has been the subject of limited epidemiologic
interest.
Q HS appears to be one of the most
disabling dermatological diseases,
with about half of patients reporting it 8.2 Descriptive Epidemiology
as a relevant problem and causing
severe distress The development of effective preventive mea-
sures starts by assessing the distribution of a
disease in a given population and, by comparing
measures between countries, making correla-
tions with other factors, i.e., ecological correla-
#ONTENTS tions. The usual measures of disease distribu-
8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .58
tion are incidence and prevalence. Incidence
refers to those cases newly developed in a popu-
8.2 Descriptive Epidemiology . . . . . . . . . . . . . . .58 lation over a given period of time. More specifi-
8.3 Analytic Epidemiology . . . . . . . . . . . . . . . . .60 cally, incidence density represents the number
8.4 Clinical Epidemiology: of new cases per person-time and is applicable
Natural History and Prognosis . . . . . . . . . . 62 to a dynamic population reflecting the speed of
8.5 Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 dissemination of the disease in the population,
while cumulative incidence is the proportion of
References . . . . . . . . . . . . . . . . . . . . . . . . . . . .64
cases that develop in a fixed group over a given
period of time. Such a measure reflects the prob-
ability of a member of the group developing the
disease over the time considered. It should be
Epidemiology Chapter 8 59
Table 8.1. Prevalence studies of hidradenitis suppurativa (HS)

Reference Country Sample Assessment Measure Estimate
Fitzsimmons, 1984 [1] UK Unclear Unclear Unclear 1:3000

Fitzsimmons, 1985 [2] UK Unclear Unclear Unclear 1:300
Lookingbill, 1988 [3] USA 1106 new Clinical examination Point prevalence 1:1000
dermatology for hidden or unrecog-
patients nized conditions
Jemec, 1988 [4] Denmark 70 female hospital Interview Lifetime 4:100
employees prevalence
Harrison, 1991 [5] UK (South Unclear Clinical examination Point prevalence 1:600
Wales)
Jemec, 1996 [6] Denmark 599 adults Interview 1-year 1:100
prevalence
Jemec, 1996 [6] Denmark 507 patients Clinical examination Point prevalence 4:100
at an STD clinic
Mahe, 1998 [7] Mali 10,575 Clinical examination Proportion 1:3000
of patientsa
TNS Sofres, 2005 [8] France 6887 Interview 1-year 1:100
prevalence
a
Not a true prevalence estimate.
noted that incidence estimates require an onset cal examination). The last one is a particularly
for the disease to be precisely defined. For many crucial issue. No validated criteria for HS are
chronic disorders characterized by prodromal available in the published literature. The best
signs and symptoms, such as HS, such an onset instrument was developed in the framework of
may be difficult to establish. Prevalence refers a genetic study in the UK [9]. A consensus ap-
to those cases that are present in a given popula- proach, combining information from the pub-
tion, irrespective of their onset, at a point in lished literature and the views of leading experts
time (point prevalence) or at any time point over in the field of HS research, was adopted. By con-
a longer interval (period and lifetime preva- sensus, three key elements were required to
lence). Prevalence depends on incidence and on make a diagnosis of HS: (1) typical lesions; (2) a
the average duration of the disease. If a disease characteristic distribution; and (3) the recurring
persists without a cure for a long time, it may nature over time. Based on these premise a set
give rise to significant prevalence rates even if of typical lesions was compiled and termed
the incidence is low. Prevalence reflects the bur- primary lesions. These were: (1) painful and/
den of the disease in the population and it is a or tender erythematous papules (<1 cm in diam-
useful measure for planning health services. eter); (2) painful and/or tender erythematous
Data concerning the descriptive epidemiolo- nodules (>1 cm in diameter); (3) painful and/or
gy of HS are sparse and are derived from studies tender abscesses (i.e., inflamed, discharging
that adopt different methods, making compari- papule or nodule); (4) dermal contractures (i.e.,
sons difficult (Table 8.1) [18]. No incidence a rope-like elevation of skin); (5) double-ended
data are available, while a number of prevalence comedones. The characteristic sites were chosen
studies have been conducted. Critical issues to in accordance with the two areas most frequent-
consider when comparing figures are: represen- ly affected by HS, namely axillae and groin.
tativeness of the examined sample, the time- These areas were defined by anatomical borders
frame of the study, diagnostic criteria, and and termed designated sites. To be classified as a
methods to assess cases (interview versus clini- case of HS a person must have either: (1) active
60 Luigi Naldi
disease: one or more primary lesion(s) in a des- 8.3 Analytic Epidemiology

ignated site plus a history of three or more dis-
charging or painful lumps (unspecified) in des- The main purpose of analytic studies, including
ignated sites since the age of 10, or (2) inactive cohort and casecontrol studies, is to identify
disease: a history of five or more discharging or factors that may influence the disease frequency
painful lumps (unspecified) in designated sites and to precisely estimate their contribution to
since the age of 10, in the absence of current pri- disease occurrence. The results of analytic stud-
mary lesions. Such a disease definition was able ies are best expressed in terms of relative risk.
to detect most cases that were judged clinically The relative risk is the ratio of the disease inci-
to represent HS in a previous study. A possible dence among those exposed to a purported
lack of sensitivity of the definition was acknowl- causal factor (risk factor), to the incidence
edged. Formal validation would be necessary among the unexposed. When derived from
before its use in epidemiologic or other studies casecontrol studies, odds ratios provide an es-
could be recommended. timate of the relative risks.
The best way to assess disease frequency Limited information is available on risk fac-
would be by taking a randomized representative tors for HS. A familial history has been repeat-
sample of the general population. Actually, most edly documented in subsets of patients [2, 9, 10].
of the available studies rely on convenient popu- In a study, 14 out of 26 consecutive probands
lation samples based on selection procedures (53.8%) had a positive family history. Data from
8 other than randomization. Prevalence estimates 11 families (42.3%) suggested a single gene
range from 3:10,000 to 4:100. These variations transmission with an autosomal dominant in-
may be largely explained by different selection heritance. However, the disease frequency in the
procedures and variations in the sex and age analyzed families felt short of the 50% expected
distribution of the examined samples. Interest- of an autosomal dominant condition [2]. Among
ingly, studies based on population samples are the reasons for the discrepancy, a possible hor-
rather consistent in suggesting a 1-year pre- monal influence on gene expression, polygenic
valence of about 1%. HS is more common in fe- rather than single gene transmission and genet-
males, with reported female:male ratios ranging icenvironmental interaction may be consid-
from 2:1 to 5:1. Moreover, the age of onset may ered.
vary from childhood to middle age, with a re- Among non-genetic factors, smoking habits,
ported average of 2123 years [6, 9]. Recently, a body weight and obesity, hormonal factors, use
French survey (TNS Sofres population survey) of antiperspirants and deodorants, hair removal
has provided a weighted estimate of HS 1-year by a safety razor, and infections have all been
prevalence based on a large representative sam- considered (Table 8.2) [4, 8, 1116]. The role of
ple of the general population [8]. The survey smoking was first assessed in a matched-pair
showed a convincingly higher prevalence of HS casecontrol study in Germany [11]. Patients
in females as compared to males (1.4% versus who had received surgical treatment for hidrad-
0.6%) and a decreasing prevalence with age from enitis suppurativa in two dermatological centers
1.5% in the age group <25 years to 0.5% in the were cases. As controls, patients admitted for
age group >55 years. The distribution of lesions various other skin diseases were selected and
may vary according to gender. In a Danish study, matched for sex and age to cases. Out of 84 pa-
active genitofemoral lesions occurred signifi- tients treated for HS, 63 subjects (27 men, 36
cantly more often in female patients, while no women) completed the questionnaire. The rate
sex difference was seen in the rarer axillary of active cigarette smokers was 88.9% among
lesions. Non-inflamed quiescent nodules were cases and 46% in the matched-pair control
also more prevalent in women and in genito- group with an odds ratio of 9.4 (95% confidence
femoral lesions [6]. interval 3.723.7). A proportion as high as 27%
of cases reported at least one affected first-de-
gree relative. A drawback of the study was the
inclusion of prevalent rather than incident cas-
Table 8.2. Selected studies concerning potential non-genetic risk factors for HS
Reference Country Study design Factor(s) Study results
Konig, 1999 [11] Germany Casecontrol Smoking OR 9.4 (95% CI, 3.723.7).
TNS Sofres, France Population Smoking Association with smoking
2005 [8] survey Alcohol consumption and BMI
BMI and meta-
bolic factors
Jemec, 1988 [4] Denmark Casecontrol Signs of andro- No difference except for
in women genization a shorter menstrual cycle
and longer duration
of menstrual flow in HS cases
Barth, 1997 [12] UK Casecontrol Endocrine factors No association after matching
in women for BMI
Morgan, 1982 [13] UK Casecontrol Shaving and the use No significant difference except
of chemical depilatories, for a more frequent application
deodorants, and talcum of talcum powder by controls as
powder compared with HS cases
Jemec, 1996 [14] Denmark Casecontrol Education, menstrual HS cases better educated,
and reproductive histo- younger and fewer pregnant. Pierced
ry, oral contraceptives, earlobes more frequent among HS
BMI, earlobe piercing, cases
use of cosmetics
Jemec, 1996 [15] Denmark Casecontrol STD history, current Genital HPV infection more
STD, STD risk factors common in HS patients
Lapins, 2001 [16] Sweden Record-linkage Association with cancer SIRa for all cancers 1.5
of hospital dis- (95% CI 1.11.8)
charge diag- SIR for NMSC 4.6
noses with the (95% CI 1.510.7)
Swedish Cancer SIR for buccal cancer 5.5
Registry (95% CI 1.812.9)
SIR for liver cancer 10
(95% CI 2.129.2)
a
SIR = standardized incidence ratio.
es, the lack of assessment of an exposure-effect several case reports and a few case series point
gradient, and the lack of control for potential to an association between HS and Crohns dis-
confounders on the exposureeffect relation- ease [17, 18]. It is well established that Crohns
ship. However, the odds ratio was so high that disease is associated with smoking and smoking
confounding by unmeasured factors was un- has detrimental effects on the clinical course of
likely. These results have been recently con- the disease [19].
firmed by data from the TNS Sofres population The relationship between body weight and
survey in France, where HS was strongly corre- HS has been repeatedly considered in the lack of
lated with cigarette smoking [8]. At this time, convincing evidence [12, 14]. Recently, the TNS
cigarette smoking appears to be a major modifi- Sofres population survey has rejuvenated such a
able risk factor for HS. The effect of quitting proposed association by documenting a higher
smoking has not been assessed in HS patients proportion of people who are overweight and
who are smokers and it is worthy of consider- obese among individuals reporting a history of
ation. In addition, the role of smoking as a prog- HS with respect to the general French popula-
nostic factor should be evaluated. Interestingly, tion (53.5% versus 44.2%) [8]. Some attention
62 Luigi Naldi
has been repeatedly drawn toward the possible hypotheses may involve a role for skin pheno-
role of hormonal factors [4, 12, 14]. No convinc- type and/or sun exposure on the development of
ing data are available. In a study of 66 women HS. Such a hypothesis is worthy of consider-
with HS, 23 had acne and 23 (34.8%) were ation in future studies.
significantly obese (body mass index, BMI,
>30 kg/m2). Plasma androgens were compared
with controls matched for BMI and hirsuteness 8.4 Clinical Epidemiology:
and no difference was documented [12]. The Natural History and Prognosis
prevalence of HS has been found to be higher
among patients attending a sexually transmit- There are limited data concerning the natural
ted disease (STD) clinic than in an unselected history and prognosis of HS. Ideally, a prognos-
general population [6]. In principle, a selection tic study should be based on a representative
bias may explain such a difference. However, an sample of affected individuals followed-up for a
association with chlamydial infections has been sufficiently long period of time. Loss to follow-
also suggested. A casecontrol study based on up should be reduced to a minimum, outcome
patients in a STD clinic was unable to confirm measures should be clearly defined at the begin-
the association with chlamydial infection [15] ning of the study, and adequate analytic meth-
but, quite unexpectedly, it found a higher preva- ods should employed (e.g., survival analysis). A
lence of genital human papilloma virus (HPV) number of studies evaluating the impact of HS
8 infection among HS cases as compared with have been based on a retrospective assessment
controls. The significance of such a finding is of patients identified from hospital records at a
unclear and a chance effect is quite plausible. point in time. These studies tend to be biased
Another unexpected finding from a casecon- toward the selection of more severe and chronic
trol study was the association of HS with pierced cases and may overemphasize the disability
earlobes [14]. Since only univariate analysis was connected with HS. To standardize disease as-
conducted and many confounding effects may sessment over time, a stage classification would
operate (e.g., social class, age, etc.) this associa- be a useful tool. A three-stage classification was
tion should be taken cautiously. proposed several years ago [20] and, more re-
An insight into potential risk factors for HS cently, a lesion, area and severity index for HS
may come from analyses of disease associations was developed [21]. The validation of these in-
since associated diseases may share common struments would involve assessment of their re-
risk factors. In principle, associations may also peatability, sensitivity to change and ability to
result from exposures which follow the develop- predict outcome in terms of morbidity and dis-
ment of one of the diseases of interest (e.g., iat- ability over time.
rogenic factors) or even represent an artifactual All the available studies indicate that HS is a
effect if the presence of a concomitant disease disease with a remarkable impact on the pa-
influences the diagnosis of another disease or tients life. An analysis of American hospitaliza-
its referral (Berksons bias). Interestingly, in a tion records shows that more patients with HS
large-scale analysis of Swedish hospital dis- receive a principal diagnosis the chief reason
charge diagnoses linked with data from the for the hospital stay than those with psoriasis.
Swedish National Cancer Registry, a strong as- This indicates that HS has a much higher mor-
sociation was documented between HS and bidity than other dermatoses such as psoriasis
non-melanoma skin cancer (NMSC), buccal [22, 23]. In Denmark, the general self-reported
cancer and liver cancer [16]. These associations level of health is poorer among HS patients. Due
may at least partly reflect chance findings de- to flare-ups, an average 2.7 days of work per
rived from multiple testing. However, the pri- year is lost by Danish patients (stages I and II)
mary hypothesis of the study was centered on [14]. The soreness, discharge, and appearance of
an association between HS and NMSC. Even if lesions are described as problems in both work
NMSCs complicating perineal or buttock HS lo- and leisure activities by 51% of all patients. For
calizations is a possible explanation, alternative grades I and II, the main problem was soreness,
which can be used to assess the efficacy of treat- bladder, rectum, or peritoneum, lymphatic ob-
ment [22, 23]. In the context of the TNS Sofres struction and lymphoedema of the limbs, scro-
survey, which is deemed to provide a represen- tal elephantiasis [26]. Chronic HS-associated
tative sample of patients with HS in France, arthritis, axial spondyloarthropathy, and sterile
47.2% of HS patients reported a medical consul- osteomyelitis-like lesions also occur [27]. Squa-
tation for their disease in the year preceding the mous cell carcinomas originating from HS le-
interview, and 47.7% of the patients reported HS sions may complicate perineal and buttock lo-
to be a relevant problem and a severe distress calizations.
[8]. In a survey of the Dermatology Life Quality
Index (DLQI) in 114 HS patients, the mean
DLQI score was 8.9 (SD 8.3) points. The high- 8.5 Perspectives
est mean score out of the 10 DLQI questions was
recorded for question 1, which measures the HS is a relatively common skin disease affecting
level of pain, soreness, stinging or itching (mean about 1% of the general population. Both genet-
1.55 points, median 2 points). Patients experi- ic and environmental factors have been identi-
enced a mean of 5.1 lesions per month [24]. In a fied as potential causative factors but assessment
questionnaire-based survey among HS patients of their importance is hampered by the lack of
identified from hospital records of three hospi- systematic analyses considering potential con-
tals in Nottinghamshire (UK) 110 HS patients founding effects and interactions. For the future
were interviewed. The average reported age of a larger collaborative research network promot-
disease onset was 21.8 years. At the time of the ing more systematic research activity would be
survey patients had suffered on average disease desirable. Relatively simple measures, such as
duration of 18.8 years. Most patients (98 of 110) prevalence rates, are of great interest if obtained
still had experienced active disease within the according to uniform methods in different
past year. In women the condition had a tenden- countries, e.g., several European countries, al-
cy to ease or subside after the menopause. For- lowing international comparison and ecological
ty-four per cent of women felt that their condi- correlations. The development of HS is likely
tion was aggravated by menstruation. The due to the effect of concurrent etiologic factors,
average duration of painful boils was 6.9 days. which should be better assessed in a simultane-
In addition, 62% of patients acknowledged the ous way. Family history and smoking habits are
presence of permanently painful boils that failed well established causes. They should be consid-
to subside. Patients developed a median of two ered in any future etiologic study including ge-
boils per month. Factors that could aggravate netic studies where a geneticsenvironmental
the condition were primarily sweating or heat, interaction may play a role. An area in urgent
stress or fatigue and tight clothing or friction. need of attention is clinical epidemiology. Per-
Factors that could improve the condition con- haps the best way to analyze outcomes and as-
sisted largely of a variety of medical treatments sociated factors (i.e., etiologic and predicting
and a number of lifestyle measures, such as factors) is through long-term cohort studies of
swimming or baths. Twenty-four per cent of pa- representative samples of newly diagnosed HS
tients had failed to find anything at all to help patients. In the context of a cohort, risk factors
their condition, despite an average disease dura- for disease relapse or other sentinel events,
tion of almost 19 years. HS appears to be one of e.g., cancer development, could be efficiently
the most distressing dermatological diseases evaluated by nested casecontrol studies or
[25]. casecohort analyses. Finally, large-scale prag-
A few case reports exist describing rare but matic randomized trials would be the best way
serious complications. Complications of long- to evaluate the impact of complex or non-phar-
standing untreated disease include amyloidosis, macological interventions (e.g., lifestyle chang-
leading to fistula formation into the urethra, es) on disease progression.
64 Luigi Naldi
15. Jemec GB, Heidenheim M, Nielsen NH (1996) A

References case-control study of hidradenitis suppurativa in an
STD population. Acta Derm Venereol 76: 482483.
1. Fitzsimmons JS, Fitzsimmons EM, Gilbert G (1984) 16. Lapins J, Ye W, Nyren O, Emtestam L (2001) Inci-
Familial hidradenitis suppurativa: evidence in fa- dence of cancer among patients with hidradenitis
vor of a single gene transmission. J Med Genet 21: suppurativa. Arch Dermatol 137: 730734.
281285. 17. Martinez F, Nos P, Benlloch S, Ponce J (2001) Hi-
2. Fitzsimmons JS, Guilbert PR, Fitzsimmons EM dradenitis suppurativa and Crohns disease: re-
(1985) Evidence of genetic factors in hidradenitis sponse to treatment with infliximab. Inflamm Bow-
suppurativa. Br J Dermatol 113: 18. el Dis 7: 323326.
3. Lookingbill DP (1988) Yield from a complete skin 18. Katsanos KH, Christodoulou DK, Tsianos EV
examination. Findings in 1157 new dermatology (2002) Axillary hidradenitis suppurativa success-
patients. J Am Acad Dermatol 18: 3137. fully treated with infliximab in a Crohns disease
4. Jemec GB (1988) The symptomatology of hidrad- patient. Am J Gastroenterol 97: 21552156.
enitis suppurativa in women. Br J Dermatol 119: 19. Birrenbach T, Bocker U (2004) Inflammatory bowel
345350. disease and smoking: a review of epidemiology,
5. Harrison BJ, Mudge M, Hughes LE (1991) The prev- pathophysiology, and therapeutic implications. In-
alence of hidradenitis suppurativa in South Wales. flamm Bowel Dis10: 848859.
In: Marks R, Plewig G (eds) Acne and related disor- 20. Hurley HJ (1996) Axillary hyperhidrosis, apocrine
ders. Martin Dunitz, London, pp 365366. bromhidrosis, hidradenitis suppurativa and fa-
6. Jemec GB, Heidenheim M, Nielsen NH (1996) The milial benign pemphigus. Surgical approach. In:
prevalence of hidradenitis suppurativa and its po- Roenigk RK, Roenigk HH Jr (eds) Dermatologic
8 tential precursor lesions. J Am Acad Dermatol 35(2 surgery. Principles and practice, 2nd edn. Marcel
Pt 1): 191194. Dekker, New York, pp 623645.
7. Mahe A, Cisse IA, Faye O, NDiaye HT, Niamba P 21. Sartorius K, Lapins J, Emtestam L, Jemec GB (2003)
(1998) Skin diseases in Bamako (Mali). Int J Derma- Suggestions for uniform outcome variables when
tol 37: 673676. reporting treatment effects in hidradenitis suppu-
8. TNS Sofres survey (2005) Enqute. Les franais et la rativa. Br J Dermatol 149: 211213.
dermatologie. Unpublished document 22. Hospital discharge data. Taken from the Health-
9. Von der Werth JM, Williams HC, Raeburn JA care Cost and Utilization Project (HCUP), April 2,
(2000) The clinical genetics of hidradenitis suppu- 2005.
rativa revisited. Br J Dermatol 142: 947953. 23. Jemec GBE, Wendelboe P (1998) Topical clindamy-
10. Knaysi GA, Cosman B, Crikelair GF (1968) Hidrad- cin versus systemic tetracycline in the treatment
enitis suppurativa. J Am Med Assoc 203: 1922. of hidradenitis suppurativa. J Am Acad Dermatol
11. Konig A, Lehmann C, Rompel R, Happle R (1999) 39(6): 971.
Cigarette smoking as a triggering factor of hidrad- 24. von der Werth JM, Jemec GB (2001) Morbidity in
enitis suppurativa. Dermatology 198: 261264. patients with hidradenitis suppurativa. Br J Derma-
12. Barth JH, Layton AM, Cunliffe WJ (1997) Endo- tol 144: 809813.
crine factors in pre- and postmenopausal women 25. von der Werth JM, Williams HC (2000) The natural
with hidradenitis suppurativa. Br J Dermatol 136: history of hidradenitis suppurativa. J Eur Acad Der-
802803. matol Venereol 14: 389392.
13. Morgan WP, Leicester G (1982) The role of depila- 26. Jemec G (2003) Hidradenitis suppurativa. J Cutan
tion and deodorants in hidradenitis suppurativa. Med Surg 7(1): 4756.
Arch Dermatol 118: 101102. 27. Rosner IA, Burg CG, Wisnieski JJ, Schacter BZ,
14. Jemec GB, Heidenheim M, Nielsen NH (1996) Hi- Richter DE (1993) The clinical spectrum of the ar-
dradenitis suppurativa characteristics and conse- thropathy associated with hidradenitis suppurativa
quences. Clin Exp Dermatol 21: 419423. and acne conglobata. J Rheumatol 20:684687.
Chapter 9
Nosology and Classification

Jean Revuz, Gregor B.E. Jemec and James Leyden
9
Key points classifying biological phenomena, we structure

our understanding of the underlying biological
Q Classification should be based complexity, and thereby make it possible for us
on explicit criteria, e.g., etiology, not only to ask meaningful positivist scientific
pathogenesis or even therapy questions, but also offer help to our patients.
Two threats exist in all classification systems,
Q The current understanding of HS splitting and lumping, and both are equally se-
identifies it as a unique disease, rious. Splitting occurs when the same disease
clearly different from acne or folliculitis entity is split into numerous diagnoses depend-
for example ing on, for example, location, a good example
being pityriasis amientacea and scalp psoriasis.
Q A better future understanding of the This overwhelms the reader with diagnoses that
etiology and pathogenesis may resolve are not essentially different, but that have been
HSs current nosological impasse classified as different because of an essentially
random aspect of the disease, e.g., location or
clinical appearance. This does not allow a mean-
ingful use of existing knowledge by direct trans-
fer, and therefore erodes the understanding of
#ONTENTS the underlying pathogenic process as well as ac-
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
cumulation of clinically relevant knowledge.
The other extreme is lumping, where all dis-
9.2 Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . .66 eases are lumped together pell-mell in large cat-
9.2.1 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .66
9.2.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . .66
egories, where little consideration is given to
significant etiological, pathogenic, and clinical
9.3 Etiology; Pathogenesis . . . . . . . . . . . . . . . . . . 67 differences between disease entities. It may be
9.3.1 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
9.3.2 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . .68
speculated that several of the more common
9.3.3 Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68 dermatological diseases fall into this trap, as
9.3.4 Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . .68 clinical experience suggests significant inter-in-
9.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
dividual differences in regard to treatment re-
sponse or prognosis.
Nosology should be based on defined param-
eters, e.g., anatomy (gross and microscopic), eti-
9.1 Introduction ology, pathogenesis or therapy. It should provide
clinically meaningful distinctions between dis-
Dermatologists are clever classifiers. We master ease entities in order not only to promote the
a repertoire of approximately 2000 different di- understanding of the disease and accumulation
agnoses, which can be classified and structured. of knowledge, but also to help practical manage-
Classification of diseases is very important. By ment.
66 Jean Revuz, Gregor B.E. Jemec and James Leyden
9.2 Morphology tention and subsequent infection and inflam-

mation in the apocrine sweat gland. Follicular
9.2.1 Anatomy abnormalities may be a key factor of HS: they
are apparent in histological as well as ultrasono-
Hidradenitis suppurativa (HS) was originally graphic studies of hair follicles in HS patients
classified according to location, and this re- (see Chaps. 4, 5). There is also clinical evidence
mains a hallmark of the disease. Shortly after suggesting a relationship between HS and an
the diagnosis was established, an erroneous as- anatomical anomaly of the pilosebaceous duct
sociation with apocrine glands was made and in the high prevalence of pilonidal cysts in HS
the name created. A classification according to patients. In one series (Faye O, Bastuji-garin S,
topography alone obviously does not improve Poli F, Revuz J. Hidradenitis suppurativa: a clin-
the understanding of pathogenesis and hence is ical study of 164 patients; manuscript in prepa-
of little help. The erroneous classification ac- ration) 30% of 164 patients are reported to have
cording to an incorrect deduction based only on co-existing pilonidal sinus ducts.
simple co-localization obviously delayed the de- HS is clearly a follicular disease located to re-
velopment of knowledge This mistake comes stricted areas of the body. The pathogenic pro-
from a paradox: the lesions of HS are predomi- cess in the hair follicle may be elucidated from
nantly or exclusively situated in the regions of histology, and appears to be rupture of the deep-
apocrine sweat glands, yet the histological pic- er parts of the follicle, with spillage of the fol-
ture is one of follicular obstruction like that licular contents into the dermis and subsequent
seen in acne lesions, and sweat gland involve- inflammation (see Chap. 4). The exact cause of
9 ment is usually absent from early lesions. The the rupture is however not established. So even
apocrine sweat glands excretory canal opens if HS can be classified as a folliculitis, just as
into the follicular duct immediately above the acne vulgaris, this classification does not aid
sebaceous duct (see Fig. 9.1). This distinctive our understanding significantly, and additional
anatomical characteristic may explain the re- aspects of the diseases must therefore be consid-
percussions of follicular obstruction, with re- ered.
9.2.2 Clinical Features
The clinical characteristics of HS, i.e., deep-

seated lesions and topography, are very specific
and the hallmark of the disease; however, they
are not explained by the histological pictures
which form the main evidence for establishing a
connection with acne and the so-called follicu-
lar obstruction diseases. Exceptional case re-
ports of an association of HS with dissecting
folliculitis of the scalp, acne conglobata, large
epithelial cysts and pilonidal cysts have focused
attention on a possible common mechanism
shared by these diseases and their grouping to-
gether under the term follicular obstruction
diseases. Some case reports of an association
with DowlingDegos pigmentation of the flex-
ure also point to a follicular obstruction. In spite
of these anecdotal reports, the prevalence of
acne in HS patients is identical to the prevalence
Fig. 9.1. The anatomy of the hair follicle in controls. The rarity of these reports and the
Nosology and Classification Chapter 9 67
Table 9.1. Similarities and differences between acne vulgaris, acne conglobata, hidradenitis suppurativa (HS), and fol-
liculitis. Etiology reflects known mechanisms such as inflection in simple folliculitis, morphology describes similari-
ties in clinical morphology, pathogenesis describes similarities in known pathogenesis, e.g., seborrhea, and treatment
describes response to similar treatments, e.g., response to isotretinoin
Similarities between follicular diseases
Acne conglobata Acne vulgaris Acne conglobata HS

Etiology ?
Morphology no
Pathogenesis ?
Treatment yes
HS Etiology no
Morphology no Etiology ?
Pathogenesis no Morphology ?
Treatment ? Pathogenesis ?
Treatment ?
Folliculitis Etiology no Etiology no Etiology no
Morphology no Morphology yes Morphology yes
Pathogenesis no Pathogenesis no Pathogenesis no
Treatment yes Treatment yes Treatment yes
potential for positive reporting bias therefore made in Table 9.1. As can be seen from this, all
raise questions about the validity of this as- these diseases have similarities and differences,
sumption. which can reasonably be said to influence their
As for individual lesions the differences be- classification.
tween acne and HS are significant: the deep-
seated nodules and the absence of closed come-
dones hallmark of acne are characteristics of 9.3 Etiology; Pathogenesis
HS. Open comedones black heads are regu-
larly observed in old lesions of HS, frequently as The etiology of HS is not known.
double or multiple comedones, but these are
secondary lesions, i.e., tombstone comedos.
Scarring is also more prominent in HS than in 9.3.1 Infection
acne. In particular, the hypertrophic cicatrizing
process, which leads to the formation of highly There are no convincing data to suggest that HS
specific rope-like scars, is another characteristic is primarily an infectious disease (see Chap. 11).
of HS, very rarely seen in acne. Finally the time- The polymicrobial infection (or colonization)
span of the diseases differ. The long-lasting evo- of HS Staphylococcus aureus, Gram-negative
lution of HS over decades is in sharp contrast rods, anaerobic bacteria is quite different from
with the usually self-healing nature of acne. The the usual colonization of acne by Propionibacte-
reclassification of the disease as acne inversa rium acnes and coagulase-negative staphylococ-
does not adequately reflect the unique features ci. The role of bacteria in HS may therefore be
of HS and carries a serious risk of drawing either secondary to some as yet unknown mech-
incorrect analogies to acne. anism, or purely secondary once anatomical
Looking at four key factors of clinical rele- disruptions are established. HS is not a primary
vance which may be used for classification of infectious disease; yet the initial inflammatory
diseases (etiology, morphology, pathogenesis, changes can be produced by a bacterial coloni-
and treatment) a comparison between acne zation of the follicular area similar to the trig-
vulgaris, acne conglobata, HS and folliculitis is gering event of acne. The amount of inflamma-
68 Jean Revuz, Gregor B.E. Jemec and James Leyden
tion and related pain is however quite different of HS, the efficacy of anti-inflammatory drugs,
from what is observed in acne, even in the nod- of anti-tumor necrosis factor (TNF) drugs, and
ular variety. This may be due to the localization the significant association with Crohns disease
of the lesions but may also point to either a spe- all point to an abnormality of immune and/or
cific non-infectious inflammatory phenome- inflammatory mechanisms in HS. The number
non, or a sequential series of events in which of candidates is large, including abnormalities
bacterial involvement occurs at specific points. of innate immunity, e.g., NOD, TLR, and defi-
Early involvement of pathogenic bacteria may ciencies of natural antibacterial substances such
be responsible for establishing inflammation, as defensins and cathelicidins (see Chaps. 6, 12).
which leads to destructive scarring and exten- The potential usefulness of anti-inflammatory
sion of the disease independently of bacteria. and immunosuppressive therapy in HS may
Eventual secondary bacterial superinfections therefore have a broader scope than is reflected
would then maintain the inflammatory process in existing literature.
without the need for permanent colonization
with pathogenic bacteria. The dramatic im-
provement observed in some patients with se- 9.3.3 Hormones
vere HS following a 3-month course of clinda-
mycinrifampicin treatment suggests a role for The absence of any significant hormonal abnor-
infection in advanced disease (see Chap. 15). mality (see Chap. 12) and above all the normal
However, it does not rule out the possibility that sebum excretion rate in HS areas as well as in
this polymicrobial infection is only a secondary seborrhea-prone areas clearly put HS apart from
9 phenomenon, or that these antibiotics exert a the acne spectrum.
predominantly anti-inflammatory effect. A spe-
cific anti-inflammatory role of some antibiotics
including tetracyclines, clindamycin and ri- 9.3.4 Treatments
fampicin has been demonstrated in in vitro
experiments. Whether this action is relevant in Classification can also be made along purely
vivo and independent from any anti-infectious practical lines, i.e., from the therapy. To classify
activity remains to be established. diseases according to their response to stan-
dardized therapies may appear non-academic
but is useful in practice and allows more spe-
9.3.2 Inflammation cific speculations to be made about the etiology
and pathogenesis when the therapeutic princi-
The exact cause of the rupture of the follicle is ple of the drug is known. In HS, clindamycin
not established, although a lymphocytic inflam- rifampicin, anti-TNF biologics, sometimes cor-
matory infiltrate appears to be present in early ticosteroids and even immunosuppressive drugs
lesions (see Chap. 4). There is some evidence may be helpful, while they are not useful in acne.
of infundibular epithelial hyperproliferation as In contrast, the retinoids, which are the most ef-
well. In older lesions, sinus tract formation pre- fective drugs in the treatment of acne, appear
dominates the histopathology. It is speculated generally ineffective in HS (see Chap. 17). Thus
that the introduction of follicular material into the terminology acne inversa may lead to an er-
the dermis as well as secondary colonization of roneous management. The lack of efficiency of
sinus tracts cause flares of HS. These mecha- retinoids is in good agreement with the absence
nisms suggest that HS can be classified as a fol- of local seborrhea and supports the classifica-
liculitis of unknown origin affecting the deeper tion of HS as a follicular disease different from
end of the hair follicle and not involving the se- the acnes.
baceous glands. The polymicrobial colonization
Nosology and Classification Chapter 9 69
9.4 Conclusion
W
HS is multifactorial. Follicular occlusion and
disruption are predisposing factors, but other
factors, including bacterial colonization and
an as yet unknown pro-inflammatory mecha-
nism, are at work. HS can be described as in-
verse recurrent suppuration according to to-
pography, clinical evolution, and morphology.
Looking at the parameters of etiology, mor-
phology, pathogenesis, and therapy, HS can
be differentiated from the acnes and from
simple folliculitis.
Chapter 10
Genetics of Hidradenitis Suppurativa

Jan von der Werth, Pam Wood, Alan D. Irvine, W.H. Irwin McLean
10
10.9 Candidate Genes Analysed

Key points in Linked HS Kindreds . . . . . . . . . . . . . . . . . 79
Q The genetics of HS has received little 10.9.1 Oestrogen receptor-A and HS . . . . . . . . . . . 79
attention so far 10.9.2 ZNF91 and HS . . . . . . . . . . . . . . . . . . . . . . . . . 79
10.9.3 TIZ Association with HS . . . . . . . . . . . . . . . .80
Q A familial form of HS affects up to 40%
10.9.4 Potential Contribution
of sufferers of the VIP Gene to HS . . . . . . . . . . . . . . . . . .80
Q Familial HS follows an autosomal 10.10 Additional Candidate Gene-Protein

Systems in HS . . . . . . . . . . . . . . . . . . . . . . . . . . 81
dominant inheritance pattern
10.10.1 Interleukin 1-A . . . . . . . . . . . . . . . . . . . . . . . . 81
Q A study of the molecular genetics 10.10.2 TNF Signalling and HS . . . . . . . . . . . . . . . . . 81
of HS has found linkage to two loci on 10.11 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
10 chromosomes 6 and 19 in three families
10.12 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
but no linkage to either of these loci
in other families References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Q HS is a genetically heterogeneous
disease with mutations in genes at 10.1 Clinical Genetics
multiple locations of Hidradenitis Suppurativa
Like many other aspects of hidradenitis suppu-

rativa (HS), its heritability has received little at-
#ONTENTS tention for many years. References to it were
made by Brunsting in 1952 in his description of
10.1 Clinical Genetics the follicular occlusion triad acne conglobata,
of Hidradenitis Suppurativa . . . . . . . . . . . . . 70 dissecting cellulitis of the scalp, and hidradeni-
10.2 Genodermatoses . . . . . . . . . . . . . . . . . . . . . . . 74 tis suppurativa [10]. As late as 1968 Knaysi re-
10.3 Methods for Identifying Disease Genes . . . 74 ported rather dismissively that only 3 out of 18
questioned patients had described a positive
10.4 Genetic Markers . . . . . . . . . . . . . . . . . . . . . . . 74
family history of the disease [36]. A case report
10.5 Positional Cloning of familial occurrence of HS in association with
of Dominantly Inherited Disease Genes . . 75 acne conglobata was published by Gold and
10.6 Genome-Wide Linkage Analysis Delaney in 1974 [22]. A structured investigation
in Familial HS . . . . . . . . . . . . . . . . . . . . . . . . .77 of the genetic basis of HS was not carried out
10.7 Linkage of Hidradenitis Suppurativa until Fitzsimmons et al. published their series of
to 6q25.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 HS families in 1984 and expanded this in 1985.
10.8 Identification of a Second HS Locus In these studies an autosomal dominant pattern
to Chromosome 19 . . . . . . . . . . . . . . . . . . . . . 79 of inheritance was postulated for a proposed
Genetics of Hidradenitis Suppurativa Chapter 10 71
familial variant of HS [1820]. Fitzsimmons re-

search analysed 23 families of probands with 4. Painful and/or tender dermal contrac-
HS and found evidence in favour of a single- tures (= rope-like elevation of skin)
gene Mendelian inheritance in 11 of these. Their 5. Double-ended comedones.
study acknowledged lacking conclusive proof of
such heritability and the existence of some in- Designated sites were chosen in accordance
consistencies. They only ascertained the disease with the two areas most frequently affected by
in 34% of first-degree relatives of HS sufferers HS, namely axillae and groin.
and found a predominance of females in their They reviewed 14 surviving probands and
group of HS sufferers by a ratio of 2:1. They also their families. Seven of these probands had pre-
struggled to explain the marked heterogeneity viously been noted to have a positive family his-
of the recorded pedigrees. Assuming incomplete tory whereas the others had been classified as
ascertainment, variable disease penetrance and having a negative or possible family history (Fig.
negative recall and reporting biases from some 10.1 a, b). In all, 132 family members were as-
patients, they nonetheless felt that HS was likely sessed for their respective disease status. Par-
to be a dominantly inherited single-gene disor- ticipants were initially contacted by telephone
der. Cautiously, though, they recommended a or letter, and those who acknowledged a history
periodic re-examination of the investigated of at least one previous boil were invited for a
families [1820]. personal examination and interview. Only per-
Such a re-examination was carried out in sonally examined individuals could be classi-
1998, when von der Werth et al. proposed a de- fied as a case.
tailed disease definition for HS and used this as In total, 28 relatives with HS were detected,
a base for a review of the Fitzsimmons families and 27 of these were in the group previously la-
15 years after the initial study [61]. The defini- belled family history positive. Nine of these
tion used for the purpose of this study was: cases had not been detected in the previous
To be classified as a case of hidradenitis sup- study and in at least seven of these the disease
purativa a person must have either: had developed after the previous study had been
conducted. Only twice did their disease criteria
Active 1 or more primary lesion(s) fail to confirm cases that had been labelled as
disease: in a designated site plus a history HS in the previous study. Both times they classi-
of 3 or more discharging or painful fied the patients as possibly affected. A further
lumps (unspecified) in designated 16 relatives were judged to be possibly affected.
sites since the age of 10 In the group with positive family history they
found 10 affected and 9 possibly affected indi-
or
viduals amongst 37 surviving first-degree rela-
Inactive a history of 5 or more discharging tives of HS sufferers [61].
disease: or painful lumps (unspecified) The findings in this study supported the con-
in designated sites since the age cept of a familial form of HS with autosomal
of 10 in the absence of current dominant inheritance. An insufficiently sensi-
primary lesions. tive disease definition, a variable degree of gene
penetrance and possibly a hormonal influence
Primary lesions had been defined as: on gene expression were considered as explana-
tions for the reduced risk to first-degree rela-
1. Painful and /or tender erythematous tives, which falls short of the expected Mende-
papules (<1 cm in diameter) lian value of 50%. The study was felt to be
2. Painful and/or tender erythematous sufficiently convincing to commence the search
nodules (>1 cm in diameter) for the proposed molecular defect behind this
3. Painful and/or tender abscesses condition [61].
(= inflamed, discharging papule
or nodule)
72 Jan von der Werth, Pam Wood, Alan D. Irvine et al.
10
Genetics of Hidradenitis Suppurativa
Chapter 10
Fig. 10.1a, b. a Pedigrees of families with previously identified positive family history. b see next page
73
10
b
Fig. 10.1a, b. b Pedigrees of families without evidence of family history in prevoius study
10.2 Genodermatoses may soon allow radical new insights into the
pathogenesis of known diseases.
The genetic basis of many common genoderma-
toses has now been identified. By 2003 over 350
single-gene skin disorders had been character- 10.3 Methods for Identifying
ized at a molecular level [41]. These represent Disease Genes
only a fraction of the well over 1000 single-gene
disorders now known [1]. The X-linked Duch- A project to fully determine the nucleotide se-
enne muscular dystrophy locus was the first dis- quence of the human genome was formally pro-
ease to be mapped. It was mapped to Xp21 in posed in 1985 and the human genome-mapping
1982 but it took several years for the gene to be project was initiated in 1990 [13]. The human
cloned [65]. The first gene causing an inherited genome-mapping project did not, however,
skin disease was discovered in 1987 and was begin until 1998. The biotechnology company,
identified as the steroid sulphatase gene under- Celera, reported the first assembly as early as
lying recessive X-linked ichthyosis [7]. The com- June 2000 and the publicly funded effort by
pletion of the human genome project has been a October 2000. The near completion of the hu-
further major milestone on the road to unravel- man genome-mapping project has greatly facili-
ling the secrets of our genetic code. It has led to tated the identification of the genetic basis un-
the creation of new genomic and proteomic da- derlying a vast range of dominant and recessive
tabases which, combined with newer technology diseases.
such as the development of DNA microarrays,
There is about 2.9 Gbp of genomic sequence average resolution of the markers was about 10
in the human genome, containing information centiMorgans (cM) and, as previously men-
for all proteins, regulatory elements and struc- tioned, they were not very informative. The de-
tural elements. The number of genes within the velopment of the polymerase chain reaction
human genome was predicted to reach around (PCR) has greatly facilitated genetic mapping by
140,000 but sequencing of the human genome allowing amplification of the marker region and
and analysis of its structure and sequence have analysis on automated gel analysers, and more
lowered the predicted number of human genes recently capillary electrophoresis [43]. Now
to about 25,000, although these probably encode markers are more commonly labelled with a
many more proteins due to alternate splicing fluorescent dye, amplified by PCR and analysed
[13]. on an automated system.
There are several ways in which to identify The most popular polymorphisms used pres-
and isolate the gene underlying the molecular ently for physical mapping are microsatellites.
basis of an inherited disease. The three main The discovery of the highly polymorphic micro-
techniques for achieving this are: (1) functional satellite sequences within the genome has al-
cloning/candidate gene approach, when there is lowed the construction of genome-wide linkage
a protein of known function missing or abnor- maps with a high resolution [51, 63]. Microsatel-
mally expressed in the patient and the nucleo- lites are abundant, dispersed throughout the
tide sequence of the gene is obtained through genome, highly informative and easy to type by
the protein in question; (2) positional cloning, PCR. Analysis on automated systems then al-
which identifies a disease gene based on its ap- lows the genotypes to be read directly as sizes of
proximate chromosomal location; and the (3) alleles in base pairs. Human genetic mapping
positional/candidate gene approach where pre- has focused on the construction of high-resolu-
viously isolated and cloned genes are screened tion linkage maps and the human genome now
with a possible link to the disease based on their contains thousands of markers covering the
function or expression pattern [4]. entire genome with a density of less than 1 cM
[58].
10.4 Genetic Markers

10.5 Positional Cloning
The mapping of human disease genes requires of Dominantly Inherited
genetic markers. Any polymorphic Mendelian Disease Genes
character can, potentially, be used as a marker
to map a disease gene. DNA polymorphisms Positional cloning utilizes linkage maps and
within the human genome have provided sets of physical maps, containing information about
markers sufficient in number and density that the position of polymorphic markers to identify
have been mapped to a specific chromosomal the approximate chromosomal location of a dis-
location. Complete genetic maps allow gene ease gene. The initial step is the identification of
localization resulting in genetic diagnosis. The a chromosomal region that is transmitted with-
first generation of DNA markers was based on in a family along with the disease phenotype of
restriction fragment length polymorphisms interest. Linkage analysis depends on informa-
(RFLP) that were typed by Southern blotting tive meioses within families and heterozygosity
from restriction digests of the test DNA and hy- of the markers. An individual will inherit a pair
bridized to radiolabelled probes. The disadvan- of alleles from the same chromosomal segment
tage of this type of mapping was the presence of from each parent. Alleles on the same chromo-
only two alleles, the site is either present or ab- somal segment will tend to be transmitted as a
sent and so is not very informative. Donis-Keller block throughout a family [52]. Families typed
et al. published the first comprehensive human with a series of nearby polymorphic markers
genetic map in 1987 based on 403 polymorphic can be assigned a haplotype that is visualized as
loci, 393 of which were RFLP markers [16]. The allele sizes for each marker. The heterozygosity
of a marker depends on the frequency of hetero- mative linked meiosis in a dominant pedigree
zygotes in the population at that locus. Markers will contribute 0.3 to the LOD score, therefore a
with a high frequency of heterozygotes are the family of at least 11 members is required to pro-
most informative and allow distinction between duce significant linkage. Offspring of unaffect-
the maternal and paternal alleles. The further ed individuals in a family with an autosomal
apart two markers are, the greater the likelihood dominant disease will not contribute to the
of a recombination event occurring during mei- LOD score. Difficulties in linkage analysis are
osis. Recombination can be calculated within a encountered with heterogeneity of disease lo-
family as the recombination fraction (RF). This cus, misdiagnosis and reduced penetrance. The
is calculated as the number of recombinants for penetrance is irrelevant for affected individuals
a given marker divided by the total number of but for unaffected individuals they have to be
possible recombinants. Therefore, the propor- scored as possibly affected or unknown. This is
tion of offspring who are recombinant is known due to the fact that they may be carrying the dis-
as the RF between two loci [52]. Genetic disease allele but will not show any physical symp-
tance, measured in centiMorgans (cM), is based toms. Where there is possible misdiagnosis,
on the recombination rate between two homol- complexity in the inheritance or heterogeneity
ogous chromosomes during meiosis. The re- of phenotype, mapping using only definitely
combination rate or RF is generally greater in affected members circumvents this problem.
females than males but, on average, 1 cM cor- Positional cloning gives the approximate
responds to 1% recombination. In many regions chromosomal location of a disease gene, but
of the genome, this equates to approximately these regions are usually large, often several
1 Mbp of DNA. megabases in length. Once a candidate region
Once the disease phenotype appears to co- has been identified, the standard procedure is to
segregate with a certain marker allele, it is pos- use higher density markers to narrow down the
10 sible to calculate the probability of these two region. This relies on informative meioses oc-
loci being linked. The RF value allows evalua- curring within families and may still leave the
tion of the likelihood of a pedigree for linkage candidate locus as a large region. Linkage dis-
based on assumptions that the loci (disease gene equilibrium (LD) has been successfully used for
and marker) are either linked (RF = 0) or not fine mapping of the candidate region. LD refers
linked (RF = 0.5) [54]. It is possible to compare to the non-independence of alleles at different
the probability of obtaining the offspring ob- sites. Single nucleotide polymorphisms (SNPs)
served if the two loci being considered are linked can be used to fine map the candidate region as
at a defined recombination fraction with the they are more abundant and more concentrated
probability of obtaining these offspring if the than microsatellite markers. Inheritance of each
loci are unlinked (RF = 0.5). The logarithm of SNP can be used to assess for co-segregation
this ratio is known as the LOD score. Positive with the disease phenotype and for SNP chang-
LOD scores point towards linkage of a disease es specific to a disease phenotype [8].
gene with a marker whereas a negative LOD Once a candidate gene has been identified,
score indicates the two loci are not linked [54]. the genes in this region undergo mutational
LOD scores of 2 or less are obtained when the analysis, usually by PCR and direct sequencing.
odds against linkage are 100:1 and this value is Candidate genes can be identified in the region
accepted as indicating that two loci are not due to their function or expression and screened
linked. A LOD score of 3 or above is the thresh- first. PCR using genomic DNA will identify any
old for accepted linkage, which corresponds to missense, splice site, frameshift or nonsense
1000:1 odds that the loci are indeed linked [51]. mutations within the region of the gene ampli-
Values between 2 and 3 are, on the whole, in- fied by primers. It may not, however, identify
conclusive. Only recombination fractions be- larger genomic deletions, intronic mutations
tween 0 and 0.5 are informative and the most that affect splice sites or promoter mutations if
likely RF for a given pedigree is the one at which the primers are not designed to specifically
the LOD score is highest. In general each infor- screen for these. In order to identify these types
of mutations it is often beneficial to screen Three families (designated Family 6, Family

cDNA, reverse transcribed from mRNA. This 13 and Family M), which showed autosomal
type of analysis can, in combination with exonic dominant inheritance of HS, were used to per-
polymorphism, indicate if both alleles are being form genome-wide linkage analysis looking for
expressed or if one has been downregulated. It co-segregation of the disease with a number of
can also demonstrate any aberrantly spliced markers. Individuals were assigned as either
transcripts. affected or unaffected based on their ability to
fulfil certain strict diagnostic criteria as out-
lined above. A number of smaller families were
10.6 Genome-Wide Linkage Analysis used to check for linkage with the regions
in Familial HS found.
Families 6 and 13 (Figs. 10.2, 10.3) were ex-
Genome-wide linkage analysis has been per- amined by one of us (JvdW) [61]. These two
formed on a number of families with autosomal families were also part of the original HS study
dominant HS. Two regions on two different by Fitzsimmons et al. [19]. Classification of each
chromosomes co-segregated with the disease member of the families as affected or unaffected
and the genes within these regions have been depended on three key elements: (1) typical le-
analysed [64]. Although no mutation has been sions; (2) characteristic distribution; (3) recur-
found some of the genes appeared to be good ring nature of the lesions, as described above.
candidates due to their function or expression. Using these criteria, 12 individuals were classi-
Fig. 10.2. Pedigrees of HS families studied (Families M and 6). Asterisks indicate the individuals used in the study
Fig. 10.3. Pedigree third family

studied (Family 13). Asterisk
indicates individual whose DNA
was used in study
fied as being affected in Family 6 and 8 affected susceptibility. These two regions were found on
in Family 13. separate chromosomes indicating that HS is a
A third family, Family M (Fig. 10.3), was ex- genetically heterogeneous disease [64].
amined by two of us (JvdW and ADI). Blood The first area of linkage was found to the
samples were obtained from 16 individuals, 12 long arm on chromosome 6 (band 6q25.2).
of whom were classified as affected and 3 as un- Linkage was originally found in Family M with
affected according to the criteria discussed three markers after screening all affected and
above. Pilonidal cysts and inguinal folliculitis unaffected members. As HS can have a variable
are associated features of HS and any individu- severity and age of onset the genome screen was
als in these families with these clinical features originally performed only on the members of
were also assigned as affected. Any individuals the family that were definitely affected. This
that were designated only as possibly affected original screen revealed a number of candidate
were excluded from the study. loci where all the affected individuals shared al-
Genomic DNA was isolated from whole leles with certain markers. Linkage analysis was
blood. Genotypes of affected and unaffected then carried out with unaffected members of
family members were generated initially using a the family using only the previously linked
set of 400 fluorescently labelled microsatellite markers. A number of markers were uninfor-
markers. These were PCR amplified and the re- mative and therefore high-density markers were
sultant PCR products were analysed on an auto- run in order to eliminate these regions. This
mated genetic analysers. Allele sizes were deter- eliminated all markers except for one that co-
mined using Genotyper 2.0 software. segregated with the disease and initially gave a
ABI Prism Linkage Mapping Set-HD5 was positive LOD score of 2.2 at recombination fac-
used in regions that were non-informative. Ge- tor (e) of 0 with D6S441. The first unlinked
netic analysis was performed using higher den- proximal and distal markers were used to define
10 sity markers spanning candidate regions in or- the boundaries of the candidate region that was
der to reduce the size of the locus. Additional between markers D6S308 and D6S1581. Geno-
markers were obtained from data in the Human typing was then performed using high-density
Genome Browser Database, April 2003 freeze markers from the ABI High Density 5 cM panel
(http://www.genome.ucsc.edu). They were am- and extra markers ordered using sequence data
plified and analysed as described above. Two- on the UCSC website to further define the re-
point LOD scores were obtained using the gion. Recombinants with markers D6S440 and
CYRILLIC 2.1 package in conjunction with the D6S442 defined the region as a 3.74-cM region
MLINK program, assuming 90% penetrance of on 6q.25, with a maximum two-point LOD
the disease. score of 2.83 in Family M obtained with marker
All genes in the chromosome 6 candidate re- D6S1577. The fluorescent markers covering this
gion were analysed. A candidate gene approach region were then run on a number of other fam-
was undertaken with the chromosome 19 locus. ilies with HS. Only one additional family, Fam-
PCR fragments that contained a deletion or ily 6, appeared to be linked across this region.
insertion and could not be sequenced were cloned Family 6 gave positive LOD score with all mark-
into a plasmid vector, pCR2.1, before being puri- ers run, with a highest combined two-point
fied and sequenced. PCR products that consis- LOD score of 4.0 with marker D6S290. New
tently produced two bands were gel purified. DNA samples were obtained from members of
Family M, which were then used to further
screen the candidate region. Recombination
10.7 Linkage of Hidradenitis events occurred with individual III.6 at D6S1577
Suppurativa to 6q25.2 and D6S441 and with a number of individuals
with D6S440, narrowing the region to only 0.53
The genome-wide linkage screen using 400 flu- cM. This region contained six confirmed genes
orescently labelled primers on a number of fam- and one predicted gene according to the Human
ilies resulted in two candidate regions for HS Genome Browser (UCSC Genome Bioinformat-
ics). These were ESR1, SYNE-1, FLJ21269, VIP, of the nuclear receptor superfamily of transcrip-
FBX05, MTRF1L and RGS17. The predicted ex- tion factors [34, 56, 62]. Oestrogen is known to
ons for all of the genes were sequenced and pos- exert an effect on reproductive activity but is
sible alternative exons obtained from expressed also involved in the circulatory system, bone re-
mRNA data. absorption and immune system. Oestrogens
have significant effects on the skin and admin-
istration of oestrogen has been correlated with
10.8 Identification of a Second HS proliferation of basal cells in the epidermis and
Locus to Chromosome 19 increased production of collagen [44, 55]. The
increased oestrogen concentration affects sec-
A genome-wide scan was performed on DNA ondary sexual characteristics in both males and
from 13 members of Family 13; 9 with HS and females as large doses of oestrogen can increase
7 unaffected. A cluster of markers on chromo- or reduce the size of sebaceous glands and also
some 19 co-segregated with the disease giving a apocrine sweat glands [44, 55]. An abnormality
highest two-point LOD score of 3.66 at recom- in the sizes of these glands has not been report-
bination fraction with D19S414 (Table 2.18). ed in HS but one report has demonstrated that
Higher density markers were then taken from the hair follicles in HS patients were larger than
data on the Human Genome Browser and were normal [28]. Oestrogen is involved in the pro-
run on the samples from Family 13 in order to duction of pubic hair and both receptors are ex-
define the limits of the candidate region. Re- pressed in the hair follicle, and therefore may
combination events narrowed the region to a also exert an influence on the size of the hair
16.8-cM region between D19S911 and D19S1170 follicles and contribute to the pathogenesis of
over the centromere of chromosome 19. The re- HS [55]. It is therefore expressed in the append-
gion contains 15 known genes and 6 predicted ages involved in HS and a mutation in one of
genes. these receptors could give a tissue-specific phe-
notype. This may be possible due to the pres-
ence of a large number of differentially ex-
10.9 Candidate Genes Analysed pressed 5 regions that are hypothesized to give
in Linked HS Kindreds the receptors tissue specificity.
Polymorphisms were discovered in the ER-A
10.9.1 Oestrogen receptor-A and HS gene of HS patients demonstrating that both ge-
nomic alleles were present. However, one or a
The apparent hormonal influence of HS made small number of exons might be deleted and
the oestrogen receptor-A a good candidate gene. thus escape detection using an exon by exon
HS symptoms usually begin post puberty and PCR strategy. Southern analysis or long-range
the average age of onset is early to mid-twenties. PCR can detect such deletions. Obtaining
There have only been a few reports of prepuber- mRNA from affected individuals carrying het-
tal HS and these cases have usually been associ- erozygous exonic polymorphisms would also
ated with precocious puberty or a hormonal reveal whether both alleles were being ex-
imbalance [42]. Women are significantly more pressed.
frequently affected by the disease then men and
also often describe a premenstrual flare of the
disease [25]. Symptoms tend to improve after 10.9.2 ZNF91 and HS
the menopause [61]. There were however no ob-
vious differences in hormone levels between pa- Zinc finger protein 91 is a repressor of the IgG
tients and controls [2] suggesting that any hor- receptor FcaRIIB promoter. FcGRIIB is an in-
monal influence may take place at the receptor hibitory receptor that contains a tyrosine-based
level. inhibition motif that is expressed on B-cells,
The physiological effects of oestrogen are macrophages, dendritic cells and mast cells [53].
mediated by the oestrogen receptor, a member Co-aggregation of FcGRIIB with the B-cell anti-
gen receptor (BCR) in mature or activated fore be more specific, for example affecting only
B-cells leads to inhibition of a number of cellu- the development of appendages. Abnormally
lar responses such as cell proliferation, antibody developed hair follicles would be likely to play a
production and activation, and instead pro- role in HS as illustrated by the report that hair
motes apoptosis, whereas co-aggregation of follicles in HS patients were abnormally dilated
FcGRIIB with FcERIIB receptor in mast cells and the epidermis surrounding the area was
leads to an inhibition of antigen-induced de- slightly thickened [28].
granulation and cytokine production [45].
ZNF91 is highly expressed in T lymphocytes
and acts to repress FcGRIIB expression in these 10.9.4 Potential Contribution
cells. Deficiency of FcGRIIB in mice leads main- of the VIP Gene to HS
ly to susceptibility to autoimmune disease.
Here, screening of the ZNF91 gene revealed TNF, as previously mentioned, activates a num-
no mutations. As no polymorphic variants were ber of proinflammatory cytokines including
identified in the ZNF91 gene it is impossible to vasoactive intestinal peptide (VIP), which is
conclude whether both alleles are present in HS located within the chromosome 6 candidate re-
patients. Haploinsufficiency of ZNF91 may gion [59]. VIP is a 28-amino-acid regulatory
cause HS by lifting the repression on FcGRIIB peptide that is widely expressed in the nervous
leading to an inhibition of cell proliferation. system and other tissues such as lung and skin.
It plays a role in a wide variety of functions such
as neurotransmission, neuroprotection and is a
10.9.3 TIZ Association with HS modulator of growth, survival and differentia-
tion [23]. Other research has shown that VIP
TIZ emerged as one of the genes with real can in fact increase the production of inflam-
10 potential as a candidate for HS. TIZ inhibits matory cytokines TNF_, IL-3, IL-1B, IL-6,
TRAF6, a tumour-necrosis-factor- (TNF-) asso- granulocyte colony-stimulating factor (G-CSF)
ciated factor that is a signal transducer in the and macrophage colony-stimulating factor
TNF receptor superfamily pathway, and also (M-CSF) [9, 27]. Inflammatory cytokines can
mediates nuclear factor kappa B (NF-KB) and stimulate VIP synthesis, which can in turn in-
JNK activation in the interleukin-1 receptor/ hibit these same cytokines in a negative feed-
Toll-like receptor (IL-1R/TLR) signalling path- back system illustrating its immunoregulatory
way. NF-KB together with activator protein 1 are function. VIP is highly expressed in the skin
activated in acne lesions with consequent ele- and is found in the sebaceous gland and sweat
vated expression of their target gene products, gland of the pilosebaceous unit and a mutation
inflammatory cytokines and matrix-degrading in VIP could potentially cause an inflammatory
metalloproteinases [31]. TRAF6 deficiency in and immune disease such as HS [5, 30]. It is ex-
mice illustrates its role in immune and inflam- pressed in the appendages involved in HS and is
matory response. These mice showed a defect in involved in signalling in the immune and in-
normal B-cell differentiation, lymph node or- flammatory response. Although these are
ganogenesis, IL-1 signalling and lipopolysac- thought to be coincidental secondary features of
charide signalling. The mice, generally, showed HS, they may cause obstruction and an aberrant
features of hypohidrotic ectodermal dysplasia immune response by activating or inhibiting
(HED) due to sweat gland, hair and dental ab- downstream effectors in these pathways.
normalities. This phenotype is not associated
with HS but TNF and IL-1 signalling pathways
have been implicated in playing a role in the dis-
ease. A gain-of-function mutation or dominant
negative mutation in the TIZ gene may act in a
different manner than a knockout of TRAF6.
The effects of such a TIZ mutation might there-
10.10 Additional Candidate flammatory disease susceptibility gene that

