Autoimmune Bullous Diseases

Dr. Abdullah ALAKEEL

Assistant Professor & Consultant
Department of Dermatology
KKUH
• Circumscribed skin lesions containing
fluid (If the size ≤ 5mm = vesicle If the
size > 5mm = bulla)
• Classification Of Vesiculobullous Diseases:
 Autoimmune bullous diseases
• A- Loss of intraepidermal adhesion: Pemphigus group :
• 1- Pemphigus vulgaris (PV) with subtypes
• a- Classic
• b- Pemphigus vegetans
2- Pemphigus foliaceus with subtypes:
a- Classic
- Fogo selvagum
- Pemphigus erythematosus ( Senear-Usher)
b- Paraneoplastic pemphigus
c- Drug induced pemphigus
d- IgA pemphigus
 Autoimmune bullous diseases
B- Loss of subepidermal adhesion :
1- Pemphigoid
a- Bullous pemphigoid
b- Pemphigoid gestationis
c- Cicatricial pemphigoid
2- Linear IgA disease
- of childhood
- Adult form
3- Epidermolysis bullosa acquisita
4- Dermatitis herpetiformis
 Autoimmune bullous diseases
• Pemphigus Group :
• A group of disorders with loss of
intraepidermal adhesion due to
autoantibodies directed against proteins of
the desmosomal complex that hold
keratinocytes together. The desmosome is a
complex structure, with many of its
components targets for autoantibodies.
 PV
• Pemphigus vulgaris (PV):
• Definition : severe, potentially fatal disease
with intraepidermal blister formation on skin
and mucosa caused by autoantibodies against
desmogleins.
• Epidemiology : 0.1-0.5/ 100000 yearly, most
patients middle aged.
 PV
• Pathogenesis:
• - Genetic predisposition: HLA-DRQ402- DQ0505
• - Antibodies against desmoglein 3 (Dsg 3) and
later desmoglein 1 (Dsg 1 ). The bound
antibodies activate proteases that damage the
desmosome, leading to acantholysis.
• - Serum antibody titer usually correlates with
severity of disease and course.
 PV
- Agents containing sulfhydryl groups
(penicillamine, captopril, piroxicam) are more
likely to cause PV.
- Those without sulfhydryl groups tend to cause
PV ( beta-blockers, cephalosporins, penicillins, &
rifampicin) .
- Note : drugs from either group can cause
either type of pemphigus.
 PV
• Clinical features:
• Sites: oral mucosa, scalp , face, mechanically stressed
areas,nail fold, intertriginous areas.
• Bliters are NOT stable, epidermis falls apart, erosions
& crusts are common
• Oral involvement: 70%, anti-Dsg3 (Dsg 3 is the main
desmoglein on mucosa)
• Additional localized disease; scalp
• Note: always check scalp when confronted with
unexplained oral erosions.
 PV
• Generalized disease due to development of
antibodies against Dsg1 which is present in
skin along with Dsg3.
• Pruritus is uncommon.
• Histology: acantholysis, retention of basal
layer keratinocytes (tombstone effect), mild
dermal perivascular infiltrates.
 PV
• Diagnostic approach:
• Clinical evaluation
• Nikolsky sign
• Pseudo-Nikolsky sign (Asboe-Hansen sign),
less specific
 PV
• Histology:
• DIF: perilesional shows deposition of IgG
(100%), C3 (80%)
• Indirect IF
• ELISA: to identify anti-Dsg3,1
 PV
• Differential diagnosis:
• When skin is involved:
• Bullous impetigo, dyskeratotic acanthoytic disorders ( Hailey-
Hailey, Grover disease)
• When oral mucosa is involved:
• Denture intolerance
• Erosive candidiasis
• Chronic recurrent aphthae
• Erythema multiforme
• Erosive lichen planus
• Herpetic ginigivitis
 PV
• Therapy :
• 1- Systemic corticoisteroids
• The main cause of morbidity & mortality in patients
is CS side effects, have to combine with steroid-
sparing agent, check for osteoporosis and latent TB
• A- combination pulse therapy : prednisolone 1g +
cyclophosphamide 7.5-10 mg/kg every 3-4 weeks
• With cyclophosphamide in interval 1-2mg/kg daily.
 PV
• Prednisolone- azathioprine therapy
• Alternative immunosuppressive agents:
cyclosporine, mycophenolate mofetil,
chlorambucil
• Topical measures: local anesthetic gels
• Therapy resistant course: IVIG
 Pemphigus vegetans
• Unusual variant of PV with hyperkeratotic
verruciform reaction (vegetans)
• Clinical features :
• Originally typical PV, then development of
white macerated plaques in involved areas
• (pyodermite végétante) : limited to
intertriginous areas, starts as pustules that
evolve into vegetating lesions.
 Pemphigus vegetans
• Diagnostic approach : as for PV
• DDx: if mild and localized can be confused
with Hailey-Hailey
• Therapy : see PV
 Pemphigus Foliaceus
• Form of pemphigus with superficial blisters
caused by anti-Dsg1
• Pathogenesis:
• Anti-Dsg1, the main desmoglein on the upper
epidermis.
• More often drug induced than PV,usually
sulfhydryl groups : captopril, penicillamine,
peroxicam
• Maybe caused by sunburn or paraneoplastic sign
 PF
• Clinical features:
• Scalp, face, chest and back, can progress to involve large areas
with diffuse scale and erosions.
• Diagnostic approach:
• Clinical
• Biopsy ? Not helpful
• DIF: superficial deposition of IgG
• ELISA: reveals IgG antibodies against Dsg1
• Medication history
• Therapy: same approach as PV, but usually more responsive to
therapy. Dapsone maybe helpful
 Pemphigus eryhthematosus

