Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta-analysis

Abstract

Background: Despite many studies suggesting an association between human leukocyte antigen (HLA)-B*5801 and allopurinol-induced toxic epidermal necrolysis (TEN) and Stevens-Johnsons syndrome (SJS), the evidence of association in different populations and the degree of association remain uncertain.

Methods: The primary analysis was based on population-control studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, positive likelihood ratios (LR+), negative likelihood ratios (LR-), diagnostic odds ratios (DOR), and areas under summary receiver operating characteristic (SROC) curves (AUC) were calculated.

Results: In nine population-control studies, HLA-B*5801 was measured in 162 patients with allopurinol-induced TEN/SJS and 7372 patients without allopurinol-induced TEN/SJS. The pooled sensitivity, specificity, LR+, LR-, DOR and AUC were 0.78 (95% CI = 0.71-0.85), 0.96 (95% CI = 0.96-0.97), 14.23 (95% CI = 7.89-25.63), 0.29 (95% CI = 0.16-0.54), 83.5 (95% CI = 50.7-137.4), and 0.97 (95% CI = 0.95-0.99), respectively. Subgroup analyses of the DORs for Chinese, Japanese, and Caucasian populations yielded similar findings for Chinese (196.1; 95% CI = 57.3-672.0), Japanese (78.8; 95% CI = 30.4-203.9), and Caucasian (58.4; 95% CI = 16.9-201.5) populations. Overall, HLA-B*5801 was associated with allopurinol-induced TEN/SJS in European and Japanese populations, but only had a 50-60% sensitivity (pooled sensitivity 56%), compared to the 80-100% sensitivity (pooled sensitivity 97%) observed in Korean, Thai, Sardinia Italian and Han Chinese populations.

Conclusions: The present study reveals that allopurinol is the leading cause of TEN/SJS in many countries. In contrast to carbamazepine, which is ethnic/population specific, the HLA-B*5801 for detecting allopurinol-induced TEN/SJS is universal. Screening of HLA-B*5801 may help patients to prevent the occurrence of allopurinol-induced TEN/SJS, especially in populations with a higher (≥ 5%) risk allele frequency.

Keywords: HLA-B*5801; allopurinol; gout; hypersensitivity; meta-analysis; screening.