Gene-Protein Systems in HS maps to 19p13 is psoriasis (OMIM 605364). Pso-
riasis has also been associated with spondyloar-
10.10.1 Interleukin 1-A thopathies and responds to infliximab, an anti-
TNFA agent [33]. This implies there may be a
Comedogenesis, which is a feature in HS, may common genetic predisposition to all these dis-
be caused by high levels of interleukin 1-A [17]. eases as both Crohns disease and inflammatory
Acne vulgaris is frequently associated and shares arthritis have an association with HS and all
many similar features with HS. Both are de- show genetic linkage to the same region on
scribed as diseases of follicular obstruction. The chromosome 19 [3, 11, 12, 21, 26, 32, 40, 48, 49,
infundibulum of comedones in acne vulgaris 50, 57].
patients possesses a thicker cornified layer than
normal. The cells have thickened cell mem-
branes which are sloughed off as a section of 10.11 Discussion
compacted cells that causes the keratinous plug
within the follicular duct [35]. Guy and Kealey Two regions have been identified that are possi-
used isolated pilosebaceous infundibulum, ble loci for HS. One of these loci, on chromo-
maintained in medium, to demonstrate the re- some 6, yielded a statistically significant 2-point
sponse to certain proinflammatory cytokines LOD score when the linkage data from two fam-
[24]. Administration of IL-1A resulted in early ilies were combined. This locus should therefore
cornification and hyperproliferation of infun- be treated with caution since it would be prefer-
dibular keratinocytes that caused scaling of the able to obtain a significant LOD score of >3.0
lumen. They hypothesized that overexpression using data from one family only, so that there is
of IL-1A may lead to the abnormal cornification less likelihood of any spurious linkage effects.
seen in comedones. IL-1A overexpression may Nevertheless, the known genes within the chro-
be responsible for the initiation of inflammato- mosome 6 locus have been fully sequenced
ry events leading to the hyperproliferation of without the identification of any potentially
the follicular lumen and resultant comedo that pathogenic mutations. Other genes in this re-
is observed in acne vulgaris and HS. Genes in- gion may yet be discovered as there are human
volved in the stimulation of IL-1A could there- mRNA sequences aligned to 6q25.2 that do not
fore be responsible for the initial pathogenic correspond to any of the known genes and may
events occurring in HS. turn out to be expressed genes that are as yet un-
known.
The region of chromosome 19 spanning the
10.10.2 TNF Signalling and HS centromere constitutes the second candidate re-
gion. This locus gave a statistically significant
Members of the TNF family are critically in- LOD score with data from one family and there-
volved in host defence and immune responses fore represents a more robust linkage result than
and often mediate either apoptosis or cell sur- the 6q locus. This linked interval contains at
vival. Anti-TNFA therapy has been shown to least 21 genes, some of which have an unknown
improve symptoms in some HS patients. In the function and some that are predicted proteins.
first of these cases HS was a secondary disease Only seven genes were chosen whose function
treatment being given for Crohns disease or homology to other proteins made them good
(OMIM 266600) or the inflammatory spondy- potential candidate HS genes. No mutations
loarthropathies such as ankylosing spondylitis were found in any of these genes but there are
(OMIM 183840). Both inflammatory diseases still a number of other genes to screen that may
responded to anti-TNFA therapy. Both Crohns carry a mutation. In addition, the causative mu-
disease and ankylosing spondylitis susceptibili- tation may have been missed, as discussed be-
ty loci show linkage to the same region on chro- low.
mosome 19 as the HS gene [37, 47]. Another in-
A number of other, smaller families and spo- taken in screening some of these genes, in par-
radic cases that were too small on which to per- ticular those that had potential due to their ex-
form a genome-wide screen did not show link- pression pattern or function. Seven genes were
age to either of the candidate loci described fully sequenced to date in the chromosome 19
here. Although HS is now known to be a hetero- region but the pathogenic mutation responsible
geneous disease it appears that it may be caused for HS has not yet been found [64].
by mutations in genes at multiple locations mak-
ing it a more complex disease than originally
thought. 10.12 Conclusions
The linkage to chromosome 6 was narrowed
down by recombinants to a small region of
6q25.2 containing only six genes. The genomic W
structure of each of these genes was established Although all the genes in the chromosome 6
using sequence data from the Human Genome candidate gene were sequenced no muta-
Browser, April 2003 freeze. Any potential alter- tions were discovered. This implies that there
native exons encoding a different isoform or may be more genes in this region that have
splice variant were obtained from gene predic- yet to be identified, although analysis of the
tion programs such as Genescan and Twinscan human mRNAs expressed here reveals only a
that were annotated on the Human Genome few other aligned mRNA sequences that did
Browser. Human aligned mRNA sequences not correspond to the known genes. The mu-
were also used for potential new spliced iso- tational analysis we performed was PCR-based
forms. Each of the genes was analysed by PCR and this method could have failed to detect
and direct sequencing. Although a number of any genomic deletions that could cause hap-
sequence changes were detected, these either loinsufficiency or larger in-frame and poten-
10 did not segregate with the disease phenotype tially dominant-acting deletions. Obtaining
and/or were detected in normal controls, and skin biopsy samples from patients and quanti-
therefore no mutations were discovered. fying the expression of these genes by quanti-
Another HS family linked to the centromeric tative RT-PCR to accurately measure expres-
region of chromosome 19 between markers sion of alleles could overcome this problem.
D19S911 and D19S1170. This region includes Seemingly benign missense mutations and
19p13.11, 19p12, 19p11, 19q11 and 19q12 cytoge- polymorphisms should also not be over-
netic bands and covers 16.8 Mb of genomic looked. These types of changes have recently
DNA but contains only 14 known genes and 7 been discovered to affect splicing and have
predicted genes. There were also several in silico been shown to cause breast cancer and cystic
predicted genes in the interval. There are a high fibrosis [39, 46].
percentage of zinc finger proteins in this region The candidate region on chromosome
and is therefore composed of very repetitive se- 19 covered a large area, 16.8 Mb of genomic
quences which often causes problems in the sequence. There were relatively few genes in
ability to specifically amplify genes. A large comparison to the size of the region and the
number of genes in these regions are involved in fact that chromosome 19 is one of the most
the immune and inflammatory response by ac- gene-rich chromosomes [58]. The candidate
tivating or inhibiting proinflammatory cyto- region links over the centromere and the re-
kines. The cytokines involved, such as IL-1, gions immediately adjacent to the centromere
IL-10, IL-6 and TNF, have roles in the develop- are not predicted to contain many genes. The
ment of epidermal appendages, hyperprolifera- linked region, defined by markers D19S911
tion and cornification of epidermal cells and and D19S1170, was rich in ZNF genes and chro-
initiation of immune signalling [6, 14, 15, 17, 24, mosome 19 has the highest repeat density
29, 38]. Therefore, a mutation in any of the genes [58]. The majority of the ZNF proteins are
controlling these functions could potentially highly expressed in T lymphoid cells, B-cells
underlie HS. A candidate gene approach was
4. Bleck O, McGrath JA and South AP (2001) Search-

and monocytic and erythroid cells. Although ing for candidate genes in the new millennium. Exp
the functions of most are unknown, as a Dermatol 26:27983
5. Bohm M, Luger TA (1998) The pilosebaceous unit
whole, ZNF proteins are thought to be in-
is part of the skin immune system. Dermatology
volved in development. ZNF91 has been 196:759
shown to function as a repressor of an IgG re- 6. Bolland S, Ravetch JV (2000) Spontaneous auto-
ceptor and therefore has an influence on the immune disease in FcaRIIB-deficient mice results
immune response as do some of the other from strain-specific epistasis. Immunity 13:27785
candidate genes studied, such as TIZ. No mu- 7. Bonifas JM, Morley BJ, Oakey RE, Kan YW and
tation was found in any of the candidate genes Epstein Jr EH (1987) Cloning of a cDNA for steroid
sulfatase: frequent occurrence of gene deletions in
analysed but there are a number of genes still
patients with recessive X chromosome-linked ich-
to be sequenced. In addition to the known thyosis. Proc Natl Acad Sci USA 84:924851
genes, mRNA alignment and gene predictions 8. Botstein D, Risch N (2003) Discovering genotypes
reveal that there may still be some genes that underlying human phenotypes: past successes for
are as yet unidentified. mendelian disease, future approaches for complex
In conclusion, the first two candidate ge- disease. Nature Genet 33:22837
netic loci for HS have been identified and this 9. Brenneman DE, Phillips TM, Hauser J, Hill JM,
will form the basis of future genetic studies, Spong CY and Gozes I (2003) Complex array of
cytokines released by vasoactive intestinal peptide.
using other families with clearly defined dom-
Neuropeptides 37:2
inant inheritance, to narrow down these loci 10. Brunsting HA (1952) Hidradenitis and other vari-
and identify the causative genetic lesions. Im- ants of acne (1952) AMA Arch Derm Syphilol
portantly, a number of other families do not 65(3):30315
link to either locus. These families were too 11. Burrows NP, Jones RR (1992) Crohns disease in as-
small to perform genome-wide linkage analy- sociation with hidradenitis suppurativa. Br J Der-
sis but it demonstrates that HS is indeed a ge- matol 126:523
12. Cohen J (1985) Arthritis occurring with hidradeni-
netically heterogeneous disease with poten-
tis suppurativa. J Rheumatol 12:12089
tially three or more genes involved in its 13. Consortium MGS (2002) Initial sequencing and
molecular pathogenesis. The eventual identi- comparative analysis of the mouse genome. Nature
fication of these causative genes will undoubt- 420:52062
edly be of benefit in understanding the 14. Delgado M, Ganea D (2003) Vasoactive intestinal
pathomechanisms of HS and form the basis peptide prevents activated microglia-induced neu-
for a rational design of new therapeutic strate- rodegeneration under inflammatory conditions:
gies. potential therapeutic role in brain trauma. FASEB
J 17:19224
15. Delgado M, Abad C, Martinez C, Leceta J and Go-
mariz RP (2001) Vasoactive intestinal peptide pre-
vents experimental arthritis by downregulating
References both autoimmune and inflammatory components
of the disease. Nature Med 7:5638
1. Antonarakis SE, McKusick VA (2000) OMIM pass- 16. Donis-Keller H, Green P, Helms C et al (1987) A
es the 1000-disease-gene mark. Nature Genet 25:11 genetic linkage map of the human genome. Cell
2. Barth JH, Layton AM and Cunliffe WJ (1996) En- 51:31937
docrine factors in pre- and postmenopausal wom- 17. Eady EA, Cove JH (2000) Is acne an infection of
en with hidradenitis suppurativa. Br J Dermatol blocked pilosebaceous follicles? Implications for an-
134:10579 timicrobial treatment. Am J Clin Dermatol 1:2019
3. Bennett RE, Wilke WS and Murphy DP (1983) 18. Fitzsimmons JS, Guilbert PR (1985) A family study
Spondyloarthropathy and hidradenitis suppura- of hidradenitis suppurativa. J Med Genet 22:36773
tiva. Ann Intern Med 98:112 19. Fitzsimmons JS, Fitzsimmons EM and Guilbert PR
(1984) Familial hidradenitis suppurativa: evidence
in favour of single gene transmission. J Med Genet
21:2815
20. Fitzsimmons JS, Guilbert PR and Fitzsimmons EM 35. Knaggs HE, Holland DB, Morris C, Wood EJ and
(1985) Evidence of genetic factors in hidradenitis Cunliffe WJ (1994) Quantification of cellular pro-
suppurativa. Br J Dermatol 113:18 liferation in acne using the monoclonal antibody
21. Goischke HK, Ochsendorf FR (2001) [Acne inversa Ki67. J Invest Dermatol 102:8992
in Crohns disease]. Z Gastroenterol 39:9659 36. Knaysi GA, Cosman B, Crikelair GF (1968) Hidrad-
22. Gold SC, Delaney TJ (1974) Familial acne congloba- enitis suppurativa. J Am Med Assoc 203(1):736
ta, hidradenitis suppurativa, pili torti and cataracts. 37. Laval SH, Timms A, Edwards S, Bradbury L, Bro-
Br J Dermatol 91(10):547 phy S, Milicic A, Rubin L, Siminovitch KA, Weeks
23. Gomariz RP, Martinez C, Abad C, Leceta J and Del- DE, Calin A, Wordsworth BP and Brown MA (2001)
gado M (2001) Immunology of VIP: a review and Whole-genome screening in ankylosing spondy-
therapeutical perspectives. Curr Pharm Des 7:89 litis: evidence of non-MHC genetic-susceptibility
111 loci. Am J Hum Genet 68:91826
24. Guy R, Kealey T (1998) The effects of inflammatory 38. Lee YA, Ruschendorf F, Windemuth C, Schmitt-
cytokines on the isolated human sebaceous infun- Egenolf M, Stadelmann A, Nurnberg G, Stander M,
dibulum. J Invest Dermatol 110:41015 Wienker TF, Reis A and Traupe H (2000) Genome-
25. Harrison BJ, Read GF and Hughes LE (1988) Endo- wide scan in German families reveals evidence for a
crine basis for the clinical presentation of hidrad- novel psoriasis-susceptibility locus on chromosome
enitis suppurativa. Br J Surg 75:9725 19p13. Am J Hum Genet 67:10204
26. Hellmann DB (1992) Spondyloarthropathy with hi- 39. Maquat LE (2001) The power of point mutations.
dradenitis suppurativa. J Am Med Assoc 267:2363 Nature Genet 27:56
5 40. Martinez F, Nos P, Benlloch S and Ponce J (2001)
27. Hernanz A, Medina S, de Miguel E and Martin- Hidradenitis suppurativa and Crohns disease: re-
Mola E (2003) Effect of calcitonin gene-related pep- sponse to treatment with infliximab. Inflamm Bow-
tide, neuropeptide Y, substance P and vasoactive el Dis 7:3236
intestinal peptide on interleukin-1beta, interleu- 41. McGrath JA (2004) Translational benefits from re-
kin-6 and tumor necrosis factor-alpha production search on rare genodermatoses. Aust J Dermatol
by peripheral whole blood cells from rheumatoid 45:8993
10 arthritis and osteoarthritis patients. Regul Pept 42. Mengesha YM, Holcombe TC and Hansen RC
115:1924 (1999) Prepubertal hidradenitis suppurativa: two
28. Jemec GB, Gniadecka M (1997) Ultrasound exami- case reports and review of the literature. Pediatr
nation of hair follicles in hidradenitis suppurativa. Dermatol 16:2926
Arch Dermatol 133:96770 43. Mullis K, Faloona F, Scharf S, Saiki R, Horn G and
29. Jeremy AHT, Holland DB, Roberts SG, Thomson Erlich H (1986) Specific enzymatic amplification of
KF and Cunliffe WJ (2003) Inflammatory events are DNA in vitro: the polymerase chain reaction. Cold
involved in acne lesion initiation. J Invest Dermatol Spring Harb Symp Quant Biol 11:26373
121:207 44. Oh HS, Smart RC (1996) An estrogen receptor path-
30. Kakurai M, Fujita N, Murata S, Furukawa Y, Demit- way regulates the telogen-anagen hair follicle tran-
su T and Nakagawa H (2001) Vasoactive intestinal sition and influences epidermal cell proliferation.
peptide regulates its receptor expression and func- Proc Natl Acad Sci USA 93:1252530
tions of human keratinocytes via type I vasoac- 45. Ott VL, Tamir I, Niki M, Pandolfi PP and Cambier
tive intestinal peptide receptors. J Invest Dermatol JC (2002) Downstream of kinase, p62(dok), is a me-
116:7439 diator of Fc gamma IIB inhibition of Fc epsilon RI
31. Kang S, Cho S, Chung JH et al (2005) Inflammation signalling. J Immunol 168:44309
and extracellular matrix degradation mediated by 46. Pagani F, Buratti E, Stuani C, Bendix R, Drk T and
activated transcription factors nuclear factor-kap- Baralle FE (2002) A new type of mutation causes a
paB and activator protein-1 in inflammatory acnes splicing defect in ATM. Nature Genet 30:4269
lesions in vivo. Am J Pathol 166(6):16919 47. Rioux JD, Silverberg MS, Daly MJ, Steinhart AH,
32. Katsanos KH, Christodoulou DK and Tsianos EV McLeod RS, Griffiths AM, Green T, Brettin TS,
(2002) Axillary hidradenitis suppurativa success- Stone V, Bull SB, Bitton A, Williams CN, Greenberg
fully treated with infliximab in a Crohns disease GR, Cohen Z, Lander ES, Hudson TJ and Simino-
patient. Am J Gastroenterol 97:21556 vitch KA (2000) Genomewide search in Canadian
33. Khan MA (2002) Update on spondyloarthropathies. families with inflammatory bowel disease reveals
Ann Intern Med 136:896907 two novel susceptibility loci. Am J Hum Genet
34. Klinge CM (2001) Estrogen receptor interaction 66:186370
with estrogen response elements. Nuc Acid Res
29:290519
48. Rosner IA, Richter DE, Huettner TL, Kuffner GH, 57. Tsianos EV, Dalekos GN, Tzermias C, Merkouro-
Wisnieski JJ and Burg CG (1982) Spondyloarthrop- poulos M and Hatzis J (1995) Hidradenitis suppu-
athy associated with hidradenitis suppurativa and rativa in Crohns disease. A further support to this
acne conglobata. Ann Intern Med 97:5205 association. J Clin Gastroenterol 20:1513
49. Rosner IA, Burg CG, Wisnieski JJ, Schacter BZ and 58. Venter JC et al (2001) The sequence of the human
Richter DE (1993) The clinical spectrum of the ar- genome. Science 291:130451
thropathy associated with hidradenitis suppurativa 59. Victor FC, Gottlieb AB (2002) TNF-alpha and
and acne conglobata. J Rheumatol 20:6847 apoptosis: implications for the pathogenesis and
50. Roy MK, Appleton MA, Delicata RJ, Sharma AK, treatment of psoriasis. J Drugs Dermatol 1:26475
Williams GT and Carey PD(1997) Probable associa- 60. von der Werth JM, Williams HC (2000) The natural
tion between hidradenitis suppurativa and Crohns history of hidradenitis suppurativa. J Eur Acad Der-
disease: significance of epithelioid granuloma. Br J matol Venereol 14:38992
Surg 84:3756 61. von der Werth JM, Williams HC, Raeburn JA (2000)
51. Spurr NK, Young BD and Bryant SP (1998) ICRF The clinical genetics of hidradenitis suppurativa re-
handbook of genome analysis. Blackwell Science, visited. Br J Dermatol 142:947953
Oxford 62. Walter P, Green S, Greene G, Krust A, Bornert JM,
52. Strachan T, Reid AP (1999) Human molecular ge- Jeltsch JM, Staub A, Jensen E, Scrace G and Water-
netics 2, 2nd edn. BIOS Scientific, Oxford field M (1985) Cloning of the human estrogen re-
53. Takai T, Ono M, Hikida M, Ohmori H and Ravetch ceptor cDNA. Proc Natl Acad Sci USA 82:788993
JV (1996) Augmented humoral and anaphylactic 63. Weber JL, May PE (1989) Abundant class of human
responses in Fc gamma RII-deficient mice. Nature DNA polymorphisms which can be typed using
379:3469 the polymerase chain reaction. Am J Hum Genet
54. Terwilliger JD, Ott J (1994) Handbook of human 44:33896
genetic linkage, 1st edn. Johns Hopkins University 64. Wood P (2003) Molecular genetic analysis of inher-
Press, London ited epidermal disorders. Thesis submitted for the
55. Thornton MJ (2002) Biological effects of estrogens Degree of Doctor of Philosophy, Molecular and Cel-
on the skin. Exp Dermatol 11:487502 lular Pathology, University of Dundee
56. Thornton MJ, Taylor AH, Mulligan K, Al-Azzawi 65. Worton RG, Thompson MW (1988) Genetics of
F, Lyon CC, ODriscoll J and Messenger AG (2003) Duchenne muscular dystrophy. Annu Rev Genet
The distribution of estrogen receptor beta is distinct 22:60129
to that of estrogen receptor alpha and the androgen
receptor in human skin and the pilosebaceous unit.
J Investig Dermatol Symp Proc 8:1003
Chapter 11
Bacteriology of Hidradenitis
Suppurativa 11
Cristina Oprica, Carl Erik Nord
Q Antibiotics do not cure the disease but

Key points
they may relieve the symptoms through
Q The pathogenesis of hidradenitis either an antibacterial or an anti-
suppurativa (HS) is still poorly under- inflammatory effect
stood and not yet clearly defined
Q A large variety of bacteria can be found

in HS lesions and many of them belong
to the normal flora of the skin #ONTENTS
11.1 Normal Microflora of the Skin . . . . . . . . . . .86

Q In the studies using the bacteria
prevalent on the surface of the lesions 11.2 Bacteria Found in HS Lesions . . . . . . . . . . . 87
there is possible contamination from 11.3 General Factors About Bacterial
the resident flora of the skin Involvement in HS Pathogenicity . . . . . . . .90
11.4 The Role of Antibiotics in the Treatment
11 Q In cases of cultures obtained from the of HS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
deeper parts of HS, Staphylococcus 11.5 Possible Consequences
aureus, coagulase-negative staphylo- for Bacterial Ecology due
cocci and anaerobic bacteria have to Antibiotic Treatment in HS . . . . . . . . . . .92
commonly been isolated References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92
Q The first event seems to be follicular

occlusion by keratinized stratified 11.1 Normal Microflora of the Skin
squamous epithelium in apocrine-
bearing areas, with subsequent inflam- Normal human skin is colonized by a large vari-
mation ety of organisms that live as commensals on its
surface. There are quantitative differences
Q The initial inflammatory change can be among different regions of the skin, related to
produced by a pyogenic bacterial temperature difference, moisture content, and
infection or by factors similar to those the presence of various amounts of skin lipids
involved in acne that may be inhibitory or lethal for some micro-
organisms. These differences characterize three
Q In chronic lesions, bacteria represent a main regions of the skin: (1) axilla, perineum,
risk factor for the destructive scarring and toe webs; (2) hands, face, and trunk; and (3)
and extension of the disease and arms and legs [20]. The skin microflora reside
secondary bacterial infections may on the skin surface and in the ducts of hair fol-
occur licles and sebaceous glands [38].
Bacteriology of Hidradenitis Suppurativa Chapter 11 87
Table 11.1. The most important genera and species of bacteria normally found on the skin
Genus Characteristics Most prevalent species
Coagulase-negative Aerobic, Gram-positive cocci S. hominis, S. haemolyticus

Staphylococcus S. epidermidis
Micrococcus Aerobic, Gram-positive cocci M. luteus, M. varians
Corynebacterium Aerobic, Gram-positive pleomorphic rods C. bovis, C. minutissimum
Propionibacterium Anaerobic, Gram-positive rods P. acnes, P. granulosum, P. avidum
Acinetobacter Aerobic, Gram-negative coccobacilli A .calcoaceticus var. lwoffi and var. anitratus
The sites affected by HS are, in order of fre- Propionibacteria are Gram-positive rod-
quency: axillary, inguinal, perianal and perine- shaped anaerobic bacteria. Propionibacterium
al, mammary and inframammary, buttock, pu- acnes and Propionibacterium granulosum are
bic region, chest, scalp, retroauricular, and the associated with follicles that have large seba-
eyelid [50]. ceous glands on the face and upper trunk and
The major groups of microorganisms present they have a role in acne pathogenesis. Propioni-
on the skin are various genera of bacteria and bacterium avidum is found in moist areas (axil-
yeasts. The predominant bacteria of the skin are lae and groin) and it is not known if it has patho-
as follows (Table 11.1) [20, 21]: genic potential [21].
Acinetobacter species are the only important
Q Coagulase-negative staphylococci Gram-negative residents of the skin and are
Q Micrococci found in the axillae and groin of 25% of the
Q Saprophytic Corynebacterium species population [21].
(diphtheroids) In addition, any bacterial species that is found
Q Propionibacterium species in nature or belongs to the normal flora on non-
Q Acinetobacter species. cutaneous areas may temporarily be found on
the skin [47]. Staphylococcus aureus is not nor-
Various coagulase-negative staphylococci are mally considered a resident of normal skin, but
found on the skin and some have special predi- it can be found on perineal skin, axillae, and in
lection for some areas, for example Staphylococ- the toe cleft. Hemolytic streptococci may be
cus hominis and Staphylococcus haemolyticus found as transients on different skin sites, more
are found principally in areas where there are often in children [38]. Atypical mycobacteria
numerous apocrine glands, such as axillae and may be found in genital and axillary regions
the pubic region [20, 32]. Staphylococcus epider- and Bacillus species or different Gram-negative
midis is also an important resident, colonizing bacilli such as Proteus, Pseudomonas, Entero-
moist areas of the skin [21]. It is found preferen- bacter and Klebsiella are rarely found on the
tially in the upper part of the body and repre- skin [20, 38].
sents over 50% of the resident staphylococci In conclusion, a large variety of bacteria are
[47]. able to colonize the most affected areas in HS:
Micrococcus species are found on the skin, axilla, perineum, and the groin.
especially in women and children, and Micro-
coccus luteus and Micrococcus varians are the
prevailing species [20, 21]. These microorgan- 11.2 Bacteria Found in HS Lesions
isms often colonize axilla, perineum, and groin
[21]. Although the HS etiology is unknown, a large
Different bacteria belonging to the genus variety of microorganisms can be isolated from
Corynebacterium are associated, but not exclu- the lesions. The clinical picture of the disease
sively, with moist areas of the skin [21]. resembles an infectious process and various
88 Cristina Oprica, Carl Erik Nord
Table 11.2. Studies describing the diversity of bacteria found in various HS lesions
Investigator Bacteria found Area of the skin
Leach et al. [35] Staphylococcus aureus, anaerobic bacteria Axillae

Brenner and Lookingbill [7] Staphylococcus aureus, Staphylococcus epidermidis Perirectal, groin, axillae
Bacteroides fragilis, Bacteroides melaninogenicus
Highet et al. [23] Streptococcus milleri Perineal
Highet et al. [24] Streptococcus milleri, Staphylococcus aureus, Perineal
anaerobic streptococci, Bacteroides species
Finegold et al. [18] Biophila wadsworthia Axillae
Bendahan et al. [5] Chlamydia trachomatis Perineal
Jemec et al. [29] Staphylococcus aureus, Streptococcus milleri, Axillae, groin, breasts,
Staphylococcus epidermidis, Staphylococcus hominis buttocks
Brook and Frazier [8] Staphylococcus aureus, Streptococcus pyogenes, Axillae
Pseudomonas aeruginosa;
Peptostreptococcus species, Prevotella species,
micro-aerophilic streptococci, Fusobacterium
species, Bacteroides species
Lapins et al. [33] Staphylococcus aureus, coagulase-negative Axillae and perineal
staphylococci, enterococci, group B hemolytic
streptococci, group C hemolytic streptococci,
Bacillus cereus, diphtheroides, enterobacteriacae-;
Peptostreptococcus species, Propionibacterium acnes,
microaerophilic streptococci, Lactobacillus species,
Bacteroides fragilis, other Bacteroides species,
Prevotella species
11
bacteria are suspected as being responsible for streptococci, Fusobacterium species, and Bacte-
the inflammation. The bacterial findings are roides species.
considered by some authors as either contami- In most of the studies samples are collected
nants from the normal skin flora or a result of from the surface of the lesions [2224] and there
secondary infection in a previously sterile pro- is a high risk of contamination with the resident
cess [33]. skin flora. In these conditions the bacteriologi-
Despite the volume of the discharge the HS cal results are difficult to interpret. Jemec et al.
lesions are often found to be sterile [29, 33], but [29] have aspirated pus from the deeper parts of
sometimes a large variety of microorganisms HS. Bacteria were found in half of active lesions:
can be isolated from the sinuses, particularly Staphylococcus aureus and coagulase-negative
staphylococci, streptococci, Gram-negative rods, staphylococci (Staphylococcus epidermidis and
and anaerobic bacteria (Table 11.2). The bacte- Staphylococcus hominis) were most commonly
rial flora are not consistent and may change un- isolated. An explanation for the large number of
predictably [31]. Brook and Frazier [8] found, in negative cultures could be that it is difficult to
a retrospective review of clinical and bacterio- localize the infected part using the aspiration
logical data from patients with axillary disease, technique. It was found that the duration of the
that the most prevalent aerobic bacteria were disease was shorter for those patients in whom
Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus aureus was detected as a possible
and Pseudomonas aeruginosa and the most fre- etiological factor, indicating that this bacterium
quent anaerobic bacteria were Peptostreptococ- may be involved early in the disease pathogene-
cus species, Prevotella species, microaerophilic sis by causing anatomical changes in the hair
Table 11.3. Possible factors responsible for coagulase- crease the pathogenic properties of these other-
negative staphylococci pathogenicity in HS lesions wise harmless members of the normal flora.
Factors Effect Lapins et al. [33] have often found coagulase-
negative staphylococci as the sole bacteria in the
deep portion of the lesions and suggested that
Sinus formation Enhances the
in HS lesions pathogenic properties
the abnormally structural tissue in HS due to
of the bacteria [33] sinus formation can provide a medium similar
to the presence of a foreign body and the result
Bacterial capacity Protects against antibiotics
of biofilm formation and from attacks by the will be enhancement of the pathogenic proper-
immune system [42] ties of coagulase-negative staphylococci. Gener-
Bacterial production Persistence in the host.
ally, the pathogenic potential of coagulase-nega-
of lipases, proteases, Tissue degradation [42] tive staphylococci is mainly due to their capacity
and other exoenzymes to form biofilms on medical devices [42]. The
Toxin production Invasion properties sinus formation in HS may be an ideal place for
[35, 36] biofilm formation and this microbiologic prin-
Production of PAS- Obstructs the delivery
ciple may be applicable to coagulase-negative
positive extracellular of sweat to the skin staphylococci in HS. Many coagulase-negative
polysaccharide substance surface [37] staphylococci produce several lipases, proteases,
and other exoenzymes, which possibly contrib-
ute to the persistence of coagulase-negative
staphylococci in the host and may degrade host
follicles. These modifications may later predis- tissue [42]. Here, the bacteria find protection
pose to inflammation independently of the against antibiotics and from attacks by the im-
presence of bacteria [29]. mune system. The biofilm model was recently
Lapins et al. [33] circumvented problems proposed to be involved in acne pathogenesis,
both of contamination and of missing the active where glycocalyx polymer secreted by Propioni-
area of infection by using a carbon dioxide bacterium acnes as a biofilm may explain the
(CO2) laser surgical method to evaporate the immunogenicity of the organism as well as the
diseased tissue level by level from the surface unpredictable course of the disease [11]. There
downwards. This allows sampling for bacterio- are also some lines of evidence that under cer-
logical cultures from each level without the risk tain conditions they may produce similar toxins
of contamination with bacteria from the level to Staphylococcus aureus and could cause inva-
above. By using this method, bacteria were sive diseases [36, 56].
found even in the deeper and closed parts of HS. Mowad et al. [37] showed that periodic-acid-
Staphylococcus aureus and coagulase-negative Schiff- (PAS-) positive extracellular polysaccha-
staphylococci were also the most commonly ride substance produced by Staphylococcus epi-
found species. After the Staphylococcus species dermidis obstructs the delivery of sweat to the
the most commonly cultured bacteria were the skin surface and these strains are involved in
anaerobic species found in the deeper levels: the pathogenesis of miliaria. It was speculated
Peptostreptococcus species and Propionibacteri- that a similar mechanism could be involved
um acnes. The aerobic bacteria were found in in HS pathogenesis [33]. It is known that the
60% of positive cultures at deep levels. pathogenic potential of coagulase-negative
The clinical significance of coagulase-nega- staphylococci varies according to species [33].
tive staphylococci is unclear because while they Staphylococcus haemolyticus and Staphylococ-
are part of the normal microflora [29, 33] they cus saprophyticus have well-known pathogenic
have also gained attention as pathogens (Table potential and Staphylococcus lugdunesis, Staph-
11.3). Coagulase-negative staphylococci are as- ylococcus schleiferi or Staphylococcus caprae are
sociated with infections in those with intravas- considered emerging pathogens [56]. Staphylo-
cular catheters [46] and prosthetic devices [14] coccus lugdunesis was found in axillary lesions
where the presence of the foreign body will in- diagnosed as HS [54].
Streptococcus milleri, a microaerophilic mi- and Cahn [49] were able to reproduce HS lesions
croorganism frequently causing pyogenic infec- by applying atropine-impregnated adhesive tape
tions [17] that often colonizes the gastrointesti- to a manually depilated axillary region. They
nal tract and female genital tract, was found by noticed subsequent dilatation, inflammation,
some investigators to be a major pathogen in and bacterial invasion of the apocrine duct and
perineal HS. Furthermore, the presence of this concluded that HS is a bacterial infection of an
bacterium correlated with the disease activity obstructed apocrine sweat gland with the caus-
and its elimination by appropriate antibiotic ative bacteria deriving from the normal flora of
therapy was accompanied by marked clinical the skin.
improvements [23, 24]. Microaerophilic strepto- However, today it is largely accepted that
cocci were found by Brunsting in 1939 in a apocrine gland involvement is not essential to
group of patients with HS [9]. Streptococcus mil- the pathogenesis, and that the inflammatory
leri, Staphylococcus aureus, anaerobic strepto- processes and involvement of apocrine glands
cocci, or Bacteroides species were frequently are secondary events [6, 28]. The disease starts
isolated in a group of 32 patients with active with follicular hyperkeratosis and dilatation of
perineal HS [24]. Other authors could not find the infundibula and most authors believe that
Streptococcus milleri in any of the specimens the bacterial contribution is a secondary event
[41]. in the disease process [27, 48]. The retention of
In perianal forms of HS, Escherichia coli, keratin in follicles and chronic sinusoids is sub-
Klebsiella and Proteus strains as well as anaero- ject to subsequent bacterial infection. Follicular
bic bacteria were isolated [27]. Brenner and occlusion leads to dilatation followed by rupture
Lookingbill [7] have recovered Bacteroides spe- and spillage of the keratin and bacteria into the
cies from perirectal, groin and axillae and the dermis. This induces a strong chemotactic re-
patients responded well to a suitable antibiotic sponse with an inflammatory cellular infiltrate
treatment regimen. They suggest that the pres- consisting of neutrophils, lymphocytes, and
ence of anaerobic bacteria may reflect the chro- histiocytes [50]. In chronic lesions, bacteria can
11 nicity of pre-existing local infection. Anaerobic be found in and around the glands and lym-
bacteria were also isolated by Leach et al. from phatics [34]. In later stages of HS, bacterial in-
recurrent axillary lesions of HS [35]. fection is a risk factor for extension of the le-
Bilophila wadsworthia is a Gram-negative sions. Sinus tracts are formed in the dermis and
anaerobic rod found as part of the normal flora subcutis from the ruptured follicular epithelium
in feces and, occasionally, in saliva and in the in an attempt by the tissue to confine the in-
vagina; in one case of HS it was isolated together flammation, and there is a high risk for second-
with other anaerobic bacteria of the Prevotella ary infections [34, 50].
species [4, 18]. Systemic infections such as bacterial menin-
Bendahan et al. [5] found an association be- gitis, bronchitis or pneumonia are possible, due
tween perineal HS lesions and Chlamydia tra- to the spread of microorganisms [27]. In the case
chomatis infection, but it was not clear whether of coagulase-negative staphylococci, the recent-
the latter was a direct cause or a predisposing ly found inflammatory peptides called phenol-
factor. These findings have not been confirmed soluble modulins (microbial products that stim-
by other authors. ulate cytokine production in host cells) play a
role in the pathogenesis and systemic manifes-
tations of sepsis [42].
11.3 General Factors About Bacterial Polypeptides from Propionibacterium acnes
Involvement in HS Pathogenicity were found to stimulate a specific immune re-
sponse in acne patients [26]. Jemec et al. [29]
The series of events in HS pathogenesis are un- tried to detect a specific serologic response to a
clear and the exact role of bacteria in the etiol- possible staphylococcal or streptococcal infec-
ogy of the disease remains controversial. Shelley tion but the results were inconclusive.
11.4 The Role of Antibiotics Table 11.4. Anti-inflammatory and immunomodulatory

in the Treatment of HS properties of antibiotics used in the treatment of HS
Antibiotic Mechanisms
Despite the fact that the clinical response to an-
tibiotics is poor and that bacteria are found in
Tetracyclines Inhibition of metalloproteases
only 50% of lesions, the recommendation for Inhibition of free radicals
systemic antibiotics is clear and this is derived Modulation of IL-1
from empirical attempts to control the disease. Inhibition of lipases
Also, it is reasonable to try antibiotic treatment, and proteases
as various bacteria are suspected as having a Inhibition of nitric oxide
role in the inflammatory process and in de- synthetase and caspase 1
structive scarring in HS patients. Approximate- and 3 production
Modulation of cytokine
ly 10% of patients have some benefit from the
expression
use of systemic antibiotics [57]. Reduction in the production
If the drainage from lesions is available, bac- of free radicals secreted by poly-
terial cultures and antibiotic sensitivity should morphonuclear leukocytes
be performed and the antibiotic treatment Reduction in the formation
should be tailored according to these results. of inflammatory granuloma
Collaboration between the dermatologist and Clindamycin Suppression of complement-
the bacteriologist is an important factor in find- derived chemotaxis of poly-
ing the best treatment option. Acute episodes morphonuclear leukocytes
and relapses are treated as bacterial infections
for a 2-week period [21]. Oral antibiotics such as
minocycline, erythromycin in combination are known as good candidates for the treatment
with metronidazole, ciprofloxacin, cephalospo- of inflammatory disorders. The anti-inflamma-
rins or semisynthetic penicillins may be used tory properties are enumerated in Table 11.4
[7, 19, 21]. Bukley and Sarkany [10] reported a [43, 44].
case of severe HS who improved after systemic Hindle et al. treated seven patients with a
clindamycin treatment. combination therapy of clindamycin (300 mg
Long-term administration of tetracyclines or twice daily) and rifampicin (300 mg twice daily)
erythromycin may be used in regimens similar for a 10-week period [25]. Three patients did not
to acne vulgaris and seems to prevent episodic tolerate the combination, two because of diar-
flares [19, 21]. rhea associated with Clostridium difficile, and
Topical clindamycin was found to be superior three of them responded well and remained
to placebo in a randomized double-blind clini- clear at 12 months. The combination of rifampi-
cal trial [12] and Jemec and Wendelboe did not cin and clindamycin was also successfully used
find any difference between systemic tetracy- for two other chronic and difficult-to-treat con-
cline and topical clindamycin in another ran- ditions: folliculitis decalvans [45] and acne ke-
domized clinical trial [30]. However, after with- loidalis nuchae [25]. Clindamycin is a lincos-
drawal of antibiotic treatment, HS very often amide antibiotic active against Gram-positive
relapses [3, 13]. cocci (except enterococci) and most anaerobic
As is the case with acne vulgaris, it is not bacteria [52]. Rifampicin is a broad spectrum
known whether the most important factor in antibacterial agent that inhibits the growth of
the treatment of HS is antibacterial or anti-in- the majority of Gram-positive bacteria as well as
flammatory. Lincosamides and tetracyclines many Gram-negative microorganisms [55]. It is
have been known for their immunomodulatory highly active against both Staphylococcus aureus
effects. Clindamycin suppresses the comple- and coagulase-negative staphylococci. Rapid
ment-derived chemotaxis of polymorphonucle- emergence of resistance when the drug was used
ar leukocytes in vitro, thereby reducing the alone has limited the use except in association
inflammation potential [43, 52]. Tetracyclines with another anti-staphylococcal drug [2]. The
combination therapy was introduced to prevent Table 11.5. Effects of antibiotic administration on the
resistance development against rifampicin and ecological balance of human microflora
to cover a broad antibacterial spectrum. Disturbances in the balance between host
and normal flora from the intestinal tract,
skin, oropharyngeal tract, and vagina
11.5 Possible Consequences Altered colonization resistance (growth control
for Bacterial Ecology due of opportunistic bacteria)
to Antibiotic Treatment in HS Overgrowth of pathogenic bacteria or yeasts
The emergence of antimicrobial resistance
The drawback to the usefulness of long-term in the normal flora
antibiotic treatments is concern about the effect
Possible transfer of resistance to pathogenic
on microbial ecology (Table 11.5). The normal
bacteria
microflora act as a barrier against colonization
by potentially pathogenic bacteria and the con-
trol of growth of opportunistic bacteria is called
colonization resistance. The normal equilibri- cocci on the skin, Staphylococcus aureus in the
um between host and microorganisms may be nares, streptococci in the oral cavity, and en-
disturbed by a number of factors, but commonly terobacteria in the gut [16].
and essentially by antibiotic therapy. To what Topical clindamycin will increase carriage of
extent disturbances occur depends of numerous Propionibacterium acnes and Staphylococcus
factors: the spectrum of the antibiotic, the dose, epidermidis resistant strains on skin and there is
the route of administration, pharmacokinetic a risk of transfer of resistance to other patho-
and pharmacodynamic properties and in vivo genic bacteria, Staphylococcus aureus and Strep-
inactivation of the drug [53]. tococcus species [15]. The skin and conjunctivae
Clindamycin administration results in major flora from untreated sites will also be affected
ecological disturbances in intestinal and oro- by transfer of antibiotic [16].
11 pharyngeal microflora: the numbers of entero- In conclusion, antibacterial drugs represent
coccal species increase and those of all anaer- an adjuvant treatment in HS. They are not cura-
obes decrease [39, 51]. A possible complication tive but they reduce odor and discharge, and
of clindamycin treatment is pseudomembra- diminish pain. Antibiotics represent a palliative
nous colitis, which occurs when antibiotics such therapy that may control the disease in early
as clindamycin, ampicillin and third-generation stages and can reduce the inflammation before
cephalosporins suppress the normal flora, al- and after surgery [28] but clinicians should be
lowing Clostridium difficile to grow and produce aware about the downside of taking them.
toxins [40]. Rifampicin treatment was shown to
lead to a decrease in total aerobic and anaerobic
oral bacteria in healthy volunteers [1]. References
The emergence of antimicrobial resistance is
strongly associated with the clinical use of the 1. Appelbaum PC, Spangler SK, Potter CR, et al (1986)
antibiotics and a balanced microflora prevents Reduction of oral flora with rifampin in healthy vol-
establishment of resistant strains of bacteria unteers. Antimicrob Agents Chemother 29:576578
2. Arditi M, Yogev R (1989) In vitro interaction between
[53]. It is well known that oral antibiotics select rifampin and clindamycin against pathogenic co-
for resistant bacteria at all body sites where there agulase-negative staphylococci. Antimicrob Agents
is a normal flora: skin, conjunctivae, oral cavity, Chemother 33:245247
nasopharynx, upper respiratory tract, intestinal 3. Banerjee AK (1992) Surgical treatment of hidradeni-
tract, and vagina [16]. A therapy administered tis suppurativa. Br J Surg 79:863866
for a long period, as was recommended in HS 4. Baron EJ, Curren M, Henderson G, et al (1992) Bi-
treatment [25], will exert a high pressure for the lophila wadsworthia isolates from clinical specimens.
J Clin Microbiol 30:18821884
development of the resistant strains of Propioni-
bacterium acnes, coagulase-negative staphylo-
5. Bendahan J, Paran H, Kolman S, et al (1992) The 24. Highet AS, Warren RE, Weekes AJ (1988) Bacteriol-
possible role of Chlamydia trachomatis in perineal ogy and antibiotic treatment of perineal suppura-
suppurative hidradenitis. Eur J Surg 158:213215 tive hidradenitis. Arch Dermatol 124:10471051
6. Boer J, Weltevreden EF (1996) Hidradenitis suppu- 25. Hindle EAO, Kirby B, Griffiths CEM (2002) Hi-
rativa or acne inversa. A clinicopathological study dradenitis suppurativa and acne keloidalis nuchae
of early lesions. Br J Dermatol 135:721725 treated with clindamycin and rifampicin: a case se-
7. Brenner DE, Lookingbill DP (1980) Anaerobic mi- ries. Br J Dermatol 147:2223
croorganisms in chronic suppurative hidradenitis. 26. Holland KT, Holland DB, Cunliffe WJ, et al (1993)
Lancet 2:921922 Detection of Propionibacterium acnes polypeptides
8. Brook I, Frazier EH (1999) Aerobic and anaerobic which have stimulated an immune response in acne
microbiology of axillary hidradenitis suppurativa. patients but not in normal individuals. Exp Derma-
J Med Microbiol 48:103105 tol 2:1216
9. Brunsting HA (1939) Hidradenitis suppurativa; ab- 27. Jansen I, Altmeyer P, Piewig G (2001) Acne inversa
scess of the apocrine sweat glands. Arch Dermatol (alias hidradenitis suppurativa). J Eur Acad Derma-
Syphilol 39:108120 tol Venereol 15:532540
10. Buckley C, Sarkany I (1989) Urethral fistula and 28. Jansen T, Plewig G (2000) Whats new in acne in-
sinus formation in hidradenitis suppurativa. Clin versa (alias hidradenitis suppurativa)? J Eur Acad
Exp Dermatol 14:158160 Dermatol Venereol 14:342343
11. Burkhart CN, Burkhart CG (2003) Microbiologys 29. Jemec GB, Faber M, Gutschik E, et al (1996) The
principle of biofilms as a major factor in the patho- bacteriology of hidradenitis suppurativa. Derma-
genesis of acne vulgaris. Int J Dermatol 42:925927 tology 193:203206
12. Clemmensen OJ (1983) Topical treatment of hidrad- 30. Jemec GB, Wendelboe P (1998) Topical clindamy-
enitis suppurativa with clindamycin. Int J Dermatol cin versus systemic tetracycline in the treatment
22:325328 of hidradenitis suppurativa. J Am Acad Dermatol
13. Dicken CH, Powell ST, Spear KL (1984) Evaluation 39:971974
of isotretinoin treatment of hidradenitis suppura- 31. Jovanovic M (2004) Hidradenitis suppurativa
tiva. J Am Acad Dermatol 11:500502 http://www.emedicine.com/derm/topic892.htm
14. Dougherty SH (1988) Pathobiology of infection in 32. Kloos W (1986) Ecology of human skin. Almqvist
prosthetic devices. Rev Infect Dis 10:11021117 and Wiksell, Stockholm
15. Dreno B (2004) Topical antibacterial therapy for 33. Lapins J, Jarstrand C, Emtestam L (1999) Coagu-
acne vulgaris. Drugs 64:23892397 lase-negative staphylococci are the most common
16. Eady EA, Holland KT, Cunliffe WJ (1982) The use of bacteria found in cultures from the deep portions
antibiotics in acne therapy: oral or topical adminis- of hidradenitis suppurativa lesions, as obtained by
tration? J Antimicrob Chemother 10:89115 carbon dioxide laser surgery. Br J Dermatol 140:90
17. Editorial (1985) Streptococcus milleri, pathogen in 95
various guises. Lancet 2:14031404 34. Lapins J (2001) Hidradenitis suppurativa with spe-
18. Finegold S, Summanen P, Hunt Gerardo S, et al cial reference to carbon dioxide laser surgery. Aka-
(1992) Clinical importance of Bilophila wadswor- demitryck, Stockholm
thia. Eur J Clin Microbiol Infect Dis 11:10581063 35. Leach RD, Eykyn SJ, Phillips I, et al (1979) Anaero-
19. Goodheart HP (2000) Hidradenitis suppurativa. bic axillary abscess. Br Med J 2:57
Dermatology Rounds 3:535543 36. Molnar C, Hevessy Z, Rozgonyi F, et al (1994)
20. Granato P (2003) Pathogenic and indigenous mi- Pathogenicity and virulence of coagulase negative
croorganisms of humans. In: Murray PR, Baron EJ, staphylococci in relation to adherence, hydropho-
Jorgensen JH, Pfaller MA, Yolken RH (eds) Manual bicity, and toxin production in vitro. J Clin Pathol
of clinical microbiology. ASM, Washington DC 47:743748
21. Hay RJ, Adriaans BM (2004) Bacterial infections. 37. Mowad CM, McGinley KJ, Foglia A, et al (1995)
In: Burns T, Breathnach S, Cox N, Griffiths C (eds) The role of extracellular polysaccharide substance
Rooks textbook of dermatology. Blackwell Science, produced by Staphylococcus epidermidis in miliaria.
Oxford J Am Acad Dermatol 33:729733
22. Hedstrom SA (1982) Recurrent anaerobic skin ab- 38. Noble WC (1990) Factors controlling the microflora
scesses. Scand J Infect Dis 14:241242 of the skin. In: Hill MJ, Marsh PD (eds) Human mi-
23. Highet AS, Warren RE, Staughton RC, et al (1980) crobial ecology. CRC, Boca Raton, Fla.
Streptococcus milleri causing treatable infection in 39. Nord CE, Heimdahl A, Kager L (1986) Antimicro-
perineal hidradenitis suppurativa. Br J Dermatol bial induced alterations of the human oropharyn-
103:375382 geal and intestinal microflora. Scand J Infect Dis
Suppl 49:6472
40. Oldfield EC 3rd (2004) Clostridium difficile-associ- 50. Slade DE, Powell BW, Mortimer PS (2003) Hidra-
ated diarrhea: risk factors, diagnostic methods, and denitis suppurativa: pathogenesis and management.
treatment. Rev Gastroenterol Disord 4:186195 Br J Plast Surg 56:451461
41. OLoughlin S, Woods R, Kirke PN, et al (1988) Hi- 51. Spizek J, Novotna J, Rezanka T (2004) Lincos-
dradenitis suppurativa. Glucose tolerance, clini- amides: chemical structure, biosynthesis, mecha-
cal, microbiologic, and immunologic features and nism of action, resistance, and applications. Adv
HLA frequencies in 27 patients. Arch Dermatol Appl Microbiol 56:121154
124:10431046 52. Spizek J, Rezanka T (2004) Lincomycin, clindamy-
42. Otto M (2004) Virulence factors of the coagulase- cin and their applications. Appl Microbiol Biotech-
negative staphylococci. Front Biosci 9:841863 nol 64:455464
43. Pasquale TR, Tan JS (2005) Nonantimicrobial ef- 53. Sullivan A, Edlund C, Nord CE (2001) Effect of an-
fects of antibacterial agents. Clin Infect Dis 40:127 timicrobial agents on the ecological balance of hu-
135 man microflora. Lancet Infect Dis 1:101114
44. Pawin H, Beylot C, Chivot M, et al (2004) Physio- 54. Till AE, Layton AM, Barth JH (1995) Staphylo-
pathology of acne vulgaris: recent data, new under- coccus lugdunensis isolated from axillary apocrine
standing of the treatments. Eur J Dermatol 14:412 glands of hidradenitis suppurativa patients. J Invest
45. Powell JJ, Dawber RP, Gatter K (1999) Folliculitis Dermatol 104:618
decalvans including tufted folliculitis: clinical, his- 55. Tsankov N, Angelova I (2003) Rifampin in derma-
tological and therapeutic findings. Br J Dermatol tology. Clin Dermatol 21:5055
140:328333 56. Vandenesch F, Eykyn SJ, Ettienne J (1995) Infec-
46. Raad II, Bodey GP (1992) Infectious complications tions caused by newly-described species of coagu-
of indwelling vascular catheters. Clin Infect Dis lase negative staphylococci. Rev Med Microbiol
15:197208 6:94100
47. Roth RR, James WD (1988) Microbial ecology of the 57. von der Werth JM, Williams HC (2000) The natural
skin. Annu Rev Microbiol 42:441464 history of hidradenitis suppurativa. J Eur Acad Der-
48. Sellheyer K, Krahl D (2004) Hidradenitis suppu- matol Venereol 14:389392
rativa is acne inversa! An appeal to (finally) aban-
don a misnomer. Int J Dermatol doi:10.1111/j.1365-
4632.2004.02536.x
49. Shelley WB, Cahn MM (1955) The pathogenesis of
11 hidradenitis suppurativa in man; experimental and
histologic observations. AMA Arch Derm 72:562
565
Chapter 12
Endocrinology
Michel Faure, Evelyne Drapier-Faure
12