• Uncommon feature of pemphigus foliaceus

with additional features of lupus
erythematosus.

• More likely to be triggered by sunlight or

medications than other forms of PF
 IgA Pemphigus
• Pustular acantholytic dermatosis with
intercellular IgA deposition in epidermis.
• Can be associated with gammopathy
• Clinical features:
• Subcorneal pustular dermatosis (Sneddon-
Wilkinson disease): broad, annular
erythematous patches with peripheral flaccid
pustules and central crusting, favours flexures
and trunk, never mouth, pruritic
 IgA Pemphigus
• Intradermal neutrophilic dermatosis (Huff
syndrome): clinically similar, sunflower lesions
• Diagnostic approach:
• DIF; showing IgA directed against
keratinocytes
• Therapy : most cases are responsive to
dapsone, if not , corticosteroids & other
immunosuppressive agents
 Paraneoplastic Pemphigus
• Most often associated with lymphoma,
leukemia, thymoma, Castleman tumor.
• Not with SCC or adenocarcinoms
• Clinical: severe persistent painful stomatitis
extending from lips to pharynx, larynx and
esophagus, conjunctival involvement may lead
to blindness.
• Cutaneous changes are polymorphic
 Paraneoplastic Pemphigus
• Note: if patient is sick and has lesions resembling
erythema multiforme, lichen planus and a
blistering disease , be highly suspicious of
paraneoplastic pemphigus.
• Histology is rarely helpful.
• Therapy : treat the underlying tumour , prognosis
correlates with the response
• No consensus on what immunosuppressive
regimen. Good success with ant-CD20 (rituximab)
 Pemphigoid Group
• Bullous pemphigoid (BP):
• Subepidermal blistering disease caused by
autoantibodies to components of
hemidesmosomes in the basement membrane
zone (BMZ).
• Most common autoiummune bullous disease,
1/100000, favours elderly male<female.
 BP
• Pathogenesis :
• Autoantibodies directed against 2
hemidesmosomal proteins:
• - BP 230
• - BP 180
• BP 180 is most likely to be more involved in
the initial immune response, since it is
transmembrane.
 BP
• Less common causes include drugs ( benzodiazepine,
furosemide, penicillin, sulfasalazine), sunlight, and
ionizing radiation.
• Clinical :
• before blisters develop, pruritus, urticarial lesions may be
present, blisters tend to develop in these areas.
• Note: always keep BP in mind when confronted with an
elderly patient with persistent « urticaria ».
• Blisters are stable and tense.
• Oral mucosal involvement in <20%.
 BP
• Histology :
• Prebullous lesions: presence of unexpected eosinophils is
a good clue.
• Later subepidermal blister formation.
• Diagnostic approach:
• Labs: elevated ESR, eosinophils, and increased IgE in 60%.
• DIF: best taken from erythematous area at periphery, not
blister itself; band of IgG & C3 along BMZ.
• Indirect IF: using NaCL split skin
• ELISA: identifies ab against both BP 230 & 180 in 60-80%
of pts.
 BP
• Therapy:
• Steroids ?
• Methotrexate 15-20 mg weekly
• Mostly widely used steroid-sparing agents,
azathiporine & mycophenolate mofetil.
 Cicatricial Pemphigoid

