Clinics in Dermatology (2015) 33, 538–541

Systemic drug reactions with skin involvement:

Stevens-Johnson syndrome, toxic epidermal
necrolysis, and DRESS
Razvigor Darlenski, MD, PhD a,⁎, Jana Kazandjieva, MD, PhD b ,
Nikolai Tsankov, MD, PhD a
a
Department of Dermatology and Venereology, Tokuda Hospital-Sofia, 51 B Nikola Vaptsarov blvd, Sofia 1407, Bulgaria
b
Department of Dermatology and Venereology, Medical Faculty, Medical University-Sofia, 1 Saint Georgi Sofiiski Street,
1433 Sofia, Bulgaria

Abstract Skin is often affected in adverse drug reactions. Although the majority of cutaneous adverse
drug reactions are benign and self-limiting, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis
(TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), affecting multiple organs and
systems, are potentially fatal. Many organs can be affected, including the mucosal membranes,
gastrointestinal tract, liver, lungs, kidneys, and eyes. We discuss the causes, pathophysiologic aspects,
and main clinical features of SJS, TEN, and DRESS as systemic diseases with skin involvement.
© 2015 Elsevier Inc. All rights reserved.

Introduction ADRs, such as Stevens-Johnson syndrome (SJS), toxic

epidermal necrolysis (TEN), and drug rash with eosinophilia
Humans are exposed to a great variety of medications and systemic symptoms (DRESS), affect multiple organs and
throughout their lifetimes. Currently, we are witnessing the systems and could have potentially fatal outcomes.3,4 The
rapid and very dynamic growth of new drug development mortality rate ranges between 1% and 5% for SJS, 10% to
with the introduction of biologic therapies and targeted 20% for DRESS, and reaches 25% to 35% for TEN.5,6
anticancer treatments. Together with the advances of
innovative therapeutic approaches, physicians and patients
face a plethora of adverse drug events. Dermatologists are
“privileged” in registering adverse drug reactions (ADRs)
SJS, TEN
because almost one third of all ADRs affect the skin.1
Whereas cutaneous ADRs represent about 5% of an Historical perspective
ambulatory dermatology practice, such unwanted events
American pediatricians Albert Mason Stevens
affect hospitalized patients with an incidence ranging from
(1884-1945) and Frank Chambliss Johnson (1894-1934)
one in 1000 to two in 100.2 Although the majority of
first described two patients with SJS having skin and
cutaneous ADRs have a benign, self-limiting course, some
mucosal lesions in 1922.7 In 1956, Alan Lyell (1917-2007)
⁎ Corresponding author. Tel.: +359 890545599. reported four cases with diffuse skin loss and coined the term
E-mail address: [email protected] (R. Darlenski). TEN.7 Earlier reports from Ernst Fuchs (1819-1892) and

http://dx.doi.org/10.1016/j.clindermatol.2015.05.005
0738-081X/© 2015 Elsevier Inc. All rights reserved.
Systemic drug reactions with skin involvement 539

Table 1 Clinical characteristics of severe cutaneous ADR

Disease SJS SJS/TEN overlap TEN DRESS
Disease onset Several days to 3 weeks Several days to 3 weeks Several days to 3 weeks 3-8 weeks
(time after drug
introduction
Skin changes Dusky erythema and Dusky erythema and Dusky erythema, Generalized maculopapular
pseudo-target lesions pseudo-target lesions pseudo-targets, erosions, rash, facial edema,
(b 10% of total skin surface) (11%-29% of total skin and bullae epidermal exfoliation, bullae
Mucosal erosions surface) detachment (N 30% of total
Mucosal erosions skin surface; positive
Nikolsky sign)
Severe mucosal
involvement
Systemic Often: Fever, malaise, Often: Fever, malaise, Always: Fever, tracheitis, Fever, lymphadenopathy,
involvement arthralgia, laryngitis arthralgia, laryngitis malaise, arthralgia, hepatitis, interstitial
pharyngitis, urethritis, pharyngitis, urethritis, bronchitis, pulmonitis, eye nephritis and pneumonia,
proctitis, tracheobronchitis, proctitis, tracheobronchitis, involvement myositis, carditis,
tubular nephritis tubular nephritis (conjunctivitis, keratitis, pancreatitis, encephalitis,
ulcerations, scaring, meningitis, colitis,
ectropion and entropion, thyroiditis
symblepharon),
gastrointestinal bleeding,
esophagitis and strictures
Laboratory Untypical: Elevated Untypical: Elevated Negative prognostic factors: Eosionphilia, leukocytosis
findings C-reactive protein and C-reactive protein and Neutropenia and with atypical lymphocytes,
erythrocyte sedimentation erythrocyte sedimentation lymphopenia elevated transaminases,
rate; elevated transaminases rate; elevated transaminases Elevated erythrocyte positive human herpesvirus
sedimentation rate; 6 serology
hypoproteinemia,
hypoalbuminemia
ADR, adverse drug reaction; DRESS, drug rash with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Louis-Anne-Jean Brocq (1856-1928) could also be attributed

to the same spectrum of disease.
Today SJS, TEN, and the SJS/TEN overlap are considered
a continuum in the spectrum of the same disease (ie, severe
epidermolytic ADR) and should not be confused with
erythema multiforme minor, which is classically a reaction
in the course of herpetic infection rather than an ADR.