Q HS does not generally appear to be In 1986 Mortimer et al. [14] reported that hi-
associated with signs of hyperan- dradenitis suppurativa (HS) responded to treat-
drogenism ment with the potent antiandrogen cyproterone
acetate. They suggested that the disease could
Q Sex hormones may affect the course of be androgen-dependent [8]. This hypothesis
HS indirectly through, for example, was also upheld by occasional reports of women
their effects on inflammation with HS under antiandrogen therapy [18]. Actu-
ally, the androgen dependence of HS (similarly
Q The role of end-organ sensitivity to acne) is only poorly substantiated.
cannot be excluded at the time of
writing
12.2 Hyperandrogenism and the Skin
Q The prevalence of polycystic ovary
syndrome in HS has not been system- Androgen-dependent disorders encompass a
atically investigated broad spectrum of overlapping entities that may
be related in women to the clinical consequenc-
es of the effects of androgens on target tissues
and of associated endocrine and metabolic dys-
functions, when present.
#ONTENTS
12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
12.2.1 Androgenization
12.2 Hyperandrogenism and the Skin. . . . . . . . . 95
12.2.1 Androgenization . . . . . . . . . . . . . . . . . . . . . . . 95
12.2.2 Androgen Metabolism . . . . . . . . . . . . . . . . . .96
One of the less sex-specific effects of androgens
12.2.3 Causes of Hyperandrogenism . . . . . . . . . . .96 is that on the skin and its appendages, and in
particular their action on the pilosebaceous
12.3 Lack of Association between HS
and Endocrinopathies . . . . . . . . . . . . . . . . . .97
unit. Hirsutism is the major symptom of hyper-
androgenism in women. Other dermatological
12.4 HS and Biological Hyperandrogenism . . .97 conditions include acne and the chronic hair
12.5 End-Organ Androgen Sensitivity? . . . . . . .98 loss usually termed androgenic alopecia (AGA).
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98 Whereas acne, hirsutism and chronic hair loss
may coexist in the same patient, it is not unusu-
al to find only one of these androgenic manifes-
tations [16].
Depending on the presence of ovarian dys-
function, extracutaneous manifestations may
include abnormalities of menstruation with
96 Michel Faure, Evelyne Drapier-Faure
anovulatory patterns, oligomenorrhoea, fertili- Sebaceous glands, but also keratinocytes

ty problems, android obesity and risks for from the acroinfundibulum and dermal papilla
metabolic complications, such as hyperinsulin- cells, can synthesize androgens de novo from
ism, insulin resistance, diabetes mellitus, and cholesterol or by locally converting weaker an-
dyslipidaemia, and for cardiovascular diseases drogens (64A and DHEA) to testosterone and
[6, 16]. DHT. As in other classic steroidogenic organs,
the pilosebaceous unit expresses the major en-
zymes involved in androgen metabolism, name-
12.2.2 Androgen Metabolism ly steroid sulfatase, 3`-, 3_- and 17`-hydroxys-
teroid dehydrogenases, and 5_-reductase, which
The causes of hyperandrogenism are multiple converts testosterone into DHT. Furthermore
(Table 12.1). Skin androgenization in women aromatase, which converts testosterone into
may be due to abnormal production of andro- oestradiol, is localized to sebaceous glands and
gens by the ovaries and/or the adrenal glands, to both outer and inner root sheath cells of ana-
and/or to an excessive response of target cells gen terminal hair follicles. This hormone may
in the pilosebaceous unit (peripheral androgen- play a detoxifying role by removing excess an-
ism) [6]. drogens [5].
Androgens [testosterone and the less po-
tent androgens in women 64-androstenedione
(64A) and dehydroepiandrosterone (DHEA)] 12.2.3 Causes of Hyperandrogenism
are synthesized by the adrenals (mostly DHEA
and its sulfate SDHEA) and the ovaries (most- As far as hyperandrogenisms due to an excess of
ly 64A) and may be subsequently transformed androgen production are concerned, tumoral
into oestrogens through the aromatization of causes and Cushings syndrome are rare. The
the molecules. Sex hormone binding globulin most common endocrine disorders are polycys-
(SHBG) synthesized in the liver is the major tic ovary syndrome (PCOS) and non-classic ad-
carrier protein for androgens and oestradiol. renal hyperplasia (NCAH) with 21-hydroxylase
Only free androgens, unbound to SHBG, are di- deficiency. Hyperandrogenism is associated
rectly active on target cells. In tissues, andro- with high levels of circulating androgens and
12 gens are first metabolically transformed into decreased SHBG levels. PCOS also requires mor-
the active form dihydrotestosterone (DHT), phological and ultrasound criteria: an increased
which then binds to androgen receptors (AR) number of subcapsular follicles and stromal
[16]. hyperplasia. Plasma levels of 17-hydroxyproges-
terone (17-HP) are increased in NCAH. If NCAH
is only suspected with moderately increased
Table 12.1. Causes of hyperandrogenism 17-HP, an adrenocorticotropic hormone (ACTH)
test must be performed [1, 6, 7].
1. Polycystic ovary syndrome (PCOS) On the other hand, hyperandrogenic skin
2. Non-classic adrenal hyperplasia changes (idiopathic hirsutism, hypertrichosis
with 21-hydroxylase deficiency in men, most cases of acne, AGA in women but
3. Skin hypersensitivity = also in men) mostly occur in fact in patients
peripheral hyperandrogenism: with normal androgen levels. Increased enzyme
with hirsutism (idiopathic) activities in the peripheral metabolism of ste-
and/or acne or androgenic alopecia
roids, and/or increased sensitivity of AR, both
4. Drugs presumed to be subjected to genetic polymor-
androgenic progestins
phisms, might account for abnormal responses
OP contraception with androgenic progestins
to androgens. The first possibility in patients
5. Others (rare): with androgen-dependent skin manifestations
adrenal and ovarian tumours
Cushings syndrome
corresponds to increased metabolic pathways
that lead to the transformation of weaker an-
Endocrinology Chapter 12 97
drogens to testosterone, increased 5_ reduction lapse after pregnancy, as well as premenstrual

to DHT and lower aromatase activity [16]. and menstrual exacerbations are usually noted,
The second possibility (the two not being suggesting that hormones, at least oestrogens,
mutually exclusive) is directly linked to AR sen- may influence the course of the disease. Oestro-
sitivity. AR is a structurally conserved member gens in fact are known to interfere with inflam-
of the nuclear receptor superfamily. The amino- matory processes, independently of a direct ge-
terminal domain is required for transcriptional nomic action of the steroids. This could account
activation and contains a region of polygluta- for their influence on the natural course of in-
mine encoded by CAG trinucleotide repeats. In flammatory diseases, such as acne, but also HS.
humans the number of CAG repeats is polymor- Other observations in HS in terms of premen-
phic. Longer repeat lengths are associated with strual and/or menstrual exacerbations may be
androgen-insensitivity syndromes. It has been unrelated to the oestrogen or androgen depen-
suggested that AR polymorphisms (CAG-repeat dency of the disease.
lengths) account for AGA, hirsutism and acne, Although HS may be associated in some
since shorter repeat lengths may be associated women with classic signs of skin androgeniza-
with the development of androgen-mediated tion such as acne and/or hirsutism, no real as-
skin disorders in men and women [17]. sociation of HS with hirsutism (the major symp-
tom of hyperandrogenism) has ever been
reported. In a series of 70 women with HS, acne
12.3 Lack of Association between HS was not more frequent than in controls [10]. The
and Endocrinopathies incidence of patients with signs of androgeniza-
tion did not differ significantly between the two
Although HS has been reported in two men groups. Only a shorter menstrual cycle and a
with acromegaly [4], which is very likely due to longer duration of menses in patients with HS
a direct effect not of androgens but of growth were noted. Although there was no evidence in
hormone on apocrine glands, HS was not found favour of or against an association with PCOS
to be associated with endocrine disorders. or with NCAH, these data indicate that HS is
In women HS has not been reported in asso- not accompanied by the usual clinical signs of
ciation with ovarian or adrenal tumours, Cush- androgenization.
ing syndrome, PCOS or NCAH, all known
causes of hyperandrogenism with increased or
abnormal androgen production. In fact, a pos- 12.4 HS and Biological
sible association of HS with functional hyperan- Hyperandrogenism
drogenism (ovarian or adrenal dysfunction)
merits investigation with modern biological and Furthermore, as far as serum levels of andro-
ultrasound markers [7]. gens and SHBG are concerned, there is no clear
HS usually begins after puberty when the evidence for biochemical hyperandrogenism.
apocrine glands are fully developed. A few cases On average, androgen levels (total plasma tes-
have been reported in children, as clinical man- tosterone and free testosterone index due to a
ifestations of premature adrenarche or early pu- low SHBG) were increased, but were normal in
berty [11, 12, 15]. This represents in fact the many individual patients, and no significant de-
strongest evidence for an influence of andro- crease of SHBG could be detected [13]. In fact,
gens on HS. However, HS is more common in SHBG is known to be regulated by factors that
women and usually affects premenopausal influence body weight and this study was not
women, although it may appear after meno- controlled for body weight, and neither was a
pause [3]. The rare incidence of HS in post- second one which found hyperandrogenism in a
menopausal women does not stand in favour of subgroup of women who did not experience a
a role for androgens, since hyperandrogenism premenstrual flare in their disease [9]. In a fur-
after the menopause has yet to be demonstrated. ther group of 66 women with HS, among which
On the other hand, improvement during and re- 23 had acne, 23 were significantly obese and 19
98 Michel Faure, Evelyne Drapier-Faure
were hirsute; testosterone and DHEAS were cal skin hyperandrogenism in women with HS.
normal in all subjects [3]. In obese subjects, On the other hand, a genetic polymorphism in
SHBG was reduced, consistent with body-mass- enzyme activities at the epithelial cell level re-
index-matched controls. No evidence for bio- mains to be demonstrated. Finally, in the
chemical hyperandrogenism could be found in absence of precise investigations, based upon
women with HS when compared with controls biological markers (testosterone, 64A, 17-OHP,
matched for age, weight, and hirsuteness [3]. SHBG levels, free testosterone index) and ovar-
ian echography [1, 7], the possibility that some
women with HS suffer from PCOS or NCAH
12.5 End-Organ Androgen cannot be excluded.
Sensitivity?
All the above data suggest that the main mecha- References
nism for the possible role of sex hormones in HS
lies in end-organ sensitivity rather than in the 1. Azziz R, Hincapie LA, Knochenhauer ES, Dewail-
plasma levels. Women can develop HS while ly D, Fox L, Boots LR (1999) Screening for 21-hy-
taking oral contraceptives especially when an- droxylase-deficient non-classic adrenal hyperpla-
sia among hyperandrogenic women: a prospective
drogenic progestins are used, and this also sug- study. Fertil Steril 72:91525
gests, as in acne, a possible androgen depen- 2. Barth JH, Kealey T (1991) Androgen metabolism by
dence of the disease [19]. In acne, not only isolated human axillary apocrine glands in hidrad-
sebocytes but also other epithelial cells are in- enitis suppurativa. Br J Dermatol 125:3048
volved in the skin hyperandrogenism that is 3. Barth JH, Layton AM, Cunliffe WJ (1996) Endocrine
responsible for the formation of the comedo. factors in pre- and postmenopausal women with hi-
Keratinocytes from the acroinfundibulum ex- dradenitis suppurativa. Br J Dermatol 134:10579
4. Chalmers RJ, Ead RD, Beck MH (1983) Acne vul-
press the key enzymes involved in the in situ garis and hidradenitis suppurativa as presenting
metabolism of androgens (in situ synthesis of features of acromegaly. Br Med J 287:13467
the weaker androgens, their transformation into 5. Chen WC, Thiboutot D, Zouboulis C (2002) Cutane-
testosterone and its reduction into DHT) [5]. In- ous androgen metabolism: basic research and clini-
vestigation for the activity of these enzymes in cal perspectives. J Invest Dermatol 119:9921007
12 the epithelial cells that are presumed to be in- 6. Cortet-Rudelli C, Dewailly D (2004) Hyperan-
volved in the first stage, i.e. follicular occlusion, drogenism in adolescent girls. In: Sultan C (ed)
Pediatric and adolescent gynecology. Karger, Basel,
of HS remains to be conducted. pp 14862
However, androgen metabolism has been in- 7. Dewailly D, Robert Y, Helin I, Ardaens Y, Thom-
vestigated in normal human apocrine glands as-Desrousseaux P, Lemaitre L, Fossati P (1994)
and in those isolated from age-matched patients Ovarian stromal hypertrophy in hyperandrogenic
with HS [2]. No increased activity of 3`-hy- women. Clin Endocrinol 41:55762
droxysteroid dehydrogenase, 64-5 isomerase, or 8. Ebling FJG (1986) Hidradenitis suppurativa: an
17 `-hydroxysteroid dehydrogenase was found androgen-dependent disorder. Br J Dermatol 115:
25962
and 5_-reductase activity was similar. These re-
9. Harrison BJ, Read GF, Hughes LE (1988) Endocrine
sults suggest that HS cannot be attributed to ex- basis for the clinical presentation of hidradenitis
aggerated activities of androgen-interconvert- suppurativa. Br J Surg 75:9725
ing enzymes within apocrine gland cells. 10. Jemec GBE (1988) The symptomatology of hidrade-
These data should not be interpreted as re- nitis suppurativa in women. Br J Dermatol 119:345
flecting a lack of apocrine sensitivity to andro- 50
gens, since they relate to the quantity of active 11. Lewis F, Messenger AG, Wales JKF (1993) Hidrad-
enitis suppurativa as a presenting feature of prema-
metabolite (DHT) and not to the androgen re-
ture adrenarche. Br J Dermatol 129-: 447-8
sponse at the receptor level. It cannot be exclud- 12. Mengesha YM, Holcombe TC, Hansen RC (1999)
ed that there is increased sensitivity of cellular Prepubertal hidradenitis suppurativa: two case re-
AR, due to genetic polymorphism of the recep- ports and review of the literature. Pediatr Dermatol
tor, that might account for the as yet hypotheti- 16:2926
Endocrinology Chapter 12 99
13. Mortimer PS, Dawber RPR, Gales MA, Moore RA 17. Saawaya ME, Shalita AR (1998) Androgen receptor
(1986) Mediation of hidradenitis suppurativa by an- polymorphisms (CAG repeat lengths) in andro-
drogens. Br Med J 292:2458 genic alopecia, hirsutism and acne. J Cut Med Surg
14. Mortimer PS, Dawber RPR, Gales MA, Moore RA 3:915
(1986) A double-blind controlled cross-over trial 18. Sawers RS, Randall VA, Ebling FJB (1986) Control
of cyproterone acetate in females with hidradenitis of hidradenitis suppurativa in women using com-
suppurativa. Br J Dermatol 115:2638 bined anti-androgen (cyproterone acetate) and oes-
15. Palmer RA, Keefe M (2001) Early-onset of hidrad- trogen therapy. Br J Dermatol 115:26974
enitis suppurativa. Clin Exp Dermatol 26:5013 19. Stellon AJ, Wakeling M (1989) Hidradenitis suppu-
16. Redmond GP (1995) Androgenic disorders of wom- rativa associated with the use of oral contraceptive.
en: diagnostic and therapeutic decision making. Br Med J 298:289
Am J Med 98:1A120SA129S
Chapter 13
Immunity
Istvn Nagy, Lajos Kemny
13
13.4 Members of the TLR Family Expressed

Key points by Keratinocytes . . . . . . . . . . . . . . . . . . . . . . 102
Q The epidermis has a powerful innate 13.5 IL-1 Receptors in the Skin . . . . . . . . . . . . . .104
immune system 13.6 Signaling Pathways via TLR/IL-1R . . . . . .104
13.6.1 MyD88-Dependent Signaling Pathway . .104
Q Keratinocytes are immunologically 13.6.2 MyD88-Independent Signaling Pathway 105
active cells, able to identify and kill 13.7 Keratinocyte-Derived Effector
invading microbes by recognizing Molecules in the Innate Immune System
highly conserved structures of the of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . .105
pathogens (pathogen-associated 13.8 Antimicrobial Peptides . . . . . . . . . . . . . . . .105
molecular patterns; PAMPs) 13.9 B-Defensins. . . . . . . . . . . . . . . . . . . . . . . . . . .106
13.10 Cathelicidins . . . . . . . . . . . . . . . . . . . . . . . . .106
Q They activate pattern recognition
receptors (PRRs) resulting in 13.11 RNase7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
the secretion of antimicrobial 13.12 Antileukoprotease (ALP). . . . . . . . . . . . . . . 107
and pro-inflammatory mediators 13.13 Pro-Inflammatory Chemokines . . . . . . . . 107
13.14 Pro-Inflammatory Cytokines . . . . . . . . . . .108
Q Antimicrobial peptides, effector
molecules of innate immunity, also act 13.15 TLR Recognition and the Commensal
as regulators of acquired immune Microbiota of the Skin . . . . . . . . . . . . . . . . .109
13 responses, inflammation and wound 13.16 Skin Infections and Innate Immune
repair Responses of the Epidermis . . . . . . . . . . . . 110
13.17 Hidradenitis Suppurativa
Q Secondary bacterial colonization of HS and the Skin Immune System . . . . . . . . . . . 110
can intensify chronic inflammation 13.18 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . 112
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Q PRR expression in the epidermis may
play a role in host defense of the skin
and in chronic inflammation
13.1 Introduction
Mild cases of hidradenitis suppurativa (HS) are

#ONTENTS characterized as recurrent isolated nodules,
while severe cases of the disease with chronic
13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .100 inflammation may lead to scarring, functional
13.2 Ancient and Modern: Innate impairment, and squamous cell carcinoma. The
and Acquired Immunity . . . . . . . . . . . . . . . 101 disease arises most commonly in any skin bear-
13.3 TLR/IL-1R Superfamily ing apocrine glands and it has recently become
and their Signaling Pathways in the Skin 102 regarded as a disorder of the follicular epitheli-
Immunity Chapter 13 101
um, with follicular occlusion giving rise to clin- ceptors (PRRs), antimicrobial peptides and pro-
ical findings. Follicular hyperkeratosis is the inflammatory cytokines/chemokines in innate
initial event, leading to occlusion followed and acquired immune responses of the skin.
by dilatation and follicular rupture, spilling
contents, including keratin and bacteria, into
the surrounding dermis with resultant second- 13.2 Ancient and Modern:
ary infection. These events induce a vigorous Innate and Acquired Immunity
chemotactic response with an inflammatory
cellular infiltrate consisting of neutrophils, Innate immunity is the most ancient and com-
lymphocytes, and histiocytes. Abscess forma- mon system for defense against microbial infec-
tion develops leading to the destruction of tions. It evolved a detection system, a limited set
the pilosebaceous unit. HS and acne vulgaris of receptors (e.g., Toll-like receptors; TLRs)
together with pilonidal sinus and dissecting against microbial signatures that remain invari-
cellulitis all share follicular occlusion as an ini- ant inside a class of microbes [33]. Given that
tial event leading to disease development. Fur- epithelial cells lie at the interface between the
thermore, bacterial colonization can increase host and the environment, the expression of
the severity of chronic inflammation both in HS TLRs on these cells provides the first line of
and acne vulgaris. defense against invading pathogens through the
In healthy individuals as well as in mild cases recognition of microbial motifs. Although
of HS, the deeper layers of the skin remain free termed PAMPs, these motifs are not restricted
of infection, although it is constantly exposed to to distinct pathogens since they include struc-
injuries and challenged by environmental mi- tural molecules such as lipopolysaccharide
croorganisms. This suggests that skin itself has (LPS), lipoteichoic acid (LTA), peptidoglycan
the ability to fight against invading microbes. (PGN), lipoarabinomannan (LAM), flagellin,
This chapter will summarize recent findings zymosan or double-stranded (ds) RNA (Table
concerning the role of pattern recognition re- 13.1), which are common to multiple species of
Table 13.1. Toll-like receptors (TLRs) expressed by keratinocytes and their ligands
Receptor Ligand Origin of ligand
TLR1 Triacyl lipopeptides Bacteria and mycobacteria
TLR2 Lipoproteins and lipopeptides Various pathogens

Phenol-soluble modulin Staphylococcus epidermidis
Lipoarabinomannan Mycobacteria
Lipoteichoic acid Gram-positive bacteria
Atypical lipopolysaccharide Leptospira interrogans and Porphyromonas gingivalis
Zymosan Fungi
Heat-shock protein 70 Host
TLR3 Double-stranded RNA Viruses
TLR4 Lipopolysaccharide Gram-negative bacteria
Heat-shock protein 70 Host
TLR5 Diacyl lipopeptides Mycoplasma
TLR6 Lipoteichoic acid Gram-positive bacteria
Zymosan Fungi
TLR9 CpG-containing DNA Bacteria and viruses
102 Istvn Nagy, Lajos Kemny
bacteria, yeast or viruses, respectively. In addi- 13.3 TLR/IL-1R Superfamily and their
tion, a number of endogenous ligands, such as Signaling Pathways in the Skin
heat shock proteins or `-defensins, are also TLR
ligands (Table 13.1). These endogenous mole- TLR/IL-1R superfamily members are character-
cules are also called danger signals released ized by the presence of a variable extracellular
from dying or dead cells in order to trigger an domain devoted to specific ligand recognition,
inflammatory response [33]. and a highly conserved intracellular Toll-inter-
The innate immune network of the skin con- leukin-1 (IL-1) receptor (TIR) domain that me-
sists of a range of pre-existing, rapidly mobi- diates signal transduction (Fig. 13.1).
lized host defense components including kerati-
nocytes, neutrophils, mast cells, eosinophils,
macrophages, and sebocytes. The key cellular 13.4 Members of the TLR Family
components of the pathophysiologic processes Expressed by Keratinocytes
of the skin are the keratinocytes, cells that are in
a unique position between the interface of the Since Gram-positive skin-infecting bacteria
environment and the host organism [61]. The such as Staphylococcus aureus (S. aureus) or
findings that keratinocytes, which form 95% Borrelia burgdorferi (B. burgdorferi) are known
of all epidermal cells, express TLRs and are a to be rich sources of LTA and lipoproteins,
potent source of antimicrobial and antiviral which are well-known ligands of TLR2 homodi-
peptides and cytokines/chemokines emphasize mers (Table 13.1), the abundant and constitutive
their key role in the innate immune responses of expression of TLR2 in the epidermis is not sur-
the skin [5, 6]. Epidermal keratinocytes express, prising [36, 49, 59]. TLR2 homodimers are also
in a constitutive or inducible manner, at least 7 involved in the recognition of lipoarabino-
out of 11 known TLRs (TLR1-TLR6 and TLR9) mannan of mycobacteria and atypical lipopoly-
[4, 36, 49, 59, 66]. Recognition of PAMPs by saccharides of Leptospira and Porphyromonas
TLRs initiates quick innate immune responses species [68]. TLR2 also forms heterodimer com-
such as phagocytosis, and the production of an- plexes with other members of the TLR family,
timicrobial compounds and inflammatory me- namely with TLR1 and TLR6 [49]. These com-
diators resulting in the killing and elimination plexes are characterized by different ligand
of microorganisms. In addition, these media- specificity, thus recognition of microorganisms
tors link innate and adaptive immunity, as they through different complexes gives specificity to
13 also function as chemoattractants for the effec- the immune response. The TLR2/TLR6 het-
tor cells of the acquired immune response [61]. erodimer is necessary for the recognition of dia-
A rapid innate immune response in the cyl lipopeptide, a common cell wall compound
skin results in cutaneous inflammation, lead- of all Gram-positive bacteria, but it is also in-
ing to extravasation and the homing of cutane- volved in the recognition of PAMPs of fungal
ous lymphocyte-associated, antigen-expressing pathogens (Table 13.1). In contrast, TLR2/TLR1
(CLA+) memory T cells to the skin, permitting heterodimers recognize tripalmitoylated lipo-
them to encounter and respond to appropriately peptides (Table 13.1) [76].
presented antigen in the skin. The ability of T TLR3 has recently been demonstrated to pro-
and also B cells to recombine antigen receptor vide a mechanism by which dsRNA species acti-
genes during development provides an efficient vate the innate immune response (Table 13.1).
and powerful acquired immune system with Signaling through TLR3 leads to the expression
nearly unlimited specificity for antigen. Al- of high levels of interferon-gamma-(IFNa) and
though a fundamental aspect of mammalian type-1-(Th1-) associated chemokines in a vari-
biology, immunologic memory is a relatively ety of cell types, suggesting that it has a key role
recent evolutionary event. in innate immune responses against viral infec-
tions [70].
Fig. 13.1. Signal transduction pathways via TLR/IL1R. way, through the IKK complex. Signal transduction via
The TLR signaling pathway is highly homologous to TLRs and/or IL1Rs leads to the expression of antimicro-
that of the IL-1R family. After binding of an appropri- bial and antiviral peptides, cytokines and chemokines.
ate ligand, both TLRs and IL-1R interact with an adap- [IKK IgB kinase kinase, IRAK IL-1R-asssociated kinase,
tor protein, MyD88, through their TIR (Toll/IL-1R) JNK c-Jun N-terminal kinase, MyD88 myeloid differen-
domains. Upon signaling, MyD88 recruits a serine/ tiation primary-response protein, NF-gB nuclear factor
threonine kinase, IRAK. IRAK is activated by phos- kappa B, TAK1 growth factor-`-activated kinase 1, TIRAP
phorylation and then associates with TRAF6, another TIR- (TLR-IL1-R1-) associated protein, TNF tumor ne-
adaptor protein, leading to activation of either the JNK crosis factor, TRAF6 TNF-receptor-associated factor,
pathway, through MAP kinase, or the NF-gB path- TRIF Toll-receptor-associated activator of interferon]
The expression level of TLR4 by keratino- first binds to CD14, which then interacts with
cytes depends on the anatomical location [49]. TLR4 and initiates intracellular signal trans-
Moreover, the expression of TLR4 (together duction. MD-2 is a protein that associates with
with that of TLR2) correlates with the state of the extracellular domain of TLR4 and enhances
differentiation of keratinocytes [60]. Interest- LPS responsiveness (Table 13.1, Fig. 13.1) [65].
ingly, the level of expression may also show in- TLR5 recognizes the bacterial motor protein
ter-individual differences or may be inducible flagellin (Table 13.1) required for the motility of
by mechanical injury or inflammation [59]. The microorganisms such as B. burgdorferi, which
recognition of Gram-negative bacteria-derived causes migratory erythema during the course of
LPS requires at least two cofactor proteins in Lyme disease, and Salmonella typhi, which
addition to TLR4. During LPS signaling, LPS causes cutaneous ulceration [46]. Keratinocytes
are able to upregulate their chemokine expres- Table 13.2. Gene polymorphisms in the second intron of
sion in response to B. burgdorferi, indicating the IL-1 receptor antagonist (IL1RN)
that TLR5 is functional on keratinocytes and Gene Allele No. of Characteristics
enables them to respond to invading flagellated repeatsa
bacteria [16].
IL1RN*1 1 4 Most common allele
TLR9 senses unmethylated bacterial CpG
DNA derived from many classes of bacteria IL1RN*2 2 2 Associated
with prolonged
during infection (Table 13.1). Its expression in
inflammation
the epidermis is inducible by either microbial
compounds or physical trauma [12, 45]. Unlike IL1RN*3 3 3 Rare
TLR1-TLR6, TLR9 is not expressed on the cell IL1RN*4 4 5 Rare
surface but in the endoplasmic reticulum [2]. IL1RN*5 5 6 Rare
a
Copies of the 86-base repeats
13.5 IL-1 Receptors in the Skin
IL-1 receptor type 1 (IL-1R1) can bind both mation, such as inflammatory bowel diseases,
IL-1_ and IL-1` resulting in the initialization of alopecia areata, psoriasis, lichen sclerosus or
MyD88-dependent signaling (see below and lupus erythematosus, IL1RN*2 homozygosity
Fig. 13.1). The receptor, expressed on the surface increases the severity of the inflammation, sug-
of a variety of cells, mediates all known biologic gesting that persons with this allele have a more
activities of IL-1 by initializing a cascade of prolonged and more severe proinflammatory
events leading to the recruitment and activation immune response than do persons with other
of macrophages and neutrophils, vascular dila- IL-1RA genotypes [73]. Interestingly, the fre-
tion, fever and a proinflammatory immune re- quency of the two-repeat allele of IL-1RN is
sponse. The central role of the IL-1 system is increased among patients with acne conglobata
protection against microbial colonization and but not among those with HS. In addition,
infection [53]. IL1RN*2 homozygosity was detected only
The second receptor for IL-1, IL-1R2, also amongst patients with severe acne conglobata,
binds both IL-1_ and IL-1`. By binding the suggesting that allele 2 of the IL-1RN gene may
functional ligands for IL-1R1, IL-1R2 serves to contribute to the development of acne conglo-
13 inhibit IL-1-mediated inflammatory responses bata but not HS [38].
[53].
IL-1 receptor antagonist (IL-1RA), the natu-
rally occurring competitive inhibitor of IL-1 13.6 Signaling Pathways
bioactivity, can bind only to IL-1R1 and not via TLR/IL-1R
IL1R2. However, it does not induce signaling
but reduces the IL-1-mediated inflammatory 13.6.1 MyD88-Dependent
response. The IL-1RA gene is polymorphic, Signaling Pathway
resulting in quantitative differences in both
IL-1RA and IL-1` production. A tandem repeat Binding of specific ligand/s to TLRs initiates a
sequence of 86 base pairs exists in the second signaling cascade mediated by the cytoplasmic
intron of the IL-1RA gene. In different individ- TIR domain (Fig. 13.1). Due to the structural
uals, the number of times this sequence is re- homology between the intracellular domains of
peated varies from two to six (Table 13.2). The TLRs and IL-1R, the TLR signaling pathway is
frequency of the individual alleles varies among highly homologous to that of the IL-1R family.
different ethnic or geographic populations, with Both TLRs and IL-1Rs interact with an adaptor
the most frequent combinations being IL1RN*1 protein MyD88, through their TIR domains
homozygotes or IL1RN*1/IL1RN*2 hetero- (Fig. 13.1). Upon stimulation, MyD88 recruits
zygotes [73]. In patients with chronic inflam- the IL-1R-asssociated kinase (IRAK), which as-
sociates with tumor necrosis factor (TNF) re- 13.7 Keratinocyte-Derived Effector
ceptor-associated factor 6 (TRAF6), leading to Molecules in the Innate
the activation of at least two distinct signaling Immune System of the Skin
pathways, JNK and NF-gB. TLR signaling
through MyD88 leads to the phosphorylation Human skin is exposed to a wide variety of
and degradation of IgB, the regulator protein of pathogenic microorganisms. Despite these mi-
NF-gB, an event allowing the nuclear transloca- crobial threats, skin is highly resistant against
tion of NF-gB (Fig. 13.1). In the nucleus NF-gB infections. TLR-mediated signaling upon chal-
binds to the promoter region of genes of proin- lenge with microbes and/or microbial-derived
flammatory cytokines/chemokines, antimicro- compounds induces a chemical cutaneous de-
bial peptides, inducible enzymes, and adhesion fense system based on the production of antimi-
molecules, which are important effectors or me- crobial peptides and pro-inflammatory cyto-
diators of innate and adaptive immune respons- kines/chemokines. These keratinocyte-derived
es [50, 81]. soluble factors are fundamental in the elimina-
In keratinocytes, various microbial com- tion of invaders and recruitment of T cells and
pounds induce a rapid TLR-dependent intracel- neutrophils into the sites of skin infection.
lular Ca2+ response. In addition, keratinocytes
respond to the challenge with S. aureus or Can-
dida albicans (C. albicans) with TLR2-MyD88- 13.8 Antimicrobial Peptides
NF-gB-dependent induction of inducible nitric
oxide synthase (iNOS), supporting the key role Activation of TLRs, expressed by epidermal ke-
of the TLR-MyD88-NF-gB pathway in innate ratinocytes, is directly involved in the induction
immune functions of the skin [49, 59]. of antimicrobial peptides [21, 55]. This diverse
family of small, mostly cationic polypeptides
exerts a broad spectrum of cytotoxic activity
13.6.2 MyD88-Independent against bacteria, fungi, parasites, and enveloped
Signaling Pathway viruses. During the inflammatory processes of
the skin, keratinocytes are the main cellular
In addition to their common activation of the sources of antimicrobial peptides and their ex-
MyD88-IRAK-TRAF pathway, individual TLRs pression levels correlate with the susceptibility
may activate different, alternative, signaling of the skin to infections. The local accumula-
pathways. These MyD88-independent pathways tion of antimicrobial proteins offers a fast and
involve the activation of interferon-regulatory very efficient way to prevent microbes from es-
factor-3 (IRF-3) and are utilized by several TLRs tablishing an infection. Expression of antimi-
such as TLR3 and TLR4/4 (Fig. 13.1). TLR sig- crobial peptides is induced upon encounter with
naling pathways are therefore not identical and pathogens and during wound healing [17, 26,
the specificity of some pathways may determine 44]. Activation of antimicrobial genes by PAMPs
the pattern of gene expression, which accounts can be further increased by proinflammatory
for the distinguishable biologic responses ob- cytokines produced at sites of inflammation by
served following the activation of specific TLRs either keratinocytes or other cell types [17, 26,
by different classes of pathogens [69]. These spe- 28, 29, 44, 64]. Most keratinocyte-derived anti-
cific responses may be particularly important in microbial peptides belong to defensin, cathelici-
the epidermis, which is constantly colonized by din or RNase gene families and are able to kill
numerous microorganisms that do not induce or inactivate a wide spectrum of microorgan-
immune response. isms mainly by forming pores and permeabiliz-
ing microbial membranes.
13.9 B-Defensins a TLR4-dependent manner [7]. In vivo, the se-

cretion of hBD-2 by keratinocytes activates
The expression of human `-defensin-1 (hBD-1), dendritic cells, inducing their migration from
the first isolated human `-defensin, is constitu- the skin into local lymphoid organs, leading to
tive in epidermal keratinocytes and shows anti- the generation of the cellular immune response
microbial activity against predominantly Gram- through the activation of antigen-specific T
negative bacteria such as Escherichia coli (E. cells [39]. Thus, hBD-2 plays multiple roles in
coli) and Pseudomonas aeruginosa (P. aerugino- cutaneous host defense: (1) it provides the first
sa) [3, 20]. The constitutive expression of hBD-1 line of defense against infection by acting as a
in the suprabasal layers of the epidermis sug- natural antibiotic against sensitive pathogens;
gests that it contributes to the innate resistance and (2) it plays a key role in the initiation of
of the skin to Gram-negative infections. adaptive immune responses against infections
The second human `-defensin, hBD-2, was by directing the migration of dendritic cells
originally isolated from the desquamated scales and/or T cells and inducing DC maturation.
of psoriatic skin [26]. Several data suggest a Taken together, hBD-2 provides a link between
complex role for hBD-2 in cutaneous host de- the innate and adaptive immune responses dur-
fense. It has a microbicidal effect against various ing skin infections.
microorganisms, such as E. coli and P. aerugi- hBD-3 has been cloned from keratinocytes
nosa, S. aureus or Streptococcus pyogenes (St. and it shows a broad spectrum of antimicrobial
pyogenes) [64], but also acts as a chemoattrac- activity against Gram-negative and Gram-
tant for immature dendritic cells and neutro- positive bacteria including multi-resistant bac-
phils, and induces the migration of memory T teria. Its expression in keratinocytes is induced
cells. The expression of hBD-2 in vivo is local- by PAMPs, inflammatory mediators such as
ized to the upper layer of the epidermis and the TNF-_, IL-1`, IFN-a, and by the state of differ-
stratum corneum. hBD-2 was also found in the entiation [27, 28].
intercellular space indicating that the lipid per- Similarly to hBD-2 and -3, the production of
meability barrier of the skin contains antimi- hBD-4 in keratinocytes is inducible by inflam-
crobial substances [57]. In correlation with the matory stimuli, PAMPs or differentiation [28].
localization of hBD-2 in the more differentiated Synthetic hBD-4 revealed antimicrobial activity
suprabasal layers of epidermis, differentiation- against P. aeruginosa and Staphylococcus carno-
regulated expression of hBD-2 was also demon- sus, implicating a role for this peptide in the
13 strated in primary keratinocytes [3, 44]. Fur- innate epidermal defense against bacterial in-
thermore, the abundant expression of hBD-2 in fections.
inflamed and in infected skin parallels with the
finding that its expression is induced by Gram-
positive (E. coli, P. aeruginosa and Propionibac- 13.10 Cathelicidins
terium acnes) and Gram-negative (S. aureus or
St. pyogenes) bacteria and also by C. albicans in LL-37 (CAP18), the only human antimicrobial
cultured keratinocytes and in reconstructed hu- peptide that has been identified in the cathelici-
man epidermis [9, 11, 13, 26, 28, 54]. din gene family, is produced in neutrophils and
hBD-2 binds specifically to CC chemokine also induced in keratinocytes during inflam-
receptor 6 (CCR6) and mediates the chemotaxis matory skin disorders [17, 43]. In vivo, LL-37
of CCR6+ cells such as dendritic cells and T provides protection against necrotic skin infec-
lymphocytes, which have an important role in tion caused by group A streptococci and it also
the adaptive immune response against patho- exerts antimicrobial activity against a wide va-
gens [77, 80]. The chemotactic activity of hBD-2 riety of Gram-positive and Gram-negative bac-
for immature dendritic cells and memory T teria [52]. Similar to defensins, LL-37 plays mul-
cells, however, requires much lower concentra- tiple roles in the fight against pathogens: in
tions than its antimicrobial activity [44]. hBD-2 addition to its antibiotic effect, it has the poten-
also induces the maturation of dendritic cells in tial to recruit mast cells, neutrophils, mono-
cytes, and T cells to inflammation foci, and it is Skin-pathogenic microorganisms such as S.

involved in the re-epithelialization of skin aureus, B. burgdorferi or C. albicans together
wounds [14, 29, 56]. with several PAMPs (e.g., LPS or PGN) induce
the abundant expression of IL-8 [a chemokine
now referred to as CXC chemokine ligand 8
13.11 RNase7 (CXCL8)] in a TLR-NF-gB-pathway-dependent
manner [15, 47, 49, 59, 75]. Pathogen-induced
RNase7 exhibits high antimicrobial activity secretion of keratinocyte-derived IL-8 initiates
against several potentially pathogenic Gram- neutrophil chemoattraction and transendothe-
positive bacteria such as S. aureus and Propioni- lial migration. In addition, IL-8 is selectively
bacterium acnes (P. acnes), Gram-negative bac- involved in the transendothelial migration of
teria such as P. aeruginosa and E. coli and yeast CLA+ T cells, emphasizing the role of IL-8 in the
C. albicans [25]. Detection of RNase7 gene and homing of specific T cells to inflamed skin
protein expression in primary keratinocytes, to- (Fig. 13.2). In addition to IL-8, pathogens and
gether with its high abundance in the stratum microbial products, such as heat-killed S. aureus
corneum and its broad antimicrobial activity and staphylococcal PGN, stimulate the expres-
stress the role RNase7 plays in cutaneous innate sion of other chemokines in keratinocytes, such
immunity. as RANTES/CCL5 (regulated on activation,
normal T expressed and secreted, RANTES) or
MCP-1/CCL2 (monocyte chemoattractant pro-
13.12 Antileukoprotease (ALP) tein-1) [47]. RANTES-expressing keratinocytes
were detected in the lesional skin of patients
Antileukoprotease, a serine protease inhibitor with atopic dermatitis and psoriasis, implying a
isolated from the stratum corneum, has anti- role for RANTES in skin inflammation, possi-
protease activity and exhibits high antimicro- bly through the recruitment of distinct leuko-
bial activity against a broad range of skin-asso- cyte subsets [19, 24, 63]. MCP-1/CCL2 displays
ciated microorganisms such as P. aeruginosa, S. chemotactic activity to blood monocytes, mem-
aureus, Staphylococcus epidermidis (S. epider- ory T helper cells, and eosinophils but not to
midis), and C. albicans [72]. Its constitutive ex- neutrophils [23, 24].
pression in keratinocytes indicates that ALP Chemokines also exert in vitro antimicrobial
actively participates in mechanisms allowing properties against a wide variety of microorgan-
the homeostasis of bacterial and yeast coloniza- isms [30, 78]. Under physiological conditions
tion on human skin. 20 out of 45 known human chemokines func-
tion as potent antimicrobial factors, providing
evidence for the close functional and evolution-
13.13 Pro-Inflammatory Chemokines ary relationships between chemokines and anti-
microbial peptides [30, 78, 79]. After challenge
Chemokines, a superfamily of chemotactic pro- with microbial constituents or inflammatory
teins induced by contact with pathogens, regu- signals, many of these antimicrobial chemo-
late the recruitment of various classes of phago- kines are expressed by epidermal keratinocytes
cytic cells, T cells and eosinophils into sites of (e.g., CCL18, CCL19, CCL20, CCL25, CXCL1,
infection. Keratinocyte-derived chemokines CXCL10), suggesting that keratinocyte-derived
regulate the migration of leukocytes and neu- chemokines are involved not only in the recruit-
trophils from peripheral blood vessels into in- ment of professional immune cells to the sites of
flamed skin, in a sequence of tightly controlled infection but in the direct killing of pathogens
events involving the activation of vessel endo- as well. Still further functional studies are need-
thelium, transendothelial migration and che- ed to elucidate the exact role chemokines play in
motaxis [31, 32]. the elimination of skin-infecting pathogens.
Fig. 13.2. Possible function/s of keratinocytes in hi- mature dendritic cells through interaction with CCR6.
dradenitis suppurativa (HS). Follicular hyperkeratosis is Additionally, antimicrobial peptides activate immature
the initial event of HS, leading to the spilling of keratin DCs through TLR4, which leads to the initialization
and bacteria into the surrounding dermis with resultant of acquired immune responses. Keratinocyte-derived
secondary infection. Attaching bacteria activate the pro- IL-8 and pro-inflammatory cytokines activate endothe-
duction of antimicrobial peptides (e.g., hBD-2) and/or lial cells allowing the transepithelial migration of neu-
pro-inflammatory cytokines/chemokines (IL-1_, IL-1`, trophils. Extravasated neutrophils follow a chemotactic
IL-8, IL-6, and TNF-_) in keratinocytes through the ac- gradient formed by IL-8 toward the site of infection. (DC
tivation of TLR/IL-1RNF-gB signaling. Keratinocyte- Dendritic cell, hBD-2 human `-defensin 2, IL interleu-
derived antimicrobial peptides either kill the pathogens kin, NF-gB nuclear factor kappa B, TLR Toll-like recep-
or regulate the recruitment of memory T cells and im- tor, TNF tumor necrosis factor)
13 13.14 Pro-Inflammatory Cytokines of sequestered IL-1 surrounding the host, wait-

ing to be released upon injury. External stimuli
Upon challenge with microbial compounds ke- such as wounding, burns, and microbial infec-
ratinocytes express numerous cytokines acting tion, or internal stimuli such as local cytokine
as cytoprotective factors in the processes of the release from stimulated leukocytes can induce
immune response. the release of IL-1 for local or systemic delivery.
In primary keratinocytes, S. aureus-derived Although high levels of IL-1RA also coexist
PGN induces the secretion of granulocyte-mac- within keratinocytes, the amount of IL-1 is suf-
rophage colony-stimulating factor (GM-CSF) ficient to overcome any potential for inhibition
[47], a cytokine essential for the survival, dif- mediated by IL-1RA.
ferentiation, and maturation of dendritic and Both heat-killed S. aureus and staphylococcal
Langerhans cells. The effects of GM-CSF on the PGN induce the expression of TNF-_, IL-1`,
antigen-presenting cells shift the immune re- and IL-6 of primary keratinocytes [47, 51, 74].
sponse to the Th2-type. Its mitogenic effect on TNF-_ enhances the bactericidal effect of neu-
keratinocytes is partially responsible for epider- trophils and promotes the adhesion of neutro-
mal hypertrophy, characteristic of chronic in- phils to endothelial cells. Thus, keratinocyte-
flammatory skin lesions. derived TNF-_ plays a crucial role in the
Skin contains a reservoir of preformed IL-1_, recruitment of phagocytic cells into sites of
leading to the concept that epidermis is a shield infection. The contribution of IL-6 and TNF-_
to granulomatous skin conditions, such as cuta- sponsiveness in keratinocytes that has been ex-
neous leishmaniasis, granuloma annulare, lep- tensively studied in macrophages by the long-
rosy or HS, is suggested by the occurrence of term presence of commensal bacteria. That
these cytokines in the granulomatous reactions commensals modulate TLR signaling is best
[1]. Upon contact with pathogens, TNF-_, shown by studies indicating that signaling
IL-1_, IL-1`, and IL-6 are also implicated in the through TLR4 or TLR2 in epithelial cells in
autocrine induction of antimicrobial peptide vitro readily occurs after initial exposure to
expression (e.g., `-defensins and LL-37) by PAMPs, but not after second exposure or pro-
keratinocytes. longed incubation with TLR agonists. This
downregulation of signaling may occur by de-
creased TLR expression on the cell surface, as
13.15 TLR Recognition well as by the inhibition of TLR signaling via the
and the Commensal Microbiota expression of a non-signaling truncated form of
of the Skin MyD88 or by the activation of IRAK-M, a nega-
tive regulatory member of the IRAK family [18,
The human skin is densely populated with resi- 58, 67]. Alternatively, members of the resident
dent microbiota, composed of commensal mi- flora may provide an inhibitory signal for kera-
croorganisms such as S. epidermidis, P. acnes, tinocytes to avoid inflammation in healthy in-
Micrococcus luteus and/or Malassezia furfur. dividuals. However, the molecular mechanisms
These microorganisms compete for nutrients involved in the induction of tolerance are not
and space, limiting each others population size entirely understood in keratinocytes and a
and also competing out pathogens that may at- deeper insight into these processes will most
tempt to colonize the skin. Despite the density probably change our understanding of the inti-
of the microbiota, epidermal keratinocytes do mate relationship between epidermal cells and
not activate pro-inflammatory signaling cas- the commensal microbiota.
cades in response to commensal microorgan- The expression of different PRRs allows
isms, suggesting a complex hostmicrobe rela- keratinocytes to identify numerous features of a
tionship in the epidermis. Thus, epidermal single microbe simultaneously. In the presence
keratinocytes may need to discriminate the of functional receptors, effective immune re-
presence of commensals from the presence of sponse occurs only upon recognition of specific
pathogens, by mechanism/s that are not yet fully antigen combinations. Blocking of TLR2 and/or
identified One possible explanation for the un- TLR4 suppresses keratinocyte activation in-
responsiveness of the skin to resident microbio- duced by P. acnes or Mycobacterium tuberculo-
ta is the anatomical localization of the TLR-ex- sis, emphasizing the role of the cooperation
pressing keratinocytes. Since TLRs are expressed between different subfamilies of TLRs in the
by the basal keratinocytes, the layer that is nor- process of discrimination between commensals
mally not exposed to commensal microorgan- and pathogens [54, 61]. The teamwork involv-
isms living on the surface of the skin, the sterile ing TLR subfamilies enables keratinocytes to
and PAMP-free anatomical site may allow the give pathogen-specific immune responses, or, in
constitutive expression of functional TLR com- the case of skin-resident microorganisms, toler-
plexes by keratinocytes. These cells initiate pro- ance.
inflammatory signaling only during destructive Skin commensals (e.g., S. epidermidis and
or invasive infection, breaching through the P. acnes) and pathogenic bacteria both induce
stratum corneum. Still, limitation of TLR ex- the expression of hBD-2 in primary keratino-
pression to certain protected anatomical sites cytes. Still, NF-gB transcription factor is not
may not be the whole explanation, since TLRs involved in the induction by commensals, sug-
are also expressed in the suprabasal layers of the gesting the presence of discrete signaling path-
epidermis [4, 36, 59]. ways that enable keratinocytes to discriminate
Another explanation may be the induction of between resident and pathogenic microorgan-
tolerance, a state of acquired functional unre- isms. The in vivo biological significance of com-
mensal-induced TLR signaling is the induction acnes in the pathogenesis of acne is well docu-
of cytoprotective factors in epithelial cells. The mented [37, 40]. Recent results describing the
lack of TLR-MyD88 signaling in mucosal epi- expression of TLRs in the pilosebaceous unit to-
thelial cells (and most probably in keratino- gether with the increased amount of bacteria in
cytes) is accompanied by decreased capacity of acne vulgaris suggest that inflammation found
the cells to produce cytoprotective factors such in acne is at least partially mediated by the TLR
as IL-6 [62]. In the absence of these compounds, signaling pathways (Fig. 13.3) [40, 54].
epithelial cells are highly sensitive to physical Gram-negative organisms such as P. aerugi-
stress-induced cell death. Thus, activation of nosa, Pasteurella multocida, B. burgdorferi, Sal-
TLRs by commensal microbiota is probably monella typhi, Bartonella sp., Klebsiella rhino-
critical for the protection against physical-inju- scleromatis and Vibrio vulnificus are not typical
ry-associated cell death through the induction residents of the skins microbiota but may cause
of cell survival and/or repair during infection. cutaneous infections [10, 71]. However, their
Finally, the correlation of follicular lipids differential recognition through various TLRs
with P. acnes in acne vulgaris, an inflammatory expressed on keratinocytes and the expression
but not infectious disease, may indicate a new of antimicrobial peptides highly effective
and unexpected role of skin commensal micro- against Gram-negative bacteria play important
organisms, such as P. acnes and S. epidermidis, roles in the rarity of Gram-negative skin infec-
on human skin. Their presence may be skin tions.
protective and required for a permanent, low
activation level of innate immunity in order to
defend skin from acute attacks by pathogens, 13.17 Hidradenitis Suppurativa
supporting the hypothesis of a genuine inflam- and the Skin Immune System
matory etiology for acne and a possible, delayed,
contribution by P. acnes [22, 54]. The involvement of the immune system in HS
remains controversial. Immunological investi-
gations of some patients with HS suggested no
13.16 Skin Infections abnormalities of the immune system [15]. In
and Innate Immune Responses contrast, other authors showed increased pe-
of the Epidermis ripheral suppressor T cell activity [48], sugges-
tive of a precipitating cell-mediated immune
13 Normal human skin supports the growth of response. This is further supported by the pres-
resident microbiota and it is colonized with a ence of activated, HLA-DR-positive lympho-
wide variety of resident microorganisms. In ad- cytes [8]. Although in lower numbers and pref-
dition to normal flora, the skin is constantly erentially located in the direct perivascular
challenged by pathogens, most of which do not compartment, Leu-8-positive immunoregula-
cause clinical symptoms. Besides microbial ad- tory lymphocytes were also present in lesions,
herence and virulence, environmental and local suggestive of a loss of Leu-8 cellular antigen in
factors as well as host immunity are important lymphocytes during further migration into the
components of cutaneous infections. In partic- dermal tissue [8]. These results indicate that the
ular, skin becomes more susceptible to infec- lymphocytic infiltrate is definitely the result of
tions when the epidermal barrier function is in vivo activation of lymphoid cells. Indeed, the
damaged or when the keratinocyte-mediated significant fall of the T-helper/suppressor ratio
innate immune functions are inhibited. over time after the initiation [8] supports the ex-
The pilosebaceous unit is an important site of istence of a precipitating cell-mediated immune
skin infections such as acne vulgaris, folliculitis, response with only a short eliciting period. Even
furunculosis, and carbunculosis. A common though more recent studies have shown that
pathogen associated with infections in the pilo- dysfunctional neutrophils may also be involved
sebaceous unit is P. acnes. Although acne vul- in the pathogenesis of HS, no primary abnor-
garis is not an infectious disease, the role of P. malities of the innate or acquired immune sys-
Fig. 13.3. Co-operative recognition of microbial-de- (c) of another flagellated Gram-negative organism (e.g.,
rived PAMPs by TLRs. Host cells use multiple TLRs for Helicobacter pylori). Keratinocytes may also recognize
the detection of several unique features of the single mi- Hsp and lipoglycans/lipoarabinomannans (d) from the
crobe simultaneously. TLR4/4 and TLR5 detect LPS (a) skin pathogens P. acnes and Mycobacterium tuberculosis
and flagellin (b), respectively, from a flagellated Gram- via TLR4/4 and TLR2/6. (Hsp Heat-shock protein, TLR
negative organism (e.g., Salmonella typhi), whereas TLR5 Toll-like receptor)
and TLR2/6 detect flagellin (b) and diacyl-lipopeptide
tem can be held to be causal in every case [8, 34, skin immune response, such as secretion of an-
42]. timicrobial peptides and pro-inflammatory cy-
In addition, the significance of bacterial find- tokines/chemokines by keratinocytes through
ings in HS is also controversial. It is generally the activation of TLR/IL-1R-NF-gB signaling
accepted that the bacterial involvement is not a (Fig. 13.3). These mediators either kill the patho-
primary pathogenic event in HS, but rather it is gens or link innate and acquired immunity by
likely that the chronic inflammation is due to the recruitment of effector cells, such as memo-
secondary bacterial colonization [34]. This is ry T cells and dendritic cells, to the sites of in-
further supported by the fact that routine cul- fection (Fig. 13.3). Besides, keratinocyte-derived
tures from the surface of the lesions are often IL-8 and pro-inflammatory cytokines activate
negative. Still, bacteria are likely to be involved endothelial cells, allowing the transepithelial
in the pathogenesis of the disease since numer- migration of neutrophils. After extravasation
ous bacteria, such as S. aureus and coagulase- neutrophils follow the chemotactic gradient
negative staphylococci, are most frequently formed by IL-8 toward the site of infection. In-
isolated from lesions [35, 41]. These findings filtration of neutrophils, dendritic cells, and T
highlight a possible polymicrobial nature and cells into the epidermis may contribute not only
predominance of anaerobic bacteria in HS, sup- to the elimination of the invading pathogens
porting the role of bacterial infections as a pos- but, as a result of constant activation by kerati-
sible pathogenic event in HS. Microbial coloni- nocyte-derived mediators, to chronic inflam-
zation may, in turn, trigger several events of the mation as well (Fig. 13.3).
2. Akira S, Takeda K (2004) Toll-like receptor signal-

