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Severe Cutaneous Adverse Reactions to Drugs (SCAR):
Definitions, Diagnostic Criteria, Genetic Predisposition
Jean-Claude Roujeau1, 2 Laurence Allanore1, 2 Yvonne Liss2, 3 Maja Mockenhaupt2, 3
This paper is a review of the clinical characteristics, diagnostic criteria and main drug
causes of the severe cutaneous adverse reactions to drugs (SCAR) that are studied by the RegiSCAR-group. These include acute generalized exanthematous pustulosis, drug reaction with
eosinophilia and systemic symptoms (also called drug-induced hypersensitivity syndrome), Stevens-Johnson syndrome, and toxic epidermal necrolysis. (Dermatol Sinica 27: 203-209, 2009)
Key words: Adverse drug reactions, Drug hypersensitivity, Stevens-Johnson syndrome, Toxic epidermal necrolysis
Adverse drug reactions affecting the skin are frequent and present with a huge variety of
phenotypes. The two most frequent are alterations of skin functions related to pharmacologic effect of medication (e.g. altered pigmentation, acne, hair loss…) and on the other hand mild “drug
eruptions”. Severe forms are rare and account for less of 5% of drug eruptions observed in hospitalized patients.1 We proposed the denomination of severe cutaneous adverse reactions (SCAR)
for very rare disorders that share the following criteria: i) being severe (associated to a significant
morbidity and mortality and usually leading to hospitalization, ii) non-predictable (idiosyncratic,
and probably of immunological mechanism) and iii) most often induced by drugs.2
A multinational collaborative research team was established since 1988 to study SCAR.3
It initially associated mainly dermatologists and epidemiologists and progressively enlarged to
geneticists and immunologists. It changed its name from SCAR-group to EuroSCAR- and lately
RegiSCAR-group when enlarging the scope of diseases of interest and aggregating new participating teams. At present (Jan. 2009) the RegiSCAR-group is active in Austria, France, Germany,
Italy, Netherlands, South Africa, Taiwan, and the United Kingdom. It is operating as a registry
collecting detailed clinical data and biological samples on 3 varieties of SCAR, Stevens-Johnson
syndrome and toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), also called drug induced hypersensitivity syndrome (DIHS) and acute
generalized exanthematous pustulosis (AGEP).
From the Ile de France Reference Center for Toxic and Auto-Immune Blistering Diseases, Hôpital Henri Mondor et Université
Paris XII, Créteil, France1 and RegiSCAR-study group2 and Dokumentationszentrum schwerer Hautreaktionen (dZh) Department of
Dermatology, University Medical Center, Freiburg, Germany3
Corresponding author: Jean-Claude Roujeau, Department of Dermatology, Hôpital Henri Mondor, 94010 Créteil, France
E-mail: [email protected]
Funding source: none
Conflict of interest: none declared
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Severe Cutaneous Adverse Reactions to Drugs
ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS (AGEP)
AGEP was described in 1980 as a
widespread pustular eruption resembling
pustular psoriasis, but usually occurring as a
drug reaction in patients without a history of
psoriasis.4 Numerous, very small and mostly
non-follicular pustules arise on a widespread
edematous erythema. Pustules are mainly located in the main folds (neck, axillae, groin),
trunk, and upper extremities. Confluence of
pustules may result in superficial (subcorneal)
detachment, not rarely misdiagnosed clinically as TEN. Edema of the face, purpura,
vesicles, erythema multiforme-like lesions,
and mucous membrane involvement are oc-
Fig. 1
Close view of typical acute generalized exanthematous
pustulosis (AGEP): edematous erythema, confluent superficial pustules, and post-pustule desquamation.
Fig. 2
Typical clinical presentation of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
Dermatol Sinica, Dec 2009
casionally present. Proposed diagnosis criteria include: 1) an acute pustular eruption;
2) fever above 38°C; 3) neutrophilia with or
without a mild eosinophilia; 4) subcorneal
or intraepidermal pustules on skin biopsy; 5)
spontaneous resolution in less than 15 days.5
The time between the beginning of drug
administration and the skin eruption is relatively short (less than 2 days) for antibiotics,
whether a history of prior sensitization is
found or not. The eruption lasts a few days,
and is followed by a superficial desquamation. AGEP may be difficult to differentiate
from acute pustular psoriasis. The pustules in
both diseases are clinically indistinguishable;
the histopathology can be helpful (absence
of epidermal changes suggesting psoriasis,
edema in the upper dermis). Antibiotics (such
as aminopenicillins, pristinamycine) diltiazem, terbinafine, chloroquine/hydroxychloroquine, are the drugs most often implicated
in AGEP.6 Drug specific T-cells were found
within the skin lesions that produced neutrophil recruiting cytokines and chemokines.7
DRESS- DIHS- “HYPERSENSITIVITY
SYNDROME”The acronym of DRESS for Drug
Reaction with Eosinophilia and Systemic
Symptoms has been proposed as more specific than “hypersensitivity” which would apply to all types of “allergic” drug reactions.8
The name of DRESS points to 2 important
characteristics: multi-systemic involvement
and frequent eosinophilia. Dermatologists in
Japan prefer the acronym of DIHS for DrugInduced Hypersensitivity Syndrome.
