Personalized Medicine for HLA-associated Drug-hypersensitivity Reactions

Mandvi Bharadwaj; Patricia Illing; Lyudmila Kostenko

Disclosures

Personalized Medicine. 2010;7(5):495-516. 

In This Article

Feprazone-induced Fixed-drug Eruptions & HLA-B22

Fixed-drug eruptions (FDE) are cutaneous reactions that recur in the same region of the skin on repeat challenge with the causative stimuli.[55] Lesions are well defined and are thought to be of immune etiology owing to the presence of intraepidermal T lymphocytes, predominantly of the CD8+ phenotype, that are activated to express cytotoxic granules.[56] Genetic studies were initiated in individuals suffering from FDE induced by the NSAID feprazone® owing to the observation of familial cases. It was found that 93% of patients suffering from feprazone–FDE in a Scandinavian population possessed HLA-B22 whilst no patients suffering FDE associated with other drugs were HLA-B22 positive. HLA-B22 was present in 4% of healthy controls.[57]

The apparent involvement of CD8+ T cells in FDE supports the theory that HLA-B22 is a risk factor due to a mechanistic role in the disease, and HLA-B22 is further implicated as the causative antigen (rather than being in LD with the causative antigen) by the observation of differing HLA-B22 haplotypes in individuals with feprazone–FDE.[57] However, although HLA-B22 shows high prevalence in feprazone–FDE compared with the wider Scandinavian population, there are several issues that still need to be resolved before consideration of HLA screening as a pharmacogenetic test. First, although HLA-B22 was not present in FDE induced by other drugs, this study does not include a feprazone-tolerant cohort, as such no comment can be made on the specificity of HLA-B22 testing for feprazone–FDE, and thus, there is no indication of whether screening could inappropriately exclude candidates from drug use. Second, study of this association should be extended to other ethnicities to determine the scope of screening. Such studies may also clarify whether HLA-B22 or another antigen in LD with HLA-B22 in the Scandinavian population is involved in the reaction. Finally, the fact that 7% of Scandinavian patients with feprazone-FDE did not possess HLA-B22, suggests either that first, these were false-positive diagnoses of feprazone–FDE, as in early cases of AHS and HLA-B*5701, second, a mechanistically involved risk factor is in LD with HLA-B22 in this population or third, other factors may cause feprazone-FDE in the absence of HLA-B22. So whilst HLA-B22 may be considered a risk factor for feprazone–FDE and could potentially serve as a diagnostic marker in the Scandinavian population, we suggest that further population studies are necessary before it can be assessed as a criterion for drug preclusion.

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