13.18 Conclusions ling. Nat Rev Immunol 4:499511
3. Ali RS, Falconer A, Ikram M, Bissett CE, Cerio R,
Quinn AG (2001) Expression of the peptide antibi-
W otics human beta defensin-1 and human beta de-
Increasing evidence suggests that keratino- fensin-2 in normal human skin. J Invest Dermatol
cytes not only participate in cutaneous im- 117:106111
mune responses against pathogens but may 4. Baker BS, Ovigne JM, Powles AV, Corcoran S, Fry
L (2003) Normal keratinocytes express Toll-like re-
in fact play key initiation roles. Keratinocytes
ceptors (TLRs) 1, 2 and 5: modulation of TLR ex-
are able to recognize a wide variety of micro- pression in chronic plaque psoriasis. Br J Dermatol
organisms through their TLRs and have 148:670679
evolved mechanisms to distinguish between 5. Barker JN, Mitra RS, Griffits CE, Dixit VM, Nick-
skin commensals and pathogens. Signaling oloff BJ (1991) Keratinocytes as initiators of inflam-
through specific TLR combinations provides mation. Lancet 337:211214
selectivity and specificity to keratinocyte im- 6. Barker JN, Jones ML, Mitra RS, Crockett-Torabe E,
mune responses. Fantone JC, Kunkel SL, Warren JS, Dixit VM, Nick-
oloff BJ (1991) Modulation of keratinocyte-derived
In epidermal keratinocytes, TLR-mediated
interleukin-8 which is chemotactic for neutrophils
signaling pathways induce the production of and T lymphocytes. Am J Pathol 139:869876
antimicrobial and antiviral peptides, cyto- 7. Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E,
kines/chemokines, and inducible enzymes. A Shakhov A, Chertov O, Shirakawa AK, Farber JM,
major factor in epidermal host defense mech- Segal DM, Oppenheim JJ, Kwak LW (2002) Toll-like
anisms of the epidermis is the secretion of an- receptor 4-dependent activation of dendritic cells
timicrobial peptides, as lesions of the skin by beta-defensin 2. Science 298:10251029
8. Boer J, Weltevreden EF (1996) Hidradenitis suppu-
characterized by low levels of antimicrobial
rativa or acne inversa. A clinicopathological study
peptides have raised susceptibility to infec- of early lesions. Br J Dermatol 135:721725
tions. Keratinocyte-derived cytokines and 9. Chadebech P, Goidin D, Jacquet C, Viac J, Schmitt
chemokines are critical in the recruitment of D, Staquet MJ (2003) Use of human reconstructed
dendritic cells, T cells, and neutrophils into epidermis to analyze the regulation of beta-defensin
sites of infection. In addition to having micro- hBD-1, hBD-2, and hBD-3 expression in response
bicidal functions, antimicrobial peptides can to LPS. Cell Biol Toxicol 19:313324
act as chemoattractants, thus providing an 10. Chiller K, Selkin BA, Murakawa GJ (2001) Skin mi-
croflora and bacterial infections of the skin. J Invest
improved immune response against patho- Dermatol Symp Proc 6:170174
13 gens. 11. Chung WO, Dale BA (2004) Innate immune re-
Taking all this into account, the epidermal sponse of oral and foreskin keratinocytes: utiliza-
keratinocytes can be regarded as potent im- tion of different signaling pathways by various bac-
mune cells, as they fulfill the requirements for terial species. Infect Immun 72:352358
the induction of both an innate and an adap- 12. Curry JL, Qin JZ, Bonish B, Carrick R, Bacon P,
tive immune response. These exciting discov- Panella J, Robinson J, Nickoloff BJ (2003) Innate
immune-related receptors in normal and psoriatic
eries extend our current understanding of the
skin. Arch Pathol Lab Med 127:178186
skins innate immune functions and may give 13. Dinulos JG, Mentele L, Fredericks LP, Dale BA,
rise to future perspectives of the treatment of Darmstadt GL (2003) Keratinocyte expression of
skin disorders such as hidradenitis suppurati- human beta defensin 2 following bacterial infec-
va. tion: role in cutaneous host defense. Clin Diagn Lab
Immunol 10:161166
14. Dorschner RA, Pestonjamasp VK, Tamakuwala S,
References Ohtake T, Rudisill J, Nizet V, Agerberth B, Gud-
mundsson GH, Gallo RL (2001) Cutaneous injury
induces the release of cathelicidin anti-microbial
1. Ahmed AA, Nordlind K, Schultzberg M, Liden S
peptides active against group A Streptococcus. J In-
(1994) Interleukin-1 alpha- and beta-, interleukin-
vest Dermatol 117:9197
6- and tumour necrosis factor-alpha-like immunore-
activities in chronic granulomatous skin conditions.
Acta Derm Venereol 74:435440
15. Dvorak VC, Root RK, MacGregor RR (1977) Host 28. Harder J, Meyer-Hoffert U, Wehkamp K, Schwich-
defense mechanisms in hidradenitis suppurativa. tenberg L, Schroder JM (2004) Differential gene
Arch Dermatol 113:450453 induction of human beta-defensins (hBD-1, -2, -
16. Ebnet K, Brown KD, Siebenlist UK, Simon MM, 3, and -4) in keratinocytes is inhibited by retinoic
Shaw S (1997) Borrelia burgdorferi activates nuclear acid. J Invest Dermatol 123:522529
factor-kappa B and is a potent inducer of chemokine 29. Heilborn JD, Nilsson MF, Kratz G, Weber G, So-
and adhesion molecule gene expression in endothe- rensen O, Borregaard N, Stahle-Backdahl M (2003)
lial cells and fibroblasts. J Immunol 158:32853292 The cathelicidin anti-microbial peptide LL-37 is
17. Frohm M, Agerberth B, Ahangari G, Stahle-Back- involved in re-epithelialization of human skin
dahl M, Liden S, Wigzell H, Gudmundsson GH wounds and is lacking in chronic ulcer epithelium.
(1997) The expression of the gene coding for the an- J Invest Dermatol 120:379389
tibacterial peptide LL-37 is induced in human ke- 30. Hieshima K, Ohtani H, Shibano M, Izawa D, Na-
ratinocytes during inflammatory disorders. J Biol kayama T, Kawasaki Y, Shiba F, Shiota M, Ka-
Chem 272:1525815263 tou F, Saito T, Yoshie O (2003) CCL28 has dual
18. Fukao T, Koyasu S (2003) PI3K and negative regula- roles in mucosal immunity as a chemokine with
tion of TLR signaling. Trends Immunol 24:358363 broad-spectrum antimicrobial activity. J Immunol
19. Fukuoka M, Ogino Y, Sato H, Ohta T, Komoriya K, 170:4521461
Nishioka K, Katayama I (1998) RANTES expression 31. Homey B, Bunemann E (2004) Chemokines and
in psoriatic skin, and regulation of RANTES and inflammatory skin diseases. Ernst Schering Res
IL-8 production in cultured epidermal keratino- Found Workshop 45:6983
cytes by active vitamin D3 (tacalcitol). Br J Derma- 32. Homey B, Alenius H, Muller A, Soto H, Bowman
tol 138:6370 EP, Yuan W, McEvoy L, Lauerma AI, Assmann T,
20. Fulton C, Anderson GM, Zasloff M, Bull R, Quinn Bunemann E, Lehto M, Wolff H, Yen D, Marxhau-
AG (1997) Expression of natural peptide antibiotics sen H, To W, Sedgwick J, Ruzicka T, Lehmann P,
in human skin. Lancet 350:17501751 Zlotnik A (2002) CCL27-CCR10 interactions regu-
21. Gallo RL, Huttner KM (1998) Antimicrobial pep- late T cell-mediated skin inflammation. Nat Med
tides: an emerging concept in cutaneous biology. J 8:157165
Invest Dermatol 111:739743 33. Janeway CA Jr, Medzhitov R (2002) Innate immune
22. Georgel P, Crozat K, Lauth X, Makrantonaki E, recognition. Annu Rev Immunol 20:197216
Seltmann H, Sovath S, Hoebe K, Du X, Rutschmann 34. Jansen I, Altmeyer P, Plewig G (2001) Acne inversa
S, Jiang Z, Bigby T, Nizet V, Zouboulis CC, Beutler (alias hidradenitis suppurativa). J Eur Acad Derma-
B (2005) A TLR2-responsive lipid effector pathway tol Venereol 15:532540
protects mammals against Gram-positive bacterial 35. Jemec GB, Faber M, Gutschik E, Wendelboe P
skin infections. Infect Immunity 73:45124521 (1996) The bacteriology of hidradenitis suppurativa.
23. Gillitzer R, Wolff K, Tong D, Muller C, Yoshimura Dermatology 193:203206
T, Hartmann AA, Stingl G, Berger R (1993) MCP-1 36. Kawai K, Shimura H, Minagawa M, Ito A, Tomi-
mRNA expression in basal keratinocytes of psori- yama K, Ito M (2002) Expression of functional Toll-
atic lesions. J Invest Dermatol 101:127131 like receptor 2 on human epidermal keratinocytes.
24. Giustizieri ML, Mascia F, Frezzolini A, De Pita O, J Dermatol Sci 30:185194
Chinni LM, Giannetti A, Girolomoni G, Pastore 37. Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uemat-
S (2001) Keratinocytes from patients with atopic su S, Legaspi AJ, Brightbill HD, Holland D, Cunliffe
dermatitis and psoriasis show a distinct chemokine WJ, Akira S, Sieling PA, Godowski PJ, Modlin RL
production profile in response to T cell-derived cy- (2002) Activation of toll-like receptor 2 in acne trig-
tokines. J Allergy Clin Immunol 107:871877 gers inflammatory cytokine responses. J Immunol
25. Harder J, Schroder JM (2002) RNase 7, a novel in- 169:15351541
nate immune defense antimicrobial protein of 38. Kis K, Koreck A, Szegedi K, Dioszegi C, Paunescu
healthy human skin. J Biol Chem 277:4677946784 V, Cioaca R, Olariu R, Kemeny L, Szell M (2005)
26. Harder J, Bartels J, Christophers E, Schroder JM Polymorphisms of interleukin-1 receptor antago-
(1997) A peptide antibiotic from human skin. Na- nist, Toll-like Receptor 2 and 4 genes in patients
ture 387:861 with acne. ESDR abstract reference number: E0349
27. Harder J, Bartels J, Christophers E, Schroder JM 39. Kopp E, Medzhitov R (2002) Skin antibiotics get in
(2001) Isolation and characterization of human beta the loop. Nat Med 8:13591360
-defensin-3, a novel human inducible peptide anti- 40. Koreck A, Pivarcsi A, Dobozy A, Kemeny L (2003)
biotic. J Biol Chem 276:57075713 The role of innate immunity in the pathogenesis of
acne. Dermatology 206:96105
41. Lapins J, Jarstrand C, Emtestam L (1999) Coagu- 52. Murakami M, Ohtake T, Dorschner RA, Schittek B,
lase-negative staphylococci are the most common Garbe C, Gallo RL (2002) Cathelicidin anti-micro-
bacteria found in cultures from the deep portions bial peptide expression in sweat, an innate defense
of hidradenitis suppurativa lesions, as obtained by system for the skin. J Invest Dermatol 119:1090
carbon dioxide laser surgery. Br J Dermatol 140:90 1095
95 53. Murphy JE, Robert C, Kupper TS (2000) Interleu-
42. Lapins J, Asman B, Gustafsson A, Bergstrom K, kin-1 and cutaneous inflammation: a crucial link
Emtestam L (2001) Neutrophil-related host re- between innate and acquired immunity. J Invest
sponse in hidradenitis suppurativa: a pilot study in Dermatol 114:602608
patients with inactive disease. Acta Derm Venereol 54. Nagy I, Pivarcsi A, Koreck A, Szell M, Urban E,
81:9699 Kemeny L (2005) Distinct strains of Propionibac-
43. Larrick JW, Hirata M, Balint RF, Lee J, Zhong J, terium acnes induces selective human `-defensin-2
Wright SC (1995) Human CAP18: a novel antimi- and interleukin-8 expression in human keratino-
crobial lipopolysaccharide-binding protein. Infect cytes through Toll-like receptors. J Invest Dermatol
Immun 63:12911297 124:931938
44. Liu AY, Destoumieux D, Wong AV, Park CH, Valore 55. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J,
EV, Liu L, Ganz T (2002) Human beta-defensin-2 Dorschner RA, Pestonjamasp V, Piraino J, Huttner
production in keratinocytes is regulated by inter- K, Gallo RL (2001) Innate antimicrobial peptide
leukin-1, bacteria, and the state of differentiation. protects the skin from invasive bacterial infection.
J Invest Dermatol 118:275281 Nature 414:454457
45. Liu L, Zhou X, Shi J, Xie X, Yuan Z (2003) Toll-like 56. Niyonsaba F, Iwabuchi K, Someya A, Hirata M,
receptor-9 induced by physical trauma mediates re- Matsuda H, Ogawa H, Nagaoka I (2002) A catheli-
lease of cytokines following exposure to CpG motif cidin family of human antibacterial peptide LL-37
in mouse skin. Immunology 110:341347 induces mast cell chemotaxis. Immunology 106:20
46. Marzano AV, Mercogliano M, Borghi A, Facchetti 26
M, Caputo R (2003) Cutaneous infection caused by 57. Oren A, Ganz T, Liu L, Meerloo T (2003) In human
Salmonella typhi. J Eur Acad Dermatol Venereol epidermis, beta-defensin 2 is packaged in lamellar
17:575577 bodies. Exp Mol Pathol 74:180182
47. Matsubara M, Harada D, Manabe H, Hasegawa K 58. Otte JM, Cario E, Podolsky DK (2004) Mechanisms
(2004) Staphylococcus aureus peptidoglycan stimu- of cross hyporesponsiveness to Toll-like receptor
lates granulocyte macrophage colony-stimulating bacterial ligands in intestinal epithelial cells. Gas-
factor production from human epidermal keratino- troenterology 126:10541070
cytes via mitogen-activated protein kinases. FEBS 59. Pivarcsi A, Bodai L, Rethi B, Kenderessy-Szabo A,
Lett 566:195200 Koreck A, Szell M, Beer Z, Bata-Csorgoo Z, Magocsi
48. McDaniel DH, Welton WA (1984) Furunculosis and M, Rajnavolgyi E, Dobozy A, Kemeny L (2003) Ex-
13 hidradenitis suppurativa response. Arch Dermatol
120:437
pression and function of Toll-like receptors 2 and 4
in human keratinocytes. Int Immunol 15:721730
49. Mempel M, Voelcker V, Kollisch G, Plank C, Rad R, 60. Pivarcsi A, Koreck A, Bodai L, Szell M, Szeg C, Belso
Gerhard M, Schnopp C, Fraunberger P, Walli AK, N, Kenderessy-Szabo A, Bata-Csorgo Z, Dobozy A,
Ring J, Abeck D, Ollert M (2003) Toll-like receptor Kemeny L (2004) Differentiation-regulated expres-
expression in human keratinocytes: nuclear factor sion of Toll-like receptors 2 and 4 in HaCaT kerati-
kappaB controlled gene activation by Staphylococ- nocytes. Arch Dermatol Res 296:120124
cus aureus is toll-like receptor 2 but not toll-like 61. Pivarcsi A, Nagy I, Kemeny L (2005) Innate im-
receptor 4 or platelet activating factor receptor de- munity of the skin: how keratinocytes fight against
pendent. J Invest Dermatol 121:13891396 pathogens. Curr Immunol Rev 1:2942
50. Mercurio F, Manning AM (1999) Multiple signals 62. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F,
converging on NF-kappaB. Curr Opin Cell Biol Edberg S, Medzhitov R (2004) Recognition of com-
11:226232 mensal microflora by toll-like receptors is required
51. Midorikawa K, Ouhara K, Komatsuzawa H, Kawai for intestinal homeostasis. Cell 118: 229241
T, Yamada S, Fujiwara T, Yamazaki K, Sayama K, 63. Raychaudhuri SP, Jiang WY, Farber EM, Schall
Taubman MA, Kurihara H, Hashimoto K, Sugai TJ, Ruff MR, Pert CB (1999) Upregulation of
M (2003) Staphylococcus aureus susceptibility to RANTES in psoriatic keratinocytes: a possible patho-
innate antimicrobial peptides, beta-defensins and genic mechanism for psoriasis. Acta Derm Venereol
CAP18, expressed by human keratinocytes. Infect 79:911
Immun 71:37303739 64. Schroder JM, Harder J (1999) Human beta-defen-
sin-2. Int J Biochem Cell Biol 31:645651
65. Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome 75. Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH,
K, Miyake K, Kimoto M (1999) MD-2, a molecule Zachary JF, Kirschning CJ, Weis JJ (2002) Toll-like
that confers lipopolysaccharide responsiveness on receptor 2 is required for innate, but not acquired,
Toll-like receptor 4. J Exp Med 189:17771782 host defense to Borrelia burgdorferi. J Immunol
66. Song PI, Park YM, Abraham T, Harten B, Zivony 168:348355
A, Neparidze N, Armstrong CA, Ansel JC (2002) 76. Wyllie DH, Kiss-Toth E, Visintin A, Smith SC,
Human keratinocytes express functional CD14 and Boussouf S, Segal DM, Duff GW, Dower SK (2000)
toll-like receptor 4. J Invest Dermatol 119:424432 Evidence for an accessory protein function for Toll-
67. Strober W (2004) Epithelial cells pay a Toll for pro- like receptor 1 in anti-bacterial responses. J Immu-
tection. Nat Med 10:898900 nol 165:71257132
68. Sugawara I, Yamada H, Li C, Mizuno S, Takeuchi 77. Yang D, Chen Q, Chertov O, Oppenheim JJ (2000)
O, Akira S (2003) Mycobacterial infection in TLR2 Human neutrophil defensins selectively chemoat-
and TLR6 knockout mice. Microbiol Immunol tract naive T and immature dendritic cells. J Leukoc
47:327336 Biol 68:914
69. Takeda K, Akira S (2004) TLR signaling pathways. 78. Yang D, Biragyn A, Kwak LW, Oppenheim JJ (2002)
Semin Immunol 16:39 Mammalian defensins in immunity: more than just
70. Takeda K, Kaisho T, Akira S (2003) Toll-like recep- microbicidal. Trends Immunol 23:291296
tors. Annu Rev Immunol 21:335376 79. Yang D, Chen Q, Hoover DM, Staley P, Tucker KD,
71. Wedi B, Kapp A (2002) Helicobacter pylori infection Lubkowski J, Oppenheim JJ (2003) Many chemo-
in skin diseases: a critical appraisal. Am J Clin Der- kines including CCL20/MIP-3alpha display anti-
matol 3:273282 microbial activity. J Leukoc Biol 74:448455
72. Wiedow O, Harder J, Bartels J, Streit V, Christophers 80. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo
E (1998) Antileukoprotease in human skin: an anti- MJ, Shogan J, Anderson M, Schroder JM, Wang JM,
biotic peptide constitutively produced by keratino- Howard OM, Oppenheim JJ (1999) Beta-defensins:
cytes. Biochem Biophys Res Commun 248:904909 linking innate and adaptive immunity through
73. Witkin SS, Gerber S, Ledger WJ (2002) Influence dendritic and T cell CCR6. Science 286:525528
of interleukin-1 receptor antagonist gene polymor- 81. Zhang G, Ghosh S (2001) Toll-like receptor-medi-
phism on disease. Clin Infect Dis 34:204209 ated NF-kappaB activation: a phylogenetically con-
74. Wollina U, Kunkel W, Bulling L, Funfstuck C, served paradigm in innate immunity. J Clin Invest
Knoll B, Vennewald I, Hipler UC (2004) Candida 107:1319
albicans-induced inflammatory response in human
keratinocytes. Mycoses 47:193199
Chapter 14
Quality of Life in Hidradenitis

Suppurativa 14
Pierre Wolkenstein

Q Quality of life is severely affected Hidradenitis suppurativa (HS) is a chronically
by hidradenitis suppurativa (HS) relapsing skin disorder characterized by recur-
ring inflammatory lesions leading to fistulae
Q Suggestions for the uniform reporting and sclerosis of apocrine-gland-bearing areas
of outcome variables are available [3]. One or several areas are affected, including
and should be used the perianal region, groin, pubis, scrotum, but-
tocks, inner thighs, and areola. The disease
Q Quality of life quantification should leads to painful nodules and malodorous dis-
be made using validated instruments charge and the available treatments are only
in all patients partially effective and unsatisfactory. Affected
patients suffer a significant morbidity and it is
Q Pain should be assessed at all visits self-evident that HS has a psychological impact
using a pain visual analog scale (VAS) especially upon quality of life (QoL) and mental
health. In this chapter we will review these two
aspects.
#ONTENTS
14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 116 14.2 Concept and Measure

14.2 Concept and Measure of Quality of Life . 116
of Quality of Life
14.2.1 Why Try to Measure Quality of Life? . . . . 116
14.2.2 Reporting the Viewpoint of Patients: 14.2.1 Why Try to Measure Quality
14 Methods of Measurement of Quality of Life?
of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
14.2.3 Reporting the Viewpoint of Physicians: Quality of life is a concept incorporating all fac-
Uniform Outcome Variables. . . . . . . . . . . . 117
tors that impact upon an individuals life [4].
14.2.4 Practical Approach Reconciling
the Viewpoints The concept has been divided into several com-
of Patients and Physicians . . . . . . . . . . . . . . 117 ponents, including psychological, social, and
14.3 Impact of HS upon Quality of Life . . . . . . 117
physical domains. All clinicians use an intuitive
14.3.1 Altered Self-Reported Health: view of how much the disease is affecting their
Qualitative Approach . . . . . . . . . . . . . . . . . . 117 patients when taking management decisions,
14.3.2 Measure of Quality of Life: but patients may assess QoL differently from
Quantitative Approach . . . . . . . . . . . . . . . . 118 their doctors. The use of simple QoL measures
14.4 Impaired Quality of Life: is usually welcomed by patients who wish to ex-
What Conclusion? . . . . . . . . . . . . . . . . . . . . . 118 press their concerns. Methods of measuring the
14.4.1 Conclusion for Patients . . . . . . . . . . . . . . . . 118 extent and severity of a disease are based on as-
14.4.2 Conclusion for Physicians . . . . . . . . . . . . . . 119 sessment of signs and symptoms. This informa-
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 tion does not necessarily correlate with QoL
measures. It is therefore important to have two
Quality of Life in Hidradenitis Suppurativa Chapter 14 117
viewpoints of a disease, the viewpoint of doc- 14.2.4 Practical Approach Reconciling

tors and that of patients. the Viewpoints of Patients
and Physicians
14.2.2 Reporting the Viewpoint The evaluation of patients with HS in a referral

of Patients: Methods of center should include QoL questionnaires, and
Measurement of Quality of Life standardized outcome variables. Pain should be
evaluated with validated instruments such as
The techniques used to measure QoL are ques- visual analog score (VAS).
tionnaire based [4]. These measures either cover
all ways in which patients lives can be affected
by any disease, or are more specific to diseases 14.3 Impact of HS upon Quality
of systems or individual diseases. In the absence of Life
of questionnaires specific to HS, two kinds can
be used: general health questionnaires and skin- 14.3.1 Altered Self-Reported Health:
disease-specific questionnaires. The question- Qualitative Approach
naires allow the calculation of either global
scores, or a profile with a score for each dimen- Many dermatologists rate HS as a heart-sink
sion. In our experience skin-disease-specific condition and would agree that it ranks among
questionnaires are more adapted than generic the most unpleasant of skin diseases. When
questionnaires to HS. looking at patients statements about their dis-
ease they emphasize that the soreness and pain
are the cause of their disability. Patients suffer
14.2.3 Reporting the Viewpoint from embarrassment and self-consciousness
of Physicians: Uniform caused by the frequent occurrence of boils with
Outcome Variables malodorous discharge. One study in Denmark
has shown impairment of self-reported health
The measures of the QoL must be correlated in HS [6]: the general self-reported level of health
with the severity of the disease. Recently sug- is poorer among HS patients. The soreness, dis-
gestions for uniform outcome variables for charge, and appearance of lesions are described
treatment effects in HS have been reported [7]: as problems for both work and leisure activities
by 51% of all patients. In the same study, Jemec
1. Anatomical region involved (axilla, groin, et al. [1996] found that patients with HS had lost
gluteal or other region or inframammary an average of 2.7 days of work in 1 year specifi-
region, left and/or right: 3 points per cally because of HS. This suggests an overall
region involved) higher morbidity, as other days lost to other
2. Number and scores of lesions (abscesses, causes were not included in the data. The dura-
nodules, fistulas, scars; points per lesion tion of 2.7 days however ranked below the aver-
of all regions involved: nodules/abscesses age number of work days lost for all reasons per
2; fistulas 4; scars 1; others 1) employed person (7.5 days) and even further be-
3. The longest distance between two low the average number of days lost by patients
relevant lesions, i.e., nodules and fistulas, with hand eczema (4 weeks) in a comparable
in each region, or size if only one lesion population. These results suggest that patients
(<5 cm 2; <10 cm 4; >10 cm 8) with HS fail to get appropriate recognition for
4. Are all lesions clearly separated by the severity of their disease. Many of them seem
normal skin? In each region (yes 0/no 6) to suffer in silence. Indeed failure to disclose the
extent or even the existence of the disease may
By assigning numerical scores to these variables, in itself increase its severity. In the absence of
disease intensity can be quantified in a clini- visible disease no support or sympathy is elicit-
cally meaning full way. A total score was calcu- ed and there is, therefore, no mitigation of suf-
lated. fering: the stigma attached to HS is because it
118 Pierre Wolkenstein
affects predominantly intimate body parts. It recommend using only one questionnaire and
has connotations of socially unacceptable be- preferably one dermatological questionnaire,
havior or a lack of hygiene and is often concealed such as DLQI, VQ-dermato or Skindex, which
even from close relatives. seem to be more sensitive [1, 4, 5].
In France, in the context of a TNS Sofres sur- The DLQI score was inversely correlated with
vey (unpublished data), which is deemed to pro- age at disease onset [2]. It was suggested that pa-
vide a representative sample of patients with tients with late-onset disease tend to have an
HS, 47.2% of patients reported a medical con- overall milder form of HS and a better chance of
sultation for their disease in the year preceding spontaneous recovery than those who develop
the interview, and 47.7% of the patients reported the condition earlier in life. This is in agreement
HS to be a relevant problem and a severe dis- with a previous observation of the outcome of
tress. simple surgical procedures in HS, where older
patients appeared to have fewer recurrences.
We used QoL questionnaires concomitantly
14.3.2 Measure of Quality of Life: with a VAS for pain. The QoL scores were
Quantitative Approach strongly and positively correlated with the pain.
Indeed, soreness and pain are the most com-
A quantitative approach for measuring QoL in monly cited reason for impaired health in HS. It
HS was performed [2]. Questionnaires widely is self-evident that pain is one of the main bur-
used in other skin diseases such as the Derma- dens of patients with HS and should be taken
tology Life Quality Index (DLQI) questionnaire, into account as an evaluation criterion for future
Skindex and VQ-Dermato [1, 4, 5] were chosen. treatment. Patients with a long disease duration
This approach allows a direct comparison of the and continuous evolution were more affected
results with those from previous studies on oth- than those with intermittent evolution. A pelvic
er skin diseases. We will discuss two studies, location had a significantly higher impact com-
one already published and our unpublished data pared to other locations. Indeed this location is
[2]. In both studies, in addition to this question- associated with boils with a malodorous dis-
naire, basic demographic data and aspects of the charge leading to an evident physical limita-
history of HS were collected: 114 patients par- tion.
ticipated in the first one [2] and 61 in the sec-
ond. In the study of der Werth and Jemec [2] the
recorded mean DLQI score was 8.9, higher than 14.4 Impaired Quality of Life:
scores found in several other dermatological What Conclusion?
conditions such as alopecia, acne, psoriasis,
14 HaileyHailey disease, vascular anomalies of 14.4.1 Conclusion for Patients
face, and atopic dermatitis. In our center (un-
published data) using two other skin-disease-
specific QoL questionnaires (Skindex and VQ- W
Dermato) [1, 5], the scores obtained were higher Questionnaires of QoL are well tolerated by
than those found in chronic urticaria, psoriasis, patients and allow one to evaluate the burden
atopic dermatitis and also neurofibromatosis 1. of HS and to compare it with other diseases.
The impact upon QoL was correlated with They demonstrated that the impact of HS is
the number of active lesions and with the sever- probably the greatest encountered in chronic
ity of the disease. Therefore, QoL questionnaires diseases in dermatology. These results are im-
can be used to measure the activity of the dis- portant for recognition of the disease and the
ease from the viewpoint of patients and could be lobbying of lay groups. These questionnaires
used in therapeutics trials as a main criterion. should be used when accounting for patients
In our study, three QoL questionnaires were ad- viewpoints during follow-up and therapeutic
ministered and the measures obtained from trials.
each of them were strongly correlated. One can
Quality of Life in Hidradenitis Suppurativa Chapter 14 119
14.4.2 Conclusion for Physicians References

1. Chren MM, Lasek RJ, Flocke SA, Zyzanski SJ (1997)
W Improved discriminative and evaluative capability of
The analysis of QoL measures confirms the a refined version of Skindex, a quality-of-life instru-
ment for patients with skin diseases. Arch Dermatol
strong impact of HS. A subgroup of patients 133:14331440
seems to be more affected; namely, patients 2. der Werth JM, Jemec GB (2001) Morbidity in pa-
with an early onset of their disease, with a tients with hidradenitis suppurativa. Br J Dermatol
long disease duration, with continuous evolu- 144:809813
tion and with a predominately pelvic location. 3. der Werth JM, Williams HC (2000) The natural his-
Future trials should be targeted on this sub- tory of hidradenitis suppurativa. J Eur Acad Derma-
group. The impact upon QoL is strongly cor- tol Venereol 14:389392
4. Finlay AY (1997) Quality of life measurement in der-
related with pain. Therefore, criteria of treat-
matology: a practical guide. Br J Dermatol 136:305
ment evaluation should include, in addition to 314
the standardized physicians report, the pa- 5. Grob JJ, Auquier P, Martin S, Lancon C, Bonerandi JJ
tients viewpoint obtained with at least a der- (1999) Development and validation of a quality of life
matological QoL questionnaire and the pain measurement for chronic skin disorders in French:
VAS. VQ-Dermato. The Reseaud Epidemiologie en Der-
matologie. Dermatology 199:213222
6. Jemec GB, Heidenheim M, Nielsen NH (1996) Hi-
dradenitis suppurativa characteristics and conse-
quences. Clin Exp Dermatol 21:419423
7. Sartorius K, Lapins J, Emtestam L, Jemec GB (2003)
Suggestions for uniform outcome variables when
reporting treatment effects in hidradenitis suppura-
tiva. Br J Dermatol 149:211213
Chapter 15
Antibiotic Therapy
James Leyden, Jean Revuz
15
Key points disease. The original descriptions of chronic,

recurrent abscesses in the axillary, mammary,
Q HS is not a primary infectious disease, and perineal skin and then the possible linkage
yet antibiotics may be helpful to apocrine glands by Verneuil in 1854 formed a
logical basis for thinking of this disease as an
Q Antibiotic therapy is hampered by the infection of apocrine glands [1]. In 1956, Pills-
difficulty of realistic bacteriologic bury, Shelley and Kligman proposed the con-
sampling cept of the follicular occlusion triad and brought
together acne conglobata, HS, and dissecting
Q A short course of antibiotics may stop cellulitis of the scalp. The central event in these
the evolution of a nodule to an abscess conditions was viewed to be follicular hyperke-
if taken very early ratinization leading to retention of corneocytes
and secondary bacterial infection [2]. This con-
Q Empirical treatment with clindamycin cept was strengthened by the work of Shelley
and rifampicin has provided long- and Cahn in 1955 [3]. They occluded the axillae
lasting remissions in some cases and of volunteers with impermeable plastic film and
seems to be a promising therapeutic reported the subsequent formation of dermal
approach abscesses. Their analysis was that poral occlu-
sion of follicles led to hyperkeratosis of the dis-
tal apocrine duct, and dilatation of apocrine
ducts with subsequent ductal rupture and in-
flammation. They described the presence of
#ONTENTS bacteria in the inflammatory infiltrate and hy-
15.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .120
pothesized that bacteria trapped beneath the
hyperkeratotic plug proliferated in apocrine
15.2 Clinical Experience. . . . . . . . . . . . . . . . . . . . 121
15 sweat milieu with neutrophils pouring into the
15.3 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 apocrine duct. Rupture of the duct leads to
References . . . . . . . . . . . . . . . . . . . . . . . . . . . .123 spread of infection and abscess formation. In
this work epithelial sinus tracks were not de-
scribed. In our view Shelley and Cahn more
likely induced bacterial furunculosis than a
15.1 Introduction chronic inflammatory process associated with
epithelial sinus tract formation.
Antibiotic therapy is widely recommended and In more recent years, the concept of infection
mentioned in all textbooks of dermatology as a of apocrine glands has been questioned. For ex-
prominent form of treatment of hidradenitis ample, the absence or paucity of apocrine glands
suppurativa (HS). Curiously, the literature re- in lesions on the buttocks, inframammary folds,
veals only a handful of primary studies on the inguinal, and thigh areas argues against apo-
use of antibiotics in this chronic, destructive crine glands being the primary site of pathology.
Antibiotic Therapy Chapter 15 121
Furthermore, histopathologic studies indicate Over the years one of us (J.J.L.) has routinely
that the dominant feature are epithelial-lined cultured HS patients (Table 15.1). All of these
cysts and sinuses of follicular origin [4, 5]. The patients are referred by other dermatologists
latter authors [5] proposed the term acne inversa and have had multiple courses of systemic anti-
and believe that lesions begin in terminal folli- biotics and in many cases have been on continu-
cles with hyperkeratosis of the infundibulum ous antibiotic therapy. The latter is rational only
giving rise comedo-like horny impactions with if one believes that the non-antimicrobial, anti-
subsequent rupture of the follicular canal, and inflammatory properties of antibiotics are ben-
dermal inflammation with strands of epithelia eficial in HS.
extending into the dermis in an attempt to en- The results of cultures in 150 patients with
capsulate the inflammatory reaction. Bacterial chronic disease indicate a low rate of recovery of
infection, when present, is a secondary, aggra- pathogens. The most common pathogen isolat-
vating factor. ed is S. aureus with MRSA seen in recent years.
In the perineum, Gram-negative bacteria in-
cluding Escherichia coli, Proteus and Pseudomo-
15.2 Clinical Experience nas species are found in a small percentage of
patients. There results support the view that
With this more modern-view pathophysiology, bacterial infection is not a primary event in HS.
it may seem rational to view antibiotic therapy These findings are in agreement with Jemec et
as useful when pathogens are recovered from al. [6] and Lapins et al. [7]. The most frequently
furunculoid lesions or draining purulent mate- isolated pathogens are S. aureus and Gram-neg-
rial, provided that the sampling and bacterio- ative species. The studies of Jemec and Lapins
logical methods allow the recovery of signifi- circumvented the problem of collecting surface
cant, i.e., deep-seated, material and the growth contaminants. If members of the resident cuta-
of relevant species, i.e., aerobic and anaerobic neous flora, e.g., coagulase-negative cocci, are
bacteria. recovered, they should not be considered patho-
Distinguishing between a non-infected, gens unless the hypothesis of biofilm formation
highly inflammatory process associated with by this resident flora in a deep-seated sinus is
nodular abscess-type lesions and a purulent dis- verified (see Chap. 11). Several authors have
charge and true secondary infection is often not recovered anaerobic bacteria from HS lesions
possible on clinical grounds alone. The presence [79]. See Chap. 11 for further information on
of fever, cellulitis, and lymphadenopathy are bacterial isolates from HS lesions.
helpful but are not common findings. Frequent
cultures are essential for making rational deci-
sions regarding the use of antibiotics. The need 15.3 Therapy
for antibiotic use driven by culture and sensitiv-
ity is even more important in view of the emer- Despite the widespread use of antibiotic therapy,
gence of methicillin-resistant Staphylococcus there is a paucity of information in the litera-
aureus (MRSA) in community-acquired infec- ture. One trial found topical clindamycin supe-
tions. rior to its vehicle while another showed no dif-
Table 15.1. Bacterial cultures in hidradenitis suppurativa

Patients Cultures No growth Staphylococcus Streptococcus GNB
(n) (n) (%) aureus (%) pyogenes (%) (%)
Axilla 60 330 90 8 1 1
Perineum 55 255 80 10 2 8
Buttocks 20 110 90 7 0 3
Submammary 15 60 95 5 0 0
122 James Leyden, Jean Revuz
Table 15.2. Published trials of antibiotics in HS

Design Number Drugs Duration Result Reference
of patients of therapy
(months)
1 Randomized 27 Clindamycin 3 10% topical clindamycin Clemmensen
controlled trial versus placebo superior to placebo [10]
2 Randomized 46 Topical clinda- 3 No significant difference Jemec and
controlled mycin versus between topical clinda- Wendelboe
double-blind trial systemic tetra- mycin and systemic [11]
cycline tetracycline
ference between topical clindamycin and 11 years [14]. All were severely affected, with 21
systemic tetracycline neither worked well [10, being at stage II of Hurleys classification and 21
11] (see Table 15.2). at stage III. All of them had more than 15 days/
Short courses of antibiotics aimed at stop- month of pain and 34 had permanent, pain-
ping an exacerbation of the disease are usually ful lesions. Twenty patients had already used
useless. In the experience of one author (J.R.) antibiotics, either as a short course of less than
there is a subset of HS patients with mild disease 15 days or as continuous treatment with tetra-
who may benefit from such treatment. These cyclines. Twelve patients were followed-up by
patient have only a few outbreaks of one or their referring physician and no data on treat-
several painful nodules during a year. If they ment results were available. In the remaining
start the antibiotic treatment immediately, 30 patients, 9 had a complete remission, 9 an
within 1 h, of the first symptom they have a 50% important improvement and 11 a moderate im-
chance of preventing the normal evolution, provement. Of these 29, 20 had had no relapse
i.e., pain, swelling, and incision of the abscess. after a follow-up of 3 months to 1 year. One pa-
Systemic clindamycin targeting anaerobic tient had to stop because of spontaneously heal-
bacteria has been used in high doses, 1200 mg ing diarrhea; eight other patients experienced
and 2400 mg respectively, in two patients with mild diarrhea, recovering without stopping the
good improvement [8]. More recently the com- treatment.
bination of systemic clindamycin (600 mg daily) Confirmation and extension of these studies
and rifampicin (600 mg daily) was given for 10 is necessary. Studies should focus on the role of
weeks to seven patients with HS [12]. Two pa- infection in severely affected patients with long-
tients experienced diarrhea related to Clostridi- lasting disease. One cannot expect such treat-
um difficile; three responded well and remained ment to cure the disease, but it raises the hope of
15 clear at 12 months. The same team has reported bringing a significant number of patients into
their experience with 14 patients 9 women and remission. Whether other drugs, namely tetra-
5 men with long-lasting HS of mean duration cyclines and non-steroidal anti-inflammatory
10.5 years [13]. Eight patients achieved long- drugs, can prolong a state of complete or near-
lasting complete remission: 14 years of follow- complete remission will have to be explored in
up without recurrence. Two other patients the future.
achieved remission after minocycline was sub- A note of caution about chronic antibiotic
stituted for clindamycin because of diarrhea. therapy, which can disrupt the normal flora of
The four other patients could not tolerate the sites including the oral cavity, gastrointestinal
course of treatment because of diarrhea. tract and vagina; this risk needs to be weighed
One of us (J.R.) has recently confirmed these against the benefit seen in patients who are not
results by treating 42 HS patients (26 women, 16 colonized by pathogens.
men) with long-lasting disease, mean duration
Antibiotic Therapy Chapter 15 123
8. Brenner DE, Lookingbill DP. Anaerobic microor-

References ganisms in chronic suppurative hidradenitis. Lan-
cet 1980; 2:921922
1. Verneuil AS. Etudes sur les tumours de la peu. Arch 9. Leach RD, Eykyn SJ, Phillips I et al. Anaerobic axil-
Gen Med 1854; 64:693 lary abscess. Br Med J 1979; 2:57
2. Pillsbury DM, Shelley WB, Kligman AM. Bacterial 10. Clemmensen OJ. Topical treatment of hidradenitis
infections of the skin. In: Dermatology. Saunders, suppurativa with clindamycin. Int J Dermatol 1983;
Philadelphia, 1956, pp 482484 22:325328
3. Shelley WB, Cahn MM. Pathogenesis of hidradenitis 11. Jemec GB, Wendelboe P. Topical clindamycin ver-
suppurativa in man: experimental and histological sus systemic tetracycline in the treatment of hi-
observations. Arch Dermatol Syphilol 1955; 72:562 dradenitis suppurativa. J Am Acad Dermatol 1998;
565 39:971974
4. Yu CC, Cook MG. Hidradenitis suppurativa: disease 12. Hindle EAO, Kirby B, Griffiths CEM. Hidradenitis
of follicular epithelium rather than apocrine glands. suppurativa and acne keloidalis nuchae treated with
Br J Dermatol 1990; 122:763767 clindamycin and rifampicin: a case series. Br J Der-
5. Plewig G, Steger M. Acne inversa (alias acne triad, matoI 2002; 147:2223
acne tetrad or hidradenitis suppurativa) In: Acne and 13. Mendoca C, Griffiths C. Combination therapy with
related disorders. Martin Dunitz, London, 1988 clindamycin and rifampicin is effective for hidrad-
6. Jemec GB, Faber M, Gutschik E et al. The bacteriol- enitis suppurativa. Poster at the American Academy
ogy of hidradenitis suppurativa. Dermatology 1996; of Dermatology Annual Meeting, 2005
193:203206 14. Faye O, Poli F, Gabison G, Pouget F, Wolkenstein
7. Lapins J, Jarstrand C, Emtestam L. Coagulase-nega- P, Revuz J. Assocation rifampicine clindamycine
tive staphylococci are the most common bacteria dans lhidradnite suppure. Oral communication
found in cultures from the deep portions of hidrad- at journes dermatologiques de Paris. December
enitis suppurativa lesions, as obtained by carbon di- 2005
oxide laser surgery. Br J Dermatol 1999; 140:9095
Chapter 16
Antiandrogens
Evelyne Drapier-Faure, Michel Faure
16

Q The role of androgens in hidradenitis In 1986, two reports suggested that hidradenitis
suppurativa (HS) is controversial suppurativa (HS) responds to antiandrogen
therapy [9, 13]. They supported the hypothesis
Q HS may correspond to an inflamma- that HS is an androgen-dependent disease. In
tory disease with an increased sensitiv- fact, no further work exists favouring this hy-
ity to circulating or in situ androgens, pothesis. Furthermore, clinical and biological
but this view is not supported by those investigations are really needed to elucidate the
few cases in which there is a positive possible participation of androgens and the pos-
response to antiandrogens sibility of hyperandrogenism in HS (see Chap.
12, Endocrinology). What a so-called response
Q Further studies are needed to investi- to antiandrogens in HS means, and the evidence
gate whether HS responds to antian- for this is really only poorly suggested, and must
drogens and to settle the controversy be discussed in terms of antiandrogen therapy.
of whether HS can be considered as a
manifestation of cutaneous hyperan-
drogenism 16.2 Antiandrogens
and Antiandrogen Therapies
Antiandrogens are molecules that bind the an-

drogen receptor (AR) and act as androgen an-
#ONTENTS tagonists at the target cell level. Cyproterone
acetate (CPA) and spironolactone are the most
16.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .124 commonly used androgenic antagonists [3, 12].
16.2 Antiandrogens and Antiandrogen Additional hormonal treatment of hyperan-
Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124 drogenism includes: (1) inhibition of the con-
16.2.1 Cyproterone Acetate . . . . . . . . . . . . . . . . . .125 version of testosterone (T) into its active me-
16 16.2.2 Spironolactone . . . . . . . . . . . . . . . . . . . . . . . .125 tabolite dihydrotestosterone (DHT) through
16.2.3 Finasteride . . . . . . . . . . . . . . . . . . . . . . . . . . .125 5_-reductase inhibition; (2) suppression of
16.2.4 Antiandrogenic Progestins . . . . . . . . . . . . .125
ovarian androgen production with oral contra-
16.2.5 Oral Contraceptives . . . . . . . . . . . . . . . . . . .125
ceptives (OC); (3) elevation of sex-hormone-
16.3 Antiandrogens in HS . . . . . . . . . . . . . . . . . .126 binding globulin (SHBG) levels through oestro-
16.3.1 Cyproterone Acetate . . . . . . . . . . . . . . . . . . .126
gens, either natural oestradiol, (E2, as oestrogen
16.3.2 Spironolactone . . . . . . . . . . . . . . . . . . . . . . . .126
therapy) or ethinyloestradiol (EE, with OC),
16.4 Finasteride . . . . . . . . . . . . . . . . . . . . . . . . . . .126 with a further decrease in plasma free androgen
References . . . . . . . . . . . . . . . . . . . . . . . . . . . .127 levels (Table 16.1).
Antiandrogens Chapter 16 125
Table 16.1. Treatments for androgenic disorders 16.2.3 Finasteride

Antiandrogens = androgenic antagonists
Cyproterone acetate
Finasteride is not an antiandrogen. It does not
Spironolactone act by blocking AR, but by inhibiting 5_-reduc-
Others
tase, which transforms T into DHT. Finasteride
5-Reductase inhibition inhibits the progressive hair loss in men with
Finasteride androgenic alopecia. It remains to be shown
Ovarian suppression whether finasteride is effective in women with
Combination OC female-pattern hair loss. In fact, due to the pos-
Progestogens (non-androgenic) sible feminization of a male fetus in the case of
Oestrogens pregnancy whilst taking finasteride, the drug
Increase of SHBG has not been approved in women [1].
Oestrogens
Combination OC (non-androgenic)
Weight loss 16.2.4 Antiandrogenic Progestins
Non-hormonal
Depilation, epilation Other progestins with antiandrogen properties
Anti-acne (retinoids, antibiotics) [11, 14] (antagonists at the AR levels) include
chlormadinone acetate (CMA), drospirenone
and dienogest. They may be used either in com-
16.2.1 Cyproterone Acetate bination with EE [5, 8, 16] as a contraceptive OC
(similarly the combination of CPA 2mg + 30 +g
CPA is a progestin with several antiandrogenic EE) or as antiandrogenic progestin alone (CMA
activities: binding to AR, inhibition of andro- for instance) according to countries where the
gen metabolism and antigonadotropic activity. drugs have been approved. In fact no evaluation
CPA has been used extensively in Europe for of the effects of these progestins exists in wom-
30 years in the treatment of hirsutism. It can be en with hirsutism, severe acne or chronic alope-
given according to various regimens (usually cia.
50 mg daily on days 120 of each menstrual
cycle, but other regimens are possible with CPA
of 50 or 100 mg) together with natural E2 or 16.2.5 Oral Contraceptives
with an OC pill. Good results may be obtained
in hirsutism and also in women with severe Androgenic symptoms in patients with hyper-
and/or persistent acne or with androgenic alo- androgenism may also be minimized with OC
pecia. Side-effects are uncommon and the anti- combinations. OC may be indirectly antiandro-
androgen is well tolerated [6, 11, 17, 18]. genic through the suppression of ovarian an-
drogen production (antigonadotropic activity)
and the oestrogen-induced elevation of SHBG.
16.2.2 Spironolactone In fact, all synthetic progestins are either pro-
gesterone or testosterone derivatives. They not
Spironolactone is the most generally used anti- only bind the progesterone receptor but may
androgen in countries where CPA has not been also bind AR, with either agonistic or antago-
approved. Spironolactone binds to AR but is de- nistic activity. Therefore, most progestins have
void of antigonadotropic activity. Doses needed androgenic properties, balancing, when com-
for antiandrogenic efficacy are 75200 mg daily bined with EE, the antiandrogenic activity of
depending upon the indication (acne, alopecia EE. Therefore, OC in women with a hyperan-
or hirsutism). Concomitant use of OC or a non- drogenic disorder should comprise oestrogen
androgenic progestin can prevent menstruation progestin combinations containing antiandro-
disorders. Tolerance is good even on long-term genic or non-androgenic progestins. However,
therapy [3, 10]. these OC cannot be considered as effective anti-
126 Evelyne Drapier-Faure, Michel Faure
androgens in women with hirsutism, severe SHBG and T/SHBG ratio (free androgen index)
acne or chronic diffuse hair loss. Their antian- that were noted.
drogenic action is limited to moderate or mild Also in 1986, Sawers et al. [13] reported the
acne, in association with other anti-acne thera- analysis of four women with HS who received
pies [3, 14, 15]. CPA in combination with EE according to the
then classic reversed sequential regimen of
Hammerstein, namely 100 mg CPA per day for
16.3 Antiandrogens in HS 10 days and 50 +g EE per day for 21 days. This
was a classic antiandrogenic regimen used to
There are only three reports suggesting a possi- treat hirsutism. All four patients were reported
ble role for antiandrogens in the management of to exhibit objective clinical improvement and to
HS. report a subjective impression of improvement
after only one to two cycles of treatment. Three
patients experienced a worsening of the symp-
16.3.1 Cyproterone Acetate toms when CPA was reduced. In fact, it is ques-
tionable whether these women, or at least two of
In 1986 Mortimer et al. [9] published the first them, were really suffering from HS and not
and only study of the effects of CPA in women from acne. Furthermore this was merely an
with HS. This was a double-blind controlled uncontrolled study, an open report of only four
cross-over trial of EE 50 +g /CPA 50 mg cases of mild HS under antiandrogen and
compared to an ordinary OC in combination oestrogen therapy.
with EE 50 +g/norgestrel 500 +g, in 24 female In fact there are presently no studies to sug-
patients for 12 cycles. They reported substantial gest a role for CPA as an antiandrogen in the
improvement in disease activity with both treat- management of HS.
ments. In fact, only 18 patients out of 24 com-
pleted the trial and only 12 patients improved,
while 4 deteriorated. No clinically significant 16.3.2 Spironolactone
differences between the two regimens were not-
ed. Indeed, objective assessments provided No study exists on the effects of spironolactone
insufficient evidence for improvement. Accu- as an antiandrogen in women with HS. Howev-
rate assessments could only be made with er, Cunliffe noted in 1989 that some clinical
knowledge of the frequency and severity of at- benefit had been obtained in an uncontrolled
tacks of the disease, as judged by the patients study with spironolactone 200 mg daily in about
themselves [9]. half of patients [2].
The fact that no difference was noted be-
tween the two groups does not favour a role for
CPA as an antiandrogen in HS. The combina- 16.4 Finasteride
tion used in the control group was an OC with
an androgenic progestin. In hirsutism, which is Two patients were reported in 1999 by Farrell
16 a major skin hyperandrogenic condition, and in et al. [4] to have a good response to finasteride
severe acne, this kind of combination with ei- (5 mg/day), a dose five times higher than that
ther 50 +g or 35 +g EE is not effective, while used in male alopecia. A 56-year-old man with a
50 mg CPA daily is. If some improvement in HS 10-year past history of HS reported significant
could be noted in 12 patients out of the initial improvement in his symptoms as early as the
24, whichever combination was used, this can- 4th week of treatment. A 55-year-old postmeno-
not be related to the antiandrogenicity of CPA. pausal woman with a history of HS since ado-
Rather, it may reflect the indirect antiandrogen- lescence and a previous absence of response
icity of EE, decreased ovarian androgen produc- to CPA received finasteride 5 mg/day. After
tion and increased SHBG synthesis, as evi- 3 months she reported an improvement of her
denced by the variations in plasma testosterone, lesions without any significant adverse effects.
Antiandrogens Chapter 16 127
Since then, seven patients of both sexes have 9. Mortimer PS, Dawber RPR, Gales MA, Moore RA
been treated with finasteride 5 mg/day in an (1986) A double-blind controlled cross-over trial
open study with follow-up periods ranging from of cyproterone acetate in females with hidradenitis
suppurativa. Br J Dermatol 115:2638
8 months to 2 years [7]. Three patients had com-
10. OBrien RC, Cooper ME, Murray RML, Seeman
plete healing of lesions and six patients were E, Thomas AK, Jerums G (1991) Comparison of
said to improve significantly. In fact, double- sequential cyproterone acetate/estrogen versus spi-
blind placebo-controlled studies are needed to ronolactone/oral contraceptive in the treatment of
clarify this situation. hirsutism. J Clin Endocrinol Metabol 72:100813
11. Raudrant D, Rabe T (2003) Progestogens with anti-
androgenic properties. Drugs 63:56392
12. Rittmaster RS (1995) Medical treatment of andro-
References
gen-dependent hirsutism. J Clin Endocrinol Metab
80:255963
1. Brenner S, Matz H (1999) Improvement in andro-
13. Sawers RS, Randall VA, Ebling FJB (1986) Control of
genic alopecia in 53-76 year old men using oral finas-
hidradenitis suppurativa in women using combined
teride. Int J Dermatol 38:92830
anti-androgen (cyproterone acetate) and oestrogen
2. Cunliffe WJ (1989) Non-acne disorders of the pilose-
therapy. Br J Dermatol 115:26974
baceous unit, hidradenitis suppurativa. In: Cunliffe
14. Sitruk-Ware R (2004) Pharmacological profile of
W (ed) Acne. Martin Dunitz, London, pp 8792
progestins. Maturitas 47:27783
3. Drapier-Faure E (1998) Traitement hormonal des hy-
15. Stanczyk FZ (2002) Pharmacokinetics and potency
perandrogenies. Reprod Hum Hormones 11:808
of progestins used for hormone replacement ther-
4. Farrell AM, Randall VA, Vafaee T, Dawber RPR
apy and contraception. Rev Endocr Metab Disord
(1999) Finasteride as a therapy for hidradenitis sup-
3:21124
purativa. Br J Dermatol 141:11389
16. Terouane B, Paris F, Servant N, Georget V, Sultan C
5. Fuhrmann J, Krattenmacher R, Slater E, Fritzmeier
(2002) Evidence that chlormadinone acetate exhib-
KH (1996) The novel progestin drospirenone and
its antiandrogenic activity in androgen-dependent
its natural counterpart progesterone: biochemical
cell line. Mol Cell Endocrinol 198:1437
profile and antiandrogenic potential. Contraception
17. Thorneycroft IH (1999) Update on androgenicity.
54:24351
Am J Obstet Gynecol 180:S288S94
6. Hammerstein J, Meckies J, Leo-Rossberg I, Moltz
18. Vexiau P, Boudou P, Fiet J, Hardy N, Conard J,
L, Zielske F (1975) Use of cyproterone acetate in the
Consoli S, Abramovici Y, Cathelineau G (1995)
treatment of acne, hirsutism and virilism. J Ster Bio-
17` Estradiol: oral or parenteral administration in
chem 6:82736
hyperandrogenic women? Metabolic tolerance in
7. Joseph MA, Javaseelan E, Ganapathi B, Stephen J
association with cyproterone acetate. Fertil Steril
(2005) Hidradenitis suppurativa treated with finas-
63:50815
teride. J Dermatol Treat 16:748
8. Moore C, Luderschmidt C, Moltz L, Oettel M,
Klinger G, Schreiber G (1999) Antiandrogenic prop-
erties of the dienogest-containing oral contraceptive
Valette . Drugs Today 35:S69S78
Chapter 17
Oral Retinoids for Hidradenitis

Suppurativa 17
Jurr Boer

Q Therapy with isotretinoin for patients Isotretinoin is well recognized as the most suc-
with HS has only limited therapeutic cessful therapy for acne vulgaris. It is tradition-
benefit ally thought that hidradenitis suppurativa (HS)
and acne are closely related, and because of this
Q There are claims that etretinate and isotretinoin has also been tested in HS, as have
acitretin are superior to isotretinoin. the related compounds etretinate and acitretin.
These data, however, wait confirmation
in larger patient series
17.2 Isotretinoin
17.2.1 Mechanism of Action [1, 2]

#ONTENTS The mechanism of action of isotretinoin in HS
17.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .128
is unknown. In HS, the initial event is believed
to be poral occlusion. Retinoids can normalize
17.2 Isotretinoin . . . . . . . . . . . . . . . . . . . . . . . . . .128 follicular cornification, although etretinate and
17.2.1 Mechanism of Action [1, 2] . . . . . . . . . . . . .128
17.2.2 Clinical Experience. . . . . . . . . . . . . . . . . . . .129
acitretin have a clearly greater effect than
17.2.2.1 Isotretinoin Monotherapy for HS . . . . . . .129 isotretinoin in disorders of keratinization [3]. It
17.2.3 Isotretinoin Therapy in Patients has also been shown that isotretinoin can re-
with Acne and Coexistent HS . . . . . . . . . .129 duce ductal hypercornification [4]. Isotretinoin
17.2.4 Isotretinoin in the Pre- possesses anti-inflammatory effects, reduces
and Postoperative Phase . . . . . . . . . . . . . . . 131 the chemotaxis of polymorphonuclear leuco-
17.2.5 Isotretinoin in Combination Treatment cytes and has been reported to enhance immune
of HS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
17.2.6 Side-Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
function [5, 6]. These properties may be of ben-
efit in the treatment of HS. The main effect of
17.3 Etretinate and Acitretin. . . . . . . . . . . . . . . . 132 isotretinoin is to decrease of the size and secre-
17.3.1 Mechanism of Action . . . . . . . . . . . . . . . . . . 132
17.3.2 Clinical Experience: Etretinate
tions of the sebaceous glands.
and Acitretin for HS . . . . . . . . . . . . . . . . . . . 132 However, in contrast to what happens in
17 17.3.3 Side-Effects . . . . . . . . . . . . . . . . . . . . . . . . . . .134 acne, the size of sebaceous glands is not in-
References . . . . . . . . . . . . . . . . . . . . . . . . . . . .134
creased in HS. Isotretinoin also reduces the
ductal population of Propionibacterium acnes,
and although this has a very important effect on
acne pathogenesis, it does not appear to be use-
ful for the treatment of HS, because Propioni-
bacterium acnes has not been cultured in HS
lesions. Isotretinoin does not affect the size of
apocrine glands.
Oral Retinoids for Hidradenitis Suppurativa Chapter 17 129
17.2.2 Clinical Experience culoid lesions exist and undermining sinus

tracts have not yet developed, isotretinoin alone
17.2.2.1 Isotretinoin Monotherapy for HS can produce complete suppression and pro-
longed remission. Boer and van Gemert [12]
Isotretinoin monotherapy for patients with HS also found some indication that the response of
has limited therapeutic benefit. This is both the HS to isotretinoin is more successful in the
general overall impression of many experts as milder (furunculoid, papulo-pustular lesions)
well as the outcome of a study in which a large cases. It may be that treatment with isotretinoin
case series of 68 patients were followed over a at the earliest stages of HS corrects the follicular
period of almost 9 years [712]. The results of abnormality that is the root of this chronic dis-
case reports and studies with case series are ease [15].
summarized in Table 17.1.
All studies lack control groups with antibiot-
ics or other agents as a comparison, so no state- 17.2.3 Isotretinoin Therapy in Patients
ment as to relative efficacy can be made. How- with Acne and Coexistent HS
ever, in all the referred case studies many
patients did not respond to oral antibiotics or It is well known that acne and HS can occur in
surgery, or relapsed after such treatment. the same person. In addition to the coexistence
It is well known that acne patients with epi- of acne and HS, there are the so-called acne tri-
thelial sinus tracts with recurrent inflammation ad (acne conglobata, HS and perifolliculitis ca-
respond poorly to isotretinoin and are in fact pitis abscedens et suffodiens) and acne tetrad
most of the isotretinoin failures, at a high cu- (original acne triad and pilonidal sinus) condi-
mulative dose of isotretinoin as well [6, 13, 14]. tions [16]. This clinical overlap of acne and HS
These lesions are identical to those found in the has led to the inclusion of inhomogeneous pa-
axillae and groin in patients with HS [13, 14]. tients in the treatment groups. It concerns two
Shalita and co-workers [13] suggested that in possible different types of HS; firstly the disease
early cases in which only inflammatory furun- that only affects the inguinal folds and the axil-
Table 17.1. Reported results of isotretinoin therapy for hidradenitis suppurativa (HS)
No. of patients with an
Dose (mg/kg
Duration of
Severity of
Author (s)
(almost) clear score

Follow-up
treatment
No. of pa-
Duration
(months)
(months)
per day)
(years)
of HS
tients
HS
At the end At the end

of treatment of follow-up
Jones et al. [7] 3 1.0 4 2030 Severe 0 (0%)

Dicken et al. 8 0.711.2 4 26 535 Severe 4 (50%) 1 (12.5%)
[8]
Norris and 6 1.0 4 2 many years Severe 0 (0%)
Cunliffe [9]
Brown et al. 1 1.0 4 4 3 Severe 1 (100%) 1 (100%)
[10]
Mengesha 1 1.0 8 12 1 Severe 0 (0%)
et al. [11]
Boer and 68 0.50.81 46 6107 130 Mild to 16 (23.5%) 11 (16.2%)
van Gemert severe
[12]
130 Jurr Boer
Table 17.2. Reported results of isotretinoin treatment of patients with acne and coexisting HS
Author (s) No. of Dose (mg/kg Duration Improvement of HS Recurrence
patients per day) of treatment
(months)
Jones et al. [18] 1 0.11.0 4 No change

Plewig et al. [19] Un- 1.02.0 3 To a certain extent
specified
Peck et al. [20] 2 High, No data Improvement
no precise data
Shalita et al. [13] Uns- 0.51.0 45 Only suppressed
pecified furunculoid lesions.
No change in sinus tracts
Harms [21] 2 0.51.0 6 Improvement
Harms [2] 5 No data No data Considerable improve- No
ment in 4 out of
5 patients
Libow and Friar [22] 1 0.21.0 9 Quiescent No
lae (Verneuils disease), and secondly inguinal apy did not always totally suppress this type of
and axillary involvement in patients with acne lesion. The conclusion of the authors was that
affecting the face and back [2, 13, 17]. The last sinus tracts require surgical removal [13, 14].
disease has also been called acne ectopica and In several initial trials of isotretinoin in acne,
acne tetrad. the investigators often included some patients
It has been suggested that patients of these with HS in addition to their severe acne. Jones,
two categories would respond to isotretinoin in Blanc, and Cunliffe reported one case who failed
different ways [2, 13, 14, 17]. The data are sum- to respond after a 4-month course on an un-
marized in Table 17.2. specified dose of between 0.1 and 1.0 mg/kg per
Harms [2] treated eight patients suffering day [18]. Plewig and colleagues treated an un-
from HS, of whom five had concurrent acne of specified number of patients with acne tetrad
the face and three did not. Four out of five who responded to a certain extent [19]. Peck et
patients with the combination of acne and HS al. included two patients with HS in the groin
improved considerably under treatment with and axilla in addition to their cystic acne, who
isotretinoin and did not suffer any recurrence. showed improvement of the HS after the cystic
The three patients who had only inguinal in- acne had begun to improve and when the dos-
volvement did not improve (data about the dosage had been further increased above the level
es, duration of isotretinoin course and follow- required to improve their acne (the actual doses
up were not mentioned). It was concluded that used were high but not specified) [20]. Harms
patients with lesions only in inverse areas (axil- described in a case series of 56 patients with
17 lae, groin) should not be treated with isotreti- nodulocystic acne including two patients with
noin and that there may be patients with HS ano-inguinal lesions which only improved on
who respond very well to isotretinoin, namely isotretinoin at a dosage of 0.51.0 mg/kg per day
those with a combination of acne and additional for 6 months [21]. Libow and Friar reported ef-
HS [2, 17]. fective treatment of a patient with arthropathy
Other authors [13, 14] found that patients with associated acne triad condition with
with sinus tracts in the areas of acne with coex- isotretinoin [22]. A patient has been described
isting HS of the axillae and groin were often with arthropathy associated with cystic acne,
isotretinoin failures, in that isotretinoin ther- HS (in this case papulo-pustules and cysts in-
volving the genital and inguinal areas, no sinus only poorly to oral antibiotics and isotretinoin
tracts), and perifolliculitis capitis abscedens et (dose were not mentioned) [27]. The authors did
suffodiens who showed a dramatic response to not observe preoperative conditioning of the
isotretinoin (1.0 mg/kg per day) for 6 months, HS regions and in their case series they did not
followed by isotretinoin (0.5 mg/kg per day ev- recognize any minimalization of the areas in-
ery other day) for another 3 months before be- volved by the HS lesions. No controlled trials
ing discontinued. At the completion of 6 months are available to assess the claims of the useful-
of therapy, his cutaneous disease was quiescent ness of this pre- and postoperative treatment
and there was no recurrence of either joint or with oral isotretinoin.
cutaneous disease (a follow-up period was not
mentioned).
So, the results of these case reports [2, 13, 17.2.5 Isotretinoin in Combination
1822] are at best equivocal compared to the ex- Treatment of HS
cellent results in acne treatment. In the same
patients the acne seemed to clear completely or One author reported on a patient with Crohns
was much improved, while in most case reports disease and HS who showed a satisfactory out-
the HS lesions obviously remained and showed come following treatment with azathioprine
only a limited response. A follow-up period was (150 mg/day) and methylprednisolone (16 mg/
never mentioned. A (partial) response of HS le- day) combined with isotretinoin (0.7 mg/kg per
sions to isotretinoin was also more slow to de- day) and periodic administration of antibiotics
velop than the response to acne. Moreover, [28]. Another report details a patient with mul-
isotretinoin has a very poor effect on sinus tiple pustular and cystic lesions located on swol-
tracts, whether located in the same area as the len and red labia majora. She was successfully
acne or in the axillae and groin [13, 14, 16, 23]. treated with prednisolone and erythromycin for
months and then long-term isotretinoin (mostly
1.0 mg/kg per day) for 15 months, and no sig-
17.2.4 Isotretinoin in the Pre- nificant relapse of the so-called vulval apocrine
and Postoperative Phase acne occurred during a follow-up period of 10
months [29].
The use of oral isotretinoin has been recom-
mended by Plewig and co-workers during the
weeks or months before surgery and even post- 17.2.6 Side-Effects
operatively [16, 24]. The drug has anti-inflam-
matory activity and may drastically reduce sup- The side-effects of isotretinoin are very numer-
puration and edema [24]. It also reduces the ous [2, 3032]. In the studies mentioned, no se-
volume of the sebaceous glands and alternates rious side-effects are reported. In patients who
the pattern of keratinization within the follicle are treated with isotretinoin (mostly for 16
[25]. It has been suggested that in this way the weeks), liver function tests and determination
area involved by HS lesions can be significantly of lipid profiles have to be performed at baseline
reduced [25, 26], although isotretinoin by itself and on one occasion after 4 weeks [31]. Terato-
is insufficient to stop the disease [16, 24]. genicity is by far the most serious of all the side-
In various German trials, patients were treat- effects of retinoids and requires responsible pre-
ed with an unspecified dose of between 0.2 and scribing by physicians and reliable patients [31,
2.0 mg/kg per day for the 24 months before 32]. Women of child-bearing age must not start
surgical intervention until some days postoper- therapy until a negative pregnancy test result
atively and, if indicated, in combination with within 1 week before starting therapy has been
glucocorticosteroids for 23 weeks at a dose of obtained. Adequate contraception, i.e., two reli-
0.21.0 mg/kg per day and systemic antibiotics able forms of birth control, must be used before
[2426]. Lentner, Rbben and Wienert then re- and during oral isotretinoin therapy, as well as
ported on 28 patients with HS who responded for 6 weeks post-therapy. Therapy should start
132 Jurr Boer
on the second or third day after the onset of the 4 months of isotretinoin at a dose of 1.4 and 2.0
next normal menstrual period. It is strongly mg/kg per day, respectively [38]; two courses at
recommended that prescribers write prescrip- a dose of 0.8 mg/kg per day for 4 and 3 months,
tions for no more than a 1-month supply at a respectively [36]; two full courses for 5 months
time and that patients undergo monthly preg- at a dose of 2 mg/kg per day [35], and in one
nancy testing [32]. patient a 4-month course of isotretinoin (1 mg/
kg per day), which cleared the patients acne
conglobata but was singularly unhelpful for his
17.3 Etretinate and Acitretin HS lesions [37]. Stewart [34] treated his six pa-
tients with ongoing doses of etretinate and they
17.3.1 Mechanism of Action were observed over periods of 639 months. Af-
ter 3 months of treatment, three patients showed
There is a broad base of clinical experience with good clearing of disease (50%75%) and after
etretinate and acitretin in the treatment of 12 months of treatment all patients eventually
chronic keratinizing disorders [33]. If ductal hy- had an excellent response. The criteria for clear-
perkeratinization is crucial in the pathogenesis ing in the HS patients were: disappearance of
of HS, etretinate and acitretin could be good al- sinuses and cessation of discharge. Two patients
ternatives to isotretinoin, because these drugs were taken off etretinate, and it took 4 months
have a clearly greater effect on hyperkeratiniza- for them to begin to show signs of disease recur-
tion [3]. In addition, etretinate and acitretin rence (increasing discharge and formation of
show considerable immunomodulatory and the old sinus tracts). Hogan and Light [35] treat-
anti-inflammatory effects [33]. Acitretin, the ed a 24-year-old women with a 6-month course
active retinoid metabolite, has generally re- of acitretin at a dosage of 0.5 mg/kg per day. Af-
placed etretinate in retinoid therapy, certainly ter 2 months of treatment with acitretin a 50%
in psoriasis because of its more favorable phar- decrease in induration of the axillae was noted.
macokinetic profile, including a significantly After 4 months of treatment there was no longer
shorter half-life. any induration or abscess formation in her
axillae. Her HS remained in remission until
11 months after discontinuation of acitretin.
17.3.2 Clinical Experience: Etretinate Therapy was reinstituted with success [35].
and Acitretin for HS Vahlquist and Griffiths [36] treated a 47-
year-old man with etretinate (0.7 mg/kg per
Etretinate and acitretin were of great benefit in day). Within a few weeks the lesions had be-
all ten patients with HS, as described in five case come less painful. After a treatment period of
reports [3338]. In 1984 Stewart [34] was the 11 months, the patient was essentially free of ac-
first to report on HS treatment with etretinate tive lesions and the etretinate therapy was dis-
in a study of six patients; four other case reports continued. Although scarring was still a prob-
followed in the period from 1988 until 2002 lem, the patient had no longer pain. A minor
[3538]. The data are summarized in Table relapse was recorded 1 year after stopping etret-
17.3. inate and this was successfully controlled by a
Overall, eight patients were treated with short course of oral antibiotics [36]. Chow and
17 etretinate at a dose of 0.351.0 mg/kg per day Mortimer [37] treated a 31-year-old man with
[34, 36, 37] and two patients with acitretin at a etretinate (0.5 mg/kg per day) for 9 months, the
dose of 0.51.0 mg/kg per day [35, 38]. Six out of first 3 months together with erythromycin 1 g
ten patients were on isotretinoin (0.82 mg/kg daily. Within 2 months, he was showing signs of
per day) before starting etretinate and acitretin, improvement, with less pain, less discharge,
of whom two were in Stewarts series [34] and and a decrease in the number of acute exacer-
their dosage is not mentioned. The results were bations. After 3 months there was no sign of dis-
unsatisfactory in all cases. The doses of isotreti- ease activity, although linear fibrotic bands of
noin were usually high, i.e., two full courses for scarring remained. Disease was still in remis-
Table 17.3. Reported results of etretinate/acitretin therapy for hidradenitis suppurativa (HS)
Author (s) No. of Region Retinoid Duration Follow-up Duration Improvementa
patients, sex, dose of treat- (months) of HS
age (in years) (mg/kg ment (years)
per day) (months)
At the end At the end

of treatment of follow-up
Stewart [34] 3F: 34, 36, 64 Mixed Etretinate 339 339 No data Clearb Clear with ongoing
3M: 31, 32, 55 0.351.1 treatment
Hogan and 1F: 24 Mixed Acitretin
Light [35]
0.5 6 At least 11 10 clear Mild flare
months 11 months; clear
with acitretin
Vahlquist and 1M: 47 Buttocks Etretinate 11 Years 12 clear Minor flare 12 months;
Griffiths [36] 0.7 clear with antibiotics
Oral Retinoids for Hidradenitis Suppurativa
Chow and 1M: 31 Mixed Etretinate 12 3 5 clear Clear