Behind the different denominations
there is a consensus of all experts on the
originality and main characteristics of this
syndrome,9, 10 which include:
1. Drug-induced immunologic phenomenon
2. Later onset than for other drug reactions
3. Longer duration than common “drug rash204
Jean-Claude Roujeau, et al
Table. 1 The RegiSCAR-Group Diagnosis Score for Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS)
es”
4. Multi-organ involvement, often including
severe skin eruption
5. Lymphocyte activation (node enlargement,
lymphocytosis, atypical lymphocytes)
6. Eosinophilia
7. Frequent virus reactivation
Compared to other denominations,
DRESS captures a little more, but still not
all, of these salient features. DRESS has been
estimated to occur in about one in 10,000
exposures to drugs such as antiepileptics and
sulfonamides. In France these reactions were
considered more frequent among persons of
African ancestry. They begin 2 to 6 weeks
205
after the onset of drug intake and may persist for several weeks after drug withdrawal.
Some of the manifestations, especially hepatitis may be life-threatening, with a mortality
rate of about 10%. DRESS is typically characterized by a severe eruption, lymphadenopathy, fever and hematological abnormalities. Visceral involvement differentiates this
syndrome from common eruptions; it may
include hepatitis, arthritis, pulmonary infiltrates, interstitial nephritis, and other.
The RegiSCAR group has elaborated a
scoring system for the diagnosis of DRESS.10
This score presented in Table 1 is complicated but in our opinion has the advantage
of remaining open enough to allow future
Dermatol Sinica, Dec 2009
Severe Cutaneous Adverse Reactions to Drugs
answers to many pending questions. In major
published case series none of the 7 “main
characteristics” of DRESS/DIHS was constant.11, 12 The respective prevalence of lymphadenopathy, “atypical” or “activated” blood
lymphocytes, eosinophilia, proof of viral activation all varied between 40 and 70%. We
think, therefore, that it is unwise to consider
the absence of any of them as exclusion criteria.
Until the mechanisms of visceral involvement (including the skin) are better understood, we estimated that the decision that
an organ is involved by DRESS should rely
on 2 criteria: clinical relevance and absence
of other causes. As an example, liver is considered involved, if alanine aminotransferase
levels are at least twice above the upper
limit of normal values in the absence of another disease. The literature on drug-induced
hepatitis and nephritis includes cases that resemble DRESS but occasionally without an
eruption. The absence of skin lesions should,
therefore, not be an exclusion criterion.
Differential diagnoses of DRESS comprise acute viral infections, multisystemic inflammatory diseases such as systemic lupus
erythematosus, idiopathic hypereosinophilic
syndrome, and cutaneous T-cell lymphoma.
Skin pathology of DRESS is not yet fully
characterized. Several reports pointed to the
presence of a relatively dense perivascular
infiltrate of lymphocytes in the dermis and/or
lichenoid features in DRESS. Totally normal
or very slightly altered skin histology is still
compatible with a diagnosis of DRESS.
Several antiepileptic agents (phenobarbital, carbamazepine, phenytoin, lamotrigine), and allopurinol are the most frequent
causes of DRESS worldwide. Anti-infectious
sulfonamides, gold salts, dapsone may also
induce this syndrome as well as many other
drugs, varying with countries maybe on the
basis of ethnic background (e.g. minocycline
in French patients of African ancestry).
Dermatol Sinica, Dec 2009
A specificity of DRESS appears to be
virus activation. Several case reports and a
few well documented series have evidenced
markers of virus reactivation in many cases
of DRESS. Human herpes virus 6 (HHV6) is
the most frequently reactivated in Japan (62%
of cases based on serology, 30% with positive PCR on serum). Two other herpes viruses: cytomegalovirus (CMV) and EpsteinBarr virus (EBV) can also be reactivated as
12
well as HHV6. This reactivation is usually
detected in the 2 weeks following the onset
of the reaction and is related (and probably
contributes) to late and prolonged clinical
manifestation, such as fever, recurrent rash
hepatitis, and encephalitis.
The mechanisms of DRESS remain unknown. The original mixture of drug “allergy” (proven by accelerated onset in cases of
rechallenge, positive skin tests, and positive
in vitro tests) and virus activation has been
the source of many hypotheses, none being
proven up to now.
