DRESS Prevention: Will Genetic Testing Become a Standard?
Thursday, April 03, 2014
DRESS was proposed as an acronym for 'drug reaction (or rash)
with eosinophilia and systemic symptoms' to provide a clearer
definition to an uncommon and serious pattern of 'drug allergy'
previously reported as 'drug hypersensitivity'.1
DRESS is considered a part of SCARs (severe cutaneous adverse
reactions), but the mortality rate of DRESS (<10%)2
is much lower than the 30% observed in epidermal necrolysis
(Stevens Johnson Syndrome [SJS]and Toxic Epidermal Necrolysis
[TEN]).3 Cases of DRESS have been attributed to dozens
of different medications,4 but more than two-thirds of
cases are related to a few 'strongly associated' drugs, such as
carbamazepine, allopurinol, lamotrigine, phenytoin, sulfasalazine
The main characteristics of DRESS
- Later onset than other mild or severe drug
- Eruption often involving more than 50% of body surface
- Association of facial edema, purpura, ilchenoid
- Involvement of internal organs (hepatitis, nephritis,
- Lymph node enlargement
- Blood count alterations: Eosinophilia, neutrophilia,
'atypical' activated lymphocytes
- Frequent reactivation of latent viral infection (human
herpes virus 6, Epstein-Barr virus, cytomegalovirus,
Since none of the above is constant, the diagnosis is
facilitated by a scoring system such as that proposed by the
Associations of SCARs to human leukocyte antigens
A few publications have suggested that severe hypersensitivity
reactions might be genetically determined, with rare occurrence of
familial cases.6 In the last decade, successive reports
of very strong associations of HLA B*57:01 with 'hypersensitivity'
to abacavir,7 of HLA-B*15:02 with carbamazepine-related
epidermal necrolysis in Taiwan,7,8 and of HLA-B*58:01
with allopurinol-related epidermal necrolysis and
DRESS,9 also in Taiwan, renewed the interest in studying
the pharmacogenetics of severe drug reactions.
The results of the largest genetic study in patients with SJS or
TEN (RegiSCAR genome wide association study) were rather
disappointing.10 This study confirmed a strong
association between the disease and the HLA region on chromosome 6,
without any other region suspected in the genome. Most of the links
observed with the HLA region was explained by allopurinol-related
The same team had previously shown that, in Europe,
carbamazepine-related cases were neither associated with B*15:02,
nor with any other single HLA allele.11 Concerning
allopurinol, the association with B*58:01 reported in Taiwan was
also true in Europe, but concerned 60% of patients instead of 100%
in Taiwan.12 For other high-risk drugs, a few alleles
were significantly associated, but the prevalence among cases was
too low to expect a possible predictive test.
Comparing RegiSCAR results with those from Taiwan uncovered some
interesting conclusions. In Taiwan, where the prevalence of
HLA-B*15:02 is high (8%), carbamazepine is the leading cause of SJS
and TEN, whereas it is only the third or fourth leading cause of
SJS in Europe, where the prevalence of B*15:02 is much lower
(<0.1%). This suggests that if B*15:02 is definitely a strong
(likely to be the strongest) genetic risk factor for SJS/TEN, then
it is not the only one. Others may include a variety of other HLA
More recently, a high frequency of HLA-B*58:01 was reported in
Portuguese patients with allopurinol-induced DRESS13 and
a significant association between HLA-A*31:01 and
carbamazepine-induced DRESS was found both in European and Han
Significant associations with HLA alleles were also reported
concerning 'hypersensitivity reactions' to several other drugs in
various countries. These reactions were not always described and
some of them would probably not fulfill the diagnosis criteria for
DRESS. The inducing drugs included nevirapine (HLA-DRB1*01:01 in
France,15 HLA-B*35:05 in Thailand16),
lamotrigine (borderline association with HLA-B*58:01 in
Europe,17 significant association with B*15:02 in Han
Chinese18), anti-tuberculosis drugs (HLA-Cw*04:01) in
Korea,19 and dapsone (HLA-B*13:01) in
Table 1. HLA associations and severe cutaneous adverse
Prevalence in cases (%)
Established† or probable‡ value of testing
for prevention in relevant population.
DRESS=drug reaction (or rash) with eosinophilia and systemic
symptoms; HLA=human leukocyte antigen; SJS=Stevens-Johnson
syndrome; TEN=toxic epidermal necrolysis.