Mortimer [37] 0.5
Scheman [38] 1M: 41 Groin Acitretin
0.60.9 12 12 No data clear Clear with ongoing
treatment
Chapter 17
a
Clear defined as no disease activity; fibrotic bands and scarring remain
b
Two patients discontinued etretinate after 3 months, for reasons not mentioned
133
134 Jurr Boer
sion 3 months after stopping etretinate [37]. or isotretinoin for as many as 15 years and had
Scheman [38] treated a 41-year-old man, who not developed any signs of severe toxicity [39].
presented with severe nodulocystic facial acne Acitretin has been established as a safe, effective
and HS on the inguinal folds, with acitretin treatment for psoriasis [3941]. Retinoids, in-
(0.6 mg/kg per day). After 2 months, the pa- cluding etretinate and acitretin, are potent
tients HS was completely controlled, and his teratogens, leading to strict requirements for
very severe acne improved to only a few in- pregnancy prevention during and after their use
flamed nondraining facial cysts. With a dosage [3941]. Etretinate can be prescribed for male
of acitretin of 0.9 mg/kg per day the patient was patients or postmenopausal female patients [41].
completely free of inflammatory lesions on his Premenopausal fertile woman should not be
face and groin. After 4 months on this dosage, treated with etretinate but can be considered for
however, alopecia and unacceptable joint pain acitretin therapy providing they use adequate
developed. After 1 month off acitretin, the pa- contraception during therapy and for 24 months
tients side-effects resolved. Treatment was re- [39, 41] or even 36 months [40] after discontinu-
sumed back at a dose of 0.6 mg/kg per day, with ation. In fertile female patients it is also sug-
results similar to those when the patient was gested to do a pre-treatment pregnancy test and
previously on this dosage. After 5 months of repeated pregnancy tests every month of thera-
therapy, improvement continued to be satisfac- py [41].
tory [38].
It is of concern that no controlled studies
have been published. Nevertheless, there seem References
to be some striking points in these case studies.
All patients (n=10) treated with etretinate or 1. Ward A, Brogden RN, Heel RC, Speight TM, Avery
acitretin at a dose of 0.351.1 mg/kg per day re- GS. Isotretinoin: a review of its pharmacological
sponded excellently. All patients were essential- properties and therapeutic efficacy in acne and re-
lated disorders. Drugs 1984; 28: 637
ly free of active lesions [36], and were completely 2. Harms M. Systemic isotretinoin. A unique therapeu-
free of inflammatory cysts [38] and sinus tracts tic effect and its implications in the pathogenesis of
[34]; any induration and abscess formation dis- acne. Editiones Roche, Basel, Switzerland, 1994
appeared [3537], although linear fibrotic bands 3. Dalziel K, Barton S, Marks R. The effect of isotreti-
of scarring remained [36, 37]. These excellent noin on follicular and sebaceous gland differentia-
responses were obviously not obtained by earlier tion. Br J Dermatol 1987; 117:317323
courses with isotretinoin in the same patients. 4. Cunliffe WJ, Jones DH, Pritlove J, Parkin D. Long-
term benefits of isotretinoin in acne. Clinical and
In addition, the decrease of disease activity
laboratory studies. In: Saurat JH, Ed. Retinoids: new
seemed to start after approximately 2 months of trends in research and therapy. Karger, Basel, 1985;
treatment. However, in a panel discussion Cun- pp 242251
liffe stated that their group treated three or four 5. Pigatto PD, Floroni A, Riva F, Brugo MA, Morandot-
patients with etretinate without too much suc- ti A, Altomare GF, Finzi AF. Effects of isotretinoin
cess (unpublished observations). The treatment on the neutrophil chemotaxis in cystic acne. Derma-
with etretinate was stopped after 6 or 8 months tologica 1983; 167:1618
[39]. 6. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotret-
inoin for acne vulgaris 10 years later: a safe and suc-
cessful treatment. Br J Dermatol 1993; 129:292296
17 7. Jones DH, Cunliffe WJ, King K. Hidradenitis suppu-
17.3.3 Side-Effects rativa lack of success with 13-cis-retinoic acid (let-
ter). Br J Dermatol 1982; 107:252
Etretinate is a prodrug of acitretin with a mo- 8. Dicken CH, Powell ST, Spear KL. Evaluation of
lecular weight about 10% greater than that of isotretinoin treatment of hidradenitis suppurativa.
acitretin, with the consequence that the daily J Am Acad Dermatol 1984; 11:500502
9. Norris JFB, Cunliffe WJ. Failure of treatment of
dose, usually 3075 mg etretinate, corresponds
familial widespread hidradenitis suppurativa with
to 2050 mg acitretin. In the early 1990s, many isotretinoin. Clin Exp Dermatol 1986; 11:579583
patients had been treated with either etretinate
10. Brown CF, Gallup DG, Brown VM. Hidradenitis 27. Lentner A, Rbben A, Wienert V. Klinische Er-
suppurativa of the anogenital region: response to scheinungsbild und Tharapie der Pyodermia fistu-
isotretinoin. Am J Obstet Gynecol 1988; 158:1215 lans significa. Symptomatology and therapy of hi-
11. Mengesha YM, Holcombe TC, Hansen RC. Prepu- dradenitis suppurativa. Z Hautkr 1992; 67:988992
bertal hidradenitis suppurativa: two case reports 28. Tsianos EV, Dalekos GN, Tzermias C, Merkouro-
and review of the literature. Pediatr Dermatol 1999; poulos M, Hatzis J. Hidradenitis suppurativa in
16:292296 Crohns disease. J Clin Gastroenterol 1995; 20:151
12. Boer J, Gemert van MJP. Long-term results of 153
isotretinoin in the treatment of 68 patients with hi- 29. Fearfield LA, Staughton RCD. Severe vulval apo-
dradenitis suppurativa. J Am Acad Dermatol 1999; crine acne successfully treated with prednisolone
40:7376 and isotretinoin. Clin Exp Dermatol 1998; 24:189
13. Shalita AR, Cunningham WJ, Leyden JJ, Pochi PE, 192
Strauss JS. Isotretinoin treatment of acne and relat- 30. Saurat JH. Side effects of systemic retinoids and
ed disorders: an update. J Am Acad Dermatol 1983; their clinical management. J Am Acad Dermatol
9:629638 1992; 27:S23S28
14. Leyden JJ. Oral isotretinoin. How can we treat dif- 31. Barth JH, Macdonald-Hull SP, Mark J, Jones RG,
ficult acne patients? Dermatology 1997; 195 [Suppl Cunliffe WJ. Isotretinoin therapy for acne vulgaris:
1]:2933 a re-evaluation of the need for measurements of
15. Webster GF. Acne vulgaris. Br Med J 2002; 325:475 plasma lipids and liver function tests. Br J Dermatol
479 1993; 129:704707
16. Jansen T, Altmeyer P, Plewig G. Acne inversa (alias 32. Perlman SE, Leach EE, Dominguez L, Ruszkowski
hidradenitis suppurativa). J Eur Acad Dermatol Ve- AM, Rudy SJ. Be smart, be safe, be sure. The re-
nereol 2002; 15:532540 vised pregnancy prevention program for woman on
17. Jemec GBE. Medical treatment of hidradenitis sup- isotretinoin. J Reprod Med 2001; 46:179185
purativa. Expert Opin Pharmacother 2004; 5:1767 33. Pilkington T, Brogden RN. Acitretin. A review on
1770 its pharmacology and therapeutic use. Drugs 1992;
18. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid 43:597627
and acne. Lancet 1983; ii:10481049 34. Stewart WD. Etretinate in other diseases of kera-
19. Plewig G, Nikolowsky J, Wolff HH. Action of iso- tinization. In: The retinoids: a significant advance
tretinoin in acne rosacea and gram-negative fol- in dermatology. Medicines Publishing Foundation
liculitis. J Am Acad Dermatol 1982; 6:766785 Symposium Series, Oxford, 1984; Series 14:5155
20. Peck GL, Olsen TG, Butkus D, Pandya M, Arn- 35. Hogan DJ, Light MJ. Successful treatment of hidra-
aud-Battandier J. Isotretinoin versus placebo in the denitis suppurativa with acitretin. J Am Acad Der-
treatment of cystic acne. J Am Acad Dermatol 1982; matol 1988; 19:355356
6:735745 36. Vahlquist A, Griffiths WAD. Retinoid therapy in
21. Harms M. Traitement de lacn par lisotretinone hidradenitis suppurativa report of a case. Reti-
par voie buccale. Etude clinique sur 56 patients. noids Today Tom 1990; 18:2830
Schweiz Med Wschr 1983; 42:15491554 37. Chow ETY, Mortimer PS. Successful treatment of
22. Libow LF, Friar DA. Arthropathy associated with hidradenitis suppurativa and retroauricular acne
cystic acne, hidradenitis suppurativa, and perifol- with etretinate. Br J Dermatol 1992; 126:415
liculitis capitis abscedens et suffodiens: treatment 38. Scheman AJ. Nodulocystic acne and hidradenitis
with isotretinoin. Cutis 1999; 64:8790 suppurativa treated with acitretin: a case report.
23. Jemec GBE. Hidradenitis suppurativa. J Cutan Med Cutis 2002; 69:287288
Surg 2003; 7(1):4756 39. Shalita AR, Fritsch PO. Retinoids: present and
24. Plewig G, Steger M. Acne inversa (alias acne triad, future. J Am Acad Dermatol 1992; 27:S1S46
acne tetrad or hidradenitis suppurativa). In: Marks 40. Katz HI, Waalen J, Leach EE. Acitretin for psoriasis
R, Plewig G, Eds. Acne and related disorders. Mar- therapy. J Am Acad Dermatol 1998; 41:S7S12
tin Dunitz, London, 1989; pp 345538 41. Lowe NJ. Psoriasis: systemic retinoid treatment.
25. Rdder-Wehrmann O, Kster W, Plewig G. Acne In: Lowe N, Marks R, Eds. Retinoids. A clinicians
inversa. Diagnose und therapie. Hautarzt 1991; 42:5 guide, 2nd edn. Martin Dunitz, London, 1998;
8 pp 5769
26. Hermann A, Preusser KP, Marsch WC. Die Acne in-
versa Hidradenitis suppurativa): Frhzeitig erken-
nen und kurativ operieren. Chirurg 2000; 71:1395
1400
Chapter 18
Immunosuppressive Therapy
in Hidradenitis Suppurativa 18
Hanne Nybk, Gregor B.E. Jemec

Q Immunosuppression is a possible Hidradenitis suppurativa (HS) is an inflamma-
therapeutic strategy in the treatment tory skin disease. The clinical presentation and
of hidradenitis suppurativa (HS) historical concept of the disease have tradition-
ally been interpreted to indicate that bacteria
Q Immunosuppressive or anti-inflamma- have a pathogenic role, but specific microbio-
tory drugs are generally safe in HS logical investigations have suggested that the
role of bacteria is generally not that of a simple
Q The use of immunosuppression in the infection. Routine cultures are more often than
absence of bacterial infection often not found to be sterile, and recognized patho-
brings rapid relief to patients gens such as Staphylococcus aureus can be found
mainly in rapidly evolving lesions [1, 2]. Heavy
Q Immunosuppressive drugs can be used bacterial overgrowth of known pathogens is
to control flares, and prepare the therefore not a main feature of the disease, and
patient for surgery, for example the pathogenic role of bacteria may be an im-
munological one. Bacteria may only be the anti-
Q Longer term immunosuppression gen that starts an immunological disease. Simi-
may help the patient gain better control lar mechanisms have been described in guttate
of their disease for a period psoriasis and atopic dermatitis. In acne, bacte-
rial antigens have also been shown to elicit an
Q Immunosuppressive therapy alone immunological response, suggesting a similar
is unlikely to be curative mechanism.
Similarly scarring is a prominent feature of
more advanced disease [3]. Whereas scarring is
currently not amenable to medical therapy, pre-
#ONTENTS ventive medical therapy may be of clinical inter-
18.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .136
est. Since the primary pathogenic event in HS is
not known, treatment directed at minimizing
18.2 What Can We Achieve With Therapy? . . . 137 scar formation is of independent interest to all
18.3 Immunosuppressive Therapies . . . . . . . . . 137 involved. Immunosuppressive therapy has a po-
18.3.1 Prednisolone and Other Corticosteroids 138 tential in reducing the inflammatory phase of
18.3.2 Ciclosporin . . . . . . . . . . . . . . . . . . . . . . . . . .138 the disease, which may result in subsequent scar
18 18.3.3 Dapsone . . . . . . . . . . . . . . . . . . . . . . . . . . . . .138
formation. Accepting the possibility of such a
18.3.4 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . .138
mechanism, a different range of therapeutic op-
18.4 Hidradenitis Suppurativa as a Side- tions becomes available to the dermatologist.
Effect of Immunosuppressive Drugs . . . .139
18.5 Practical Use of Immuno-
suppressive Therapy . . . . . . . . . . . . . . . . . . .139
References . . . . . . . . . . . . . . . . . . . . . . . . . . .140
Immunosuppressive Therapy Chapter 18 137
Table 18.1. Immunosupressive treatment of HS

Drug Author Number Location Dosage Outcome
of patients and duration
Ciclosporin Gupta et al. [8] 1 (male, 6 mg/kg for 6 weeks Moderate response
60 years)
Buckley 1 4.5 mg/kg Good response
and Rogers [9]
Rose et al. [5] 2 a. Groin a. 4 mg/kg a. Continuous therapy
a. Female b. Axillae (3 months) with good effect
38 yearsa and groin then tapered b. Remission
b. Male to 2 mg/kg for for 4 months
31 years continuous therapy after 3 months
b. 3 mg/kg of treatment
for 3 months
Dapson Hofer 5 Axillae 25100 mg/day Effect within 24 weeks,
and Itin [11] and groin described as very good
by 2 and good by 3 patients
Methotrexate Jemec [12] 3 Axillae 12.515 mg per week No effect on primary
and groin for 6 weeks lesions or recurrence rates,
to 6 months but slight weakening
of flare intensity
a
Patients previously treated with corticosteroids.
18.2 What Can We Achieve 18.3 Immunosuppressive Therapies

With Therapy?
A limited body of data exists to describe the
The obvious goal of therapy in HS is to heal ex- therapeutic experience of using immunosup-
isting lesions and prevent the development of pressants in HS. It is not clear whether it is the
new lesions. This is potentially possible in early immunosuppressive or the anti-inflammatory
lesions (Hurley stage I), where scarring does not effect of these drugs which is the stronger when
dominate the clinical picture, although this used for HS, although it may be speculated that
form of treatment is more likely to alleviate long-term results stem from immunosuppres-
symptoms than to cure patients. Therapy may sion rather than anti-inflammatory therapy.
furthermore not influence established fibrosis, The therapies are however at best described
although intralesional steroids, for example, are through small case series, and the evidence base
commonly used to treat hypertrophic scars. of these therapies therefore needs to be expand-
Immunosuppression however has immediate ed. Dose-finding or testing observations are
benefits for patients. The main symptom for both necessary and interesting, and any positive
most patients with HS is pain, which in turn findings have to be confirmed in actual ran-
is due to inflammation. By offering patients domized controlled trials (see Table 18.1).
immunosuppressive therapies inflammation is
reduced and pain alleviated. Immunosuppres-
sive therapy therefore has both immediate and
potential long-term benefits for patients.
138 Hanne Nybk, Gregor B.E. Jemec
18.3.1 Prednisolone 18.3.2 Ciclosporin

and Other Corticosteroids
Single cases have been presented showing the
Early studies of adrenocorticotrophic hormone beneficial effects of ciclosporin (CsA) in the
(ACTH) and corticosteroids suggested that gen- management of HS [8, 9]. CsA has been used
eral immunosuppression was beneficial to the successfully where patients responses to sys-
well-being of HS patients [4]. These studies temic corticosteroids were found to be unsatis-
however do not conform to current require- factory because of rapid relapses [5]. One case
ments for evidence as they are anecdotal rather found that a 4-month remission was induced by
than randomized and controlled. Relief is how- CsA therapy, and that subsequent flares were
ever regularly offered to patients with flares of milder, but CsA has also been used as a low-
HS by treating with prednisolone, either as dose, long-term suppressive therapy.
monotherapy or in combination with other A beneficial effect of CsA would be in accor-
therapies. In this manner systemic corticoste- dance with the described early changes of HS,
roids may be used in a manner analogous to where a perifollicular lymphocytic infiltrate has
their use in acne fulminans. Usually doses of been found [10]. In other diseases the use of CsA
0.50.7 mg/kg are sufficient to achieve control has furthermore been characterized by a rapid
of the inflammation. Initial doses can then be onset of effect, which may be of particular inter-
tapered over weeks to control the disease. How- est to HS patients because of the associated pain
ever, in some cases tapering is not possible due reduction. No long-term results (years) or larger
to rapid flares and alternative therapies must case series have been reported.
therefore be instituted. The patients reported by
Rose et al. [5] are examples of such cases. Sys-
temic corticosteroids are therefore often used in 18.3.3 Dapsone
conjunction with other therapies such as antibi-
otics [6, 7]. This traditional drug has been widely used in
Careful swabbing and biochemical control the treatment of acne conglobata. A case series
are necessary to identify ongoing clinically sig- has been published suggesting its efficacy in HS
nificant infections when prednisolone therapy as well [11]. Potentially this drug may have anti-
is instituted. Similarly patients must be in- bacterial effects as well, but the main effect is
formed of possible side-effects of the treatment. immunosuppressive. Any effect in HS should be
Intralesional steroids are also an important suspected as being due to general immunosup-
tool for HS management, although their use is pression rather than a specific effect on neutro-
again unsupported by formal studies. Intrale- philic granulocytes, which are not common in
sional steroids are most often used to treat recal- HS lesions.
citrant nodules in HS (see Chap. 21). Triamcino-
lone (10 mg/ml) is the most commonly used
drug, but other drugs may be as efficient. The 18.3.4 Methotrexate
effect of the injection occurs after a few days,
either as the disappearance of the lesion, or The histological similarities and co-occurrence
spontaneous rupture. Pain is generally reduced of HS and Crohns disease have led to specula-
significantly in a short space of time. The long- tion that treatments used for Crohns disease
term effect of using intralesional corticosteroids may have a role in the management of HS as
is not known. In our experience complications, well. This is further supported by the beneficial
18 with for example superinfection, are rare, and effects of biologics in HS (see Chap. 20). Metho-
can be monitored through more aggressive trexate is another drug used in Crohns disease
microbiological sampling with regular swabs that has been evaluated in a small open case se-
from lesions that do not react in the described ries. The results were variable, and although in-
manner but persist or develop in spite of treat- dividual patients experienced some relief from
ment. symptoms, an overall evaluation suggested only
Immunosuppressive Therapy Chapter 18 139
a weak effect on the severity of HS flares and no though proper randomized controlled trials are
apparent effect on the recurrence rate [12]. It is lacking. By viewing HS as any other inflamma-
possible that a higher dose of methotrexate than tory skin disease, parallel conclusions may
the one examined could influence the results however be drawn about the benefits of such a
positively. therapeutic strategy. It may be speculated that
long-term immunosuppression and a subse-
quent reduction of the inflammatory processes
18.4 Hidradenitis Suppurativa may stop or delay the subsequent fibrosis which
as a Side-Effect of Immuno- forms a major factor in the perpetuation of this
suppressive Drugs disease.
In contrast, treatment of flares is a short-term
HS has also been described as a side-effect of treatment, in which the immunosuppression is
immunosuppression associated with rapamycin aimed at easing the patients problems, but most
(Sirolimus) treatment [13]. This drug has been often it is used in conjunction with other thera-
reported to be associated with acne-like and pies that may be perceived as being more cura-
other follicular inflammation in renal trans- tive. Particularly in the early stages of the disease
plant patients. The study was carried out with immunosuppression may help gain sufficient
stringent dermatological evaluation of patients, control of a lesion to allow more curative
and an incorrect diagnosis of HS is therefore surgery, as this is made easier if the tissue is
relatively unlikely. Specific immunosuppressive not highly inflamed at the time of the operation.
mechanisms may therefore play a role and not Intralesional therapy may be used to achieve
all immunosuppressants may be suitable for use this (see Chap. 21). Similarly, immunosuppres-
in HS. In addition, bacterial infections may sim- sion at later stages may be combined with, for
ulate HS to non-dermatologists and cause addi- example, antibiotics to treat the combined
tional confusion. effects of long-standing HS and superinfection
more effectively.
Just as for most other forms of therapy, the
18.5 Practical Use of Immuno- data on which these treatments are used are very
suppressive Therapy limited. Publication of additional, larger case
series is therefore strongly encouraged, particu-
Immunosuppressive therapy can be used at all larly if the observations are structured so as to
stages of the disease for the benefit of the pa- provide information about possible doseeffects
tient. Essentially it may be directed at two dif- relationships, which may help determine the
ferent aspects of the disease: disease progression optimum dosage of a given drug for use in a
and flares. subsequent randomized controlled trial.
When used to treat disease progression it is a In general, immunosuppressive therapy is of-
long-term therapy aimed at controlling the inten perceived to be in conflict with the clinical
flammation-induced fibrosis of the tissue, and presentation of HS. This is however a view with
helping the patient to take more control of their a limited understanding of the disease process,
disease. The treatment should be continued for which involves considerable, sterile inflamma-
at least 3 months with monitoring of the effect tion. Therefore, as with many other dermato-
as well as possible side-effects specific to the logical conditions it may often be treated with
drug chosen. Very often patients have experi- anti-inflammatory or immunosuppressive ther-
enced a relentless progression of their disease apies. In addition, these therapies offer the ad-
and are therefore highly encouraged by the al- vantage of alleviating patient suffering effec-
leviation provided by these drugs. The clinical tively, if not permanently.
impression is therefore generally favorable, al-
140 Hanne Nybk, Gregor B.E. Jemec
8. Gupta AK, Ellis CN, Nickoloff BJ et al. Oral ci-

References closporin in the treatment of inflammatory and
non-inflammatory dermatoses: a clinical and im-
1. Lapins J, Jarstrand C, Emtestam L. Coagulase-nega- munohistopathologic study. Arch Dermatol 1990;
tive staphylococci are the most common bacteria 126:33950.
found in cultures from the deep portions of hidrad- 9. Buckley DA, Rogers S. Cyclosporin-responsive hi-
enitis suppurativa lesions, as obtained by carbon di- dradenitis suppurativa. J R Soc Med 1995; 88:289P
oxide laser surgery. Br J Dermatol 1999; 140:905. 290P.
2. Jemec GBE, Faber M, Gutschik E, Wendelboe P. The 10. Boer J, Weltevreden EF. Hidradenitis suppurativa
bacteriology of hidradenitis suppurativa. Dermatol- or acne inversa. A clinicopathological study of early
ogy 1996; 193:2036. lesions. Br J Dermatol 1996; 135:7215.
3. Jemec GBE, Thomsen BM, Hansen U. The homoge- 11. Hofer T, Itin PH. [Acne inversa: a dapsone-sensitive
neity of hidradenitis suppurativa lesions. A histologi- dermatosis.] Hautarzt 2001; 52:98992.
cal study of intra-individual variation. APMIS 1997; 12. Jemec GBE. Methotrexate is of limited value in the
105:37883. treatment of hidradenitis suppurativa. Clin Exp
4. Kipping HF. How I treat hidradenitis suppurativa. Dermatol 2002; 27:5289.
Postgrad Med 1970; 48:2912. 13. Mahe E, Morelon E, Lechaton S, Sang KH, Man-
5. Rose RF, Goodfield MJD, Clark SM. Treatment of souri R, Ducasse MF, Mamzer-Bruneel MF, de Prost
recalcitrant hidradenitis suppurativa with oral ciclo- Y, Kreis H, Bodemer C. Cutaneous adverse events
sporin. Clin Exp Dermatol 2005; 31:1545. in renal transplant recipients receiving sirolimus-
6. Camisa C, Sexton C, Friedman C. Treatment of hi- based therapy. Transplantation 2005; 79:47682.
dradenitis suppurativa with combination hypotha-
lamic-pituitary-ovarian and adrenal suppression. A
case report. J Reprod Med 1989; 34:5436.
7. Fearfield LA, Staughton RC. Severe vulval apocrine
acne successfully treated with prednisolone and
isotretinoin. Clin Exp Dermatol 1999; 24:18992.
18
Chapter 19
Zinc and Other Experimental

Medical Treatments 19
Brigitte Dreno, Anabelle Brocard
Key points tory lesions (superficial and deep lesions). Zinc

gluconate was about 15% less effective than
Q New drugs are being studied for the minocycline in a randomized trial [12].
medical therapy of hidradenitis In Verneuils disease, the drugs usually pre-
suppurativa (HS) scribed in acne (cyclines, isotretinoin) are poor-
ly effective, and a need for additional therapy
Q Zinc salt may have an anti-inflamma- exists. So, owing to the in vitro anti-inflamma-
tory effect in HS tory effect of zinc and its clinical efficacy against
inflammatory, even nodular, acne lesions, zinc
Q Botulinum toxin may play a role in the gluconate has been used in Verneuil s disease.
treatment of HS
19.2 Zinc Salts
19.2.1 Mechanisms of Action:

#ONTENTS Modulation of the Proliferation
19.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 141
and Differentiation of Keratino-
cytes and Cell Apoptosis
19.2 Zinc Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
19.2.1 Mechanisms of Action: Modulation
of the Proliferation and Differentiation
Zinc is a cofactor of many metallo-enzymes [1]
of Keratinocytes and Cell Apoptosis . . . . 141 implicated in the replication of DNA, gene tran-
19.2.2 Anti-Inflammatory Activity . . . . . . . . . . .142 scription, RNA and proteomic synthesis. Thus,
19.2.3 Activity Against 5A-Reductase . . . . . . . . .142 it increases the proliferation of keratinocytes
19.2.4 Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .142 and modulates their differentiation. This physi-
19.3 Zinc Salts in Verneuils Disease . . . . . . . . .142 ological role is altered by a severe shortage of
19.4 Other Experimental Drugs . . . . . . . . . . . . 143
zinc [2] (congenital or acquired). At the clinical
level, it induces an ichtyosiform aspect of the
References . . . . . . . . . . . . . . . . . . . . . . . . . . .144 skin, which is, moreover, atrophic. At the histo-
logical level, a parakeratosis aspect is noted,
with necrosis of keratinocytes, and at the elec-
19.1 Introduction tron microscopy level a decrease of keratohyalin
granules and tonofilaments in the keratinocytes
Zinc salts have been used for a long time in the is observed.
treatment of mild and moderate acne. The usual In the dermis, zinc also stimulates the prolif-
dose is between 30 mg and 60 mg zinc metal eration of fibroblasts, increasing collagen and
daily (corresponding to two and four respec- elastin production. This is mainly related to its
tively capsules of 15 mg zinc gluconate per day action on lysyl oxidase. In addition, it is a co-
in France). Clinical studies have shown a sig- enzyme of several metallo-enzymes of the der-
nificant effect of zinc salts mainly on inflamma- mis.
142 Brigitte Dreno, Anabelle Brocard
Zinc also has a role in the apoptosis of kerati- 19.2.3 Activity Against 5A-Reductase
nocytes. In vitro, the addition of a chelator of
zinc to the culture medium decreases the nucle- Zinc salts have anti-androgenic activity, by in-
ar concentration of zinc in keratinocytes, induc- hibiting the activity of 5A-reductase type I and
ing cell apoptosis. This activity is related mainly II (mainly I in vitro [7]). This enzyme induces
to its role as a co-enzyme of different transcrip- the transformation of testosterone to dihy-
tional factors implicated in apoptosis, such as drotestosterone, which binds to androgenic re-
P53 or FP1 (ferroportin 1). In addition, zinc, as ceptors expressed by sebaceous glands stimulat-
an antagonist of calcium, inhibits the activation ing the production of sebum. This activity
of endonucleases, which have an anti-apop- remains to be demonstrated in vivo.
totic activity. Recently it has been shown that
zinc salts stimulate the production of insulin-
like growth factor, which induces the prolifera- 19.2.4 Healing
tion of keratinocytes in the epidermis.
Zinc stimulates the migration of keratinocytes,
which play an important role in the healing of
19.2.2 Anti-Inflammatory Activity cutaneous wounds, by stimulating _3, _5 and
`1 integrin functions [8, 9].
Zincs efficacy in Verneuils disease is probably
due to its anti-inflammatory activity. It has ac-
tivity against various targets implicated in the 19.3 Zinc Salts
cutaneous inflammatory reaction and the in Verneuils Disease
mechanism of action is still only partially un-
derstood. Until now there have been no reports on zincs
As for non-specific immunity, 30 mg zinc efficacy in HS. At the Department of Dermatol-
metal [3] inhibits the chemotactic migration of ogy of Nantes (France), we have treated 22 pa-
granulocytes, both in vitro and in vivo. It acti- tients with Verneuils disease with zinc gluco-
vates natural killer cells and the phagocytic nate (Rubozinc) [10].
function of granulocytes [4]. In total, 15 women and 7 men were included
Zinc also inhibits the expression of integrins in the study. The mean age was 38.3 years, the
by keratinocytes in inflammatory lesions, i.e. mean age at the onset of lesions was 24. 6 years
ICAM 1 and LFA 3, which play an important and the mean duration between the beginning
role in the interactions between keratinocytes of the illness and diagnosis was 6.5 years. Eleven
and lymphocytes [5]. patients were at Hurleys grade I, 10 at grade II,
The production of two main inflammatory and 1 at grade III. Zinc gluconate was used at a
cytokines produced by keratinocytes in inflam- dose of six capsules of 15 mg zinc gluconate per
matory lesions, namely tumour necrosis factor day (Rubozinc). The mean follow-up was 23.7
alpha (TNFA) and interleukin-6 (IL-6), is inhib- months. Results were assessed depending on the
ited by zinc salts [6]. In addition, zinc has an degree of remission.
anti-oxidant activity, by inducing the expres- Of the included patients 8/22 (36%) experi-
sion of the enzyme Zn-Cu superoxide dismutase, enced complete remission. Complete remission
which is present in keratinocytes and fibro- was defined as no new lesions for 6 months or
blasts; thus, it increases the elimination of free more (Figs. 19.1, 19.2). For these patients an at-
radicals. As for T-cell-mediated immunity, zinc tempt to decrease the doses of zinc was made
is a cofactor of thymulin, which is a thymic cyto- but relapses were seen at a dose of between two
kine implicated in the maturation of T lympho- and four capsules. Recurrences disappeared
19 cytes. when the dosage of zinc salts was increased
again. Thus, the treatment appears clearly to be
suppressive rather than curative. A dosere-
sponse relationship may be present, as it would
Zinc and Other Experimental Medical Treatments Chapter 19 143
The efficacy of zinc salts in Verneuils disease

probably relies mainly on its anti-inflammatory
activity. A similar effect is seen in acne, where
zinc salts are used at a lower dose (30 mg metal
zinc) and treatment appears to be brought about
essentially by action on inflammatory lesions
[11, 12]. A prospective study is now ongoing to
confirm this preliminary result.
19.4 Other Experimental Drugs
Apocrine glands produce sweat, which becomes

Fig. 19.1. Before treatment smelly after bacterial degradation. Heckmann
et al. [13] reported that botulinum toxin may
decrease the production of sweat by apocrine
glands, similarly to the effect on eccrine glands.
The mechanism is related to the cholinergic
stimulation of apocrine glands, which is inhib-
ited by the botulinum toxin. Although based on
an erroneous concept of apocrine gland involve-
ment, botulinum toxin has been tried in the
treatment of HS. Two cases of treatment of Ver-
neuils disease (HS) with botulinum toxin have
been reported [14].
The first patient was a 29-year-old woman
with recalcitrant HS, who experienced relapses
after isotretinoin, zinc gluconate and antian-
drogen therapy. The lesions were located in the
Fig. 19.2. After 6 months of zinc gluconate, six capsules/ axillary regions and mammary folds. Botuli-
day num toxin A (Botox) was injected at a dose of
50 units in each axillary region and 10 units in
appear that a clinically suppressive effect only each of the mammary folds. A complete remis-
occurred at high doses. sion was observed after 1 month. The duration
Partial remissions were seen in 4/22 (18%) of the effect was 6 months, with a disappearance
patients. Partial remission was defined as a de- of the lesions after new injections.
crease in the number of nodules and a shorter The second patient was a 24-year-old woman
cycle of each inflammatory lesion, based solely who had experienced a minor therapeutic effect
on the patients opinion. For an outcome to be of antiandrogen and isotretinoin treatment. In
classified as a partial remission, the patients as- her case botulinum toxin (100 units) was inject-
sessments should remain stable for 1 year. ed in the left axillary region, allowing a left
Stabilization was defined as no progression right comparison of the effect. A clinical effect
under treatment, and categorized as the lesser of was observed as soon as 15 days after the injec-
the positive outcomes. Almost half (10/22, 45%) tion. The right side was subsequently injected
of the included patients experienced stabiliza- with 100 units 1 month later, when the differ-
tion. None of the patients experienced deterio- ence between the two sides was dramatic. The
ration of their HS during treatment. Gastro- nodules recurred after 6 months, disappearing
intestinal side-effects (diarrhoea, gastralgia, after a new injection of botulinum toxin. Later,
nausea, abdominal pains) were noted in four pa- the same treatment was successfully used in the
tients. One patient had to stop the treatment. pubic region of the patient.
144 Brigitte Dreno, Anabelle Brocard
Although based on an erroneous understand- 6. Sainte Marie I, Jumbou O, Tenaud I, Drno B. Com-
ing of the tissues involved in HS, these seren- parative study of the in vitro inflammatory activity
dipitous observations appear promising, and of three nickels salts on keratinocyte. Acta Derm
Venereol 1998; 78: 169 72.
need confirmation in more structured trials.
7. Sugimoto Y, Lopez-Solachez I, Labrie F, Van-Luu-
The possible mechanism may also be interpret- The. Cations inhibit specifically type I 5 alpha re-
ed to be a reflection of reduced eccrine sweat ductase found in human skin. J Invest Dermatol
gland activity, which leads to reduced sweating 1995; 104: 7758.
and thereby indirectly to a reduction of the 8. Tenaud I, Sainte Marie I, Jumbou O, Litoux P,
shear forces on the surface of the skin and the Dreno B. In vitro modulation of keratinocyte
hair follicles. The appropriate doses must also integrins involved in cutaneous wound heal-
ing by means of trace elements (zinc, copper and
be identified more precisely. Finally, the poten-
manganese). Br J Dermatol 1999; 140: 2634.
tial side-effects after several injections should 9. Tenaud I, Leroy S, Chebassier N, Dreno B. Zinc,
be studied, as the treatment appears only to be copper and manganese enhanced keratinocyte mi-
suppressive, with a 6 months duration of effect. gration through a functional modulation of kerati-
nocyte integrins. Exp Dermatol 2000; 9: 40716.
9. Brocard A. Maladie de Verneuil et zinc: une nou-
References velle approche thrapeutique. Thse Mdecine,
April 2005.
1. Dreno B. La pathologie lie au zinc. LEurobiologiste 10. Dreno B, Amblard P, Agache P, Sirot S, Litoux P.
1993; 27: 2018. Low doses of zinc gluconate for inflammatory acne.
2. Stephan F, Revuz J. Sels de zinc en dermatologie. Ann Acta Derm Venereol 1989; 69: 5413.
Dermatol Vener 2004; 131: 45560. 11. Dreno B, Moyse D, Alirezai M, Amblard P, Auffret
3. Drno B, Trossaert M, Boiteau HL, Litoux P. Zinc N, Beylot C, Bodokh I, Chivot M, Daniel F, Hum-
salts effects on granulocyte zinc concentration and bert P, Meynadier J, Poli F and private practice
chemotaxis in acne patients. Acta Derm Venereol Dermatologists coordinated by the Acne Research
1992; 72: 2502. and Study Group (GREA). Multicenter randomized
4. Chvapil M, Stankova L, Zukoski C IV, Zukoski C III. comp gluconate versus minocycline hydrochloride
Inhibition of some functions of polymorphonuclear in the treatment of inflammatory acne vulgaris.
leukocytes by in vitro zinc. J Lab Clin Med 1977; 89: Dermatology 2001; 203: 13540.
13546. 12. Heckmann M, Teichmann B, Pause BM. Ameliora-
5. Guniche A, Viac J, Lizard G et al. Protective effect tion of body odor after intracutaneous axillary in-
of zinc on keratinocyte activation markers induced jections of botulinium toxine. Arch Dermatol 2003;
by interferon or nickel. Acta Derm Venereol 1995; 75: 139: 579.
1923. 13. Bodokh I. Traitement de la maladie de Verneuil par
injection de toxine botulique A. Poster Journes de
Paris, December 2004.
19
Chapter 20
Biologics For Hidradenitis Suppurativa

(Verneuils Disease in the Era of Biologics) 20
Sharon E. Jacob, Francisco A. Kerdel

Q Hidradenitis suppurativa (HS) is Verneuils disease, better known as hidradenitis
resistant to current medical manage- suppurativa (HS), is a chronic inflammatory
ment options disease that is clinically hallmarked by multiple
abscesses and sinus tracts distributed in areas
Q The association with Crohns disease densely populated with apocrine glands. Stage I
(CD) suggests an inflammatory HS is characterized by the presence of abscesses
etiology without scarring or sinus tracts. With progres-
sion to Stage II, scarring and sinus tract forma-
Q Infliximab has been shown to induce tion are seen. By definition, patients with Stage
durable remissions in patients with HS III disease have multiple interconnected sinus
and HS/CD tracts and scarring, typically involving multiple
regions [1]. The significant morbidity of this
Q The efficacy of infliximab suggests a disease is important, and is emphasized further
role for tumor necrosis factor alpha by the limited effectiveness of the currently
(TNFA) in the etiology and pathogen- available standard medical therapies, includ-
esis of HS ing antibiotics (Chap. 15), antiandrogens (Chap.
16), retinoids (Chap. 17), immunosuppressants
Q The efficacy of infliximab in HS (Chap. 18), and/or complementary and alterna-
suggests a role for broadening the tive medicines (Chap. 19) [2].
therapeutic applications of TNFA
inhibitors
20.2 Background
Similar to most chronic diseases in the current

medical milieu, there is a constant interplay be-
#ONTENTS tween therapeutics and pathophysiology. With
20.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 145
the development of novel therapeutic agents
with specific mechanisms of action and the
20.2 Background . . . . . . . . . . . . . . . . . . . . . . . . . . 145 knowledge of such mechanisms, new inroads
20.2.1 CrohnsDisease and Hidradenitis
Suppurativa Co-Occurrence: A Rationale
have been made into our understanding of the
for Anti-TNF Therapy . . . . . . . . . . . . . . . . . . 147 pathophysiology of several diseases. This in
turn has spawned further development of medi-
20.3 Anti-TNF Drugs in HS . . . . . . . . . . . . . . . . . 147
cal pharmacological therapies. The closer we get
20.4 Future Prospects . . . . . . . . . . . . . . . . . . . . . . 148 to understanding the molecular mechanisms of
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 a disease, and in particular of HS, the greater
our opportunity to pinpoint directed medical
management. Nowhere does this ring more true
146 Sharon E. Jacob, Francisco A. Kerdel
Table 20.1. Biologic therapy in HS [5, 811]. (CD Crohns disease, CR case report, CS case series, HS hidradenitis sup-
purativa, PC personal communication, UC ulcerative colitis)
Author Case Year Strength Age Disease Bio- Outcome Outcomes
report of evi- (years)/ dura- logic measures
no. dence sex tion
(years)
Martinez 1 2001 CR 30/F, 6 Inflixi- Resolution of Remission

et al. [8] HS + CD mab refractory nod- 6 months after
ules two infusions,
maintained
with azathio-
prine
(adverse
reaction noted
after 2nd dose)
Katsanos 2 2002 CR 39/M Unknown Inflixi- Remission Remission
et al. [5] HS + CD mab after 2 years
of infusions
Lebwohl and 3 2003 CR 21/M 2 Inflixi- Complete re- Disease
Sapadin [9] HS +/ CD mab epithelializa- resolution
tion
Adams 4 2003 CR 17/M 3 Inflixi- Complete re- Complete

et al. [10] HS + UC mab mission resolution
of pain,
tenderness,
purulence,
draining and
odor Induc-
tion of disease
remission
Adams et al. 5 2003 PC Unknown Unknown Inflixi- Remission Successful
[10] (K.B.G.) HS mab remission
Sullivan 610 2003 CS 51/F 20 Inflixi- Patient report- Patients
et al. [11] 28/F 10 mab ed disease reported
36/F 20 activity scale disease activity
57/F 44 Ability to significantly
45/M 25 decrease decreased
standard within
All HS systemic 37 days
medications (p=0.0001)
(ciclosporin, paired t test
prednisone)
Patients
reported de-
creased pain
after 24 h
Rosi et al. 11 2005 CR 30/F 1.5 Inflixi- Improvement No evidence

[12] HS + CD mab of symptoms of active in-
flammation
5 weeks into
therapy
20
Biologics For Hidradenitis Suppurativa Chapter 20 147
than for the new biologic therapies. This is par- gree of efficacy of infliximab therapy for long-
ticularly important in HS, given that there is no standing HS and that in some cases improvement
universally effective medical therapy, and, fur- was observed in as little as 3 days.
thermore, current medical management is mar-
ginally beneficial even when claimed to work.
20.3 Anti-TNF Drugs in HS
20.2.1 Crohns Disease and Hidradenitis Infliximab is the only biologic with reported
Suppurativa Co-Occurrence: use in HS. It is a chimeric monoclonal antibody
A Rationale for Anti-TNF Therapy with high affinity for TNFA. The molecular
structure encompasses the human IgG constant
While the etiology and pathogenesis of HS re- region spliced with a murine variable antigen-
main largely unknown, the disease has been binding region. This therapeutic antibody scav-
shown to occur in association with other disor- enges free TNFA, neutralizing its proinflamma-
ders of follicular occlusion, such as acne conglo- tory biological effects. Mitigation of the target
bata and dissecting cellulitis of the scalp. In immunological endpoints for TNFA include:
these disorders, follicular occlusion leads to
overgrowth of bacteria and subsequent neutro- 1. Induction of proinflammatory cytokines
philic inflammation. Many observations have interleukin-1 (IL-1), IL-6, and IL-8
been reported regarding the role of androgens/ 2. Activation of neutrophils, lymphocytes,
hormones, obesity, and genetics, which may in and eosinophils
addition influence the clinical picture [3, 4]. It is 3. Upregulation of adhesion molecule
the reported association with Crohns disease expression by endothelial cells [13, 14].
(CD), however, which has led to speculation and Additionally, infliximab binds mem-
opportunities for novel management. It has brane-bound and receptor-bound TNFA
been postulated that the two conditions share leading to complement-induced antibody-
similar pathological immune mechanisms, such mediated CD4+ T cell cytotoxicity.
as increased levels of tumor necrosis factor al-
pha (TNFA) and neutrophilic chemotaxis [5]. Infliximab is currently approved by the Food
This interesting co-occurrence of HS and CD and Drug Administration (FDA) for the treat-
highlights both the inflammatory nature of the ment of rheumatoid and psoriatic arthritis,
disease and the rationale for using biologics Crohns disease and ankylosing spondylitis.
known to be effective in CD [6]. Many off-label uses of this agent have addition-
There is evidence that infliximab is effica- ally been reported in the literature and not sur-
cious at stopping fistula drainage when used as prisingly many relate to inflammatory skin dis-
a maintenance agent in fistulizing CD [7]. It is ease.
reasonable to suppose that if a patient sees inf- The drawbacks to infliximab therapy are few.
liximab-induced improvement of their CD fis- Commonly reported side-effects include diar-
tulization, they would also see the healing of rhea, headache, pharyngitis, upper respiratory
any co-existing HS with skin fistulization. A re- tract infection, and urinary tract infection [15
view of the literature demonstrates that this is 20]. Rare instances of re-activation of tubercu-
indeed the case. The first three cases of effective losis (TB), aseptic meningitis, systemic lupus
treatment of HS with infliximab were in pa- erythematosus and antibody-mediated anaphy-
tients who had undergone the treatment for CD. lactic shock have also been reported. In the
At the time of writing this chapter, 11 cases of 147,000 cases throughout the world that have
HS treated with infliximab have been reported received infliximab that Keane et al. [21] re-
in the literature. Of the 11 reported cases, 4 viewed in 2001, there were 70 cases of TB, and
(36%) had been patients with associated CD (see approximately 60% of these represented extra-
Table 20.1) [5, 812]. Nevertheless, these pre- pulmonary disease. The current understanding
liminary cases demonstrate both the high de- suggests that re-activation of TB is associated
148 Sharon E. Jacob, Francisco A. Kerdel
with disruption of the immune systems ability patients were reported to have had concurrent
to compartmentalize the bacilli in granulomas CD. Patients age ranged from 17 to 57 years
and inhibition of macrophage apoptosis. Thus with a mean age of 35.4 years. There were four
the FDA requires that patients have a negative men and six women. HS disease duration was
purified protein derivative (PPD) test prior to reported as being between 1.5 and 44 years, with
the onset of infliximab therapy. Infusion-asso- a mean duration of 14 years. As the majority of
ciated anaphylactoid reactions, while rare, can the reports are single case reports of successful
be avoided by slowing the infusion rate and pre- therapy, long-term effects were not known or
treating the patients with antihistamines and described. Importantly, 9 of the 11 patients re-
steroids. ported a significant reduction in disease activity
Antibody formation can be seen with long- within 5 weeks of infliximab infusion therapy.
term use and is inversely proportional to total The five patients treated in a dermatological
infliximab dose. The concern regarding the de- inpatient ward were observed to have marked
velopment of antibodies to infliximab with or moderate improvement within 37 days after
long-term use follows the observation that 13% each infusion [11].
of Crohns patients treated with repeated infu-
sions had indeed formed antibodies [22]. As ex-
pected, loss of clinical efficacy accompanies the 20.4 Future Prospects
antibody formation, as does the development of
infusion-related chest pain, bronchospasm, and While no specific reports exist regarding the
anaphylactic shock. The development of anti- other FDA-approved anti-TNF agents on the
bodies can be reduced by treating the patients market, one of the authors (F.A.K.) has treated
on a scheduled, regular basis (i.e., every 8 weeks) two patients with HS with etanercept. The pa-
and with the concomitant use of low-dose im- tients appeared to improve, however not as
munosuppressants [16]. markedly as seen with infliximab. This is not
In the reported cases of HS treated with inf- surprising given that etanercept has not been
liximab therapy, the demographics for ten pa- found to be effective in CD. The other anti-TNF
tients are known (one case was reported without agent approved by the FDA, namely adalimum-
specifications) (see Table 20.1) [5, 811]. Four ab, has not been reported in association with
Table 20.2. Biologics used in CD [2224]. (AS Ankylosing spondylitis, CD Crohns disease, JRA juvenile rheumatoid
arthritis, PsA psoriatic arthritis, Pso psoriasis, PsoA psoriatic arthritis, RA rheumatic arthritis, TNF tumor necrosis
factor, UC ulcerative colitis)
Generic Company Subset Structure Target FDA indication
name
Infliximab Centocor IgG1 Chimeric: human Fc TNF, complement CD, RA, AS, PsA
and murine Fab fixation, T cell apop-
tosis
Adalimumab Abbott IgG1 Fully human TNF, complement RA
fixation, T cell apop- CD Phase III
tosis
CDP571 Abbott IgG4 Humanized, murine TNF, decrease C CD failed Phase III
complementarity reactive protein, UC Phase IIa
determining region no complement fix
CDP 870 UCB Humanized Fab, TNF, CD Phase III
linked to polyethylene no complement fix
glycol
Etanercept Amgen/ Recep- Human Fc backbone TNF, TNF RA, AS, JRA, Pso, PsoA
20 Wyeth tor IgG1 CD failed Phase II
Biologics For Hidradenitis Suppurativa Chapter 20 149
treatment of HS; additionally, CDP571 is in 10. Adams DR, Gordon KB, Devenyi AG, Ioffreda MD.
phase III trials for CD (see Table 20.2) [2224]. (2003) Severe hidradenitis suppurativa treated with
If we are to follow the infliximab lead, it infliximab infusion. Arch Dermatol 139:15402.
11. Sullivan TP, Welsh E, Kerdel FA, Burdick AE,
stands to reason that agents shown to be prom-
Kirsner RS. (2003) Infliximab for hidradenitis sup-
ising in CD clinical trials, such as the fully hu- purativa. Br J Dermatol 149:10469.
man IgG1 anti-TNF monoclonal antibody adali- 12. Rosi YL, Lowe L, Kang S. (2005) Treatment of hi-
mumab and the fully humanized anti-alpha4 dradenitis suppurativa with infliximab in a patient
integrin IgG4 antibody natalizumab, would of- with Crohns disease. J Dermatol Treat 16(1):5861.
fer opportunities for effective management of 13. Mouser JF, Hyams JS. (1999) Infliximab: a novel
HS [7] (see Table 20.2) [2224]. At this time, the chimeric monoclonal antibody for the treatment of
Crohns disease. Clin Ther 21:93242.
efficacy of these agents in inflammatory disor-
14. Old LJ. (1988) Tumor necrosis factor (TNF). Sci Am
ders such as rheumatoid arthritis has proven 258:5960.
impressive and the short-term side-effects have 15. LaDuca JR, Gaspari AA. (2001) Targeting tumor
been minimal with regard to the risk/benefit ra- necrosis factor alpha. Dermatol Clin 19(4):617635.
tio. As we proceed to develop our experience 16. Lebwohl M. (2003) Psoriasis. Lancet 361:1197204.
and monitor the long-term effects, we are pre- 17. Mease PJ. (2002) Tumour necrosis factor (TNF) in
sented with determining the utility of each bio- psoriatic arthritis: pathophysiology and treatment
logic therapy and ultimately finding the most with TNF inhibitors. Ann Rheum Dis 61(4):298
304.
appropriate diseasetherapeutic pairing. Not all 18. Provenzano G, Termini A, Le Moli C, Rinaldi F.
biologics are equally effective, but finding the (2003) Efficacy of infliximab in psoriatic arthritis
optimal target disease may level the playing resistant to treatment with disease modifying anti-
field. rheumatic drugs: an open pilot study. Ann Rheum
Dis 62(7):6801.
19. Van den Bosch F, Kruithof E, Baeten D, De Keyser
References F, Mielants H, Veys EM. (2000) Effects of a loading
dose regimen of three infusions of chimeric mono-
clonal antibody to tumour necrosis factor alpha
1. Trent JT, Kerdel FA. (2005) Tumor necrosis factor
(infliximab) in spondyloarthropathy: an open pilot
alpha inhibitors for the treatment of dermatologic
study. Ann Rheum Dis 59(6):42833.
diseases. Dermatol Nurs 17(2):97107.
20. Williams JDL, Griffiths CEM. (2002) Cytokine
2. Wiseman MC. (2004) Hidradenitis suppurativa: a re-
blocking agents in dermatology. Clin Exp Dermatol
view. Dermatol Ther 17:504.
27(7):58590.
3. Ostlere LS, Langtry JAA, Mortimer PS, Staughton
21. Keane J, Gershon S, Wise RP, Schwieterman WD et
RCD. (1999) Hidradenitis suppurativa in Crohns
al. (2001) Tuberculosis associated with infliximab,
disease. Br J Dermatol 125:3846.
a tumor necrosis factor alpha-neutralizing agent. N
4. Tsianos EV, Dalekos GN, Tzermias C, Merkouropou-
Engl J Med 345(15):1098104.
los M, Hatzis J. (1995) J Clin Gastroenterol 20(2):151
22. Tan MH, Gordon M, Lebwohl O, George J, Lewohl
3.
MG. (2001) Improvement of pyoderma gangreno-
5. Katsanos KH, Christodoulou DK, Tsianos EV. (2002)
sum and psoriasis associated with Crohns disease
Axillary hidradenitis suppurativa successfully treat-
with anti-tumor necrosis factor alpha monoclonal
ed with infliximab in a Crohns disease patient. Am J
antibody. Arch Dermatol 137(7):9303.
Gastroenterol 97:21556.
23. Hanauer SB. (2004) Efficacy and safety of tumor
6. Jemec GBE. (2004) Medical treatment of hidradenitis
necrosis factor antagonists in Crohns disease: over-
suppurativa. Expert Opin Pharmacother 5(8):1767
view of randomized clinical studies. Rev Gastroen-
70.
terol Disord 4(3):S18S24.
7. Van Assche G, Vermeire S, Rutgeerts P. (2005) Medi-
24. Baker DE. (2004) Adalimumab: human recombi-
cal treatment of inflammatory bowel diseases. Curr
nant immunoglobulin G1 anti-tumor necrosis fac-
Opin Gastroenterol 21(4):4437.
tor monoclonal antibody. Rev Gastroenterol Disord
8. Martinez F, Nos P, Benlloch S, Ponce J. (2001) Hi-
4(4):196210.
dradenitis suppurativa and Crohns disease: response
25. Sandborn WJ. (2005) New concepts in anti-tumor
to treatment with infliximab. Inflamm Bowel Dis
necrosis factor therapy for inflammatory bowel dis-
7(4):3236.
ease. Rev Gastroenterol Disord 5(1):1018.
9. Lebwohl B, Sapadin AN. (2003) Infliximab for the
treatment of hidradenitis suppurativa. J Am Acad
Dermatol 49:S2756.
Chapter 21
21 Topical Treatment
Karin Sartorius, Jurr Boer, Gregor B.E. Jemec
21
21.5 Intralesional Therapy . . . . . . . . . . . . . . . . . .157