EPIDERMAL NECROLYSIS (SJS/TEN)
Based on the results of a large casecontrol study,13 we established that SJS and
TEN can be considered as severity variants
of a single disease, different from erythema
exsudativum multiforme majus (EEMM).
Actually, SJS/TEN and EEMM differ by
demographic characteristics of patients, associated diseases, severity, causality and
treatment. Some unifying denomination
could be helpful. Several were proposed:
acute disseminated epidermal necrolysis
(ADEN),14 acute syndrome of apoptotic panepidermolysis (ASAP),15 to which we could
add epithelial necrolysis. Waiting for a larger
agreement, the RegiSCAR-group stays with
SJS/TEN.
The main features of SJS/TEN are well
known by dermatologists: acute onset and
rapid progression of painful lesions of the
skin and mucous membranes that develop to
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Jean-Claude Roujeau, et al
blisters and erosions with severe constitutional symptoms and extensive detachment
of the epidermis. The mortality rate is 25%
during hospitalization for SJS/TEN, depending on age and the extent of skin detachment.
The majority of survivors suffer from sequelae that impair often seriously their quality of
life.
Extensive death and detachment of the
epidermis resulting from apoptosis of keratinocytes on the full or nearly full thickness of
the epidermis is characteristic. Direct immunofluorescence is negative. Differential diagnoses include rare cases of acute autoimmune
blistering disorders that may mimic SJS/
TEN, especially paraneoplastic pemphigus
and drug-induced linear IgA bullous disease.
Thermal or caustic burns are occasionally
diagnosed as TEN when history is unclear. In
very early stages SJS is often misdiagnosed
as chickenpox (varicella).
Medications are the main cause of SJS/
TEN.16 A drug causality can be established in
two third of cases.17 The remaining one third
of cases comprises a very small minority
(much less than 5%) of cases with another
cause (acute infection, especially with Mycoplasma pneumoniae). About thirty percent of
cases remain idiopathic.
Recent progresses were done on the
mechanisms of SJS/TEN. Drug specific cytotoxic T-cells are found at the site of the
lesions. 18 Widespread apoptosis seems to
results from the massive release of a variety
cytokines and especially granulysin.19 In our
experience, no specific treatment has been
proven to be effective. The best available
evidence has been provided by the EuroSCAR-cohort analysis.20 The results showed
no benefit from using intravenous immunoglobulin and a strong (but not significant)
potential reduction of mortality with the use
of corticosteroids. These results should lead
to further studies on the possible usefulness
of corticosteroids and immunosuppressive
207
agents.
ARE SUCH SUB-CLASSIFICATIONS
USEFUL?
Many dermatologists still feel uncomfortable with the above classifications because they often see patients with ambiguous
diagnosis. That is in large part dependant
on the need to get information on pathology
and on the course of the disease for a final
diagnosis. When using all our scoring systems simultaneously in a large population
of patients suspected of SCAR we obtained
several “possible” diagnoses in about 20%
of cases but in less than 2% at the level of
“probable/definite” diagnoses. These observations suggest that the use of our classifications is feasible. We also consider they are
useful because associated disorders are different, drug causes are not similar and effector mechanisms also differ.
ADVANCES ON PREDISPOSITION
GENES
Two papers from Taiwan found a 100%
association between SJS/TEN and HLA-B
for two high risk drugs: carbampazepine and
allopurinol.21, 22 These results strongly re-enforced the hypothesis of predisposing genes
in SJS and TEN and raised the hope that genetic testing could become an effective way
of prevention.
In Europe, among 12 cases related
to carbamazepine, four were positive for
B*1502, an allele so rare in Europe that the
association would be highly statistically significant. But all four positive patients were
from Asian ancestry, while none of 8 European patients had neither B*1502, nor any
other associated allele.23
On the other hand, among allopurinolrelated SJS/TEN-cases we observed the same
association with HLA-B*5801 as in patients
from Taiwan.24 The association was weaker
than in Taiwan anyhow (60% instead of
Dermatol Sinica, Dec 2009
Severe Cutaneous Adverse Reactions to Drugs
100%)
CONCLUSION
Tremendous advances were made in
the last 10 years on knowledge of SCAR.
Despite being rare SCAR deserve continuous
interest, not only for improving the safety
of medications but also because improved
knowledge on the mechanisms of lesions in
SCAR will apply to other fields of medicine.
Because of the extreme rarity of SCAR, international collaboration is critical to further
progress.
ACKNOWLEDGEMENT
This article was presented in part at the
34th Annual Meeting of the Taiwanese Dermatological Association, Taipei, November
2008.
REFERENCES
1. Hunziker T, Kunzi UP, Braunschweig S, et al.:
Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey.
Allergy 52: 388-393, 1997.
2. Roujeau JC, Stern RS: Severe adverse cutaneous
reactions to drugs. N Eng J Med 331: 1272-1285,
1994.