Theoretical implications of the HLA
Intense and innovative research has produced fascinating results
on the pathomechanisms of the HLA associations observed with severe
reactions. For carbamazepine21 and for
abacavir,22 as already suggested years ago for
penicillin23 and anticipated by the
'pharmaco-immunological' concept,24 it was demonstrated
that the drug established direct links with the relevant HLA
molecule. These non-covalent links with specific amino-acids
occurred within the antigen-presenting site, but without needing
any intermediate peptide, in contrast with common antigens. Recent
publications demonstrated that the non-covalent link of abacavir to
B*57:01 modifies the repertoire of oligopeptides that can be
presented by the HLA molecule (Figure 1) and 'bypasses' the
tolerance induced by thymic depletion.22,25,26 The
recognition of the HLA molecule as 'altered self', may explain the
severity of the reactions and the frequent associations of DRESS
and other severe hypersensitivity reactions to auto-immune
The above findings demonstrated that the HLA molecule is not
only a marker but is directly implicated in the reaction. This
strongly suggests that in populations where HLA-B*58:01 or B*15:02
are not, or only partially associated, other HLA molecules have
probably the same capacity of linking the drug in a way resulting
in 'altered self' reactivity. The fact that no single alternative
allele was detected in European patients suggests that in this
population several different alleles are probably able to link to
carbamazepine or allopurinol.
Figure 1. Schematic representation of differences in HLA
presentation for 'usual' antigen and some
drugs. Left: Usual immune response to foreign
antigen. Right: Direct link of medication (e.g. abacavir) to HLA
altering the repertoire of associated peptides (altered-self
Practical implications of HLA associations
Up to now, pharmacogenetics resulted in only two, but very
important, clinical applications: severe reactions to abacavir in
Caucasian populations and carbamazepine-related SJS/TEN in Taiwan
were virtually eradicated by testing for the relevant HLA allele
Such advances were possible in these specific groups due to very
strong associations (about 100% in both examples), reactions that
were less rare (about 5% for abacavir 'hypersensitivity', 0.25% for
carbamazepine-related SJS/TEN in Taiwan)29 and a
relatively high prevalence of the relevant allele (8% for
HLA-B*15:02 in Taiwan, 5.6% for HLA-B*57:01 in the abacavir
hypersensitivity prevention trial).
Testing for HLA-B*57:01 before prescribing abacavir in Caucasian
patients is now widely done. Testing for HLA-B*15:02 before
prescribing carbamazepine should be routine clinical practice in Western countries for
patients from South-East Asia origin (as recommended by the
FDA in the USA and by the EMA in Europe).
Such recommendations should incorporate the observation that
patients harboring HLA- B*15:02 also have an increased risk of
severe reaction to oxcarbazepine, phenytoin and to a lesser degree,
to lamotrigine.18,30 These anticonvulsants should be
avoided as an alternative choice.
Testing for HLA-B*58:01 before prescribing allopurinol may be
cost-effective in Asia. It is already recommended by some Taiwanese
teams, but there is not yet a consensus on that
All other associations reported to date, even if statistically
strong, cannot lead to practical recommendations because of poor
positive predictive values.
Even with 'strongly associated' medications such as
carbamazepine or allopurinol, SCARs are actually very rare.
Incidences are in the range of 1/10,000 to 1/1000 for
DRESS.14 In European populations, the prevalence of
HLA-A*31:01 is about 4%14 and that of HLA-B*58:01 is
about 1%.12 This means testing for HLA-A*31:01 before
prescribing carbamazepine in Europe would have a positive
predictive value for the occurrence of DRESS of 0.9%. The number of
patients to test to prevent a single case of DRESS was estimated to
be 3300 in Europeans and 5000 in Chinese.14
In Europe, the positive predictive value of HLA-B*58:01 for the
occurrence of DRESS in relation to allopurinol would be less than
1%. For weaker associations, the potential use as a predictive test
would have an even lower positive predictive value.
Whilst waiting for further progress, which may come more slowly
than hoped 10 years ago, prescribers should keep in mind less
expensive ways than pharmacogenetics to prevent DRESS and other
life-threatening reactions. For example, allopurinol, the most
frequent cause of SCARs in Europe, is often prescribed for
non-validated indications and initiated at high doses, when slow
increase in doses are recommended.32 Better usage could
decrease substantially the number of reactions related to this
- Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and
drug hypersensitivity syndrome (Drug Rash with Eosinophilia and
Systemic Symptoms: DRESS). Semin Cutan Med Surg
- Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS): an
original multisystem adverse drug reaction. Results from the
prospective RegiSCAR study. Br J Dermatol
- Sekula P, Dunant A, Mockenhaupt M, et al; RegiSCAR
study group. Comprehensive survival analysis of a cohort of
patients with Stevens-Johnson syndrome and toxic epidermal
necrolysis. J Invest Dermatol 2013;133:1197-1204.