Key points
21.6 The Use of Local Therapy . . . . . . . . . . . . . . .158
Q Effective local treatments exist 21.7 Publication Bias . . . . . . . . . . . . . . . . . . . . . . .158
References . . . . . . . . . . . . . . . . . . . . . . . . . . . .159
Q Local treatment may be sufficient for
some patients
Q Different local treatments can be 21.1 Introduction

combined for better effect
Topical or local therapy is traditionally often
Q Local treatment should be part of a used in dermatology. It holds a number of ad-
systematic treatment plan for each vantages over systemic therapy, primarily by
patient reducing the risk of a number of side-effects and
being easy for the patients to administer them-
Q If local treatment does not control the selves, but also its low cost. On the other hand,
disease adequately within 3 months a topical or local therapy is often less potent than
more aggressive treatment, in combina- systemic therapy when dealing with more gen-
tion with continued topical therapy, eralized or recalcitrant diseases. Accurate as-
should be used sessment of disease severity is therefore of im-
portance when choosing therapy.
In hidradenitis suppurativa (HS), topical
therapy is best used in very early lesions or for
the maintenance of a therapeutic result. In con-
#ONTENTS trast, intralesional or local therapy is better suit-
21.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . .150
ed for early advancing or intermediate lesions,
before switching to surgery or systemic therapy.
21.2 Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 The choice of topical/local versus systemic ther-
21.2.1 Topical Clindamycin . . . . . . . . . . . . . . . . . . 152
apy therefore depends not only on the individu-
21.3 Keratolytics. . . . . . . . . . . . . . . . . . . . . . . . . . . 152 al characteristics of the patient and the disease,
21.3.1 Resorcinol as a Keratolytic Agent but also on the developmental stage of the dis-
in Hidradenitis Suppurativa . . . . . . . . . . . 152
21.3.1.1 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . .154
ease.
21.3.1.2 Mechanism of Action . . . . . . . . . . . . . . . . . .154 Several different types of topical therapy have
21.3.1.3 Side-Effects of Resorcinol . . . . . . . . . . . . . . 155 been tried in HS, although there are few actual
21.3.1.4 Treatment Schedule trials. The paucity of trials opens the possibility
with Resorcinol Creams . . . . . . . . . . . . . . .156 of biased reporting of results, and therefore
21.3.1.5 Clinical Experience . . . . . . . . . . . . . . . . . . .156 slows the development of new treatments. Anti-
21.4 Topical Anti-Inflammatory Therapy . . . .157 biotics have been extensively used, and form a
21.4.1 Azelaic Acid . . . . . . . . . . . . . . . . . . . . . . . . . .157 mainstay of early therapy with some of the few
21.4.2 Fusidic Acid . . . . . . . . . . . . . . . . . . . . . . . . . .157 controlled trials in HS. Keratolytics have also
Topical Treatment Chapter 21 151
been used because of the histological similari- and number of elements, as well as the frequen-
ties between HS and acne, although the evidence cy and duration of recurrences. An overall esti-
base for this is more restricted. Finally, anti-in- mation of the effect of treatment was based on a
flammatory preparations are on occasion help- cumulated score of the parameters recorded
ful to patients when applied to predisposed (patients assessments, number of inflammatory
areas as preventive or adjuvant therapy. In con- nodules, abscesses, and pustules). In all, 13 pa-
trast, intralesional therapy with corticosteroids tients received active treatment and 14 received
is frequently used, and often effective at treating placebo. An overall improvement was seen in
individual recalcitrant lesions. the clindamycin group at each monthly evalua-
Failing local pharmacological therapy, minor tion, and statistically significant improvement
local surgical procedures may be of help to some was found in the clindamycin group for each
patients. This spectrum of therapies will be re- parameter except for inflammatory nodules at 1
viewed in this chapter. and 2 months of treatment. Clindamycin was
more effective than placebo.
Jemec and Wendelboe [3] compared topical
21.2 Antibiotics clindamycin with systemic tetracycline in a
double-blind, double-dummy controlled trial.
The significance of bacterial findings in HS is In total 46 patients with HS stage I and II dis-
controversial. While bacteria are likely to be in- ease, according to Hurleys classification, were
volved in the pathogenesis to some extent, it is included, of which 34 (28 women, 6 men) were
probably in a role similar to that in acne in early available for evaluation. After computerized
lesions. In later stages of the disease bacterial blinded randomization the patients received a
infection seems to be a risk factor for the de- minimum of 3 months of therapy with active
structive scarring and progression of HS lesions. systemic plus topical placebo or systemic place-
Coagulase-negative staphylococci are the most bo plus active topical treatment. The active sys-
common bacteria found in cultures from the temic treatment consisted of tetracycline 1 g
deep portions of HS lesions, as seen following (capsules 250 mg, 2s2) daily per os; active topi-
carbon dioxide laser surgery [1]. An extensive cal, 1% clindamycin phosphate in a vehicle of
review of HS bacteriology is found in Chaps. 11 propylene glycol, isopropyl alcohol and water,
and 15. Although the influence of bacteria is applied twice daily. Uniform containers, place-
unclear, topical as well as systemic antibiotics bo tablets and placebo lotion were used. At
are frequently used in treatment of HS. monthly visits the following outcome variables
There are two published randomized con- were evaluated: patients global evaluation using
trolled trials of topical treatment of HS, both of a 100-mm visual analog scale (VAS) score, VAS
them evaluating the use of clindamycin [2, 3]. score of soreness, physicians global evaluation
Clemmensen [2] included 30 patients with HS of (VAS score) and the number of abscesses and
axillae and/or groin. In total 27 patients (21 nodules. No significant differences were found
women, 6 men) of mean age 31.3 years and mean between the two treatments, but significant
duration of HS 5.5 years were included in the changes occurred in the course of the study. Ab-
study. The patients were stratified according to scesses were reduced during the first 3 months
the severity of HS, but the overall disease activ- of the study while nodules became reduced in
ity was moderate. A double-blind trial was per- numbers after 3 months of treatment. There was
formed with either a solution of clindamycin a progressive improvement in both the patients
hydrochloride 1% in a vehicle of isopropanol and the physicians overall assessment, although
80%, propylene glycol 10% and water 9%, or pla- the VAS score of soreness did not change during
cebo (vehicle) applied for 12 weeks. The patients the study.
were evaluated every 4 weeks and the number of
pustules, inflammatory nodules, and abscesses
were counted. Self-assessment by the patients
was made in diaries by recording the intensity
152 Karin Sartorius, Jurr Boer, Gregor B.E. Jemec
21.2.1 Topical Clindamycin for HS treatment although, to our knowledge,

21 there are no published reports and their clinical
Clindamycin is a lincosamide antibiotic that is effects on HS remain to be shown.
bacteriostatic and works by inhibiting protein
synthesis in sensitive bacteria. Its antibacterial
spectrum includes Gram-positive bacteria, in 21.3 Keratolytics
particular the genera Staphylococcus and Strep-
tococcus, and several of the anaerobic bacteria. HS is a disease of the hair follicle with histologi-
Clindamycin also suppresses the complement- cal signs of poral occlusion [911]. Although
derived chemotaxis of polymorphonuclear leu- there are only a few publications about the use
kocytes (in vitro), thereby reducing the inflam- of keratolytics in HS [12, 13], the follicular oc-
mation potential [4]. Topical clindamycin 1%, clusion brought about by hyperkeratosis may be
which is widely used in the treatment of acne, is a therapeutic target. Therefore, by analogy to
applied to affected areas once or twice daily. Ab- acne, this also appears to be a good target for
sorption of topically administered 1% clinda- keratolytics. In acne, another disease of the fol-
mycin is estimated to be 15% [5]. Adverse ef- licle with abnormal keratinization (microcom-
fects are mostly local: irritation, erythema, edo), the mainstay in classical therapy of early
peeling, itching, dryness, and burning. As rare lesions is topical treatment with peeling agents,
events, episodes of diarrhea and even two cases especially topical retinoids [8, 14, 15]. Here, the
of pseudomembranous colitis have been report- rationale is that all acne lesions arise out of a
ed after topical clindamycin treatment [6, 7]. comedo and so it makes sense to treat acne pa-
One complication of the use of topical antibi- tients with comedolytic agents [8, 14, 15]. Topi-
otics is the development of bacterial resistance. cal comedolytic agents are also recommended
The number of patients carrying Propionibacte- for use in maintenance therapy in acne by some
rium acnes and Staphylococcus epidermidis re- authors [8, 14, 15].
sistant to topical antibiotics has increased over Although topical retinoids such as tretinoin,
the last few years. A potential risk is the transfer isotretinoin, adapalene and tazarotene are
of resistance to other bacteria, specifically Strep- strongly recommended in the management of
tococcus spp. and Staphylococcus aureus [4]. In most patients with acne vulgaris, there are cur-
acne therapy it is now often recommended to rently no reports about the use of these comedo-
use topical antibiotics for shorter periods and lytic agents in HS. One possible reason for this is
preferably in combination with topical reti- that the relatively weak peeling effect (consid-
noids, benzoyl peroxide or azelaic acid to en- ered as a side-effect) of topical retinoids is not
hance the efficacy and slow down the develop- strong enough for therapy of HS lesions. An-
ment of resistance [8]. other reason could be that physicians do not be-
The two randomized controlled trials relieve that a topical peeling agent can have any
ferred to above [2, 3] have shown the effect of therapeutic influence on deep-seated nodules
topical clindamycin used in mild or moderate and sinus tracts of HS.
cases of HS. The results of these studies fit well
with the experience of more than 300 cases of
HS treated at the Department of Dermatology, 21.3.1 Resorcinol as a Keratolytic Agent
Karolinska Huddinge, Stockholm, Sweden. in Hidradenitis Suppurativa
Clindamycin, preferably combined with azelaic
acid, effectively suppresses acute exacerbations In the Netherlands, we have been gathering ex-
of at least milder forms of HS. The therapeutic perience with the use of topical resorcinol for
effect of clindamycin on HS could be due to bac- the treatment of HS since the 1970s [16]. Since
teriostatic as well as anti-inflammatory effects. 2000, two case series have been published about
There are other commercially available topical this topic, see Table 21.1 [12, 13].
antibiotics including erythromycin, mupirocin Resorcinol [(BP, USP) C6H4(OH)2,1,3-dihy-
and neomycin, which probably have been tested droxybenzene] is a phenol derivative, used in
Table 21.1. Long-term response of HS to topical resorcinol. Outcome variables for pain and disease activity as felt
by the patients as well as judged by the physician. Outcome in longest follow-up only concerns the score for resor-
cinol treatment (as given mainly by the patient) and not for surgical intervention and/or medication. [AB Antibiotics,
Re retinoid (isotretinoin)]
Patient no., Duration Area of Improvement score a
age (years), of HS HS, Hurley
sex (years) stage
At the end Longest follow-up

of treatment
(2 months)
1, 17, F 3 Groin, 2 +2 AB, Re, + 1, 6 years

2, 30, F 9 Mixed, 2 +3 Deroofing, + 3 , 1 years
3, 32, F 3 Mixed, 2 +2 Deroofing, + 1 , 2 years
4, 39, F 2 Mixed, 2 +2 + 2, 1 years
5, 40, F 1 Mixed, 2 +2 Deroofing, + 2 , 1/2 years
6, 39, F 4 Groin, 2 +2 + 3, 1 years
7, 36, F 8 Mixed, 2 +2 Surgical excision, 0, 2 years; resorcinol stop
8, 25, F 1 Mixed, 2 +2 + 2, 1/2 years
9, 50, M 6 Mixed, 2 +2 AB, Re, + 1, 1.5 years, resorcinol stop
10, 31, F 7 Mixed, 2 +2 AB, Re, deroofing, + 2, 5 years
11, 20, F 4 Mixed, 2 +2 Deroofing, + 2, 3 years
12, 30, F 6 Mixed, 2 +1 AB, Re, 0, 3 years, resorcinol stop
15, 28, F 7 Mixed, 2 +2 Surgical excision, + 1, 4 years
17, 24, F 2 Axillae,2 +2 Deroofing, + 3, 2 years
18, 30, F 8 Mixed, 3 +1 Surgical excision, + 1, 1/2 years, resorcinol stop
19, 46, F 24 Mixed, 3 +1 Surgical excision, + 1, 1/2 years, resocrinol stop
21, 28, F 10 Mixed, 3 +1 AB, Re, surgical excision, + 1, 1/2 years,
resorcinol stop
22, 40, F 19 Mixed, 3 +2 AB, surgical excision, 0, 3 y, resorcinol stop
23, 38, F 15 Mixed, 3 0 Resorcinol stop
a
Improvement scores: +3 clear, +2 marked improvement, +1 improvement, 0 no change.
dermatology for more than 100 years because of The data on resorcinol in acne are variable.
its antipruritic, keratolytic and antimycotic In a screening program searching for effective
properties [17] (see Fig. 21.1). Topical drugs in- drugs in the treatment of acne, it was concluded
cluding resorcinol are nowadays mainly used that resorcinol lotion was an ineffective agent
for the treatment of acne vulgaris as a peeling [20, 21]. The studies, however, used only low
agent [1719], at concentrations of 515% in concentrations of 5% and 10% resorcinol [20,
creams, fat or drying pastes [17]. 21], which may be too low and therefore intro-
It has been observed [12, 24] that acute early

21 single lesions of HS develop in three different
ways: firstly, they can be permanently painful
and fail to settle completely; secondly, the boils
rupture and pain is relieved; and thirdly, the le-
sions resolve and pain disappears. After such an
acute period the lesions remain inactive for a
variable period, called the maintenance phase.
Maintenance therapy therefore could be impor-
tant in HS because the disease tends to recur
Fig. 21.1. Resorcinol [C6H4(OH)2]. Synonyms: m-dihy- without an ongoing treatment regimen. In addi-
droxybenzene; 1,3-benzenediol; resorcin; 1,3-dihydroxy- tion, it may be hypothesized that the whole re-
benzene; 3-hydroxyphenol; m-hydroxyquinone; m-ben- gion for example axillae and groin can be
zenediol; 3-hydroxyphenol thought of as an HS-prone area, which needs
preventive therapy. It has been suggested that
resorcinol targets lesions in the acute and main-
duce false-negative results. It is known mainly tenance phases as well the HS-prone areas gen-
from the German literature that the peeling erally [12, 13].
effect of resorcinol starts only at a concentration The above-mentioned could be substantiated
of 10% or more [22]. Also, from our own experi- by results in acne research, in which it has been
ence, we have observed that 10% resorcinol in shown that even normal-looking skin from acne
an oil-in-water (o/w) cream used for patients patients may already be developing very early
with HS causes no, or at the most minimal, des- microcomedones. To treat acne, comedolytic
quamation. In the overwhelming majority of therapies need to be applied topically to acne le-
patients the peeling effect starts only at a con- sions, but just as importantly to the normal-
centration of 15% and will almost always be looking skin of acne-prone areas [8, 15, 25]. It
present at a concentration of 20%25% [12, 13]. has been stated that maintenance therapy of
In prescription regulations for treatment of acne sustains acne remission [8, 15, 25].
acne, a resorcinol concentration of 20% is rec-
ommended in peeling pastes [22, 23].
In high concentrations, resorcinol has a 21.3.1.2 Mechanism of Action
marked peeling effect. Siemens used resorcinol
in concentrations of up to 30% to obtain peeling Topical resorcinol targets the follicular keratin
in acne conglobata [17]. Higher concentrations plug, a potential first event of all HS lesions. The
(35%50%) cause a very strong keratolytic effect concentration-dependent desquamation effect
but are generally not used because of the associ- of resorcinol is strong; in practice it is obvious
ated danger of systemic toxicity. that resorcinol is a much more powerful agent
than the current comedolytic agents, e.g., topi-
cal retinoids or azelaic acid (see Fig. 21.2).
21.3.1.1 Indications It has been observed that in the acute (pain-
ful) phase of HS, the peeling agent resorcinol
It was found that HS patients referred to the sec- will cause an earlier breakthrough or an earlier
ondary sector develop a median of two boils per resorption (shrinkage) of the lesions. In the
month and that the individual duration of pain- maintenance phase, when the lesions are settled
ful boils is about 1 week [24]. In the acute phase, down, it may be hypothesized that drainage
many patients have very bad experiences lanc- from the follicle is improved by the removal of
ing their painful boils, with later irrevocable re- hyperkeratosis. The discharge from the boils
currence. So there is a need for a fast-acting and sinus tracts will also be improved and le-
non-invasive boil treatment, preferentially per- sions will leak minimal amounts of pus contin-
formed by the patient himself or herself. uously. It may be speculated that this effect of
20 g resorcinol) for 33 days and with 160 g oint-

ment (= 80 g resorcinol) for 3 days. Following
this, the patients presented recognizable toxic
effects such as cold sweating, dizziness, collapse,
purple-black urine, and hyperthyroidism [23].
There are also reports of acute poisoning in ba-
bies after percutaneous absorption of resorcinol,
in two cases with a fatal outcome [28].
In conclusion, it can be stated that the use of
resorcinol in concentrations up to 15% [1719,
23] to 20% [17, 23] can be considered safe. In the
past, these resorcinol preparations for patients
with mainly acne, but also other skin diseases,
were continued for months or years with little
concern. As far as can be gathered from the
(mostly older) literature, resorcinol concentra-
tions of up to 30% can be used in a safe way for
acne. Whether this is also valid for HS is un-
clear, because the HS lesions are situated mainly
Fig. 21.2. Patient with HS after 6 weeks of treatment with in the axillae and groin, which causes an occlu-
resorcinol in increasing concentrations from 10% to 20% sion effect. Therefore, we advise not exceeding a
(in the maintenance phase decreased to 15%). The brown concentration of 20% resorcinol in general for
coloration (reversible) is a side-effect of resorcinol HS therapy. Concentrations of 30% and more
are too high for HS therapy because of the dan-
ger of systemic toxicity.
resorcinol will ultimately result in a delay or There are insufficient data on the use of res-
lack of recurrences. orcinol in pregnancy to assess the risk accurate-
ly. In answer to enquiries made to the Office of
Side-effects of Drugs in the Netherlands it was
21.3.1.3 Side-Effects of Resorcinol stated that the Office did not know of any report
in which a relationship between a birth defect
Resorcinol can cause cutaneous irritation, in- and the topical application of resorcinol could
cluding erythema and sometimes substantial be established, although this does not rule out
desquamation, depending on the resorcinol the existence of such an effect.
concentration and sensitivity of the patients There are at least two classification systems
skin. The concomitant use of a simple moistur- for drug safety in pregnancy, i.e., the Swedish
izer can minimize the irritation. Contact sensi- (FASS) and the US (FDA) systems. Many older
tization appears to be rare [26]. Resorcinol may drugs, including resorcinol, have not been given
produce (reversible) discoloration of the skin. a letter rating by their manufacturers, and the
Systemic toxicity due to resorcinol through risk factor assignments were made by one of
percutaneous absorption is extremely rare, but the authors (J.B.). In the Swedish (FASS) system
the physician must be aware of this potential resorcinol is placed in category B2, which in-
risk [26]. Systemic toxicity has been reported in cludes drugs with limited experience in preg-
the older literature and in one recent case report nant women, no increase in frequency of fetal
in which high concentrations (40%50%) were malformations or other harmful effects; animal
used in large measures for large (injured) sur- studies are inadequate or lacking. In the US
faces [22, 27]. Two young adults were treated for (FDA) system, it is included in category C, which
acne vulgaris involving their entire back with, includes drugs whose risk cannot be ruled out
respectively, a daily quantity of 50 g ointment (= because of inadequate data.
21.3.1.4 Treatment Schedule vised to apply the cream once a day every 2 or
21 with Resorcinol Creams 3 days (twice a week) prophylactically. In the
event of new activity the patient should imme-
One of the authors (J.B.) has frequently used the diately resume the resorcinol fast-acting boil-
treatment schedule shown in Table 21.2 for pa- therapy strategy and increase the application
tients with HS, mostly in patients with Hurley frequency of resorcinol up to twice daily. Main-
Stage II disease. Normally, resorcinol is used at tenance therapy is also strongly advised after
a varying concentration of 5%20% incorpo- successful initial therapy with, for example, an-
rated in an o/w cream with emulsifying waxes, tibiotics, surgical excisions in extreme cases or
i.e., cremor lanette II F.N.A. (Genfarma, Maars- the deroofing method for sinus tracts and per-
sen, The Netherlands). Resorcinol is incompati- sistent boils [13, 29]. Patients should be informed
ble with cetomacrogol creams [17]. very clearly about the multifocal character of
Therapy with topical resorcinol is started at the disease, i.e., in addition to the high risk of
the patients first visit at a concentration of 10%. recurrence, there is also the possibility of devel-
The concentration of resorcinol is then in- oping new lesions in the same region at some
creased at 1-week intervals, thus in the first distance from the original ones and also in oth-
week resorcinol 10% cream is applied twice a er anatomical regions. Patients also need to un-
day. If there is no desquamation, the resorcinol derstand that treatment with topical resorcinol
concentration is increased to 15% in the second in general does not cure the HS lesions, but
week and this treatment is then continued for a clearly gives more control over disease activity.
period of weeks.
With resorcinol 15% some degree of desqua-
mation will normally be present, but if neces- 21.3.1.5 Clinical Experience
sary the concentration can be increased to 20%
to achieve an acceptable degree of desquama- There is more than 15 years of experience with
tion. Once a peeling effect is achieved, the re- this peeling therapy. In a multicenter pilot study
duction or disappearance of pain will start in a more than 100 patients applied resorcinol once
few days instead of the average duration of 1 or twice daily to HS-involved areas for up to
week, and the patients experience correspond- many years with the above-mentioned protocol
ing relief. (Table 21.2). In another study topical resorcinol
In cases where the lesions are completely or cream in a vehicle was compared with the vehi-
partially settled after 46 weeks of treatment, cle alone, by using the bilateral comparison
topical resorcinol is also the preferred agent for technique (to be published). It was found that
maintenance therapy. Here the patient is ad- resorcinol was more effective than placebo.
The most striking effect noticed by the pa-
Table 21.2. Treatment regimen for the use of resorcinol tient is the disappearance of the pain after ap-
proximately 2 days instead of the median time
1. Treat new inflamed lesions with resorcinol in of 7 days. In addition the patients appreciate
increasing concentrations until peeling occurs that they can apply resorcinol as a fast-acting
2. Once peeling occurs continue maintenance boil therapy at the very first sign of a painful
therapy of the lesions at unchanged concentrations boil. The empowerment of patients to self-treat-
(normally 15%) ment may be an important factor in helping
3. Resorcinol at peeling strength (individually them to cope with this disease.
variable) can be used for twice-weekly prophylactic The result can vary from complete resolution
treatment of predisposed regions of all symptoms (in exceptional cases) to a de-
4. The keratolytic treatment regimen can be used in crease in subjective complaints, mainly in the
combination with the deroofing method for sinus early stages of the disease (Hurley stages I and
tracts and persistent boils, a conservative surgical
II), but it also depends on whether the patient
technique with long-term oral antibiotic therapy
and, in extensive cases, with surgical excision
has the discipline to continuing applying resor-
cinol cream as maintenance treatment. Some
patients with Hurley Stage III disease were ini- acne and is used in hyperpigmentary disorders
tially enthusiastic about their pain relief, how- [35, 36].
ever in almost all cases this feeling fell away af- In HS there are no formal studies of the ef-
ter a couple of months, mainly because of the fects of azelaic acid, but occasionally patients
ongoing widespread disease activity. Neverthe- achieve control of their disease by using it as a
less, some patients continue the resorcinol treat- preventive therapy. Typically the drug is used in
ment. Compliance is crucial for a good effect. combination with other treatments of acute le-
The degree of symptom relief (pain, pus dis- sions, e.g., topical clindamycin or intralesional
charge, malodor) often makes it worthwhile for steroids.
the patient to continue using the cream once the Azelaic acid is a very safe drug and its side-
effect sets in. There is obviously no cure of sinus effects are correspondingly restricted to mild
tracts and nodules may also persist. Overall, it is local irritation of the skin. The exact role of this
estimated that in approximately 80% of the pa- drug in the treatment awaits formal studies.
tients (Hurley Stages I and II) the (subjective)
complaints are relieved by this treatment. More-
over, the usefulness of this therapy has been 21.4.2 Fusidic Acid
supported by the continued patient demand for
it. Formal contemporary studies are however Fusidic acid is a steroid-like molecule with a
necessary to substantiate these clinical impres- strong anti-staphylococcal effect [37]. It is effec-
sions further. tive in the treatment of superficial infection,
and may aid the treatment of superinfection in
HS. However, on its own it is less effective in the
21.4 Topical Anti-Inflammatory treatment of primary HS lesions, presumably
Therapy due to penetration problems. On occasion it
may be useful for reducing inflammation and
No formal studies have been published on the superinfection of established HS lesions, par-
use of topical anti-inflammatory treatment of ticularly when used in combination with a topi-
HS. Experience nevertheless suggests that some cal corticosteroid.
preparations may prove useful to selected pa-
tients. The preparations tried are azelaic and
fusidic acid, the latter both alone and in combi- 21.5 Intralesional Therapy
nation with topical corticosteroids (personal
observation, G.B.E. Jemec). In contrast to topical therapy the use of intrale-
sional anti-inflammatory therapy has been used
more extensively. This therapy represents an in-
21.4.1 Azelaic Acid termediate form of treatment between pharma-
cological therapy and surgery. The intralesional
Azelaic acid occurs naturally on the skin. It is a injection of corticosteroids is aimed at reducing
straight-chained nine-carbon-atom dicarbox- inflammation rapidly, and may even be sug-
ylic acid, which is non-toxic, non-teratogenic, gested to have an atrophogenic effect on formed
and non-mutagenic [30]. It has numerous bio- sinus tracts, which is desirable from a theoreti-
logical effects. These include inhibition of mito- cal point of view. There is a long tradition of us-
chondrial oxidoreductases of the respiratory ing this modality in acne cysts, where the results
chain and of enzymes concerned with DNA are often most convincing. Early studies found
synthesis. Reportedly it has antiproliferative that low-dose therapy using intralesional triam-
and cytotoxic effects on a variety of tumor cell cinolone for acne cysts was often as successful
lines in culture [31, 32]. In vitro it can influence as more potent preparations, and carried less
the growth of keratinocytes and has antifungal risk of atrophy or other complications [38, 39].
and bacteriostatic effects [33, 34]. Clinically az- No proper studies of the effects of intrale-
elaic acid is registered for the treatment of mild sional corticosteroids in HS are available. How-
ever, the use of local anti-inflammatory treat- further indicated because this group of patients
21 ment is in good accordance with the use of is very well acquainted with the natural evolu-
systemic anti-inflammatory therapies (see tion of lesions, and can therefore start therapy at
Chap. 18), and the low prevalence of recognized a very early point in any flare of the disease.
pathogenic bacteria. Local treatment can be carried out as mono-
In practice this is particularly useful for pa- therapy, but most often a better result is achieved
tients with few intermediate lesions, and may by combining several treatment modalities,
often be combined with topical therapy to keep such as topical antibiotics and intralesional ste-
the disease under control. roids. By combining local therapies with differ-
If there is clinical suspicion of suprainfection ent mechanisms of action it may be possible to
with, for example, Staphylococcus aureus this contain disease progression without having to
treatment is not recommended. Patients with use systemic therapies or surgery. Just as for
S. aureus infection are often characterized by other therapies the long cycles of HS require
rapidly evolving, painful, red, and suppurating that a therapy is used for at least 3 months be-
lesions. fore its efficacy can be adequately assessed. It is
When using this treatment 0.51.0 ml triam- therefore of benefit to the patient and the treat-
cinolone (10 mg/ml) is injected into the lesions ing physician if a plan for the containment of
with a no. 27 or thinner needle. Weaker concen- the disease is drawn up for each patient. If the
trations of triamcinolone may also be useful, disease is progressive treatment should be in-
whereas betamethasone has been reported as tensified every third month until adequate relief
being less effective in acne lesions [38]. On occa- is achieved. This could involve progressively
sion the injected triamcinolone will leak from more aggressive therapy, starting with topical
the sinus tract, and paralesional injections may therapy and moving on in a predetermined
therefore also be used. The use of intralesional manner to combinations of topical therapies, to
steroids has been successfully combined with intralesional steroids, to systemic therapy and
topical and systemic use in the treatment of acne then to surgery.
sinus tracts, and may also be combined with
systemic therapy in the treatment of HS [39].
Relief usually occurs within days of the injec- 21.7 Publication Bias
tion. In early lesions it is the authors (G.B.E.J.)
impression that resolution of nodules may oc- The paucity of controlled trials is apparent for
cur, whereas more developed boils respond with local therapy of HS. There is therefore a strong
spontaneous drainage after a few days, offering bias towards anecdotal therapies. For anecdotal
relief similar to that reported with the use of therapies there is a strong and well known bias
strong keratolytics. towards false-positive reports.
In this review of treatments the authors have
attempted to assess the local therapies in view of
21.6 The Use of Local Therapy personal experience with the treatment modali-
ties, but this does obviously not substitute for
Initial treatment of early or minor lesions is controlled trials or careful follow-up studies of
usually local. Provided the local therapy is part cohorts of patients.
of a therapeutic strategy for each patient, this is Just as in the development of new surgical
a rational approach, in terms of both traditional techniques a lower degree of evidence is accept-
clinical assessments such as effect and cost-ef- able in order to establish the necessary data for
ficiency and also cost-benefit to the patient. Ef- planning a future trial and providing immedi-
ficient forms of local treatment exist, although ate information. The key features of any investi-
none is universally effective. They have a low gations should therefore be an explicit random-
potential for side-effects and many can be used ization procedure, appropriate documentation
for both prophylactic therapy and self-treatment and a follow-up of not less than 3 months.
of early lesions. Self-treatment of early lesions is
For bilateral HS lesions randomized intra-in- 13. Boer J, Bos WH, Meer JB van der. Hidradenitis sup-
dividual left to right comparison of physical purativa (acne inversa): behandeling met deroofing
therapies is possible, but it is not advised to di- en resorcine [English abstract]. Ned Tijdschr Derm
Venereol 2004; 14:274278
rectly compare axillary and genitofemoral le-
14. Braun Falco O, Plewig G, Wolff HH, Burgdorf
sions, for example, as their natural prognoses WHC. Diseases of the sebaceous Glands. In: Braun
often differ significantly (it is better for axillary Falco O, Plewig G, Wolff HH, Burgdorf WHC (eds)
lesions). Dermatology, 4th revised edn. Springer, Berlin Hei-
delberg New York, 1996; pp 10511082
15. Webster GF. Acne vulgaris. Br Med J 2002; 325:475
References 479
16. Stienstra P. Hidradenitis suppurativa. In: Jansen LH
(ed) Huid en geslachtsziekten. Scheltema en Holke-
1. Lapins J, Jarstrand C, Emtestam L. Coagulase-nega-
ma, Utrecht, 1975; pp 121125
tive staphylococci are the most common bacteria
17. Polano MK. Topical therapeutics. Churchill Living-
found in cultures from the deep portions of hi-
stone, Edinburgh, 1984
dradenitis suppurativa lesions, as obtained by car-
18. Groot de AC. Dermatological drugs, topical agents
bon dioxide laser surgery. Br J Dermatol 1999; Jan,
and cosmetics. In: Dukes MNG, Aronson JK (eds)
140(1):905
Meylers side effects of drugs, 14th edn. Elsevier,
2. Clemmensen OJ. Topical treatment of hidradenitis
Amsterdam, 2000; p 473
suppurativa with clindamycin. Int J Dermatol 1983;
19.Degreef H, Hulsebos HJ, Marin KJC, Schroeff JG
22:325328
van der. Behandelingsprincipes. In: Vloten WA,
3. Jemec GB, Wendelboe P. Topical clindamycin ver-
van, Degreef HJ, Stolz E, Vermeer BJ, Willemze R
sus systemic tetracycline in the treatment of hi-
(eds) Dermatologie en Venereologie, 3rd edn. Else-
dradenitis suppurativa. J Am Acad Dermatol 1998;
vier, Amsterdam, 2000.
39:971974
20. Mills OH, Kligman AM. Assay of comedolytic ac-
4. Akhavan A, Bershad S. Topical acne drugs: review
tivity in acne patients. Acta Dermatovenereol 1982;
of clinical properties, systemic exposure, and safety.
63:6871
Am J Clin Dermatol 2003; 4:473492
21. Mills OH, Kligman AM. Drugs that are ineffective
5. Krautheim A, Gollnick H. Transdermal penetra-
in the treatment of acne vulgaris. Br J Dermatol
tion of topical drugs used in the treatment of acne.
1983; 108:371374
Clin Pharmacokinet 2003; 42:12871304
22. Wthrich B, Zabrodsky S, Storck H. Perkutane Ver-
6. Parry MF, Rha CK. Pseudomembranous colitis
giftungen durch Resorcin, Salicylsure und weisse
caused by topical clindamycin phosphate. Arch
Prcipitatsalbe. Pharmaceutica Acta Helvetiae
Dermatol 1986; 122:583584
1970; 45:453460
7. Milstone EB, McDonald AJ, Scholhamer CF Jr.
23. Hckh G, Schwarzmller E. Codex dermatologisch-
Pseudomembranous colitis after topical application
er Wirkstoffe. In: Niedner R, Ziegenmeyer J (eds)
of clindamycin. Arch Dermatol 1981; 117:154155
Dermatika. Wissenschaftliche Verlagsgesellschaft,
8. Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay
Stuttgart, 1992; pp 447448
A, Leyden JJ, Shalita A, Thiboutot D. Management
24. Werth von der JM, Williams HC. The natural histo-
of acne. Topical retinoids. J Am Acad Dermatol
ry of hidradenitis suppurativa. J Eur Acad Dermatol
2003; 49 [Suppl 1]:S5S11
Venereol 2000; 14:389392
9. Yu CC, Cook MG. Hidradenitis suppurativa: a dis-
25. Cunliffe WJ. Looking back to the future acne.
ease of follicular epithelium rather than apocrine
Dermatology 2002; 204:167172
glands. Br J Dermatol 1990; 122:763769
26. Cassano N, Alessandrini G, Mastrolonardo M,
10. Attanoos R, Appleton MAC, Douglas-Jones AG.
Vena GA. Peeling agents: toxicological and allergo-
The pathogenesis of hidradenitis suppurativa: a
logical aspects. J Eur Acad Dermatol Venereol 1999;
closer look at apocrine and apoeccrine glands. Br J
13:1423
Dermatol 1995; 133:254258
27. Bontemps H, Mallaret M, Besson G, Bochaton H,
11. Boer J, Weltevreden EF. Hidradenitis suppurativa
Carpentier F. Confusion after topical use of resor-
or acne inversa: a clinicopathological study of early
cinol. Arch Dermatol 1995; 131:112
lesions. Br J Dermatol 1996; 135:721725
28. Cunningham AA. Resorcine poisoning. Arch Dis
12. Boer J, Dijkstra AT, Baar TJM, Meer JB van der.
Child 1956; 31:173176
Hidradenitis suppurativa (acne inversa): Lokale be-
29. Plas M van der, Bos WH. Chirurgische behandel-
handeling met resorcine. Ned Tijdschr Derm Vene-
ing (epitheliale adnexcysten) door de dermatoloog
reol 2001; 11:348349
[English abstract]. Ned Tijdschr Derm Venereol
1994; 4:101103
30. Breathnach AS. Azelaic acid: potential as a general 35. Galhaup I. Azelaic acid: mode of action at cellu-
21 antitumoural agent. Med Hypotheses 1999; 52:221
226
lar and subcellular levels. Acta Dermatol Venereol
Suppl (Stockh) 1989; 143:7582
31. Brasch J, Christophers E. Azelaic acid has anti- 36. Bojar RA, Holland KT, Leeming JP, Cunliffe WJ.
mycotic properties in vitro. Dermatology 1993; Azelaic acid: its uptake and mode of action in
186:5558 Staphylococcus epidermidis NCTC 11047. J Appl
32. Detmar M, Mayer-da-Silva A, Stadler R, Orfanos Bacteriol 1988; 64:497504
CE. Effects of azelaic acid on proliferation and ul- 37. Wilkinson JD. Fusidic acid in dermatology. Br J
trastructure of mouse keratinocytes in vitro. J In- Dermatol 1998;139 [Suppl] 53:3740
vest Dermatol 1989; 93:7074 38. Levine RM, Rasmussen JE. Intralesional corticoste-
33. Topert M, Rach P, Siegmund F. Pharmacology and roids in the treatment of nodulocystic acne. Arch
toxicology of azelaic acid. Acta Dermatol Venereol Dermatol 1983; 119:480481
Suppl (Stockh) 1989; 143:1419 39. Jansen T, Romiti R, Plewig G, Altmeyer P. Disfigur-
34. Passi S, Picardo M, Mingrone G, Breathnach AS, ing draining sinus tracts in a female acne patient.
Nazzaro-Porro M. Azelaic acid biochemistry Pediatr Dermatol 2000; 17:123125
and metabolism. Acta Dermatol Venereol Suppl
(Stockh) 1989; 143:813
Chapter 22
Surgery
Jan Lapins, Lennart Emtestam
22
#ONTENTS
Key points
22.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 161
Q The surgical method chosen in each
22.2 Methods of Closure . . . . . . . . . . . . . . . . . . .164
case depends on several factors,
including the region(s) involved, 22.3 Anatomical Regions Involved . . . . . . . . . . 165
as well as the type and severity of 22.3.1 Axillary HS . . . . . . . . . . . . . . . . . . . . . . . . . . 165
22.3.2 Inguinal Disease . . . . . . . . . . . . . . . . . . . . . . 165
hidradenitis suppurativa (HS) 22.3.3 Gluteal-Perianal-Perineal Disease . . . . . . 165
Q Incision and drainage may sometimes 22.4 Excision Margins . . . . . . . . . . . . . . . . . . . . .166

lead to temporary control of symptoms 22.5 Complications . . . . . . . . . . . . . . . . . . . . . . . .166
but is best avoided since the abscesses 22.5.1 Recurrent Disease After Surgery . . . . . . . . 167
almost inevitably recur 22.6 Carbon Dioxide Laser Surgery in HS . . . . 167
22.6.1 Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . .168
Q Simple excisions with primary closure 22.6.2 Postoperative Wound Care . . . . . . . . . . . . .168
or exteriorization, curettage and 22.6.3 Practical Hints and Comments . . . . . . . . .168
22.6.3.1 The Carbon Dioxide Laser Technique . . .168
electrocoagulation of the sinus tracts 22.6.3.2 The Use of Scanners . . . . . . . . . . . . . . . . . . . 169
may be sufficient in milder forms 22.6.3.3 How Radical Should the Therapy Be? . . . 170
22.6.3.4 Concluding Remarks . . . . . . . . . . . . . . . . . . 171
Q Wide and radical excision, well beyond References . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
the clinical borders of activity, serves as
the golden standard treatment, regard-
less of the localization of HS
22.1 Introduction
Q Vaporization with carbon dioxide laser
is a sufficient surgical method for early Hidradenitis suppurativa (HS, synonym acne
treatment in moderate forms inversa) is a cicatrizing and frequently persis-
tent inflammatory disorder of the sebaceous
Q Healing by secondary intention is a follicles and terminal hair follicles of apocrine-
convenient alternative to reconstruc- gland-bearing areas in the adult [12, 31]. The
tion using skin grafts or flaps condition may remain relatively mild but never-
theless distressing [32], ranging from a few but
recalcitrant suppurating lesions to an advanced
widespread and disabling disease lasting for
years or decades. Possible consequences of long-
standing, recurrent disease are multiple surgery
and considerable social burden caused by chron-
ic infection, with purulent discharge, odor, and
pain [35]. In addition, there is a risk of develop-
ing a squamous cell carcinoma [9, 36, 40, 73],
162 Jan Lapins, Lennart Emtestam
22
Fig. 22.1 ac. A 30-year-old man before (a), directly af- eated by ink, and 6 weeks later (c), without closure of the
ter (b) scanner-assisted carbon dioxide laser vaporization defect, i.e., only secondary healing
of hidradenitis suppurativa of the axilla, the lesions delin-
especially in the perianal region [70]. The etiol- most severe cases (Stage III) are described as
ogy of HS is obscure. having multiple interconnected tracts and ab-
Hyperkeratosis of the follicular infundibu- scesses throughout the entire affected area. The
lum forming comedo-like impactions occludes Hurley grading system is very useful for overall
the pilosebaceous apparatus [5, 34, 69]. This is classification of cases and may form the basis
followed by rupture of the follicular canal and for selection of appropriate treatment in a se-
the spilling of foreign-body material into con- lected anatomical region. Most patients seen in
nective tissue. The dumping of foreign material Departments of Dermatology and many of those
such as corneocytes, bacteria, sebaceous matter, with HS have a milder course, usually Hurley
and hairs into the connective tissues excites an Stage II. Hurley Stage II is the commonest type
inflammatory infiltrate. The infiltrate consists of HS [35]. Milder cases may be manageable
initially of granulocytes, followed by mononu- with medical therapy; Hurley Stage II cases need
clear cells, and forms a foreign-body granuloma. local surgery including carbon dioxide laser
Epithelial strands are formed and evolve to ker- treatment with secondary intention healing (see
atin-producing sinuses lined with squamous later; Fig. 22.1). Hurley Stage III cases generally
epithelium, and fistulas and secondary comedo- require wide surgical excisions of the entire af-
nes are typical features [5, 34, 69]. The tissue fected region and referral to a Department of
reaction is complicated by extensive inflamma- Plastic and Reconstructive Surgery.
tion and enhanced by secondary bacterial colo- Evaluation of the various surgical HS treat-
nization and secondary bacterial infection [28, ment procedures is difficult because of incom-
39, 48]. This chronic inflammatory process pro- plete reporting of results and lack of controlled
duces richly deforming and contracting fibrotic data. Also, the recurrence rate of certain patient
scar tissue with subsequent functional defects material, for example troublesome cases referred
[5, 34, 37, 72]. to us because no successful treatments have yet
Many therapies have been tested, often frus- been found, varies with the severity of the dis-
tratingly with limited or temporary results. In ease. For surgical studies double-blinded con-
refractory cases surgery is essential and recom- trolled investigations are not useful, and the re-
mended as early as possible. sults of individual techniques are therefore best
In the classic Hurley clinical grading system documented through careful follow-up studies.
[29], Stage I consists of one or more abscesses The terms wide and radical excision are of-
with no sinus tract and cicatrization and Stage ten poorly defined in published papers, and thus
II consists of one or more widely separated re- it is difficult to compare and evaluate the meth-
current abscesses, with a tract and scarring. The ods and results of different published series.
Surgery Chapter 22 163
When the papers are written, emphasis is often perianal region, and 34% in other regions [57].
placed on the technique used to cover an exci- In a total of 241 surgical procedures the recon-
sion defect rather than the extent of excision or struction type was healing by secondary inten-
the success or failure of the treatment. The need tion in 20%, primary suture in 41%, local flap in
for prolonged follow-up, even after radical sur- 11%, free skin grafts in 26%, and combinations
gery, is important to determine late recurrence, in 1%. It seems that the patients from Rompels
as local recurrence is seen for several years after center generally had less severe disease com-
surgery. Early surgical treatment is indicated pared to the above-mentioned material reviewed
when medical treatment fails and invariably by Banerjee [6], since 41% of the procedures
when the disease is extensive. In established HS were primary sutures. The rate of recurrence
there is no evidence that treatment other than within the operated fields was 2.5%, which was
surgery has any effect on the natural story of the not affected by choice of reconstruction meth-
condition. Only wide surgical excision can cure od, but rather the severity of the disorder, and
the patient in the chronic, recurrent stage of the there were very few complications. Radical exci-
disease. Wide excisions, well beyond the clinical sion was suggested to be the treatment of choice
borders of activity, are mandatory, regardless of and the use of intra-operative color marking of
the localization of HS. The surgical methods sinus tracts was reported to minimize recur-
chosen in each case depend on several factors, rence rates [57].
including the region(s) involved [6], as well as Incision and drainage, performed in acute
the type and severity of HS [29, 59]. Simple exci- situations in various surgeries, are probably the
sions with carbon dioxide laser [62], primary most common treatments for HS patients, and
closure or exteriorization, curettage and elec- may sometimes lead to temporary control of
trocoagulation [11, 16] of the sinus tracts can be symptoms; however, they are best avoided since
sufficient, but in cases involving the entire apo- the abscesses almost inevitably recur [3, 6, 10,
crine-gland-bearing area more extensive sur- 55, 58]. Deroofing and exteriorization of the
gery is sometimes considered necessary [23, 58, sinus tracts may be of value [7]. Proper exterior-
69, 71]. The large wounds from major excisions ization involves removal of the roofs of sinus
have either been covered by flaps or meshed tracts, removal of all granulation tissue, which
grafts, or left to heal by secondary intention [2, in some cases may be rather extensive, and slow
4, 68, 10, 11 1315, 17, 19, 21, 25, 26, 27, 30, 33, healing by secondary intention. It is speculated
4244, 49, 50, 52, 5557, 60, 61, 65, 67]. In 1992, that optimal exteriorization is highly dependent
Banerjee reviewed 12 studies with a total of 284 on the skill and training of the surgeon, and
patients, who were treated with various surgical that optimal results may therefore be easier to
excision methods [6]. The patients selected obtain with an excision. It is common to find
probably had a somewhat more aggressive clini- large areas of skin undermined with tracks run-
cal type than normal HS patients, since all were ning for long distances, but usually at the same
hospitalized for 542 days after surgery. The depth. Care must be taken not to create false
follow-up time was 18 years and the recurrence passages. The complete roof of the track is then
rate varied from 0% to 68%. It was concluded cut off, leaving the floor exposed. The true pas-
that radical excision and healing by secondary sages are recognizable by their well-established
intention gave good symptomatic control in ax- margins and partly epithelialized floor and
illary, inguino-perineal and perianal regions, walls. Care must be taken not to damage the
but was less satisfactory for the submammary floor of the exposed tracts. In severe cases the
location. Skin grafting and flaps should be re- treatment is limited at each operating session to
served for severe recurrent disease [6]. Rompel an extent that enables mobilization and mini-
and coworkers analyzed data from their clinic: mizes postoperative discomfort. Sometimes this
106 HS patients in all (61 women and 45 men) of method can be used in patients whose disease is
which 61% were treated in the axillary region, so extensive that wide excision could not be
75% in the inguinal region, 16% in the genito/ contemplated.
22.2 Methods of Closure of daily activities and minimal analgesic re-