• Chronic subepidermal blistering disease

favoring mucus membrane especially
mouth and eyes.
• Patients > 65 years. Women > men
 Cicatricial Pemphigoid
• Clinical features:
• Conjunctiva affected in 75% of cases. Starts unilaterally
, within 2 years usually bilateral. Adhesions, ectropion,
corneal damage
• Oral mucosa: much less painful than PV.
• Esophagus and larynx can develop strictures, requiring
surgery.
• Genitalia: narrowing of vaginal orifice; adhesions
between glans & foreskin.
• Skin: only involved in 25%
 Cicatricial Pemphigoid
• Diagnostic approach :
• DIF
• Indirect IF
• Therapy:
• Ocular: topical or systemic corticosteroids, OPH
consultation
• Mucosal: topicals
• Widespread: Pred + azathoiprine or pred+
cyclophosphamide pulse therapy
• IVIG
 Pemohigoid Gestationis
• Synonym : herpes gestationis
• Form of BP occuring during pregnancy.
• Occur in 1/10000-40000 pregnancies.
• No maternal risk, no increase in birth defects but
complications of pregnancy in 15-30% with fetal death rate.

• Pathogenesis:
• mothers often HLA-88, -DR3, -DR4, father often HLA-DR2.
possible that mothers are sensitized against placental
antigens. Target antigens are BP 180
 Pemohigoid Gestationis
• Erythematous urticarial plaques, alone or with papules,
vesicles, blisters in sub-epidermal area, erosions.
• Intense pruritus.
• Sites: abdomen, proximal extremities.
• Rarely appears postpartum, resolve within 3 months.
Occasionally recur with menses or ingestion of OCP, tends
to be worse in next pregnancy.
• The ab cross the placenta, the newborn can have blisters for
a few weeks.
 Pemohigoid Gestationis
• Diagnostic approach: Labs : eosinophilia, DIF,
Indirect IF
• Management:
• Systemic Potent steroids: For blisters, avoid the systemic
in the 1st trimester (topicals)
• Skin care : to prevent infections
• Anti-histamines: For pruritis .
 Dermatitis Herpetiformis
• Pruritic vesicular disease caused by IgA ab
directed against epidermal transglutaminase
& presenting with granular pattern in papillary
dermis.
• M>F 1:2, disease of young adults.
• DH & gluten-sensitive enteropathy are closely
related (i.e. celiac disease).
 Dermatitis Herpetiformis
• Grouped papules/vesicles/urticarial wheals on
an erythematous base, associated with intense
pruritus, burning, stinging, excoriations.
• sites: extensor surfaces of elbows/knees,
sacrum, buttocks, scalp .
• Spontaneous remissions may occur, but
disease often lifelong.
 Dermatitis Herpetiformis
• Histology:
• Neutrophilic microabcesses in the papillary dermis are
the hallmark
• Approach:
• Skin biopsy
• DIF: granular deposits of IgA in dermal papillae
• Indirect IF:
• ELISA: identifies IgA ab against transglutaminase in at
least 80%
• Jejunal biopsy: flattening of villi
 Dermatitis Herpetiformis
• Therapy:
• Gluten free diet.
• Dapsone: amazingly effective
 Linear IgA disease
• Subepidermal blistering disease caused by deposits
of IgA along BMZ.
• Maybe identical to DH but without GI involvement ,
or resemble BP.
• Over 50% have mucosal involvement
• Approach:
• DIF
• OPH, and to exclude celiac (jejunal biopsy..)
• Therapy: CS, Dapsone
 Linear IgA disease
• Childhood type:
• Before 5 years of age and resolves
spontaneously
• Large tense blisters arranged in a rosette
fashion, predilection of abdomen, groin ,
axillae and face mucosal disease very common
90% approx. GI disease extremely rare.
 Linear IgA disease
• Diagnostic approach:
• DIF: IgA deposits
• IIF: IgA
• Therapy:
• Dapsone , sulfapyridine
• If CI or failure: CS
Summary
Summary
Summary
• Thank you !