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Research Updates

Jean-Claude Roujeau, MD

DRESS Prevention: Will Genetic Testing Become a Standard?

Jean-Claude Roujeau

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 and vancomycin.2

The main characteristics of DRESS are:1,2,4

  • Later onset than other mild or severe drug eruptions
  • Eruption often involving more than 50% of body surface area
  • Association of facial edema, purpura, ilchenoid infiltration, desquamation
  • Involvement of internal organs (hepatitis, nephritis, pneumonitis etc.)
  • 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, etc.)

Since none of the above is constant, the diagnosis is facilitated by a scoring system such as that proposed by the Regiscar group.5

Associations of SCARs to human leukocyte antigens (HLAs)

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 cases.

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 alleles.

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 Chinese patients.14

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 China.20

 

Table 1. HLA associations and severe cutaneous adverse reactions

Medication

Reaction

Population

HLA

Prevalence in cases (%)

Abacavir

'Hypersensitivity'

Caucasian

B*57:01

≈100%

Allopurinol

SJS/TEN

Taiwan

Europe

B*58:01

B*58:01

≈100%

≈60%

DRESS

Taiwan

Portugal

B*58:01

B*58:01

≈100%

≈60%

Carbamazepine

SJS/TEN

South-East Asia

Europe

B*15:02

None established

≈100%

DRESS

Taiwan

Europe

A*31:01

A*31:01

≈50%

≈70%

Dapsone

'Hypersensitivity'

China

B*13:01

≈85%

Lamotrigine

SJS/TEN

Taiwan

B*15:02

≈30%

Nevirapine

'Hypersensitivity'

France

Thailand

DRB1*01:01

B*35:05

≈50%

≈20%

Phenytoin

SJS/TEN

South-East Asia

B*15:02

30-50%

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 associations

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 diseases.2,27

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 hypothesis).21,24,25

Figure 1 T-cell receptor

 

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 before prescription.28,29

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 point.31

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 medication.33

References

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