quirements after healing by secondary inten-
Several different techniques have been de- tion; wound closure was uncomplicated, with
scribed, and the techniques employed include: unrestrictive, stable, and cosmetically accept-
22 excision and primary closure, excision followed able scars. As soon as patients are confident that
by secondary healing, excision and split thick- they can handle these areas with sitz baths or
ness skin grafting, excision and delayed graft- compresses, as the case may be, they are dis-
ing, and skin excision and plastic reconstruc- charged. To decrease healing time, free skin
tion using rotation flaps and pedicle flaps. grafts can be secondarily applied to the granu-
Controversy exists about closure of the skin de- lating surface.
fect. Adequate excision will usually result in a The principle reason for skin grafting is to
defect that precludes primary closure, and vari- prevent contracture and shorten the period of
ous techniques are described to obtain skin morbidity. Split-skin grafting, either immediate
cover, such as applying split skin grafts, trans- or delayed, has the advantage of rapid healing
posed or pedicle flaps. Primary closure and ro- with complete wound healing, often in 23
tation flaps, including the use of wide under- weeks. Excision and free skin grafting is most
mining and elliptical sutures, VY-plasty, and satisfactory for shallow axillary, suprapubic,
WY-plasty, are rarely used because of the exten- and buttock defects. For the perineum, pubis,
sive nature of the excisions; however, they usu- and intercrural regions, split thickness grafts
ally give satisfactory results for small axillary yield shortest healing times and satisfactory
defects, the inguinal regions, mammary folds, cosmetic results [8]. Disadvantages include an
and the upper part of the thighs. Primary clo- unsightly cosmetic result and the discomfort
sure is reported to be more effective in axillary and poor cosmesis associated with the donor
excisions in women because of the extra skin site [12]. In addition, the affected limb must be
available in the lateral mammary area. Pollock immobilized for several days. These can be
et al. [50] have demonstrated the use of a trans- applied immediately at the time of excision.
verse primary closure. Another possibility is a Otherwise, a delay of 46 days will allow for a
combination of primary closure and healing by healthy bed of granulation tissue to form which
granulation. does not bleed if the dressings are soaked off and
The excision defect can be left open to granu- split grafts can be applied at that time. Mustafa
late and epithelialize. The certainty of wound et al. [46] reported a preference for a 1-week de-
healing, avoidance of a donor site, rapid mobili- lay before skin grafting to avoid missing any re-
zation with minimal discomfort, and uncom- tained sinus tracts not completely excised. Oth-
plicated management of the wound after dis- ers recommend a shorter (4872 h) delayed skin
charge from hospital recommend its use. graft to speed up the process [8]. Free grafts are
Healing by granulation (secondary intention) is complicated by the technical problems of fixa-
associated with a predictable result that is as tion and immobilization, lengthy hospitaliza-
good or even superior to that obtained by skin tion, time-consuming dressings, possible partial
grafting. However, complete wound closure may loss, and contraction of the grafted axilla.
take up to 23 months. Healing by granulation Excision and closure with a pedicle rotation
is a method especially suitable for the nape of flap or tube flap is used mainly in deep defects
the neck and the perianum and perineum, and of the axilla [20, 27, 47, 63] and occasionally the
furthermore for controlling severe HS of the ax- inguinal, scrotal, and perineal regions, where
illary and inguino-perineal areas [61, 68]. A vessels or vital organs may be exposed and a
study by Morgan et al. [44] of patients with bi- healthy protective covering is required immedi-
lateral axillary involvement compared granula- ately. The rotation of a regionally based flap is
tion on one side with grafting on the other. Most advantageous in closure when the disease pro-
patients preferred granulation with a silastic cess has penetrated deeply. Total excision results
foam dressing. In another study, subjects re- in an especially cavernous defect, which is likely
ported minimal inconvenience or interruption to expose the large vessels. It is particularly ad-
vantageous in repairing the axillary wound of subcutaneous tissue with its own blood supply.
obese robust patients. Posteriorly based flaps In cases where primary closure is not possible,
are elevated from the inframammary area and rotation of a flap, usually from the chest wall, is
rotated into the defect of the axilla [25]. The required. The axillary region in HS is discussed
submammary donor site is closed primarily. Lo- more below.
cal flaps have been used by many for this repair.
The combination of a regional flap and split
thickness skin graft furnishes another means of 22.3.2 Inguinal Disease
axillary repair. Z-plasty is one of the most use-
ful plastic surgery procedures and deserves first Higher recurrence rates are seen in the inguino-
consideration in the prevention and contracture perineal region [63]. Despite a high recurrence
of scars. Generally, the length of the arms of the rate most patients are well satisfied after ingui-
Z should be equal. In modified Z-plasty, first no-perineal excision because local areas of re-
the upper and lower portions of the wound are currence are trivial compared with the disease
approximated to form an elliptical central de- before surgery. Excision and healing by granu-
fect, which lies in the line of election. The Z- lation can be applied [61]. All tissue is excised
plasty is then carefully planned and the flaps down to the fascia and the wound is allowed to
developed. Free skin grafts, tubed and pedicle granulate and epithelialize spontaneously. The
flaps can be used to reconstruct large deep de- excision must not go deeper than the fascia, to
fects of the perineum, pubis, and groin. Such protect the vas deferens and the testis from ex-
flaps provide satisfactory coverage for exposed posure.
testicles and large vessels or other important
structures. Rotation flaps and Z-plasty have
certain disadvantages. When the axillary defect 22.3.3 Gluteal-Perianal-
is long and wide, the arms of the Z may have to Perineal Disease
extend and disfigure the anterior chest.
Grafting is associated with high failure rates in
the perineal and perianal areas and is not ad-
22.3 Anatomical Regions Involved vised for closure of the anal canal either. Grafts
in this area may contract, leading to anal steno-
The choice of surgical techniques varies accord- sis [12]. Some authors argue that cases with ex-
ing to region. Wide excision surgery gives good tensive tissue resection over the buttocks and
symptomatic control of severe HS of the axilla perianal region benefit from skin grafting [8,
and perianal regions but higher recurrence rates 71], while others find that the overwhelming
in the inguino-perineal region and it is less sat- majority of perineal resections do well with clo-
isfactory for submammary disease [63]. Despite sure by secondary intention [21]. Simple wide
a high recurrence rate most patients are well sat- excision, early discharge, and home care until
isfied after inguino-perineal excision because healing is complete minimize operative and
local recurrences are trivial compared with the hospitalization costs and the risk of immobiliza-
disease before surgery. tion. Complete healing requires from 2 to 5
months depending on the extent of initial dis-
ease and the surgical intervention. The patients
22.3.1 Axillary HS are quite familiar with dressing techniques and
therefore require little reinforcement to main-
Primary closure can be more effective with axil- tain themselves during the prolonged interval of
lary excisions in women because of the extra healing. A better cosmetic result is obtained and
skin available in the lateral mammary area. If many patients are quite concerned about the
the dissection has extended to the point where cosmetic appearance of their buttocks. Large ar-
axillary vessels are exposed, this must be cov- eas will granulate in a period of several months
ered with substantial tissue, namely skin and and the patients begin to live a productive life
long before healing is complete. Digital exami- essary to avoid local recurrence. If any part of
nation of the anus and rectum should be per- the fistula is left behind the inflammatory pro-
formed in perianal HS to diagnose anal fistula cess will soon start again and often also dissect
[16]. The diagnosis is based on the presence of an through the healthy scar and recur. In general
22 indurate fistula in the anal canal with the pri- small recurrences or new lesions seen can be ex-
mary lesion of the anal gland palpated close to cised as they occur. This will leave a lot of pa-
the dentate line. Fistulas connecting with deep tients with a minor surgical scar and with fewer
organs such as the anal canal, rectum or urethra of the complications associated with major sur-
have been rarely mentioned in the literature. Re- gery. Even in cases where very wide excisions
garding perianal surgery, some authors prefer are performed, local recurrences or new lesions
the use of a colostomy to prevent fecal contami- are seen and there is always a risk of new lesions
nation of the wound [71]. However, most often it in a new region. Local excision of more ad-
is unnecessary if a thorough mechanical bowel vanced HS (most of or the whole of a region is
preparation is done preoperatively, if bowel ac- fistulated, Hurley Stage III) is often followed by
tivity is suppressed postoperatively, and local recurrence and many authors agree that wide
hygiene is aggressive during healing. excision of affected skin is to be preferred. It is
reasonable to excise at least all the hair-bearing
skin in cases where a large area is affected. In
22.4 Excision Margins these advanced cases most of the region is al-
ready involved by HS lesions and the aim is not
The choice of the surgical borders for radical ex- to leave axillary skin that has a preponderance
cision is important. Usually the excision reaches to develop HS lesions. Therefore, in the axilla, it
the deep subcutaneous fat or the fascia. Three is recommended to excise all of the hair-bearing
types of excisional limits can be discussed (after skin. An extra margin of 2 cm is advocated by
Soldin et al. [63]): some authors [6, 55, 63]. In skin close to in-
flamed tissues an estimated free margin should
1. Limited local excision. Only the obviously be added. If radical surgery of the whole area
diseased tissue is excised. Usually this is cannot be done, the patient can still gain the re-
within the area of the hair-bearing skin. lief of having a reduced disease burden follow-
2. Hair-bearing skin excision the area of ing local excisions of the fistulating process.
axillary tissue containing terminal hair is There are also cases that can be assessed as be-
excised. The excision is performed down ing somewhere between these two extremes.
to the fascia. Other information about the patients general
3. Wide local excision all hair-bearing health, surgical risks, surgical possibilities for
tissue and an additional 2-cm margin of closing specific defects and the patients will-
surrounding skin are removed, down to ingness to accept an unsightly scar must be bal-
the fascia (mainly for axillary disease). anced against the risk of recurrences. The con-
sequences of a recurrence in the area are major
The choice of margins is very much dependent surgery or a small excision.
on the extent and development of HS in the
individual patient. Excision of inflammatory
tissue including all occluded follicles and all fis- 22.5 Complications
tulas is mandatory, otherwise immediate recur-
rence will follow surgery. In cases where the Complications include suture dehiscence,
disease is limited, with fistulated processes sep- wound separation, postoperative bleeding, he-
arated by healthy skin (disease Stage II accord- matoma, and loss of flap or skin graft. Local
ing to Hurleys classification), and when most of wound and septic infections are rare and not
the region is spared, excision of the skin con- prevented by preoperative antibiotics. The late
fined to the diseased tissues is satisfactory. In sequelae involve different types of problems re-
cases confined to a fistulating process, it is nec- lated to scar formation, especially when in the
axilla, and on occasion require release of the dustries). A focusing handpiece from a Sharplan
contracture or even Z-plasty. In the perineum, carbon dioxide laser 1030 is attached to the
scar contractures occur quite regularly but pres- miniature optomechanical flash scanner deliv-
ent little functional disability. ery system, which generates a focal spot that
rapidly and homogeneously carries out a spiral
scan and covers a circular area of tissue at the
22.5.1 Recurrent Disease After Surgery focal plane.
The symptomatic lesions, according to the
When single or adjacent elements are excised patients opinion regarding discharge, inflam-
recurrences do occur locally even after surgery, mation, infiltration or suspected abscesses, are
and patients may develop new foci of HS in an- selected for treatment. Areas that had been si-
other region. Local recurrences may appear rap- lent for more than 2 years but with signs of ear-
idly and in direct association with the scar, sug- lier activity, i.e., scars with postinflammatory
gesting that diseased tissue was left at the time hyperpigmentation, sometimes with dry come-
of operation, or they may appear over a longer dones but with no actual inflammatory activity
period suggesting de novo occurrence of disease detected, are judged as burned out and left
[33]. The appearance of new foci strongly sug- untreated. The diseased skin is macroscopically
gests that the disease is of a multifocal nature. scrutinized for scarring, tissue distortion and
Sometimes attempts to obtain primary skin discoloration, dry or suppurating sinuses, mac-
cover may lead to inadvertent compromise of rocomedones and other superficial signs. The
the excision margin and an increased risk of re- examination is completed with palpation of the
currence. defects for bulky indurations and small, firm
subcutaneous nodules or fluctuating purulent
tissue. The selected area is ablated with the laser
22.6 Carbon Dioxide Laser Surgery beam by passing it over the tissues with as much
in HS power as is controllable in the surgical situation.
After wetting the surface with a 0.9% sodium
In the early 1990s we were looking for a treat- chloride solution to remove devitalized tissue
ment for the most common type of HS, with a and drying it with a swab, the treated area can
high likelihood of cure, a low recurrence rate, be evaluated and repeated ablations are possible
and one that avoided hospital admission and in the same manner. The depth of each level of
general anesthesia, with minimal inconvenience vaporization is controlled by the selection of
and time off work for the patient. One of us power, focal length, scanner-controlled spot size
(J.L.) developed a modified minimally invasive and the velocity of the movements of the hand-
carbon dioxide laser procedure followed by heal- held scanner. We use 2030 W, 3- to 6-mm spot
ing by secondary intention [38, 41]. There now size, and 12.5 or 18 cm focal length setting. The
follows a detailed description of this method. resulting depth of the vaporization procedure is
The method involves using the simple, fast, determined after inspection for signs of healthy
hand-movement-controlled paintbrush tech- and diseased cutaneous tissue. The vaporization
nique and a Sharplan carbon dioxide laser (CO2) procedure is repeated downward and outward
1030 (Laser Industries, Tel Aviv, Israel) operat- until fresh yellow fat tissue is exposed in the
ing at 30 W [38]. Since 1993 the method has deep and relatively thin and anatomically nor-
been modified, taking advantage of the intro- mal skin margins laterally, with no remaining
duction of carbon dioxide laser scanners (rapid dense or discolored tissue. Usually the vapor-
beam optomechanichal microprocessed scan- ization reaches the deep subcutaneous fat or the
ner systems). From 1993 to 1994: SwiftLase fascia. In the axillary region, major vessels and
(the optomechanical flash scanner, SwiftLase, the nerve plexus have to be protected but this
model 755, Laser Industries); from 1995 to the depth is seldom reached in patients with Hurley
present day: SilkTouch (the optomechanical Stage II [29] HS as treated in this manner. The
flash scanner, Silktouch, model 765, Laser In- smaller blood vessels are readily and conve-
niently coagulated by the laser and little or no the maximal safety limit of local anesthetics
bleeding occurs during the surgical procedure. should not be exceeded.
Bleeding from vessels larger than 0.51 mm in
diameter is preferably stopped using electroco-
22 agulation or ligation. 22.6.2 Postoperative Wound Care
The treatment is terminated by a final soak
with 0.9% sodium chloride solution and exami- Immediately after the wounds are surgically
nation for remaining diseased areas and bleed- dressed, the patients are instructed to stand up
ing. The wound, left to heal by secondary inten- and take a short walk. The patients remain at
tion, is immediately covered after the surgical the clinic for 3 h following the procedure, which
procedure with dry dressings or ointment-im- allows them to check for functional impairment
pregnated dressings with an outer covering and gives them the opportunity to empty their
bandage attached using surgical adhesive tape, bowels and bladder and also to discover any
or with gauze underwear. bleeding before leaving. The dressings are ini-
When patients are on acetyl salicylic tially left on for 23 days without being changed,
acid or non-steroidal anti-inflammatory drugs to avoid early bleeding. Thereafter, the wound is
(NSAIDs) it is recommended to stop medication cleansed and rinsed with tap water and the ban-
for 3 weeks (acetyl salicylic acid) or 1 week dage changed as often as necessary, sometimes
(NSAIDs) before surgery. No perioperative anti- on a daily basis, until complete healing is
biotics are used. In patients with heart murmurs accomplished. Since 1998 a hydrofibre dressing
and prosthetic heart valves the use of preopera- (Aquacel, ConvaTec, Deeside, UK) has been
tive antibiotics is common. In general no pre- used for this purpose. Usually the patient does
medication is necessary but 10 mg diazepam this procedure without any need for medical
orally or per rectum 1 h before surgery is used in professional assistance. In our experience the
anxious patients. pain felt during wound care when changing the
dressings is the most problematic event for pa-
tients in the postoperative period. In our opin-
22.6.1 Anesthesia ion the hydrofibre bandage is less painful to re-
move than previously used dry dressings or
The diseased area resulting from recurrent re- ointment-impregnated dressings, although this
lapses of abscesses and chronic inflammation is has yet to be studied in a controlled manner.
delineated with ink. Following cleansing with Analgesic requirements are controlled with
0.05 mg/ml chlorhexidine solution the area is standard doses of paracetamol. Antibiotics are
anesthetized with injections of lidocaine (0.5 used if clinical signs of secondary infection are
1.0 mg/ml) and epinephrine (Xylocaine adren- found. The patients are followed-up for a wound
alin, Astra, Sdertlje, Sweden) with sufficient check after 1 week and subsequently if there are
margins. Richly innervated areas, such as the signs of complications until they are healed;
groin, are pretreated with a lidocaine/prilocaine they are then followed-up at 6 weeks and at
cream (EMLA, Astra) prior to the injections. 6 months, and thereafter only when there are
The solution is injected and infiltrates around complications or other clinical reasons for med-
and not directly into the affected site, forming a ical intervention.
square around the area, thus avoiding direct
contact with inflamed tissue as well as injection
into the abscess itself, thereby preventing an in- 22.6.3 Practical Hints and Comments
crease of pressure and pain or eruption of puru-
lent discharge. This procedure leads to almost 22.6.3.1 The Carbon Dioxide
complete anesthesia within 510 min. Recently Laser Technique
we have started to use highly diluted local an-
esthetics in large volumes, the tumescens The poor prognosis regarding complete healing
method. When larger areas require treatment, in long-standing cases of HS and the need for
prompt surgical intervention encouraged us to beam drills downwards into the tissue and re-
develop a fast and convenient surgical method moves it in a fast, even, and fully controlled way.
suitable for an outpatient setting that was radi- Before 1995 a prototype named Flashscan was
cal but at the same time tissue-sparing and that used. The device worked along the same prin-
had minimally priced post-operative profes- ciples but used a figure-of-eight scanning pat-
sional wound care. Carbon dioxide laser has tern. It was useful, but had some shortcomings
previously been used in HS treatment [18, 24, with rougher tissue surfaces and gave rise to
40]. Before there was access to scanner devices, some splashing of blood and tissues; it was sub-
we used what we called the carbon dioxide laser sequently exchanged for the Silktouch in 1995.
stripping second intention technique [38]. A In our opinion, the laser is a suitable tool for
carbon dioxide laser was used, operating at working with the contaminated and infected
30 W with a manually controlled hand piece. tissues of HS. It has the further advantages of
The beam was set to give the shortest possible allowing the surgeon to kill any bacteria present
exposure times with as much power as is (through the heat applied) and to deal with the
controllable in the surgical situation, thereby highly inflamed and purulent tissues without
causing the least lateral heat conduction and touching them. The carbon dioxide laser cuts
non-specific thermal injury as possible, with a and seals small blood and lymphatic vessels. It is
narrow coagulation margin and minimal char also advantageous in that it prevents the spread
production. If irradiation of a charred surface is of bacteria to the surrounding tissues or blood-
continued, it will be heated to more than 400 C, stream, while at the same time providing a
causing heat injury within the underlying tis- blood-free operating field with its inherent pos-
sues and margins [1, 22, 54]. Tissue vaporization sibilities for macroscopically examining tissue
by a defocused beam being moved quickly in a pathology. Favorable effects on the healing of
freehand manner in a circular motion in the experimentally infected wounds after carbon
paint brush pattern method is very dependent dioxide laser sterilization have previously been
on the surgeons experience. suggested [53, 66].
We have further developed the techniques
and strategies of the carbon dioxide laser to op-
22.6.3.2 The Use of Scanners timize its use in the different stages of HS. In-
stead of using the laser as a substitute for a scal-
We use a focused continuous-wave (CW) pel and cutting vertically into the surface around
carbon dioxide laser with a rapid beam minia- the diseased tissue, we start from another point.
ture microprocessor-controlled optomechani- Layer by layer we vaporize the tissue from inside
cal scanner system that moves the laser spot at the central surface of the diseased area down-
constant velocity in a pattern that covers the wards and outwards until all of the macroscopi-
treatment site at a dwell time of less than 1 ms. cally pathological tissue is removed and healthy
This scanner uses parallel mirrors to produce a tissue is reached. If we discover that the disease
fine spiral beam. By laying down (approximate- is more widespread than initially expected, the
ly 1618 tracks across the entire diameter of the ablated area can be extended. The principle is to
scanner) adjacent sets of concentric spirals, a be as radical as possible and still save sufficient
full scan is produced in 0.2 s. An ideal way to healthy tissue for the secondary healing process
reduce the conduction of thermal injury to the in order to obtain fast healing and to avoid un-
skin is to combine high fluency (energy/unit necessary scarring and contraction. From our
area) with a very short laser exposure time, thus own experience of scalpel excisions of HS, ini-
obtaining the ablation of tissue with minimum tially there is an increased risk of removing un-
thermal injury. The scanners are usually used to necessary amounts of tissue, since we have to
ablate very thin layers of skin, as in the treat- estimate how much tissue should be excised to
ment of actinic keratoses or rhytides in re- give sufficient margins. Further, the surgical
surfacing procedures, with short pulses (0.2 s). wound edges bleed a lot and are very hard to in-
Used in a continuous mode, the scanned laser vestigate for the presence of remnant pathologi-
cal tissues, which carries the inherent risk of mation is secondary and reactive to this foreign
recurrence. The carbon dioxide laser has been body material and not the cause of the recur-
applied to HS by others [24] for excision use. rence.
The excision technique is mandatory when
22 pathological anatomical examination to exclude
suspected squamous cell carcinoma is indicat- 22.6.3.3 How Radical Should
ed. It is also reasonable sometimes to debulk the Therapy Be?
heavier parts of HS lesions with wide excision,
to save time and reduce the amount of fumes for The target area for surgery should be diseased
the vacuum filter, but as soon as the border with and damaged skin but nothing beyond the ac-
healthy tissues is reached, the value of treating tively diseased area [61, 72]. A study of the ex-
from the inside out, starting with pathological tent of surgery and the recurrence rate of HS by
tissue, is obvious. Every millimeter of healthy Ritz in 1998 [55] and an extensive review by Ba-
skin tissue is valuable and should be left unless nerjee in 1992 [6] give a helpful picture of the
there is a reason to do otherwise. The use of a problems and complexity involved in compara-
scanner makes the ablation smoother and more tive assessments of surgery in HS. The majority
precise, enabling the early recognition of healthy of patients seen in dermatology units and the
or vascular tissue and the avoidance of uninten- majority of patients with HS have a relatively
tional damage. Special caution is recommended mild disease course and most often are at Hur-
in patients with a low ratio of diseased skin to ley Stage II [29], i.e., recurrent abscesses with
healthy subcutaneous tissue underlying the le- tract formation and cicatrization, and single or
sions, and in those in whom the procedure is multiple widely separated lesions that have not
limited by muscular fascias or vital parts other yet turned into the more advanced stage of dis-
than subcutaneous fat, i.e., nerves, blood ves- ease. These patients cannot be considered as
sels. The laser optical density used for treatment candidates for advanced major plastic surgery,
is considerably higher than the threshold for va- but still suffer from a chronic and disabling dis-
porization without residual carbon char and it ease [35]. New abscesses outside the clinically
generates a clean, almost char-free crater in the symptomatic skin area cannot be prevented by
tissue [64]. The scanners used with a continuous any known surgical method and they should be
emission mode give a faster, safer and more even regarded as an indicator of underlying disease
ablation with less bleeding and better visualiza- activity rather than as a shortcoming of the sur-
tion of HS macropathology during surgery com- gical method [6]. Our patients are predomi-
pared to the freehand surgical technique. Dur- nantly women and that may be a reflection of
ing the laser treatment the endpoint is healthy the fact that the disease more often presents in
tissue in all directions. The hypothesis behind otherwise healthy females during their fertile
the surgical method is that, by radically remov- years, especially the inguinal and genito-peri-
ing and vaporizing the macroscopically active neal forms [32, 45, 46, 51]. Surgery alone is only
HS disease, tissue recurrences are avoided. Ac- permanently curative in a select group of pa-
tually one is tempted to speculate that it is the tients, and only temporarily in others. The re-
cause of inflammation that is the target of laser sults of our method accord well with results
vaporization: perhaps the cause of inflamma- from other types of surgery [6, 25] and the need
tion is destroyed along with the hypertrophi- for repeated treatment sessions should be con-
cally deformed follicle and its content of foreign sidered. This method is conveniently repeated,
material such as keratin from corneocytes and and as it is tissue-sparing the risk of contrac-
debris from hair and bacteria. Hypothetically tures is reduced. In recurrent disease after
the sources of recurrence are the epithelial si- carbon dioxide laser surgery, repeated carbon
nuses that line this debris, as they produce kera- dioxide laser surgery in conjunction with sup-
tin and harbor bacteria that have the potential plementary medications, such as long-term
to be pathogenic in this environment. Accord- immunological modulating antibiotics, e.g.,
ing to this hypothesis the surrounding inflam- tetracyclines, retinoids or cyproterone acetate
combination medication, should be considered. wide excision and reconstructive surgery. Our
The largest group of HS patients, i.e., the early impression is that the most common form of HS
cases or the cases of mild to moderate severity, is Hurley Stage II and that most patients seem to
probably suffer a lot from their disease despite stay at this stage without progressing to Hurley
their relatively limited symptoms. For both eco- Stage III. When patients were thought to be suit-
nomic and practical reasons, in clinical practice able for surgery they were operated on at our
there is a tendency for surgery to be withheld clinic and a few were referred for wide excision
except for the most advanced cases. The patients surgery.
we have shown to gain considerably from laser In conclusion, for patients with HS, modified
surgery in our clinic had previously been treated minimally invasive carbon dioxide laser treat-
conservatively. There are reasons to believe that ment is a safe, simple, fast and economical sur-
our method will prove to be an adequate surgi- gical method with satisfactory cosmetic and
cal choice for early surgical treatment and a functional results that is suitable for the outpa-
study of carbon dioxide laser treatment of early tient setting. The use of carbon dioxide laser
HS lesions is in progress. microprocessor-controlled scanner devices has
The better safety and accuracy that come made the technique safer and less surgeon de-
with the use of microprocessor-controlled scan- pendent. The technique allows early and simple
ners make this technique available for more treatment of HS lesions that previously perhaps
general use and enable it to be used in other ar- tended to be left to less effective, local and con-
eas of treatment for HS patients, i.e., dermato- servative remedies.
logic surgeons, general and plastic surgeons,
and gynecologists. It will be possible to treat le-
sions completely and radically very early on in Acknowledgements
the course of the disease, i.e., the acute primary
HS, and this could be done in outpatients with We thank Dr. Anders Johannesson for his valu-
the wound left to heal by secondary intention able comments about previous versions of the
rather than the current option of ineffective in- manuscript, Dr. Karin Sartorius for useful ad-
cision and subsequent expensive wound care vice, Dr. Zoe and Francis P. Walsh for linguistic
with painful tamponade. Some of our chronic revision and Gun-Britt Karlberg and Barbro
patients would be much better off under this Andersen for their help. This work was support-
type of regime. ed by grants from Karolinska Institutet, the
Edvard Welander Foundation, Finsen Founda-
tion and the Foundation for Cancer and Allergy
22.6.3.4 Concluding Remarks Research.
No exact estimates of the costs have been made

but, but there are at least three reasons why car- References
bon dioxide laser is less expensive than tradi-
tional excisional surgery. Firstly, the total opera- 1. Absten GT (1991) Physics of light and lasers. Obstet
tion time is shorter, which keeps the need for Gynecol Clin North Am 18: 407427
qualified personnel to a minimum, and permits 2. Amarante J, Reis J, Santa Comba A et al (1996) A
new approach in axillary hidradenitis treatment: the
a more rational use of room facilities. Secondly, scapular island flap. Aesthetic Plast Surg 20: 443
there is no need for nursing assistance postop- 446
eratively. Thirdly, the postoperative symptoms 3. Anderson BB, Cadogan CA, Gangadharam D (1982)
are less and fewer patients have to refrain from Hidradenitis suppurativa of the perineum, scrotum,
work. A more detailed costbenefit analysis of and gluteal area: presentation, complications, and
this method remains to be done. The patients treatment. J Natl Med Assoc 74: 9991003
we selected were at Hurley Stage II, which we 4. Ariyan S, Krizek TJ (1976) Hidradenitis suppurativa
of the groin, treated by excision and spontaneous
predefined as operable by our method. Patients
healing. Plast Reconstr Surg 58: 4447
classified as Hurley Stage III were referred for
5. Attanoos RL, Appleton MA, Douglas-Jones AG 24. Finley EM, Ratz JL (1996) Treatment of hidradenitis
(1995) The pathogenesis of hidradenitis suppurati- suppurativa with carbon dioxide laser excision and
va: a closer look at apocrine and apoeccrine glands. second-intention healing. J Am Acad Dermatol 34:
Br J Dermatol 133: 254258 465469
22 6. Banerjee AK (1992) Surgical treatment of hidrad- 25. Harrison BJ, Mudge M, Hughes LE (1987) Recur-
enitis suppurativa. Br J Surg 79: 863866 rence after surgical treatment of hidradenitis sup-
7. Barron J (1970) The surgical treatment of perianal purativa. Br Med J (Clin Res Ed) 294: 487489
hidradenitis suppurativa. Dis Colon Rectum 13: 26. Hartwell SW Jr (1975) Surgical treatment of hidrad-
441443 enitis suppurativa. Surg Clin North Am 55: 1107
8. Berger GL, Habal MB, Sadlowski RW et al (1981) 1109
Surgical management of pus-pot perineum. J Urol 27. Hermanson A (1982) Surgical treatment of axillary
126: 193196 hidradenitis suppurativa. Scand J Plast Reconstr
9. Black SB, Woods JE (1982) Squamous cell carci- Surg 16: 163165
noma complicating hidradenitis suppurativa. J Surg 28. Highet AS, Warren RE, Staughton RC et al (1980)
Oncol 19: 2526 Streptococcus milleri causing treatable infection in
10. Broadwater JR, Bryant RL, Petrino RA et al (1982) perineal hidradenitis suppurativa. Br J Dermatol
Advanced hidradenitis suppurativa. Review of sur- 103: 375382
gical treatment in 23 patients. Am J Surg 144: 668 29. Hurley HJ (1996) Axillary hyperhidrosis, apocrine
670 bromhidrosis, hidradenitis suppurativa and famil-
11. Brown SC, Kazzazi N, Lord PH (1986) Surgical ial benign pemphigus. Surgical approach. In: Roe-
treatment of perineal hidradenitis suppurativa nigk RK, Roenigk HH Jr. Dermatologic surgery.
with special reference to recognition of the perianal Principles and practice. Marcel Dekker, New York
form. Br J Surg 73: 978980 30. Hyland WT, Neale HW (1976) Surgical manage-
12. Brown TJ, Rosen T, Orengo IF (1998) Hidradenitis ment of chronic hidradenitis suppurativa of the
suppurativa. South Med J 91: 11071114 perineum. South Med J 69: 10021004
13. Chalfant WPD, Nance FC (1970) Hidradenitis sup- 31. Jansen T, Plewig G (1998) Acne inversa. Int J Der-
purativa of the perineum: treatment by radical exci- matol 37: 96100
sion. Am Surg 36: 331334 32. Jemec GB (1988) The symptomatology of hidrad-
14. Chapman J (1972) The surgical treatment of hidradenitis suppurativa in women. Br J Dermatol 119:
enitis suppurativa. J Natl Med Assoc 64: 328330 345350
15. Cocke WM Jr. (1967) Surgery of hidradenitis sup- 33. Jemec GB (1988) Effect of localized surgical exci-
purativa of the perineum. Plast Reconstr Surg 39: sions in hidradenitis suppurativa. J Am Acad Der-
178181 matol 18: 11031107
16. Culp CE (1983) Chronic hidradenitis suppurativa of 34. Jemec GB, Hansen U (1996) Histology of hidradeni-
the anal canal. A surgical skin disease. Dis Colon tis suppurativa. J Am Acad Dermatol 34: 994999
Rectum 26: 669676 35. Jemec GB, Heidenheim M, Nielsen NH (1996) Hi-
17. Cutting KF, Thomas F (1992) Lasting relief from a dradenitis suppurativa characteristics and conse-
distressing condition. Surgical intervention in hi- quences. Clin Exp Dermatol 21: 419423
dradenitis suppurativa. Prof Nurse 8: 106112 36. Kaplan RP (1987) Cancer complicating chronic ul-
18. Dalrymple JC, Monaghan JM (1987) Treatment of cerative and scarifying mucocutaneous disorders.
hidradenitis suppurativa with the carbon dioxide Adv Dermatol 2: 1946
laser. Br J Surg 74: 420 37. Kurzen H, Jung EG, Hartschuh W et al (1999)
19. Duncan WC (1976) Surgical treatment of hidrad- Forms of epithelial differentiation of draining sinus
enitis suppurativa. J Dermatol Surg 2: 153157 in acne inversa (hidradenitis suppurativa). Br J Der-
20. Elliot D, Kangesu L, Bainbridge C et al (1992) Re- matol 141: 231239
construction of the axilla with a posterior arm fas- 38. Lapins J, Marcusson JA, Emtestam L (1994) Surgical
ciocutaneous flap. Br J Plast Surg 45: 101104 treatment of chronic hidradenitis suppurativa: CO2
21.Endo Y, Tamura A, Ishikawa O et al (1998) Perianal laser stripping-secondary intention technique. Br J
hidradenitis suppurativa: early surgical treatment Dermatol 131: 551556
gives good results in chronic or recurrent cases. Br J 39. Lapins J, Jarstrand C, Emtestam L (1999) Coagu-
Dermatol 139: 906910 lase-negative staphylococci are the most common
22. Fairhurst MV, Roenigk RK, Brodland DG (1992) bacteria found in cultures from the deep portions
Carbon dioxide laser surgery for skin disease. Mayo of hidradenitis suppurativa lesions, as obtained by
Clin Proc 67: 4958 carbon dioxide laser surgery. Br J Dermatol 140:
23. Fazio VW, Tjandra JJ (1996) The management of 9095
perianal diseases. Adv Surg 29: 5978
40. Lapins J, Ye W, Nyren O et al (2001) Incidence of 57. Rompel R, Petres J (2000) Long-term results of wide
cancer among patients with hidradenitis suppura- surgical excision in 106 patients with hidradenitis
tiva. Arch Dermatol 137: 730734 suppurativa. Dermatol Surg 26: 638643
41. Lapins J, Sartorius K, Emtestam L (2002) Scanner- 58. Rubin RJ, Chinn BT (1994) Perianal hidradenitis
assisted carbon dioxide laser surgery: a retrospec- suppurativa. Surg Clin North Am 74: 13171325
tive follow-up study of patients with hidradenitis 59. Sartorius K, Lapins J, Emtestam L et al (2003) Sug-
suppurativa. J Am Acad Dermatol 47: 280285 gestions for uniform outcome variables when re-
42. Letterman G, Schurter M (1974) Surgical treatment porting treatment effects in hidradenitis suppura-
of hyperhidrosis and chronic hidradenitis suppurativa. Br J Dermatol 149: 211213
tiva. J Invest Dermatol 63: 174182 60. Shaughnessy DM, Greminger RR, Margolis IB et
43. Masson JK (1969) Surgical treatment for hidradeni- al (1972) Hidradenitis suppurativa. A plea for early
tis suppurativa. Surg Clin North Am 49: 10431052 operative treatment. J Am Med Assoc 222: 320321
44. Morgan WP, Harding KG, Hughes LE (1983) A 61. Silverberg B, Smoot CE, Landa SJ et al (1987) Hi-
comparison of skin grafting and healing by granu- dradenitis suppurativa: patient satisfaction with
lation, following axillary excision for hidradenitis wound healing by secondary intention. Plast Re-
suppurativa. Ann R Coll Surg Engl 65: 235236 constr Surg 79: 555559
45. Mortimer PS, Dawber RP, Gales MA et al (1986) 62. Slade DE, Powell BW, Mortimer PS (2003) Hidrad-
Mediation of hidradenitis suppurativa by andro- enitis suppurativa: pathogenesis and management.
gens. Br Med J (Clin Res Ed) 292: 245248 Br J Plast Surg 56: 451461
46. Mustafa EB, Ali SD, Kurtz LH (1980) Hidradenitis 63. Soldin MG, Tulley P, Kaplan H et al (2000) Chronic
suppurativa: review of the literature and manage- axillary hidradenitis the efficacy of wide excision
ment of the axillary lesion. J Natl Med Assoc 72: and flap coverage. Br J Plast Surg 53: 434436
237243 64. Sporri S, Frenz M, Altermatt HJ et al (1996) Treat-
47. OBrien J, Wysocki J, Anastasi G (1976) Limberg ment of human papillomavirus-associated vulvar
flap coverage for axillary defects resulting from ex- disease with the CO2-laser. Physical and histologi-
cision of hidradenitis suppurativa. Plast Reconstr cal aspects with use of a new scanning device, the
Surg 58: 354358 SwiftLase. Arch Gynecol Obstet 259: 2535
48. Paletta C, Jurkiewicz MJ (1987) Hidradenitis sup- 65. Storino WD, Engel GH (1978) Office surgical man-
purativa. Clin Plast Surg 14: 383390 agement of recalcitrant axillary lesions. Cutis 21:
49. Pittam MR, Ellis H (1984) A comparison of skin 338341
grafting and healing by granulation following ax- 66. Stranc MF, Yang FW (1992) Wound sterilisation:
illary excision for hidradenitis suppurativa [letter]. cautery vs CO2 laser. Br J Plast Surg 45: 536539
Ann R Coll Surg Engl 66: 73 67. Temelkov T, Troshev K (1984) Surgical treatment of
50. Pollock WJ, Virnelli FR, Ryan RF (1972) Axillary chronic hidradenitis suppurativa. Acta Chir Plast
hidradenitis suppurativa. A simple and effective 26: 246252
surgical technique. Plast Reconstr Surg 49: 2227 68. Thornton JP, Abcarian H (1978) Surgical treatment
51. Radcliffe KW (1991) Hidradenitis suppurativa. of perianal and perineal hidradenitis suppurativa.
Genitourin Med 67: 58 Dis Colon Rectum 21: 573577
52. Ramasastry SS, Conklin WT, Granick MS et al 69. Watson JD (1985) Hidradenitis suppurativa a
(1985) Surgical management of massive perianal hi- clinical review. Br J Plast Surg 38: 567569
dradenitis suppurativa. Ann Plast Surg 15: 218223 70. Williams ST, Busby RC, DeMuth RJ et al (1991) Per-
53. Reid AB, Stranc MF (1991) Healing of infected ineal hidradenitis suppurativa: presentation of two
wounds following iodine scrub or CO2 laser treat- unusual complications and a review. Ann Plast Surg
ment. Lasers Surg Med 11: 475480 26: 456462
54. Reid R (1991) Physical and surgical principles gov- 71. Wiltz O, Schoetz DJ Jr., Murray JJ et al (1990) Peri-
erning carbon dioxide laser surgery on the skin. anal hidradenitis suppurativa. The Lahey Clinic ex-
Dermatol Clin 9: 297316 perience. Dis Colon Rectum 33: 731734
55. Ritz JP, Runkel N, Haier J et al (1998) Extent of sur- 72. Yu CC, Cook MG (1990) Hidradenitis suppurativa:
gery and recurrence rate of hidradenitis suppura- a disease of follicular epithelium, rather than apo-
tiva. Int J Colorectal Dis 13: 164168 crine glands. Br J Dermatol 122: 763769
56. Rogers IW, Ryan RF (1983) Surgical treatment of 73. Zachary LS, Robson MC, Rachmaninoff N (1987)
hidradenitis suppurativa. J La State Med Soc 135: Squamous cell carcinoma occurring in hidradenitis
2124 suppurativa. Ann Plast Surg 18: 7173
Chapter 23
Radiation Therapy
Renato G. Panizzon
23
23

Q Radiation therapy is an option for There is a revival of interest in the use of radio-
recalcitrant disease therapy for benign skin diseases and among
these for hidradenitis suppurativa (HS) even
Q Even a minute dosage appears to have a though we do not consider radiotherapy to be
clinical effect the treatment of first choice. It can be a support-
ive measure, especially in cases difficult to treat.
Q In chronic disease higher doses are In order to promote evidence-based practice, we
used have to search through the data from several de-
cades to find enough on HS (Table 23.1).
Q The majority of patients in the pub-
lished case series have had beneficial
Table 23.1. Evidence-based literature review
effects from radiation therapy
Reference Year Cases
Q The total dose should not exceed 12 Gy
Rtz (in [8]) 1925 60
Q An interdisciplinary approach to Heidenhain (in [8]) 1926 46
radiotherapy is recommended and Sulger (in [8]) 1930 82
should include a dermatologist with Tachau (in [8]) 1934 25
radiotherapy experience Erikson (in [8]) 1942 225
Cocchi (in [8]) 1943 295
Pulvermacher (in [8]) 1948 82
Lange-Hansen (in [8]) 1949 375
#ONTENTS Lyndrup-Krause (in [8]) 1949 60
Hess (in [8]) 1949 660
23.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Eilermann (in [8]) 1949 50
23.2 Treatment Regimens . . . . . . . . . . . . . . . . . . 175
Pape and Glles [1] 1950 142
23.3 Case Series Reports . . . . . . . . . . . . . . . . . . . . 175
Strauss (in [8]) 1951 132
23.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Glauner (in [8]) 1951 215
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Dornuf and Schnwald (in [8]) 1951 300
Buchtala and Viehweger [2] 1952 100
Mller and Sittig (in [8]) 1955 42
Fischer [3] 1957 12
Seegenschmiedt et al. [6] 2000 221
Frhlich et al. [5] 2000 231
Radiation Therapy Chapter 23 175
23.2 Treatment Regimens In the same year Seegenschmiedt et al. [6] ex-
amined patients treated with radiotherapy for
In general, the earlier the treatment begins, the benign diseases; among them were 221 HS pa-
better the outcome. tients. They found significant geographic and
Another aspect of the treatment regimen to institutional variations in the treatment sched-
consider is the dose, which ideally should be as ules. The doses prescribed were mostly in the
small as possible [1, 2] for the acute stage of HS. low dose range and the treatments were mostly
Fischer [3] called this Rntgenkleinstdosen carried out by radiation oncologists. There was
(very small Rntgen dose), namely a treat- a decrease of orthovoltage units and a demand
ment schedule in which only 0.05- to 0.2-Gy for more mega voltage units, which compromis-
single doses are used. The total doses of these es the treatments cost-effectiveness. Side-effects
series amount to between 1 and 4 Gy. If the HS with this treatment modality are very rare, es-
is chronic and recurrent, the success rate is not pecially if the dose schedules are carefully fol-
as good, and higher single doses of between 0.5 lowed. Even after several series of treatments
and 1 Gy have to be applied [4] (Table 23.2). In the total dose per lifetime per field should not
the case of chronic disease treated with the exceed 12 Gy.
aforementioned doses, the recurrence rate is at
least 38%, whereas with the early application of
very small doses, the rate is only 19% [1]. Radia- 23.4 Conclusion
tion therapy can be adapted easily to the depth
of the lesion between 5 and 30 mm, and this is
calculated using the half value depth (HVD). W
Machines that deliver the treatment are mostly In all cases we recommend an interdisciplin-
of the superficial X-ray type with a radiation ary approach [7] in order to offer our patients
quality of 20150 kV. The irradiation field is the best possible and customized treatment
chosen to be as large as possible. In recurrent for this debilitating disease.
cases, two or more series may be applied, but a
total dose of 12 Gy should not be surpassed.
Table 23.2. Practical guidelines: recommended dose References

schedule for the treatment of hidradenitis suppurativa.
Radiation quality (kV and filter) depend on the depth of 1. Pape and Glles (1950) Cited in: Goldschmidt H
hidradenitis suppurativa (1959) Rntgentherapie von Dermatosen, Hidrad-
enitis suppurativa, Handbuch der Haut und Ge-
Stage Single Frac- Frequency schlechtskrankheiten, Ergnzungsband V/2. Spring-
dose tions er, Berlin Heidelberg New York, pp 541544.
Acute 0.2 Gy 412 Daily 2. Buchtala and Viehweger (1952) Cited in: Gold-
stage schmidt H (1959) Rntgentherapie von Dermatosen,
Hidradenitis suppurativa, Handbuch der Haut
Recurrent 1.0 Gy 412 3 times per week
und Geschlechtskrankheiten, Ergnzungsband V/2.
stage
Springer, Berlin Heidelberg New York, pp 541544.
3. Fischer E (1957) Rntgenkleinstdosen. Cited in:
Goldschmidt H (1959) Rntgentherapie von Der-
matosen, Hidradenitis suppurativa, Handbuch der
Haut und Geschlechtskrankheiten, Ergnzungs-
23.3 Case Series Reports band V/2. Springer, Berlin Heidelberg New York,
pp 541544.
Frhlich et al. [5] examined 231 patients and 4. Panizzon RG (2004) Radiation therapy of benign
found complete relief of symptoms in 89 pa- dermatoses. In: Renato G. Panizzon, Jay S. Cooper
tients (38%); in 92 patients (40%) there was clear (eds) Radiation treatment and radiation reactions in
improvement and only 2 patients did not react dermatology. Springer, Berlin Heidelberg New York,
pp 3340.
to radiotherapy. No side-effects were noted.
176 Renato G. Panizzon
5. Frhlich D, Baaske D, Glatzel M (2000) Radiother- 7. Slade DE, Powell BW, Mortimer PS (2003) Hidrad-
apy of hidradenitis suppurativa still valid today? enitis suppurativa: pathogenesis and management.
Strahlenther Onkol 176:286289. Br J Plast Surg 56:451461.
6. Seegenschmiedt MH, Katalinic A, Makoski HB, 8. Goldschmidt H (1959) Rntgentherapie von Der-
Haase W, Gademann G, Hassenstein E (2000) Ra- matosen, Hidradenitis suppurativa, Handbuch der
diotherapy for benign diseases: patterns of care study Haut und Geschlechtskrankheiten, Ergnzungs-
in Germany. Int J Radiat Oncol Biol Phys 47:195 band V/2. Springer, Berlin Heidelberg New York,
23 202. pp 541544.
Chapter 24
Experimental Physical Therapies

Gregor B.E. Jemec
24
Key points achieve the desired therapeutic effect, unless

specific biological targets can be found in the
Q Depilation may prove to be a useful epithelial tissue lining the sinus tracts. The
adjunct therapy treatment options for Hurley Stage III and unre-
sponsive Stage II disease are therefore currently
Q New physical therapies should be tissue restricted to physical destruction of the diseased
conserving tissue using different treatment modalities [1].
A series of physical therapies have been suggest-
Q New therapies should be tested in a ed (see Table 24.1).
standardized and clinically significant
manner
24.2 Photodynamic Therapy
Photodynamic therapy (PDT) provides semi-se-

lective tissue destruction and a general antimi-
#ONTENTS crobial effect. It is currently used extensively for
24.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .177
the treatment of precancerous lesions or non-
melanoma skin cancer [2]. The treatment is
24.2 Photodynamic Therapy . . . . . . . . . . . . . . . .177 based on the activation of a photosensitizer ap-
24.3 Depilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 plied to the tissue (usually absorbed through the
24.4 Cryosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . 179 skin surface), and subsequent tissue destruc-
24.5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . .180
tion. The photosensitizer most commonly used
at the time of writing is either aminolevulinic
24.6 Practical Guidelines acid (ALA, 20% cream) or esterified aminolevu-
for Testing New Physical Therapies . . . . . .180
linic acid. Other photosensitizers are available
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 for intravesical therapy, for example, but their
effects on skin diseases are as yet unproven.
Similarly, potential photosensitizers, such as
24.1 Introduction methylene blue, are limited in their effects to
being antimicrobial. ALA can be purchased
Whenever there is more than one therapy avail- from a supplier of analytic substances, or bought
able for a particular ailment, it is often suspect- as one of two commercially available products
ed that none of them is universally effective. (Metvix, Photocure, Norway or Levulan, Dusa
There is definitely scope for improving the Pharmaceuicals, USA).
physical and surgical methods for treating hi- It has been shown that ALA penetrates the
dradenitis suppurativa (HS). The rationale for skin and is absorbed, theoretically allowing it to
physical therapies in the later stages of disease is reach superficial lesions of HS. Following ab-
strong. After the formation of sinus tracts it is sorption of the substance it is metabolized along
unlikely that pharmacological treatment can the heme pathway to protoporphyrin IX, which
178 Gregor B.E. Jemec
Table 24.1. Experimental physical therapies in hidradenitis suppurativa (HS)

Treat- Patients Location Treatment Follow- Effect Complications Refer-
ment up ence
1 PDT Four One axillary, 20% 5-ALA 3 months Three None [5]
women, one axillary for 1530 min, patients:
aged and inguinal followed by blue 75% im-
1946 areas, two in- light, 1- to provement;
years guinal areas 2-week intervals; one patient:
three to four 100% im-
24 treatments provement
2 PDT Four Three axillary 20% 5-ALA 8 weeks No One dropout be- [6]
patients disease, one for 4 h, followed significant cause of discom-
groin disease by 533 nm laser improvement fort,
or 570670 nm one experienced
broad band light worsening
giving 15 J/cm2
once weekly
for 3 weeks
3 Cryo- Ten Three axillary, Cryotherapy Not Four Average healing [13]
therapy women, one breast, using liquid stated marked im- time 25 days,
aged four groin, nitrogen to freeze clearly, provement, 6/10 experienced
2445 one axillary single nodules but ap- four im- postoperative
years and groin, to a core temper- parently provement, infection,
one all three ature of 20 C up to two no two experienced
sites 6 weeks response ulceration,
(end of three graded
healing) pain during heal-
ing as maximum
on a 14 score
is a potent photosensitizer. The process occurs and at follow-up 3 months afterwards all cases
naturally as the main pathogenic process in had improved 75100%, suggesting that the
porphyria. In healthy tissue the protoporphyrin treatment may be of benefit. The exact outcome
IX is further metabolized by the enzyme fer- variables were not stated, e.g., VAS scores or
rochelatase to non-phototoxic substances. In Sartorius scores. The study is interesting but not
metaplastic or neoplastic tissue the activity of well documented, and the inclusion criteria
ferrochelatase is lower than that in healthy tis- open the possibility that simple furunculosis
sue, and a semi-selective accumulation of pho- rather than HS was treated. In a subsequent se-
tosensitizer therefore occurs, which allows more ries of cases Strauss et al. [6] described four pa-
targeted destruction of the metaplastic or neo- tients treated with generic 20% ALA and either
plastic tissue. 633 nm laser or a 570670 nm broad band light
PDT has recently been tested in a number of source without significant effect. A longer incu-
non-neoplastic diseases. These include acne ro- bation time and better case definition were used.
sacea [3], acne vulgaris [4] and HS [5, 6] (see Furthermore the use of red light allows deeper
Table 24.1). For HS two studies have been pub- penetration of the light energy and therefore
lished. The first study, by Gold et al. [5], de- this is theoretically more suitable for the treat-
scribes four cases treated with PDT (Levulan ment of HS. The authors limited experience is
and blue light). Only a short incubation period in better accordance with the latter report than
was used, and the treatment was repeated three with the former. For HS the lesions treated
to four times. No co-morbidity was reported, most successfully have apparently been those of
Experimental Physical Therapies Chapter 24 179
Stage I disease, suggesting that sinus tracts are acting as foreign objects and evoking a chronic
not affected and that either the inflammatory inflammatory response with, among others,
process itself or pro-inflammatory substances multinucleated giant cells [9]. Removal of hairs
are targeted. may therefore not only aid drainage, but also re-
The mechanisms by which PDT affects these move the necessary seeds for perpetuation of
diseases is not known, but it has been suggested established lesions.
to be via tissue destruction of, for example, hy- Depilation has however traditionally been
perplastic infundibular epithelium in acne, or suspected as a possible causative factor in HS,
by a simple antibacterial effect analogous to the but the pattern of use of cosmetic procedures in
use of blue light in acne. Additional practical the areas predisposed to HS does not appear to
problems are however involved in the use of be different in patients and healthy controls [10,
PDT for HS. It is well established that up to one- 11]. Furthermore, many patients with HS have
third of all PDT patients experience consider- never used depilatories in the areas where lesions
able pain during illumination. In the study by occur. This makes it unlikely that any depilatory
Strauss et al. [6] one of four patients dropped procedure forms a significant etiological factor
out due to pain and discomfort. This appears to in the development of HS.
be particularly associated with larger areas be- In general, laser depilation has been shown to
ing treated, and with the sensitivity of the areas, be a useful technique for hirsute patients, appar-
e.g., it is usually worse on the nose than on the ently using any of several types of available
back. Even if PDT is found to be effective, this lasers. The absorption of laser light in the hair
factor may prove to be significantly restrictive follicle induces transition to a telogen phase,
for the use of PDT in HS. and apparently shortens subsequent anagen
The discrepancy between the results ob- phases of the follicle, consequently resulting in
served strongly suggests the need for a con- the growth of a shorter and thinner hair shaft
trolled trial, and may be due to the stringency of [12].
inclusion criteria, variation in the stage of HS Several unpublished cases among the authors
being treated, and a number of other factors. of this book appear to substantiate this claim,
although the success rate and duration of any
beneficial effect are not known. Some patients
24.3 Depilation apparently experience long-lasting remission,
whereas others only have shorter periods of re-
Theoretically depilation could offer some relief lief. Based on the available information, laser
to patients with HS. Previously X-ray therapy depilation nevertheless appears to be a promis-
has been used to treat HS [7, 8]. The dosage var- ing area for further studies.
ied, but often successful therapy induced depila-
tion of the treated areas. Earlier papers on the
topic have suggested that the positive effects 24.4 Cryosurgery
were due as much to depilation as to the anti-
inflammatory effects of the treatment (Chap. Cryosurgery has been used extensively in the
23). treatment of both benign and malignant skin
Such an effect may be hypothesized from the tumors. Usually liquid nitrogen is used as the
histology of the early lesions. An element of fol- coolant, and the effect of the cryotherapy is to
licular occlusion is found in early lesions, and induce necrosis based on hypothermic damage
although pharmacological treatment with reti- of both cell membrane and cytoplasmic organ-
noids, for example, has been disappointing in elles.
most cases, the physical removal of an obstruct- A study reporting the follow-up of ten pa-
ing hair shaft may prove even better at draining tients treated with cryotherapy has been pub-
the follicle. Furthermore, free hair fragments lished suggesting that cryotherapy is a feasible
may on occasion be found in lesions, suggesting form of therapy in select HS cases [13]. The
that they may help to maintain the lesions by treatment is however not unproblematic, and
several and considerable practical restraints ex- tizer into the hair follicles. The use of red light is
ist. The treatment is associated with additional theoretically sufficient, but even here there is
pain, which is already a dominant clinical prob- room to improve the scope of this modality. In
lem to HS patients. Additional iatrogenic pain is general the paucity of data requires additional
therefore an a priori drawback of the method. A well-designed studies, which should initially be
significant proportion of the cases published relatively small, strongly structured proof-of-
furthermore experienced complications with concept studies. With current technology the
postoperative infection. Finally, cryotherapy is a justification of an actual randomized controlled
destructive process and commonly associated trial is debateable.
24 with a long healing time. In the published study Destructive methods have to respect the gen-
[13] the healing time was on average 25 days. On eral surgical principle of tissue conservation,
the whole cryotherapy does therefore not appear i.e., that healthy tissue should be left intact. In
to hold any clinically significant advantages HS sinus tracts normally occur under healthy
over other forms of physical therapy. Theoreti- skin which need not be destroyed. Precision in
cally a more precise delivery of the cryotherapy the application of destructive methods is there-
could overcome some of these drawbacks, but fore very important. While indiscriminately
would also obliterate the immediate practical destructive methods such as cryotherapy, and
benefits of the method, namely being fast and probably also electrodesiccation, may be ex-
easy. pected to work, they also induce unacceptable
collateral damage. In addition unnecessary tis-
sue destruction induces significant iatrogenic
24.5 Discussion morbidity in the patients, as the lesions are of-
ten slow to heal, are susceptible to suprainfec-
Physical therapies may be directed against ei- tion and cause additional scarring. With im-
ther the secondary prevention of early lesions or proved imaging techniques and more targeted
the destruction of established lesions. For true delivery of treatment this could be overcome to
primary prevention of early lesions the patho- some degree, but is unlikely to be removed alto-
genic process is insufficiently described to allow gether.
a causal therapy, although the use of laser de- A number of hypothetical and speculative
pilation may yet prove to be fruitful in proper physical approaches may be imagined. Im-
studies. The possible effect of PDT on the hair proved lesion imaging may for instance also
follicle is at present unclear. It is not convinc- allow future intralesional therapies with appli-
ingly proven that the penetration of ALA-PDT cation of light or pharmaceutical substances di-
is sufficiently deep to allow treatment of estab- rectly into the lumen of the lesion. Similarly,
lished lesions of Hurley category II or III. Nor is radiofrequency devices may provide relief via
it established that ALA-PDT has any effect on an effect on the connective tissue surrounding
sinus tracts. The effects may therefore be more the lesions. Finally, UVA1 therapy may provide
in line with the effects of this treatment in acne an anti-inflammatory effect as well as scar re-
vulgaris, where a significant clinical effect has duction if applied locally. It is most likely that
been shown in some studies. ALA-PDT is how- the potential of a series of novel physical thera-
ever associated with considerable post-treat- pies will be explored over the coming years.
ment pain and inflammation in acne patients
and this may also limit its use in HS.
These reservations however stem partly from 24.6 Practical Guidelines for Testing
the paucity of data, and partly from the practi- New Physical Therapies
cal consideration of penetration. It is entirely
conceivable that the photosensitizers used do The option of randomized controlled trials is
not penetrate the tissue sufficiently because of generally not available for surgical techniques.
their formulation. A more liquid preparation In lieu of the randomized controlled trial a lower
may allow deeper penetration of the photosensi- degree of evidence is therefore acceptable. The
Experimental Physical Therapies Chapter 24 181
key features of any investigations should remain possibly because of differing shear forces and
the randomization, which has independent value other local phenomena. Study requirements are
even when assessed in an open or a single-blind- summarized in Table 24.2. Early exploratory
ed fashion. The central problem is one of control, studies should similarly be aimed at providing
but in an exploratory period abstention from ac- the necessary data for the planning of larger
tive treatment is enough. In future cases sham controlled and randomized studies, and should
procedures may be carried out when possible, therefore preferably use the same outcome vari-
providing there are objective documentation ables.
and an adequate follow-up. There must be ran-
domization of both patients and lesions to pre-
vent bias. Follow-up should be for a minimum of References
36 months and it is advisable to include both
patient-centered subjective methods of assess- 1. Jemec GBE. Hidradenitis suppurativa. J Cut Med
ment as well as more objective methods. Subjec- Surg. 2003; 7: 4756.
tive methods can include health-related quality 2. Larko O. Photodynamic therapy. Aust J Dermatol
Suppl. 2005; 46: S12.
of life questionnaires developed for skin diseas- 3. Nybk H, Jemec GBE. Photodynamic therapy of
es, e.g., DLQI or Skindex [14, 15], and VAS scores acne rosacea. Dermatology 2005; 211: 135138.
of pain and disease severity. Objective quantifi- 4. Charakida A, Seaton ED, Charakida M, Mouser P,
cation may include standardized clinical scores Avgerinos A, Chu AC. Phototherapy in the treat-
such as the Sartorius score [16], ultrasound im- ment of acne vulgaris: what is its role? Am J Clin
aging and photography. Dermatol. 2004; 5: 211216.
For bilateral HS lesions randomized intra-in- 5. Gold M, Bridges TM, Bradshaw VL, Boring M.
ALA-PDT and blue light therapy for hidradenitis
dividual left to right comparisons of physical
suppurativa. J Drugs Dermatol. 2004; 3 (1 Suppl):
therapies are possible. However it is not advised S3235.
to compare lesions in different regions directly, 6. Strauss RM, Pollock B, Stables GI, Goulden V, Cun-
for example axillary and genitofemoral lesions; liffe WJ. Photodynamic therapy using aminolaevu-
this is because the results of therapy often indi- linic acid does not lead to clinical improvement in
cate different regional susceptibility in patients, hidradenitis suppurativa. Br J Dermatol. 2005; 152:
803804.
7. Zeligman I. Temporary x-ray epilation therapy of
Table 24.2. Factors to consider when planning experi- chronic axillary hidradenitis suppurativa. Arch
mental studies of physical therapies. Controls are es- Dermatol. 1965; 92: 690694.
sential and should be set up for each lesion and for the 8. Frohlich D, Baaske D, Glatzel M. [Radiotherapy
patient. Inguinal lesions are not appropriate controls for of hidradenitis suppurativa still valid today?]
axillary lesions. (DLQI Dermatology Life Quality Index, Strahlenther Onkol. 2000; 176(6): 286289.
IPL intense pulsed light) 9. Jemec GBE, Hansen U. The histology of hidradenitis
Element of study Example suppurativa. J Am Acad Derm 1996; 34: 994999.
10. Morgan WP, Leicester G. The role of depilation and
Classification and Hurley classification deodorants in hidradenitis suppurativa. Arch Der-
characterization matol. 1982; 118: 101102.
of cases 11. Jemec GBE, Heidenheim M, Nielsen NH. Hidrade-
Randomization of Flipping coins nitis suppurativa: characteristics and consequences.
patients and lesions or drawing lots Clin Exp Dermatol 1996; 21: 419423.
12. Tack B. [Laser and intense pulsed light for hair re-
Outcome Should include subjective, moval.] Ann Dermatol Vener. 2005; 132: 7579.
variables defined e.g., DLQI, and objective, 13. Bong JL, Shalders K, Saihan E. Treatment of per-
e.g., Sartorius score, elements sistent painful nodules of hidradenitis suppurativa
Standardization of Depilation using a IPL device with cryotherapy. Clin Exp Dermatol. 2003; 28:
therapy at a specific setting for a set 241244.
number of treatments 14. Lewis V, Finlay AY. 10 years experience of the Der-
Follow-up Minimum 3 months, matology Life Quality Index (DLQI). J Investig Der-
and preferably longer matol Symp Proc. 2004; 9: 169180.
15. Finlay AY. Quality of life assessments in dermatol- 16. Sartorius K, Lapins J, Emtestam L, Jemec GB (2003)
ogy. Semin Cutan Med Surg. 1998; 17: 291296. Suggestions for uniform outcome variables when
reporting treatment effects in hidradenitis suppu-
rativa. Br J Dermatol 149:211213.
24
Chapter 25
Treatment
Gregor B.E. Jemec, Jean Revuz
25
#ONTENTS
25.2 Staging the Disease
25.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 183
Treatment of any disease should be graduated to
25.2 Staging the Disease . . . . . . . . . . . . . . . . . . . 183 reflect disease intensity. For HS this means that
25.3 Treatment of Hidradenitis Suppurativa staging according to Hurleys criteria is benefi-
Hurley Stage I . . . . . . . . . . . . . . . . . . . . . . . .184 cial and should be done prior to therapy (see
25.4 Treatment of Hidradenitis Suppurativa Table 25.1). It is however important to realize
Hurley Stage II . . . . . . . . . . . . . . . . . . . . . . . .184 that disease evolution in individual patients is
25.5 Treatment of Hidradenitis Suppurativa not simply linear, and that the stages imply dif-
Hurley Stage III . . . . . . . . . . . . . . . . . . . . . . . 185 ferent needs and therapeutic opportunities be-
cause of the predominant features of each stage,
25.6 Hidradenitis Suppurativa with Cysts . . . . 185
e.g., scarring in Stage III (see Fig. 25.1). Of all
25.7 Experimental Therapies . . . . . . . . . . . . . . .186 patients, it is estimated that as many as 75% re-
25.8 General Requirements for Treatment . . .186 main in Hurley Stage I, 24% progress to Hurley
Stage II and only a small minority progress fur-
ther. In addition to the staging of the disease it is
25.1 Introduction mandatory to obtain information about the fre-
quency of flares before the start of therapy. The
The current requirements of evidence-based use of the lesional score of Sartorius (see Chap.
medicine find little support in the existing lit- 3) and the counting up of the number of painful
erature on the treatment of hidradenitis suppu- days and of the intensity of pain may be very
rativa (HS). Very few randomized controlled helpful for that purpose.
trials have been performed, and where this has
happened the trials are small with a weak pre-
Table 25.1. Hurleys criteria for staging hidradenitis sup-
dictive value. The existing literature is mostly purativa (HS)
based on cases and case series, and in an effort
to strengthen these we have asked for expert Stage I:
evaluations in the previous chapters of this Abscess formation, single or multiple,
book. This should however not stimulate thera- without sinus tracts and cicatrization
peutic nihilism! Expert assessment combines Stage II:
anecdotal evidence and personal experience to Recurrent abscesses with tract formation
suggest possible approaches to therapy, but this and cicatrization
needs to be supplemented with formal struc- Single or multiple, widely separated lesions
tured studies. Nevertheless, it is possible to sug- Stage III:
gest a strategy for the treatment of HS based on Diffuse or near-diffuse involvement,
existing knowledge. or multiple interconnected tracts
and abscesses across the entire area
184 Gregor B.E. Jemec, Jean Revuz
Fig. 25.1. Prevalence and

strategies for therapy
The goal of treatment is to reduce the extent Table 25.2. Treatment of HS Hurley Stage I disease
and progression of the disease so as to bring the
Topical treatment:
25 patient back to a milder stage (see Fig. 25.1). Clindamycin 1% (lotion)
Clindamycin 2% (cream)
Resorcinol
25.3 Treatment of Hidradenitis Short course systemic treatment:
Suppurativa Hurley Stage I Tetracycline
Erythromycin or other macrolides
This most limited form of disease is the most Amoxicillin + clavulanic acid
amenable to medical therapy, and can often be Clindamycin
held in check by prophylactic treatment. In Others
Stage I disease the patients often have only a few Adjuvant preventive therapy:
flares per year. Treatment is therefore most of- Azelaic acid
ten aimed at reducing the duration of the flares Zinc gluconate
(Table 25.2), and may consist of:
Q Topical clindamycin 12%.

Q A short course of systemic antibiotics therapy alone may suffice to control the disease.
(710 days). A large number of various For patients with frequent (one per month or
antibiotics have been tried in this more) and severe flares, treatment should how-
situation. The patients previous ever be intensified to the level required for Stage
experience may help the choice. II disease (see Table 25.3).
Q Resorcinol.
Q Intralesional steroids.
25.4 Treatment of Hidradenitis
Such a treatment aimed at shortening the dura- Suppurativa Hurley Stage II
tion of a flare cannot be effective unless it is
given very early, i.e., within hours of the first Patients seen at the specialist level are frequently
symptoms of a new flare. In the case of a short Stage II patients. The treatment aims to cure
course of systemic antibiotics, that means that these patients or at least reduce them to Stage I
the patient has to keep the drug with him/her disease. The presence of sinus tracts and scar-
and use it before seeing the doctor. In the case ring requires a combined treatment involving
of intralesional steroids the specialist has to be both medical and surgical therapies. The bal-
reached in an emergency. ance between the two depends on the amount of
If flares are more frequent most patients ben- scarring and permanent suppuration present.
efit from adjuvant preventive therapy, which The medical therapy aims to control acute in-
may include azelaic acid applied daily. For this flammation and may also be used to prepare the
group of patients prophylactic therapy com- patient for surgery.
bined with treatment of flares may allow them For patients with little scarring and much
to gain control of their disease, and in some inflammation, intensive, long-term antibiotic
cases the routine use of adjuvant preventive therapy with systemic clindamycin and rifam-
Treatment Chapter 25 185
Table 25.3. Treatment of HS Hurley Stage II Table 25.4. Treatment of HS Hurley Stage III. (TNF Tu-
mor necrosis factor)
Medical treatment (systemic only):
Clindamycin + rifampicin Medical treatment (palliative):
Dapsone Corticosteroids
Systemic adjuvant or maintenance therapy: Ciclosporin
Zinc gluconate Methotrexate
Tetracyclines TNF-alpha inhibitors
Surgical treatment: Surgical treatment:
Exteriorization Wide excisions
Local excision Radiation therapy?
Laser evaporation
picin is recommended. Treatment should last ment is stopped. The antibiotic combination of
for 3 months. If pain, suppuration and frequen- clindamycin and rifampicin may also be help-
cy of flares are reduced to an acceptable level, a ful.
maintenance treatment with tetracyclines or An alternative viable strategy for gaining
high-dosage zinc or dapsone may offer long re- better control of the disease at this stage may be
missions. In some patients the level of improve- an immunosuppressive therapy. Traditionally
ment is so high as to permit the use of Stage I corticosteroids and ciclosporin have been used.
therapy, i.e., therapy of flares only. Recently the use of tumour necrosis factor alpha
For patients with scarring and sinus tracts (TNF-alpha) inhibitors has been suggested by
the medical treatment should always be supple- several authors (see Chap. 20), and randomized
mented with local surgery, either using cold studies may confirm these observations in the
steel or laser evaporation. In milder cases exteri- future. Currently this therapy should be seen as
orization of sinus tracts may suffice, whereas experimental.
actual excisions may be necessary for larger le- At this stage, however, the only possibilities
sions. Limited excisions are particularly useful for curative treatment are extensive surgery and
when an abscess-sinus tract recurs frequently radiation therapy, if one is not afraid of the risk
with flares at the same location. This kind of of cancer promotion (see Table 25.4). Healing by
limited surgery may be performed in the outpa- secondary intention has generally been advo-
tient setting with local anaesthesia and is well cated, although this extends the postoperative
accepted by the patients who are frequently re- need for additional nursing and wound care. In
luctant to have major excisions. On the other general, postoperative scarring is less of a prob-
hand, general experience shows that the larger lem than scarring from the disease itself.
the excision, the lower the potential for recur-
rence. So a balance between the advantages and
drawbacks of the two approaches has to be 25.6 Hidradenitis Suppurativa
weighed up by the patient (see Table 25.3). with Cysts
Occasionally HS may be associated with multi-

25.5 Treatment of Hidradenitis ple large cysts generally involving flexural ar-
Suppurativa Hurley Stage III eas. In this case treatment may be attempted
with acitretin. Isotretinoin appears to be less
No curative effect can be expected with medical effective in this rare form of HS as well. Excision
therapy in Stage III disease. All medical therapy of multiple cysts is bothersome but may be more
therefore aims to be palliative and temporary, effective on the long term. This subtype should
i.e., the disease recurs shortly after the treat- not be confused with steatocystoma multiplex.
186 Gregor B.E. Jemec, Jean Revuz
25.7 Experimental Therapies event and treat heavily with antibiotics. Most
available antibiotics have been used to varying
HS is not an easy disease to treat. Often stan- effect in individual cases.
dard therapies fail, and both patient and physi-
cian are left with a therapeutic challenge. Most
often one of two general approaches is used in 25.8 General Requirements
off-label/experimental therapy. One avenue of for Treatment
approach is to regard the disease as a predomi-
nantly inflammatory disease, and consequently The difficulties of treatment mean that there is
treat with immunosuppressive drugs as in so a strong need for additional randomized con-
many other dermatological diseases. The use of trolled trials in HS therapy. Such trials however
25 topical immunosuppressants is rarely sufficient, require data for planning, and any successful
and systemic therapy has been tried with corti- treatment regimens should therefore be report-
costeroids, ciclosporin, methotrexate, dapsone ed. This requires individual physicians to keep a
and TNF-alpha inhibitors. All these treatments strict log of standardized outcomes, i.e. Sartori-
require special precautions, but may be useful us score, pain VAS, number of flares, etc. in or-
for gaining control over an otherwise debilitat- der to enumerate the results obtained. With im-
ing disease. proved reporting sufficient data may become
The other avenue of approach is to regard the available for a better assessment of the relative
presence of microbes as the primary pathogenic value of various experimental therapies.
Chapter 26
Hidradenitis Suppurativa Patients

Frequently Asked Questions 26
Jean Revuz
#ONTENTS 4. Where can it develop?