- Cacoub P, Musette P, Descamps V, et al. The DRESS
syndrome: a literature review. Am J Med
- 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 2007;156:609-611.
- Johnson-Reagan L, Bahna SL. Severe drug rashes in three
siblings simultaneously. Allergy 2003;58:445-447.
- Mallal S, Nolan D, Witt C, et al. Association between
presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity
to HIV1 reverse-transcriptase inhibitor abacavir. Lancet
- Chung WH, Hung SI, Hong HS, et al. A marker for
Stevens-Johnson syndrome. Nature 2004;248:486.
- Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele
as a genetic marker for severe cutaneous adverse reactions caused
by allopurinol. Proc Natl Acad Sci USA
- Genin E, Schumacher M, Roujeau JC, et al. Genome-wide
association study of Stevens-Johnson syndrome and toxic epidermal
necrolysis in Europe. Orphanet J Rare Dis 2011;6:52.
- Lonjou C, Thomas L, Borot N, et al. A marker for
Stevens-Johnson syndrome ...: ethnicity matters.
Pharmacogenomics J 2006;6:265-268
- 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 2008;18:99-107.
- Gonçalo M, Coutinho I, Teixeira V, et al. HLA-B*58:01
is a risk factor for allopurinol-induced DRESS and Stevens-Johnson
syndrome/toxic epidermal necrolysis in a Portuguese population.
Br J Dermatol 2013;169:660-665.
- Genin E, Chen DP, Hung SI, et al. HLA-A*31:01 and
different types of carbamazepine-induced severe cutaneous adverse
reactions: an international study and meta-analysis.
Pharmacogenomics J 2013 Dec 10. [Epub ahead of
- Vitezica ZG, Milpied B, Lonjou C, et al. HLA-DRB1*01
associated with cutaneous hypersensitivity induced by nevirapine
and efavirenz. AIDS 2008;22:540-541.
- Chantarangsu S, Mushiroda T, Mahasirimongkol S, et al.
HLA-B*3505 allele is a strong predictor for nevirapine-induced skin
adverse drug reactions in HIV-infected Thai patients.
Pharmacogenet Genomics 2009;19:139-146.
- Kazeem GR, Cox C, Aponte J, et al. High-resolution HLA
genotyping and severe cutaneous adverse reactions in
lamotrigine-treated patients. Pharmacogenet Genomics
- Hung SI, Chung WH, Liu ZS, et al. Common risk allele
in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and
toxic epidermal necrolysis in Han Chinese.
- Kim SH, Lee SK, Kim SH, et al. Antituberculosis
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- Zhang FR, Liu H, Irwanto A, et al. HLA-B*13:01 and the
dapsone hypersensitivity syndrome. N Engl J Med
- Wei CY, Chung WH, Huang HW, et al. Direct interaction
between HLA-B and carbamazepine activates T cells in patients with
Stevens-Johnson syndrome. J Allergy Clin Immunol
- Illing PT, Vivian JP, Dudek NL, et al. Immune
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- Claas FH, Runia-van Nieuwkoop R, van den Berge W, van Rood JJ.
Interaction of penicillin with HLA-A and -B antigens. Hum
- Pichler WJ. Delayed drug hypersensitivity reactions. Ann
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- Ostrov DA, Grant BJ, Pompeu YA, et al. Drug
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- Norcross MA, Luo S, Lu L, et al. Abacavir induces
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- Mockenhaupt M, Viboud C, Dunant A, et al.
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- Mallal S, Phillips E, Carosi G, et al. HLA-B*5701
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- Chen P, Lin JJ, Lu CS, et al. Taiwan SJS Consortium.
Carbamazepine-induced toxic effects and HLA-B*1502 screening in
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- Cheung YK, Cheng SH, Chan EJ, et al. HLA-B alleles
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- Yeo SI. HLA-B*5801: utility and cost-effectiveness in the
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- Halevy S, Ghislain PD, Mockenhaupt M, et al; EuroSCAR
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- Lee HY, Ariyasinghe JT, Thirumoorthy T. Allopurinol
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