Pathophisiology with systemic involvement

Genetic predisposition is a key factor in the development of
SJS/TEN. Human leukocyte antigen B (HLA-B) is responsible
for presenting the drug (antigen) to the immune system and thus
triggering the cytotoxic cascade and apoptosis. This is mediated
by a variety of cytokines, including tumor necrosis factor α as
well as other mediators (eg, granzyme B and perforins).8 The
result is necrosis of the epidermis. HLA*B1502 has been
associated with carbamazepine and HLA*B5801 in allopur-
inol-induced reactions in Han Chinese, in contrast to Cauca-
sians, in whom such correlation could not be found.9,10 Slow
acetylators and human immunodeficiency virus–infected pa-
tients, as well as people receiving anticonvulsant treatment, are
at greater risk for developing SJS/TEN.5 Other factors, including
infections and malignant comorbidities, have been blamed for
Fig. 1 Generalized maculopapular eruption. causing SJS but are beyond the scope of this review.
540 R. Darlenski et al.

position has been found, as in the case of abacavir-induced

DRESS and HLA-B*5701 allele in certain ethnic groups.12
The most commonly involved drugs in DRESS are
aromatic antiepileptic medications (carbamzepine, pheny-
tion, phenobarbital, lamotrigine), sulfones, sulfonamides,
allopurinol, minocyline, azothioprine, and terbinafine.

Clinical features

Clinical manifestations develop 3 to 8 weeks after

exposure to the culprit drug. Table 1 illustrates the distinctive
features of SJS/TEN and DRESS. A report describes three
cases of DRESS with skin manifestations identical to TEN.17
This corroborates the controversies regarding the classifica-
tion of DRESS and SJS/TEN and the criteria for the
separation of these entities.18

Our patient
Fig. 2 Positive reaction to olanzapine (10% in petrolatum and 10%
in distilled water) on day 7 of patch testing with the patient’s drugs.
A 48-year-old white man developed generalized exan-
thema 2 weeks after starting several psychotropic drugs for a
The most common drugs associated with drug allergies major depressive episode, including olanzapine, biperiden,
are antimicrobials and antiepileptic drugs.11 Others include mirtazapine, venlafaxine, lithium carbonate, and sodium
allopurinol, valproates, nonsteroidal anti-inflammatory valproate. Curiously, the patient had a similar reaction
drugs, antimycotics (fluconazole, nystatin), antivirals, and several months prior, when these agents were initiated.
isotretinoin.5,11–13 On admission to the hospital, the patient was febrile and
had lymph node enlargement in the inguinal and axillar
Clinical features regions. The exanthema was disseminated on his face, trunk,
and extremities and included coalescent macules and papules
The disease spectrum can be defined according to the (Figure 1). Laboratory investigation revealed increased liver
extent of skin lesions, with lesions covering less than 10% of transaminases, leukocytosis, eosinophilia, and elevated
the body in SJS, 11% to 29% in SJS/TEN overlap, and more C-reactive protein.
than 30% in TEN.13 Table 1 summarizes the clinical features All psychotropic medications were stopped. Systemic
of the three disease subgroups. steroid therapy with methylprednisolone at an initial does of
40 mg/day was introduced, together with hepatoprotective
treatment. The patient experienced almost complete resolu-
Drug rash with eosinophilia and systemic tion of skin changes in 14 days, and liver enzymes returned
symptoms (DRESS) to normal by 30 days. Six weeks later, patch testing was
performed with all suspected drugs, placed in petrolatum and
Historical perspective distilled water (10%). Readings at days 2, 3, and 7 revealed
positive reactions to olanzapine (Figure 2). To confirm that
Several terms have been used for DRESS, including an- olanzapine patch testing did not create a false positive
ticonvulsant hypersensitivity syndrome, drug hypersensitiv- reaction, patches were applied to five normal participants;
ity syndrome, and drug-induced hypersensitivity syndrome. none reacted to olanzapine.
Bocquet coined the term DRESS in 1996.14 The syndrome is
defined by the clinical triad of fever, skin rash, and internal
organ involvement, representing a life-threatening condition. Conclusions

Pathophysiology Skin is affected in SJS/TEN and DRESS, as well as

multiple internal organs and mucosal membranes (oral,
Slow acetylation and defects in the enzymes responsible genital, ocular). Drugs may interact with the immune system
for drug metabolism, such as arene oxydase for anticonvul- and, together with genetic factors, affect the whole organism,
sants, have been linked to the development of DRESS.15 In although the skin may be the first and the most commonly
certain subgroups, reactivation of human herpesvirus 6 has affected organ. We can accept SJS/TEN and DRESS as
occurred in patients with DRESS.16 Finally, genetic predis- classic examples of multiorgan, systemic diseases.
Systemic drug reactions with skin involvement 541

10. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for
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