Essentially in the armpits, between and under
26.1 General Questions. . . . . . . . . . . . . . . . . . . . . 187
the breasts and the groin. It may also involve the
26.2 Heredity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .188 glueal cleft and the perineum, and in some cases
26.3 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . .188 the entire ano-perineal-inguinal region. In rare
26.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . .188 cases it can involve buttocks, ears and other re-
gions.
26.5 Practical Questions . . . . . . . . . . . . . . . . . . . . 189
26.6 Hints For Daily Life . . . . . . . . . . . . . . . . . . .190 5. Can it affect the face?
26.7 Relations To Other Factors . . . . . . . . . . . . .190 No, except if it is associated with acne, which is
26.8 Psychological Aspects . . . . . . . . . . . . . . . . . 191 not very frequent.
26.9 Children and Adolescents . . . . . . . . . . . . . .192
6. Is it a contagious disease?
26.10 Social Security . . . . . . . . . . . . . . . . . . . . . . . .192 No.
7. Does it get worse with time?

26.1 General Questions One cannot say. Generally it is considered to be
worst during the first few years, but there are
1. Which doctor should I see? exceptions to this.
Depending on the severity of the disease it could
be a dermatologist, a plastic surgeon or a proc- 8. Can you die from it?
tologist. What is important is that the doctor No, except in very rare cases if cancer develops
knows about hidradenitis suppurativa (HS). in one of the lesions and is not treated early
enough. Historically amyloidosis has been de-
2. Is it a rare disease? scribed in untreated but chronically infected
No, it affects an estimated 1% of the population. patients; but this probably no longer occurs.
It is therefore a relatively frequent disease, but it
is often not diagnosed. Many patients do not 9. What are the stages of the disease?
know what they have and are only told of their Hurleys classification is used to classify the
correct diagnosis after many years. stages of the disease. Stage I is characterized by
lesions, flares and sinus tracts that are separated
3. How do I distinguish between a simple boil from each other. In Stage II the flares are linked
and HS? to each other by tunnels and/or by excessive de-
The location (groin and armpits), and the chro- velopment of thickened (hypertrophic) scar tis-
nicity of the flares are important guidelines. sue. Stage III is characterized by the develop-
That is to say, if a patient with HS has a lesion ment of a large area of suppurating (oozing),
outside the predilection areas it is impossible to fibrous tissue. In Stage III, surgery is the only
tell the difference. effective treatment.
188 Jean Revuz
10. Is it necessary to operate when the first 4. Can you screen for the disease?
symptoms of the disease are diagnosed? No.
If the patient is suffering from inflamed lesions
without chronic suppuration and without thick
scar (hypertrophic) tissue, and especially in the 26.3 Pregnancy
case of a single lesion, it is best to try medical
treatment. But surgery may be necessary in the 1. How does the illness develop
early stages: an incision in a boil may be the only during pregnancy?
way to relieve the pain and empty it of pus, but There is often an improvement during pregnan-
the effect is short-lived and we do not recom- cy, but this is not always the case.
mend the procedure; the surgical removal of a
single but chronic boil, or recurrent nodule in 2. Is there a risk to the baby during birth?
the same place, is an effective form of early The risk is practically nonexistent. There may
treatment. be a risk of bacterial infection if there is serious
26 and persistent suppuration at the time of deliv-
11. Why after surgery do I see new lesions ery. But in this case a caesarean delivery is al-
appear in new areas? ways an option, or otherwise it is possible to
New lesions appear after excision, but one can prevent the infection of the child with antibiot-
also see them appear in the absence of surgical ics. In any event there is no serious risk.
treatment. The appearance of new lesions in
new areas does not depend on whether or not 3. Is it possible to breast-feed the baby?
surgery has taken place. Isnt there a risk that the disease can appear
in the region of the breasts?
12. Can this disease be sexually transmitted? It is perfectly all right to breast-feed. There is no
No. reason why this should provoke an outbreak of
lesions in the region of the breasts.
13. Is this an autoimmune disease?
In all probability not. 4. Is sterilization advisable?
No.
14. Is it a disease due to a hospital infection?
No. 5. Is the disease related to hormonal
abnormality (irregularity?)
No.
26.2 Heredity
6. What type of contraceptive pill is best-suited
1. Is this an inheritable disease? if one has this disease?
Partly. In about one-third of cases there is some- In some cases treatment with very big doses of
one in the family who is affected by the disease. cyproterone acetate (Androcur 100/mg per day)
leads to an improvement, but firstly these cases
2. What are the risks of transmitting are rare and secondly it is difficult for the pa-
the disease to my children? tient to tolerate heavy doses for very long. The
There is little risk, but it is difficult to calculate. use of the pill Diane (which contains 2 mg cy-
The risk is probably greater if there are other proterone acetate) is felt to be beneficial by some
cases in the family, but the possible degree of se- women: there is no harm in trying. As a general
verity cannot be predicted on the basis of your rule, however, the fact that you have HS should
own experience. not affect your choice of pill.
3. Has a gene responsible for the disease 7. Does the disease disappear
been found? with the menopause?
No. Normally it does, but there is no guarantee.
Hidradenitis Suppurativa Chapter 26 189
26.4 Treatment 7. What does treatment by laser consist of?

There are at least three types of laser that can be
1. Is there one particular treatment used:
that is successful? a. The CO2 laser is used for surgery under a
No. general anesthetic in place of surgery using
the scalpel. The advantages of this type of in-
2. Should I take anti-inflammatory drugs? tervention are dubious; it is up to the surgeon
Anti-inflammatory drugs may reduce pain in to decide.
the short term: there are no indications to the b. Lasers used for the removal of hair have been
contrary. Their only benefit is to relieve pain. tried in some cases. It is too early to say
They are sometimes suspected of encouraging whether this has an effect on the occurrence
the spread of, or aggravating, infections, but this of new lesions.
has never been convincingly demonstrated. c. The smooth beam is another technique,
However, it is advisable to be careful. which seeks to destroy (sweat) sudoral and
(fat) sebaceous glands without touching the
3. Can I use Roaccutane? surface skin. This, too, is a technique in its
Isotretinoin (Roaccutane, Curacne) is almost infancy and only at some future date shall we
never effective. One can try retinoids for pa- know whether it is of interest.
tients who also suffer from severe acne, but (a)
these cases are rare and (b) one usually sees an 8. Does definitive depilation stop new lesions?
improvement in the acne, but not in the HS. See Question 7.
4. When suppuration is permanent,

can I take antibiotics? And for how long? 26.5 Practical Questions
Antibiotics are sometimes useful. They can stop
suppuration, deter an inflammatory growth 1. Can one use sanitary tampons?
and make it less painful, but this is not always Yes; HS lesions do not penetrate the vagina.
the case. Each patient must try them for him or
herself. An antibiotic that targets a bacteria 2. Should linen be washed separately?
identified by bacterial analysis can be used, but No; this disease is not infective.
this is not obligatory. When there is permanent
suppuration, surgery must be considered. 3. Is it possible to shave or remove hair
by waxing?
5. How can I relieve itching? There are no contraindications. However, some
Itching is frequently a secondary effect of using patients experience further inflammation fol-
local remedies or deodorants, antiseptics or lowing depilation; others benefit. You just have
other remedies. It is best to stop using them if to try.
they are doing little or no good. Chronic sup-
puration is the other factor involved in itching, 4. Is it better to take a bath or a shower?
and this takes us back to the problem of treat- It makes no difference.
ment to stop chronic suppuration.
5. What soap should I use: is an anti-septic
6. What kinds of analgesic should I use? soap advisable?
Should I use them for long periods? Any soap will do; it is not necessary to use anti-
Analgesics are not very effective against pain septic soap.
from inflammation. The essential thing there-
fore is to try to fight the infectious inflamma- 6. Can you catch this from a toilet seat?
tion itself. However, all analgesics can be used. No; it is not contagious.
190 Jean Revuz
7. How do I get rid of the smell of suppuration? 3. How can attach a compress without
When the smell is very strong, in cases of chron- using adhesives?
ic suppuration it is often because there are an- There are dressings made with elastic net (Sur-
aerobic germs present. These can be controlled gifix) adapted to a limb, a part of a limb, or a
by clindamycin or metronidazole, but in such depression, which keep a dressing in place with-
cases surgery has to considered. out using adhesive plaster. This may be difficult
in the folds of the groin, but the idea of using
8. Can I use talcum or deodorants? this kind of fixture is sound.
In principle, yes. Try and see how it goes.
4. Can I benefit from help in the home when I am
9. Does the climate have an influence able to resume doing things about the house?
on the disease? Yes; ask the social security services.
There is no firm evidence on this. Some patients
say that they feel less well when it is very hot or 5. Should I take something to help me get through
26 very humid. the nights, or to sleep better?
Yes, with the reservation that analgesics are not
10. Should I take precautions against certain always very effective against pain caused by in-
foods? flammation.
In principle, no.
6. Are thermal cures advisable? And where?
There are no data.
26.6 Hints For Daily Life
7. How can I keep up physical activity if sport
1. How can I make the lesions mature has become impossible?
more quickly? Ask a physiotherapist or rehabilitation medic,
When it is a case of deep lesions covered by nor- but there are opportunities for using muscular
mal skin, it is useless to hope to make the lesions contraction without movement, or movement of
mature more quickly by using alcohol-impreg- areas of the body not affected by the disease..
nated wet dressings. This may perhaps be pos- Remember, too, that walking is one of the best
sible with superficial dressings. In some cases forms of physical activity there is, and no suf-
an antibiotic treatment adapted to suit the case ferer from HS should be kept for long in a state
may cause the lesion to disappear, but this is far that prevents a brisk walk.
from always the case. In fact, faced with the
most typical lesions that is to say deep lesions 8. Can I swim in the sea or in swimming pools?
only an intralesional injection of corticoste- As far as the sea goes, yes. Regarding swimming
roids or excision with a scalpel will relieve pain pools, it obviously depends on the type of lesion
and release pus. Depending on the place, the pa- you have. Using swimming pools should be
tient, the type of lesions and their seriousness avoided if you have oozing or suppurating le-
and topography, the lancing of an abscess takes sions, out of consideration for other people.
place under a general or a local anesthetic, with
or without hospitalization.
26.7 Relations To Other Factors
2. Can I try to drain an abscess myself,
without danger? 1. Is articular (arthritic) pain related
This depends on the depth of the lesion deep to the illness?
lesions are best left to the surgeon as well as the Articular pain can be related to the disease, but
topography. The ability to resist pain will depend this is not true for all articular pains. It is known
on the size of the lesion. Any danger may arise that some rheumatic inflammations may ac-
from trying to lance an abscess that is close to a company diseases such as suppurating hidra-
vital organ, such as an artery or large vein. denitis and that these joint symptoms may be
Hidradenitis Suppurativa Chapter 26 191
either peripheral (such as arms, legs, fingers) or 9. Why should I have a colonoscopy?
in some cases central (such as pelvis or back). A colonoscopy may help to diagnose Crohns
disease, an inflammatory disease of the intes-
2. Does tobacco provoke or aggravate tine, which can be accompanied by cutaneous
the disease? symptoms, particularly perineal ones, and
It has been demonstrated that HS is more preva- which can be confused with HS. However, faced
lent among smokers than in the population as a with anal lesions not characteristic of HS or ac-
whole, but it is not clear whether this is a cause companied by digestive symptoms, a diagnosis
or an effect, and it is not clear whether ceasing of Crohns disease simulating HS or associated
to smoke brings about an improvement and with HS should be made, as there are specific
indeed this cannot be proved either. treatments for Crohns.
3. Is this a disease of the obese? 10. Can one develop the disease as the result
No, it is not a disease of the very fat. It also af- of a blood transfusion?
fects thin people, but being overweight is one of No.
the factors that aggravates the disease and causes
poor tolerance of the lesions. 11. Can one give blood?
Yes.
4. Why should I not eat sugar,
even if I am not diabetic? 12. Can frequent general anesthetics cause
There is no reason why you should not eat sug- loss of memory?
ar. No.
5. Is a condition of extreme fatigue related

to the disease? 26.8 Psychological Aspects
It is difficult to interpret conditions of extreme
fatigue. Permanent suppuration may lead to ex- 1. Is stress a factor that may cause or aggravate
treme fatigue, but extreme fatigue is also a the illness?
symptom of depression, and HS can lead to a In many people stress may contribute to a wors-
degree of depression. ening of the symptoms, but stress not a cause of
the disease.
6. Hair loss, brittle nails, dental abscesses,
the loss of many teeth are these related 2. How do I break the news to my partner?
to the illness? There is no recipe for this! This question and
No, they have no relation to the disease. the next two require careful consideration.
7. Is there a risk of septic shock? 3. How do I tell the family?

The risk exists in the form of an acute spread of See Question 2 above.
the infection by means of a secondary strepto-
cocci infection, but this is extremely rare. 4. Should I tell the family?
The same answer. But in any case you should
8. Are suppurations in the fold between make it clear that there is no risk to anyone else.
the buttocks a form of HS? It is also important to have someone with whom
An infection in the upper part of the fold be- you can talk about the illness relatives, friends
tween the buttocks is usually a pilonidal sinus, or a doctor. It is essential to be able to give ex-
which is frequently associated with HS, but is pression to the fact that you are ill in order to
different. The treatment is surgical and should gain a little distance before considering the
be carried out by a surgeon very experienced in problems that the illness brings with it.
this type of intervention. HS lesions can be pres-
ent in all of the perianal and perineal areas.
192 Jean Revuz
5. How should I tell my employer about the 3. How do you talk about this illness with a young
illness and the possibility that I may be absent adolescent?
from work? The important thing is to let the young person
The employer does not necessarily have to know know that there is someone who is ready to talk
the nature of the illness or the reasons for ab- with him or her. Let the adolescent talk, listen to
sence from work. However, if the disease affects his or her concerns, provide the information
your wok, perhaps raising a problem of your that he or she demands, without dramatizing
suitability for a job, the company doctor is the too much, but without understating the situa-
person to see. tion too much either. Dont drown the child in
information by trying to explain everything to a
6. What should I do if I get the blues? young person who does not want to listen or
See your GP, who can see if you are suffering who is not ready for it. It is important to empha-
from depression and if so recommend treat- size that the illness is not contagious, is not sex-
ment, perhaps by a psychiatrist or a psycholo- ually transmissible, has no consequences for
26 gist. It is never normal to feel depressed. You fertility, and the fact that some forms of the ill-
should not have to suffer the additional pain of ness remain mild.
depression because you have HS. An effective
treatment of depression will not cure HS, but it
will relieve you of some of the suffering that the 26.10 Social Security
illness may cause.
1. Is the disease recognized as chronic?
It is not on the list of illnesses deemed long and
26.9 Children and Adolescents costly, but see Question 2.
1. What should I tell my childs teachers? 2. Can the patient receive 100% cover by social
Your child may have trouble remaining seated security?
for long periods, may need physical attention, Yes, in certain cases and in some countries when
and may be absent from school. This is a deli- a very detailed medical certificate is provided
cate problem, as it may be unacceptable to the and a discussion is held with the relevant social
child, especially if an adolescent, if all the teach- security official and when the illness really is
ers are aware of the health problem. The best expensive.
solution may be to ask for a meeting with the
school doctor or nurse. They can be informed in 3. Can the patient be recognized as disabled?
confidence about the problem, and they can Yes.
provide teachers with information that may be
necessary for practical reasons without divulg-
ing medical confidentiality.
2. What sports can a child pursue without risk of

aggravating the disease?
In principle there is no reason why sports should
aggravate the illness. But if the disease affects
certain regions of the body, some sporting ac-
tivities may become a source of difficulty (see
below).
Chapter 27
An Uncommon Valor
Sylvia Shawcross
27
#ONTENTS
cians not to take these last statements lightly.
27.1 Kevin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .194 I urge you to think about this in light of the
biographies that I am presenting to you here. In-
27.2 Deborah. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .195
dividuals who have this disease from my experi-
27.3 Elizabeth . . . . . . . . . . . . . . . . . . . . . . . . . . . . .195 ence want knowledgeable and honest caregivers.
27.4 Melony . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .195 In light of the lack of success with most treat-
27.5 Kerrie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .196 ments, compassion goes hand and hand with
that care.
27.6 John . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .197
I could indeed write here about the issues this
27.7 Caroline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .197 disease highlights. I could discuss antibiotic re-
27.8 Arnold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .197 sistance, controversial treatment options, physi-
27.9 Mabel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .198 cian care that drives many to self-care, depres-
sion, suicide, lack of pain-management options,
27.10 Nassim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .199
the physical problems of odor and leakage, lack
27.11 Mira . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .199 of diagnosis or misdiagnosis, disability, health-
27.12 Mindy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .200 care costs, loss of self-esteem, disfigurement,
secrecy, isolation, lost relationships, cultural
taboos and nomenclature, confusion over and
This chapter of this remarkable book does not between treatment advisors, lack of treatment
take the form of a clinical paper: It is instead a guidelines and the list goes on. Indeed I could
collection of biographies given here specifically discuss many things including a host of mythol-
to impart to practitioners and health care pro- ogies that have followed this disease for 150
fessionals a glimpse into the world of their pa- years, but individuals with this disease can
tients. It is, after all, the individuals with the speak for themselves. Collectively they have that
disease hidradenitis suppurativa who are the power now. They are finally free of their long,
reason why this book has been written. Their lonely and painful silence.
voices have long been silent. The advent of the All that I have done and learned during those
internet as a means of communication has 6 years can be stated fairly succinctly: living
changed this silence into a chorus and perhaps with this disease creates a special human being,
now a deafening roar. I certainly hope so. one infused with an uncommon valor in the
From 1996 to 2002 I had the privilege to work face of overwhelming odds. Those odds are
with and for fellow sufferers of the disease on changing for the better. I believe that hope lies
the internet at a time when the 150-year silence right now in your hands in the form of this book
was finally broken. At that time, we discovered and the researchers, sufferers and the friends
caregivers were, for the most part, the only hu- and families of sufferers who have made it their
man beings that people with hidradenitis sup- mission to change the situation for us all.
purativa would admit to having this disease in These biographies were collected from 1996 to
their non-internet lives. For some, even this 1997 and are from some of the first people who
was more than they could manage. I urge physi- joined our internet support group. It was, at the
194 Sylvia Shawcross
time, the only such support list available. The tor said was an abscess on my bum probably
names of individuals have been changed other- from stress, bad diet or too much drinking or
wise the content remains as it was given. something which healed with a course of anti-
biotics. This thing recurred from time to time
for the next few years without any treatment. At
27.1 Kevin the same time I got a pimple in my armpit which
was never painful but seemed to fill up with a
I have been searching the web for nearly a year clear yellow fluid from time to time. I never re-
now for HS information and every now and ally took much notice of it.
again I do another search in the hope I may find To be honest I wish I had, but I was too busy
something new. Today I was delighted to find having a fun time. I spent from 2329 travelling
your pages and especially the visitors book with the world I visited over 40 countries and it was
remarks from fellow sufferers which made me a fantastic experience... When I arrived back
feel so much better about the way I feel. in NZ in 1991 all hell broke loose. It was like
I have been a chronic HS victim for a few someone or something had said the partys
years now and despite much sympathy from over sunshine your lifes gonna be like shit
27 those in the medical profession no ACTION. from now on!!
I visited a Naturapath nearly 2 months ago who My armpit swelled up like a tennis ball and
put me on a natural diet and some homeo- my groin got worse and worse. Over the next
pathic-type pills with ingredients youd expect couple of years it just spread to the point where I
in a witches brew! The results so far have been couldnt move without feeling like I had been
very good and I can finally sleep uninterrupted stabbed with a hot knife.
and the swelling has nearly disappeared. So for Minocycline kept it in check apart from the
the first time in years I am not in pain every sec- odd flare up for about a year. Then last sum-
ond of the day... with the power of positive mer I was almost suicidal as it all erupted again.
thinking I hope this will continue. A double dose of Minocycline simmered this
Im a white male born 1962 in New Zealand down but since then I knew it was just in a hold-
(South Pacific Ocean). Fairly normal childhood ing pattern and any minute it would spark up
in clean, green NZ. Mum, Dad and my 2 young- again and where would that leave me.
er brothers went on a trip to California to visit I dont know what has caused this terrible
an aunt in 1972. We sailed on the Canberra via condition in me we have no immediate family
Tonga, Hawaii and Vancouver. During this 6 history of it or any other connections. Im not
month stay in USA I developed boils on my be- really overweight either. One thing I have puz-
hind and thighs which were like volcanoes zled over is that when I was a teen and into my
very painful and not much fun for a 10 year old early 20s, I used to suffer from allergies (sneez-
who had never really been sick before. One after ing and runny nose, etc.) Then after I left NZ for
another after another for months. It was thought those 7 years, these allergies pretty well went
I had contracted some tropical bug in Tonga. I away then I returned and this bloody thing
dont know if it was HS then but no doctor we erupted (could be something in the air my
visited in California could diagnose what it was body rejects ??) but I dont suffer from hayfever
and tried different antibiotics, penicillin, etc. (I or the sneezing fits from dust or pollen etc any-
dont remember any exact details). Finally we more I cant help thinking this is somehow
went to see a specialist who prescribed some- connected.
thing which worked almost immediately and I wish my life was more normal. I wish I
the problem appeared to go away. I remember could play cricket again. I wish I didnt have to
having these boils again maybe twice or three cover up all the time. I wish I could take my
times during my teenage years. I had no acne shirt off at the beach. I wish I could look for-
problem as a teen, just normal zits. Later on, I ward to the future. I wish my son could climb
would have been 22 or 23... I had what the doc- on me.
An Uncommon Valor Chapter 27 195
27.2 Deborah prone to blockage and inflammation, and sec-

ondarily, infection. He also believes this genetic
I dont mind sharing info. Im 33. I have suffered defect causes an androgen imbalance. He does,
with hidradenitis since I was about 10. Many though, acknowledge that there are different
doctors told me over the years that I had boils. theories about the cause. Ive been on cephalex-
These were very deep, open holes, leaving ex- in for one month, with a slight improvement
tensive scaring. They put me on many different since starting it I have an average of 68 ab-
medications, none of them worked so I went the scesses continuously instead of the usual 810.
surgery route. I have had 4 surgeries with my He wants me to continue the antibiotic, and I
first in 1993. In 94 I had my arms and legs done. will give it another month, but I dont want to
My legs alone required 80 stitches! My last take antibiotics long term unless the improve-
surgery involved my groin area and they re-did ment is significant, which so far it isnt.
my arms. Now Im having problems on my back.
I do not desire surgery again! I am frustrated
and looking for suggestions and understanding. 27.4 Melony
Your group is the first Ive found and Id like to
belong! Hello!! I am 38 years old and I have had Hidrad-
enitis Suppurativa since puberty. I get these
cysts on my buttocks, inside of my thighs, and
27.3 Elizabeth the groin area. I am very discouraged with this
disease, as you probably know, there is no cure.
Im 42 years old (43 next month) and have been That is what the doctors have told me. I have
getting lesions all my adult life. Its been much been on every kind of medication even Accu-
worse in the past 5 years I always have 610 tane. I have had surgery on my buttocks, have
active abscesses. Areas affected mostly in my had some of the glands taken out, however, the
groin and under my breasts. I hadnt had one in cysts will come back as they cannot take every
my armpits for years, but guess where I feel one gland out of your body. I have had them lanced,
starting now? (We all know that old feeling, which is really humiliating, because it just hurts
dont we?!) My dermatologist and I are presently so bad, but afterwards it is such a relief to have
trying different antibiotics so far erythromy- the cyst and the swelling gone. I have a cyst
cin and minocycline have failed to make the as we speak. I believe that stress causes these,
slightest difference. Im now on cephalexin so and I tend to get them around that time of the
far there seems to be a very slight improvement month.
well see. I think there might be something to I really hate the way this disease has scarred
the theory that HS may be linked to the immune me. Not only physically but emotionally. I am
system maybe our immune systems are at- single, and I dont know who would want some-
tacking our sweat glands. This may be why one one that has this. Im really discouraged with
member sees such relief from prednisone. Most this disease, I just cannot believe there is not a
physicians think that HS is an infection, start- cure. I am very embarrassed with this, as my
ing either in the eccrine and/or apocrine glands buttocks are really, really scarred, and the inside
themselves or in the follicles. If it is strictly an of my thighs are pretty bad also.
infection, cortisone an immune suppressant I am happy to find that there is support for
would be contraindicated. Interesting. this. I have never spoken to anyone that suffers
My experience with physicians has been from this. I sincerely know what they are going
mostly positive my internist and my derma- through. It really is comforting to know that I
tologist are very sympathetic. I saw my derm. on may be able to correspond with others that suf-
Monday. He doesnt buy into the theory that fer from this.
HS is autoimmune, he believes that its a genetic I work at a college. I am a secretary, and I sit
defect that causes the apocrine glands to be most of the time, which can be difficult at times.
I really try to do the best that I can do. I have 27.5 Kerrie
resolved that I will have this forever and I will
probably will be single the rest of my life. I am My first outbreak, if you can call it that, showed
really scarred. up right before a vacation to Florida, which is
It seems that all the doctors that I went to why I remember it so clearly. I wore shorts at the
were not sympathetic at all. I really dont think beach as opposed to a bathing suit. It started
that humiliation and embarrassment begins to then with one swollen red painful lump on the
describe our feelings when we have to expose left side of my genital region. Since then, its
ourselves to doctors, etc. I remember, the last spread a bit. They are on both sides now about
doctor that I seen, he was a plastic surgeon, and 6 or more each side with little tunnels running
he really was the best doctor that I have seen. I between them. Around the time of my period
really loved him. He was full of concern, and one side or the other, rarely both, will become
hated to see me in such pain. Unfortunately, he severely inflamed and horribly painful. I work
retired, and I try not to go to doctors unless it is twelve hours a day with a lot of walking, but ibu-
absolutely necessary. Ill always remember go- profen seems to help some. Ive only had a cou-
ing to his office. They always put me in this ple come to a head. When theyre not inflamed,
27 room that had a print of this little girl huddled they range from pea sized to marble sized lumps
in a corner, hiding her face, and there was this under the skin. And some of them have what
little dog sitting right next to her. The title of the seem to be permanent holes in them that never
print was In Disgrace. How appropriate. I close up. I went to my doctor about a year ago
would cry as soon as I got in the room and seen and he called them infected ingrown hairs and
the print. I could have been that little girl. I was said theyd go away on their own. Sure. He put
in disgrace, but why. I searched and searched for me on Tetracycline for my pimples I started get-
a print of that, and finally found one. I truly re- ting after my son was born. Thats why I think
lated to that little girl. Every time, I went to his they are hormone related. Since his birth, the
office, I left feeling disgraced. HS appeared, pimples appeared, Ive had some
This doctor performed a surgery on me. He excessive hair grown in the nether regions, and
went into detail about what he was going to do. I have horribly painful and heavy periods that
He was going to go in and remove the glands, last up to two weeks every month. Im going to
and he said that where he removed those, I see about birth control to help with that part of
shouldnt get anymore cysts. He explained that it. Ive heard that can help HS too? I havent
he couldnt take out all of the glands in my body, needed birth control for years. I was divorced
as we have millions of them. The surgery was on shortly after my son was born and since the HS
my buttocks. He did the surgery. I laid in the appeared, I havent even dated anyone. It seemed
bed, on my back for four days. The nurses had to too embarrassing. Anyhow, I started surfing the
come and turn me over, as I couldnt move. On net the other night looking up diseases and dis-
the fourth day the nurses came in, got me out of orders of the skin, hoping I could find some-
bed, had me lean across the bed, and proceeded thing that sounded like what I have. I came
to remove the bandages. I have never felt so across a reference to HS and recognized myself
much pain. Where I had lain so long, they had immediately. I belong to an HMO and its fun
to use forceps to pull the bandages from the trying to see a doctor. Later today I plan to call
wounds. (Ouch, doesnt even touch it.) To add my HMO and get a different doctor (the doctor
insult to injury, they put me in a tub of salt water I have now did a complete physical on me in less
afterwards. Just how much humiliation should than five minutes. He was slamming patients in
one person have to go through??? I just dont and out as fast as they could undress and dress),
know. I guess the surgery helped in some ways. and then make an appointment for my official
However, my doctor told me to stay away from diagnosis. Since I spent a couple years in school
nudist camps (ha, ha). learning med, Im 99.993% sure that HS is what
I have. Its such a relief to have a name to put to painful and tender that all I could do after try-
my condition, and Im pretty happy today, ing to sit all day at work, or even just walk, was
knowing what it is. to go home, sit in the bathtub, and cry, and
sometimes just drink a lot to try to forget the
pain. I again talked to my doctor, who respond-
27.6 John ed in the usual fashion and told me I just needed
to make sure to wash more often. The worst part
Ive been having trouble with hidradenitis since was I couldnt even talk to anyone about it be-
my teens, Im 44 now. Over the years it seems to cause it was so personal and embarrassing.
flare up and give me trouble for extended peri- If I had to take time off at work because I just
ods and then subside, sometimes for a year or couldnt sit any longer, I always had to come up
more with no trouble, except for mild acne with another excuse like having a migraine,
mostly on my back. etc.
For the first 10 years or so I didnt know what Last week I had to see a dermatologist for an-
the problem was except that I would occasion- other reason and happened to tell her about this
ally have to have a flare-up lanced. I just as- problem. She knew right off what it was. I was so
sumed they were boils and just the nature of my relieved to finally have a name for this problem.
skin. Nobody (doctors) said anything. Then one I was even half expecting for her to be able to
time when I went to the doctor in need of lanc- just give me some antibiotics and it would go
ing he referred me to a surgeon who referred me away, so, of course, I was shocked to hear that
to a dermatologist. The dermatologist diagnosed I would have to deal with this problem for the
my problem as hidradenitis. He prescribed Mi- rest of my life. Although she was able to diag-
nocin in a low dosage, long term, along with nose it, she wasnt very forthcoming about pro-
cortisone injections into the infected sites. I feel viding any information about the disease (other
the Minocin was a waste of money. I havent had than it may be related to hormones) and I should
any success with any antibiotic in any form. The consider taking estrogen. I was so dumbfound-
cortisone shots did help but would last only ed by having a lifetime illness, and that I
about 10 days and I could never get an appoint- would have to deal with this pain, that I couldnt
ment within the needed time frame so it would even think of questions to ask her. I went home
just flare up again and I would start all over. and did some research and was really happy to
My personal feeling is that the flare-ups are come across this list and what it could mean for
related to both stress and hygiene. anyone that suffers from this illness.
I seem to have some success by using Dial At this point, Im still at the angry and con-
anti-bacterial soap both as a preventive and of fused stage. This illness has not only affected
course during flare-ups. my ability to work at times, but it also has (and
is) affecting social and intimate relationships.
But, I also know that half the battle is won now
27.7 Caroline that I know what is it; I think the other half of
the battle is being able to talk about it and get
I began to develop what I initially called acne advice and support from others that suffer the
and now know to be HS quite a number of years same thing.
ago, probably when I was in my late 20s (Ill be
35 tomorrow). It began as very small cysts or
pimples in my groin area or on my buttocks that 27.8 Arnold
initially would go away in a few days. I men-
tioned it briefly to a few doctors and was simply I understand your concern for keeping the
told I had ingrown hairs or folliculitis or it was group inclusive. Having suffered this disease
from wearing jeans most of the time. Over the for about 10 years now, it is a bit exciting and a
years, the frequency, size, and duration of them bit embarrassing to share the experience with
increased to the point where they became so others.
First, just to let you know who is writing, ful period, in fact, up to six hours. By the way,
I am a 58 year-old white male that has the dis- just to prove most recent studies done on pain
ease in the groin, upper thigh and buttock areas. medications, I had no trouble withdrawing from
There is no known similar disease anywhere in the narcotic type medicines nor did I display
the family that is known to me. I am within 10 any addiction.
pounds of my correct weight for height and age My doctors have been pushing me to undergo
and have never had a weight problem. Marital the radical surgery required of serious hidrade-
status is currently single (my wife left me two nitis sufferers. I have insisted they continue to
years ago as a result of my various restrictions explore alternative potential remedies. Lo and
associated with the disease not liking to be behold, they have come to the conclusion that
around sick people). So much for the in sick- there is a very good possibility that I might be
ness and in health bit. helped by low-level radiation treatments. Ap-
Over the years, I have been treated primarily parently, there is a disease that mainly affects
with antibiotics (the whole gamut changing fre- Afro-Americans with very similar type lesions
quently) with little or no success. In November on the scalp and, Im sorry, Ive forgotten the
1995 and February 1996, I underwent surgery to name of that disease. Recent experiments with
27 excise portions of my upper thighs and but- this low-level radiation have proven to be ex-
tocks. Healing did not go well with about 20 tremely helpful. My doctor has consulted with
inches of incisions taking the best part of a year the chief of radiology at the hospital performing
to close and heal. These operations did nothing these experiments and they seem to think it
to slow down the spread of the disease. could be helpful to me. Im certainly willing.
In June 1996, I began a 20-week (80 milli-
gram per day) treatment of Accutane which
showed minor promise beginning about the 27.9 Mabel
12th week with some of the more minor lesions
healing (perhaps a 1015% improvement?) and I live in South San Francisco, California and am
continued in that state until the course ended. a 40 year old female suffering from hidradenitis
My doctors and Im being treated at Johns suppurativa since the onset of puberty. It has be-
Hopkins Hospital in Baltimore, Maryland become progressively worse and in 1994 I had sur-
gan a second round with the Accutane in June gery to remove the abscesses from the groin
1997 but at a much lower dosing of just 20 mil- area. I remained in the hospital for 3 months
ligrams a day. To date, this has had no notice- due to complications from the surgery (i.e. sec-
able effect and the spread of the lesions is con- ondary infection). I had relief from the hidrad-
tinuing. By the way, I suffered none of the enitis for only about 9 months after which time
side-effects associated with Accutane other than it returned to the areas under both arms. Since
dry, chapped lips during the first course and then I have been in constant pain and fatigue.
nothing with this lighter than useless second I have been seeing a dermatologist who has me
course. taking Eulexin, an androgen medication used
Pain is intense with every movement of my for patients for prostate cancer. I also take the
legs and while in the sitting position. After sev- antibiotic dycloxicillin and vicodin for pain.
eral months following the surgeries of control- The wounds seem to be responding to the
ling pain with narcotic pain relievers (Vicodin Eulexin albeit ever so slowly. Ive taking the Eu-
and Percocet), the doctors were unwilling to lexin for a year come this November. The doctor
continue this treatment more out of concern has told me that I am only the second patient he
for themselves than with my pain, I might add. has seen with such a severe case of hidradenitis.
Through searching the Internet and talking I cant tell you what a revelation it was to find a
with a chemist specializing in pain control sub- support group for those with this affliction!
stances, I stumbled upon Ultram. This is a won- I truly thought I was the only one in the world
derful non-narcotic pain reliever that is every with hidradenitis. And to cause even more frus-
bit as effective as Percocet but with a longer use- tration, no one had ever made the correct diag-
nosis during my early years. I wonder if they In 1985, I was in the military and seen by a
had diagnosed it early, if I might have gotten a doctor there who said they were not boils but
jump on the disease and not become such a cysts and that I should let him cut them out.
severe case. I did notice that during my two Well I was afraid of the scarring and said no.
healthy pregnancies, this condition seemed to In 1987, those boils cysts abscessed and I
disappear for those wonderful nine months. As had to have emergency surgery as they became
soon as the babies were born though, it reap- one big gray mass on my right buttock and didnt
peared and became progressively worse after look like it would go down by itself as usual.
each birth. This leads me to believe that it has a They found approx. 10 cystic like masses when
connection with some type of hormonal imbal- they operated. The scar was very small and I
ance. It would be wonderful to have someone to didnt think much about it. I still didnt have a
talk to and who understands this terrible diagnosis except of inclusion cysts on right
affliction. buttock. About 4 months after the surgery, an
infected mass came up over the surgery site
and I was put on various strong antibiotics and
27.10 Nassim told it was some kind of infection and it was
tracking. The mass would come up and burst
I really understand why you are asking for bios, open eventually and drain a lot of blood and
I sometimes find it hard to share even with my pus. Finally one doctor sent me to the hospital
familyI am 18 years old female from Turkey as he felt I probably had more cysts down deep
(so excuse me if my English is sometimes not that needed to be cut out. Well, they did find
good enough) I have had 3 surgeries until now, what they described as about 15 cysts and a lot
the first one 5 years ago from both of my arm- of strange tissue, so much so that they re-
pits And the others at anal zone. But Ive been moved a lot of tissue from my right buttock (but
informed that I have this illness only 6 months I didnt know that until I went home and the
ago Ive used a lot of antibiotics, only Tetra- bandage fell off prematurely). I didnt realize
dox was a little bit useful for me. I am using how much they had to cut, and assumed it would
Roaccutane since 2 months right now, and I be similar to the first surgery, but I was wrong.
hope I wont have to have another surgery, cause They had to remove so much tissue that I have
it really doesnt work! :) three scars going in all directions and about 1/3
of my tissue removed and my right buttock has
a caved in look. I have lived with this many
27.11 Mira years and am very ashamed and embarrassed to
let anyone (even another doctor) see it. At the
I do realize that this disease is a painful and beginning, nurses who saw it used to ask me if
very embarrassing one, as it has been that way I have had radiation to the area.
for me also for many years. I am a 41 year old Well, finally in 1995, I was sent to a doctor
woman and have been suffering with this for 19 because more of these cysts boils were com-
years. I first noticed this disease (although I ing up around the surgery site, but not on the
didnt have any idea it was a chronic disease or scar tissue of the surgery and small ones on
that it had a name) when I was pregnant with my face in front of my ears that were different
my first child in 1977. I started getting what from the ones on my buttocks as they didnt
looked like boils that would come up and then hurt and never went away. She diagnosed me
go down on my buttocks. When one got big with having hidradenitis and I finally had a
enough or painful enough to make me want to name to put on it. The ones on my face seem to
see a doctor, I was usually told it was a boil be spreading towards my nose as the years go on
and that I should go home and put hot com- and I am very afraid of what my face will look
presses on it until it came to a head, then come like a few years down the road. I was seen by a
back to see him. Well they never came to a plastic surgeon attached to a teaching hospital
head, but just eventually went back down. and he refused to operate on the ones in front of
my ears as he said that it would be dangerous to giving me cortisone shots right into the sore
try to remove them as they wouldnt have a way I dont even know how many different medica-
to drain and might become a large inflammations I have been on.
tion with more scarring due to the surgery. I am About the time I was 18 and my mother could
also getting them on my left buttock now and no long force me to go the doctor, I quit going.
am afraid that one day I will have to have sur- After at least 56 years of treatment, nothing
gery on that side which will then leave me with was workingso I just decided to save all the
both buttocks very deformed looking. money and quit throwing it away on pills and
I have recently gotten remarried and will not office visits. I have not received any further
let my husband see or feel my buttock, as it is treatment since then and I am now 27. I have
very embarrassing to me, although he says that sores in the groin area, armpits and under my
it doesnt matter to him. Well it does matter to breasts. I also have a nasty little bugger right on
me as the first time my ex-husband had seen the my tailbone. That one comes and goes more
area after surgery in 1988, his face dropped. For than any of the othersat least once every
the last 8 years of our marriage, I never again let 2 weeks that one will flare up and finally drain.
him see it if I could help it. I feel like a woman Overall, I would say that the flare-ups are mild-
27 who has had a mastectomy. Between having a er than they have ever been since I have been
very deformed right buttock with more lesions afflicted with this condition. Nonetheless, after
coming out around the surgical site and now years of flare-ups, I have so much scar tissue
having the lesions coming out on my left but- that the groin area looks like a war zone. Much
tock, I feel like I am totally disgusting and unat- of the skin in the area is purple and shiny from
tractive. The ones on my face so far I have been scarring. I have a constant open wound in the
able to cover with makeup, but I pray that they right armpit, but it doesnt seem to fill upit
dont spread or get bigger. just doesnt heal.
While this disease is very uncomfortable for
me, physically and emotionally, I have always
27.12 Mindy been thankful that it is a problem that no one
knows about unless I tell them. All the marks
I have had Hidradenitis since I was 12 or 13. It and scars can be covered with clothes. There are
kicked in not too long after I started menstruat- a lot of diseases out there that cannot be hidden
ing. I saw my family doctor, who sent me to an- at all.
other doctor, who sent me to a dermatologist, Editors note: Since this manuscript was
who sent me to a gyno. Those 2 worked in con- completed a new patient organization has
junction with each other. My gyno had me on been launched with an international perspec-
birth control pills my dermatologist had me on tive. Further information can be found at:
antibiotics, blood pressure medication, steroids, www.hs-foundation.org.
Subject Index
A apoptosis of keratinocytes 142 chemokines 107

abscess 12, 28, 59 aromatase 96 chemotactic migration of granulo-
acinetobacter species 87 arthritis 42, 190 cytes 128, 142, 157
acitretin 128, 132, 185 autosomal dominant inheri- chlamydia trachomatis 62, 90
acne 39, 42, 67 tance 60, 70, 77 chlormadinone acetate 125
conglobata 39, 40, 67 axillary HS 16, 87, 165 chronicity 19
ectopica 130 azelaic acid 156, 184 ciclosporin 138, 185
triad/tetrad 9, 39, 129 ciprofloxacin 53, 91
acquired immune response 102 B circulating immune
acromegaly 97 bacteria found in HS lesions 88 complex 43
actinomycosis 23, 45 bacterial classification 65
adhesion 147 colonization 67,88 clindamycin 91, 122, 151, 184
adjuvant treatment in HS 92 fragment 43 clofazimine 53
adrenocorticotrophic hormone nucleic acids 51 clostridium difficile 91
(ACTH) 138 Bacteroides 90 co-existence of HS
aerobic and anaerobic bacteria 67, Bartholins gland 23 and Crohn disease 55, 147
87, 121 B cells 79, 102 coagulase-negative staphylo-
age at onset 18, 60 Berksons bias 62 cocci 67, 87, 89
age distribution 18 betamethasone 158 colonoscopy 55
anal canal 53 bilophila wadsworthia 90 combined therapy 158, 184
anal fistula 45 biofilms 89 comedones 15, 59, 81
analgesic 164, 168, 189 blue light 178 comedolytic agents 154
analogies to acne 67 BMI 19 commensals 86, 109
anatomical anomaly 66 body weight 60 compliance 157
androgenism 62, 95, 124 Borrelia. burgdorferi 103 complications 21, 63, 166
android obesity 96 botulinum toxin 143 contaminants 88
anemia 55 breast 17 continence 53
anesthesia 168 bridged scarring 14 continuous disease 20
ankylosing spondylitis 81 burden of the disease 59 contraceptive pill 188
anti-androgenic 142 buttocks 17 contracture 164
anti-apoptotic activity 142 controlled trials 158
anti-inflammatory C corticosteroids 42, 68, 138, 185
drugs 42, 189 cancer 21, 43, 62,187 corynebacterium species 87
properties of antibiotics 121 carbon dioxide laser 167, 170 cosmetic result 164
anti-nuclear antibodies 42 carbuncles 23 cost-benefit 158
anti-oxidant activity 142 carriage 92 costs 171
antibiotics 120, 122, 184, 186, casecontrol studies 60 C-reactive protein 55
189 caspase 91 criteria for HS 59
antileukoprotease 107 cat-scratch disease 23 Crohns disease 23, 32, 45,
antimicrobial cathelicidin 105, 106 50, 81
chemokines 107 CD4+ T cell cytotoxicity 147 cryosurgery 179
peptides 101, 105 CD4 helper cells 30 curettage 163
antiperspirants 60 cell-mediated response 30, 110 Cushing syndrome 97
apocrine glands 27, 30, 87 cephalosporins 91 CXCL 107
apoeccrine glands 27 chemoattractants 102 cycles 158
202 Subject Index
cyproterone acetate (CPA) 95, end-organ sensitivity 98 grafting 163

124, 126 enthesopathy 42 Gram-negative bacteria (rods) 67,
cysts 15, 157 eosinophils 102, 147 88, 121
cytokines 108 epidemiology 63 Gram-positive bacteria 87, 102
epidermal cyst 23 granulation tissue 28, 31, 164
D epithelioid granulomas 52 granuloma 54
D -Penicillamine 42 erosions 42 inguinale 45
Dapsone 138, 185 erysipelas 45 Groin 16, 87
days of work 117 erythema 12
debulk 170 erythromycin 91 H
defensin 105 escherichia coli 90, 121 hBD 106
dehydroepiandrosterone 96 ethinyloestradiol 124 hair-bearing skin excision 166
delayed grafting 164 etiologic factors 63 hair removal 60
delay in diagnosis 22 etretinate 128, 132 hallmark of HS 13
dendritic cells 79 excision 166, 185 haplotype 75
deodorants 60, 190 exploratory studies 181 healing time 180
depilation 179 exteriorization 163, 185 health-related quality of life
Dermatology Life Quality Index questionnaires 181
(DLQI) 22, 63, 118 F heat shock proteins 102
deroofing 163 familial heredity 188
diabetes mellitus 96 form of HS 71 heritability 70
diagnosis 22, 59 history 18, 22, 60 hidrosadnite phlegmoneuse 6
differential diagnoses 23 fatigue 191 hirsutism 95, 125, 179
digestive symptoms 55 fertility problems 96 histiocytes 28, 101
dihydrotestosterone fibrosis 13, 28 HLA B27 42
(DHT) 96,124 finasteride 125, 126 honeycomb-like structure 14
Disability 58 fistulas 53, 166 hormonal factors 60, 96, 142
disease fistulizing 52 hospitalization 164
control 158 flaps 163 hostmicrobial interactions 51
definition 60, 71 flares 184 human papilloma virus
frequency 60 follicular (HPV) 44, 62
progression 139 abnormalities 66 Hurleys clinical staging 21, 162,
severity 21 hyperkeratosis 27 183
Dissecting cellulitis (folliculitis) keratin plug 154 hyperandrogenism 96, 124
of the scalp 39 lipids 110 hyperhidrosis 12
distress 63, 118 obstruction 9, 26, 66 hyperinsulinism 96
DNA polymorphisms 75 diseases 39 hyperkeratinization 132
double-stranded (ds) RNA 101 papules 15 hyperostosis 42
DowlingDegos disease 41 Folliculitis 6, 67, 68 hypertrichosis 95, 125, 179
draining sinus 13 follow-up 168, 181 hypertrophic fibrous scarring 14
dressings 164, 168, 190 FoxFordyce disease 31 hypoechoic focal nodular
ductal hypercornification 128 furunculosis 23 lesions 35
duration of disease 63 fusidic acid 157 hypoferritinemia 55
dysfunctional neutrophils 110 hypohidrotic ectodermal
dyslipidaemia 96 G dysplasia 80
GCSF 80
E gender predilection 18 I
early lesions 27 genetic iatrogenic
early puberty 97 basis of HS 70 factors 62
eccrine environmental interaction 63 pain 180
differentiation 30 susceptibility 55 ICAM 1 142
glands 27 genodermatoses 74 IFNG 102
Echogenicity 35 giant cells 28 Interleukins (IL) 80, 108, 142, 147
ecological disturbances 92 gluteal-perianal-perineal imaging of HS 36
electrocoagulation 163 disease 165 immobilization 164
Subject Index 203
immune system 110 lipopolysaccharide (LPS) 51, 101 oligomenorrhoea 96

immunohistochemical examina- lipoteichoic acid (LTA) 101 optomechanical flash scanner 167
tion 30 lithium 45 oral contraceptives (OC) 98, 124
immunosuppressive drugs 53, 68, living with this disease 193 osteoporosis 42
136,186 lymphadenitis 23 other localizations 17
incidence 58 lymph node enlargement 15 outcome 62
incision and drainage 163 lymphocytes 101, 147 outer root sheath in normal hair
infection 60, 67 lymphocytic inflammatory follicles 30
inflammation 14, 137 infiltrate 68 ovarian dysfunction 95
inflammatory lymphogranuloma venereum 45
bowel disease (IBD) 5, 52 P
cellular infiltrate 101 M paintbrush technique 167
cytokines 80 macrophages 79, 102 pain 12, 20, 118, 137, 138, 156,
granuloma 91 magnetic resonance imaging 36 168, 185
Infliximab 53, 55, 147 maintenance therapy 154 papules 59
infundibular epithelial hyper- malassezia furfur 109 paraneoplastic
proliferation 68 Marjolins ulcers 44 hypercalcaemia 44
inguinal disease 16, 165 mast cells 79, 102 neuropathy 45
inhibition menopause 63, 97 pathogen-associated molecular
of cell proliferation 80 menstruation 63 patterns (PAMPs) 51, 101
of free radicals 91 meshed grafts 163 patient history 22
of lipases 91 metabolic complications 96 pattern recognition receptors
of metalloproteases 91 metallo-enzymes 141 (PRRs) 101
of nitric oxide synthetase 91 methotrexate 138, 185 peeling effect 154
innate immunity 101 metronidazole 53, 91 peptidoglycan (PGN) 51, 101
insulin resistance 96 microorganisms 87 perianal lesions 17, 52
integrin functions 142 microsatellites 75 perifollicular inflammation 6
interleukin-1 receptor/Toll-like migration of keratinocytes 142 perifolliculitis capitis abscedens
receptor (IL-1R/TLR) 80 minocycline 91 et suffodiens 39, 40
Interleukins (IL) 80, 108, 142, 147 morphology 66 perineum 17, 87
intermediate course 20 mucosal T cells 51 photodynamic therapy (PDT) 177
intermittent/benign course 20 muramyl dipeptide (MDP) 51 photography 181
intra-articular corticosteroid 42 mutation 76, 82 pilonidal cyst sinus 31, 39, 66
intralesional mycobacterium tuberculosis 109 pilosebaceous unit 27
anti-inflammatory therapy 157 MyD88 104 plugging 27
steroids 138, 157, 184 polycystic ovary syndrome
IRAK-M 109 N (PCOS) 96
Isotretinoin 42, 128, 130, 189 natural history 62 polymicrobial infection 68
itching 12, 189 negative cultures 88 polymorphonuclear leukocytes 91
neutrophils 31, 101, 102, 147 postoperative wound care 168
K nocardia 45 prednisolone 138
keratinocytes 102, 108 NOD2 gene 51 pregnancy 188
keratolytics 152 nodule 12, 59 premature adrenarche 97
Kitamuras reticulate acropigmen- non-classic adrenal hyperplasia premenstrual flare 19
tation 41 (NCAH) 96 preoperative
Klebsiella 90 non-melanoma skin cancer 44 conditioning 131
non-steroidal anti-inflammatory antibiotics 168
L drugs 122 prevalence 58
laser 167, 179, 189 nosology 65 prevotella species 90
late-onset disease 118 nuclear factor kappa B primary closure 163, 164
left to right comparisons 181 (NF-KB) 51 proctectomy 53
LFA 3 142 prodromal signs 59
lidocaine 168 O progestins 125
lifestyle measures 63 obese 191 prognosis 62
lipases 89 odour 13 proinflammatory cytokines/
lipoarabinomannan (LAM) 101 Oestrogen 79, 97, 124 chemokines 101
204 Subject Index
propionibacterium seborrhoea 68 tertiary lesions 14

acnes 67, 87, 109, 128 secondary intention healing 163, testosterone 124
species 87 168 tetracyclines 122, 151, 185
proteases 89, 91 secondary lesions 13 therapeutic strategy 158
proteus 90, 121 self-reported level of health 62 therapy of flares 185
pruritus 12, 189 self-treatment 158 therapy (local) 150
pseudo-neoplastic changes 43 sex hormone binding globulin tissue vaporization 169
pseudomonas 121 (SHBG) 96 T lymphocytes 80
psoriasis 81 sexually transmitted disease 62 TNF-alpha inhibitors 185
purine analogs 53 silent nodule 12 tumor necrosis factor (TNFA) 43,
pustules 15 simple excisions 163 68, 80, 108, 142, 147
pustulosis 42 sinus tracts 13, 28 tobacco 20, 44, 50, 55, 60, 191
pyoderma gangrenosum 45 skindex 22, 181 tolerance 109
Skin toll-like receptors (TLRs) 101
Q cancer 62 tombstone comedones 15
quality of life 116 tags 53 topical antibiotics 151
smell 190 triamcinolone 138, 158
R smoking 20, 44, 50, 55, 60, 191 tuberculosis 23, 45
Radiation therapy 44, 45, 174, 185 social and sex life 20 tularaemia 45
randomized controlled trials 180, sources of recurrence 170
183 specific immune response 90 U
RANTES/CCL5 107 spironolactone 124, 125, 126 ulcer 53
rapamycin 45, 139 sport 190 ulceration 20
reconstruction 163 spread of disease 35 ultrasound imaging 34, 181
recurrence 163 squamous cell carcinoma 44
recurrences (local) 167 stages 187 V
repeated treatment sessions 170 standardized outcomes 186 vaporization 167
resolution 18 Staphylococcus vasoactive intestinal peptide
resorcinol 152, 153, 184 aureus 67, 87, 121 (VIP) 80
retinoids 68, 128 epidermidis 87, 109 Velpeau 5
rheumatoid factor 42 species 87, 89 visual analog scale (VAS) 22, 117,
rheumatological disease 42 steatocystoma multiplex 23 181
rifampicin 122, 184, 185 steroid sulfatase 96 VQ-Dermato 118
RNase 105 strategy for the treatment 183 vulva 53
streptococci 88
S streptococcus milleri 90 W
Sacroiliitis 42 stress 191 wide excision 45, 163, 185
safety razor 60 sudoral tumors 5 work 62
salmonella typhi 103 sugar 191 worst years 19
SAPHO 42 sulfasalazine 43
sarcoidosis 32 surgery 188 X
sartorius score 21, 181 sweat glands 7 x-ray examination 36
scarring 67 syndesmophytes 42
scar tissue 31 synovitis 42 Z
scent production 27 Z-plasty 165
sebaceous T Zinc finger protein 91 79
cysts 23 T-cell-mediated immunity 142 zinc gluconate 141, 185
glands 26 talcum 190 zymosan 101
Sebocystomatosis 23 taxonomists 1
sebocytes 102 teratogens 134

Hidradenitis Suppurativa

Uploaded by

Copyright:

Available Formats

Hidradenitis Suppurativa

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Hidradenitis Suppurativa

Uploaded by

Copyright:

Available Formats

'REGOR"%*EMEC *EAN2EVUZ *AMES*,EYDEN%DS

Jean Revuz, MD, DMedSc

Library of Congress Control Number: 2006928941

ISBN-10 3-540-33100-X Springer Berlin Heidelberg New York

Springer is a part of Springer Science + Business Media

Springer-Verlag Berlin Heidelberg 2006

Editor: Marion Philipp, Heidelberg

Printed on acid-free paper 27/3100 YL 5 4 3 2 1 0

Chapter 1 3.3.2 Atypical Localizations

4.6 Comparison with Other Disorders . 31 Chapter 7

9.3.3 Hormones . . . . . . . . . . . . . . . 68 Chapter 12

Chapter 14 16.3.2 Spironolactone . . . . . . . . . . . . 126

Chapter 19 21.4.2 Fusidic Acid . . . . . . . . . . . . . 157

*URR"OER %VELYNE$RAPIER &AURE

*EAN &RANOIS#ONTOU ,ENNART%MTESTAM

Hidradenitis Suppurativa Introduction

#ONTENTS sweat glands [1]. This concept held sway over

Verneuil and Verneuils Disease:

Key points 2.1 Biographical Landmarks

irritations of the sebaceous follicles, by the ab-

4. Velpeau ALA. Aisselle, phlegmons, abcs. In Dic-

Q There is an extreme variety

of the distinctness of HS it is commonly misdi- 3.2 Individual Lesions

Fig. 3.1 a, b. a Early

Fig. 3.2. Incision of an abscess yielding pus

Chronicity and recurrences are the hallmark of

3.2.3 Tertiary Lesions

The final stage of the disease (Hurley stage III,

Fig. 3.7. Severe inflamed

a limb, particularly abduction of the arm (see 3.2.4 Other Lesions

3.3.1.1 Two Main Zones

The axillary and the inguino-crural zones are

Fig. 3.13. Epidermal (epithelial) cyst

(35 cm) epidermal cysts, which can also be ob-

3.3.1 Involved Areas

The typical distribution of HS lesions closely

The breast may be involved in women, particu-

The buttocks are one of the most frequent of

Fig. 3.16. Inter-mammary HS

folds and the eyelids. Some of these reports stem

3.4.1 Age at Onset and Resolution

HS develops after puberty, usually in the second

Fig. 3.21. Age at onset in

severe disease as evaluated by the Sartorius in-

3.5 Clinical Course

In this stage of the disease long-lasting sup-

3.7.3 Differential Diagnoses (also called sebocystomatosis). Steatocystoma

Pathology of Hidradenitis Suppurativa

Q Apocrine gland involvement appears

was evident in all of the specimens regardless of

4.2.3 Eccrine Glands

Eccrine glands are derived from a specialized

4.2.4 Apoeccrine Glands

These represent axillary glands in adults and

4.2.2 Apocrine Glands 4.3.1 Early Lesions (Fig. 4.3 ad)

Fig. 4.4 ae. Histological changes in established HS.

4.4 Immunohistochemistry These changes mirror those found in experi-

Fig. 4.6. Normal pilosebaceous unit, CK17 was present

Fig. 4.7. Dissecting folliculitis of the scalp

4.6 Comparison 4.6.3 Follicular Occlusion Triad

'REGOR"%EMECEAN2EVUZAMES,EYDEN%DS