3. Kelly JP, Auquier A, Rzany B, et al.: An international collaborative case-control study of severe
cutaneous adverse reactions (SCAR). Design and
methods. J Clin Epidemiol 48: 1099-1108, 1995.
4. Beylot C, Bioulac P, Doutre MS: Pustulose exanthématique aigue généralisé e, 4 cas. Ann Dermatol Venereol 107: 37-48, 1980.
5. Sidoroff A, Halevy S, Bavinck JN, et al.: Acute
generalized exanthematous pustulosis (AGEP)--a
clinical reaction pattern. J Cutan Pathol 28: 113119, 2001.
6. Sidoroff A, Dunant A, Viboud C et al.: Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational casecontrol study (EuroSCAR). Br J Dermatol 157:
989-996, 2007.
7. Britschgi M, Steiner UC, Schmid S, et al.: T-cell
involvement in drug-induced acute generalized
exanthematous pustulosis. J Clin Invest 107:
1433-1441, 2001.
8. Bocquet H, Bagot M, Roujeau JC: Drug-induced
pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and SysDermatol Sinica, Dec 2009
temic Symptoms: DRESS). Semin Cutan Med
Surg 15: 250-257, 1996.
9. Shiohara T, Inaoka M, Kano Y: drug-induced
hypersensitivity syndrome (DIHS): a reaction
induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. Allergol Int 55: 1-8, 2006.
10.Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et
al.: Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J
Dermatol 156: 609-611, 2007.
11.Peyriere H, Dereure O, Breton H, et al.: Variability in the clinical pattern of cutaneous side
effects of drugs with systemic symptoms: does
a DRESS syndrome really exist? Br J Dermatol
155: 422-428, 2006.
12.Seishima M, Yamanaka S, Fujisawa T, et al.:
Reactivation of human herpesvirus (HHV) family members other than HHV-6 in drug-induced
hypersensitivity syndrome. Br J Dermatol 155:
344-349, 2006.
13.Auquier-Dunant A, Mockenhaupt M, Naldi L,
et al.: SCAR Study Group. Severe Cutaneous
Adverse Reactions. Correlations between clinical patterns and causes of erythema multiforme
majus, Stevens-Johnson syndrome, and toxic
epidermal necrolysis: results of an international
prospective study. Arch Dermatol 138: 10191024, 2002.
14.Ruiz-Maldonado R: Acute disseminated epidermal necrosis types 1, 2, and 3: study of sixty
cases. J Am Acad Dermatol 13: 623-635, 1985.
15.Ting W, Stone MS, Racila D, et al.: Toxic epidermal necrolysis-like acute cutaneous lupus
erythematosus and the spectrum of the acute syndrome of apoptotic pan-epidermolysis (ASAP):
a case report, concept review and proposal for
a new classification of lupus erythematosus vesiculobullous skin lesions. Lupus 13: 941-950,
2004.
16.Roujeau JC, Kelly JP, Naldi L, et al.: Medication
use and the risk of Stevens-Johnson syndrome or
toxic epidermal necrolysis. N Engl J Med 333:
1600-1607, 1995.
17.Mockenhaupt M, Viboud C, Dunant A, et al.:
Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks
with emphasis on recently marketed drugs. The
EuroSCAR-study. J Invest Dermatol 128: 35-44,
2008.
18.Nassif A, Bensussan A, Boumsell L, et al.: Toxic
epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol
114: 1209-1215, 2004.
19.Chung WH, Hung SI, Yang JY, et al.: Granulysin
208
Jean-Claude Roujeau, et al
is a key mediator for disseminated keratinocyte
death in Stevens-Johnson syndrome and toxic
epidermal necrolysis. Nat Med 14: 1343-1350,
2008.
20.Schneck J, Fagot JP, Sekula P, et al.: Effects of
treatments on the mortality of Stevens-Johnson
syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol
58: 33-40, 2008.
21.Chung WH, Hung SL, Hong HS, et al.: A marker
for Stevens-Johnson syndrome. Nature 428: 486,
2004.
209
22.Hung SL Chung WH, Liou LB, et al.: HLAB*58-
01 allele as a genetic marker for severe cutaneous
reactions caused by allopurinol. Proc Natl Acad
Sci USA 102: 4134, 2005.
23.Lonjou C, Thomas L, Borot N, et al.: RegiSCAR
Group. A marker for Stevens-Johnson syndrome
...: ethnicity matters. Pharmacogenomics J 6:
265-268, 2006.
24.Lonjou C, Borot N, Sekula P, et al.: RegiSCAR
study group. A European study of HLA-B in
Stevens-Johnson syndrome and toxic epidermal
necrolysis related to five high-risk drugs. Pharmacogenet Genomics 18: 99-107, 2008.
Dermatol Sinica, Dec 2009