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Methotrexate-induced interstitial lung disease (MI-ILD) can occur in rheumatoid arthritis (RA) patients.1 It is believed that Japanese RA patients are more susceptible to MI-ILD than other ethnic groups,2 ,3 suggesting that genetic factors are involved in the pathogenesis of MI-ILD. To date, biomarkers to predict development of MI-ILD in RA have not been established. A striking association between human leukocyte antigen (HLA) class I and cutaneous adverse reactions has been reported for several drugs.4–6 Here, we investigated HLA class I associations with MI-ILD in Japanese RA patients.
A case-control association study was performed on 55 Japanese RA patients (mean age ± SD: 69.3±8.5 years; 15 men, mean dose of methotrexate±SD: 6.7±2.6 mg/week; mean duration of methotrexate treatment±SD: 3.0±4.4 years) with episodes of MI-ILD, and 709 control Japanese RA patients (63.6±11.5 years; 146 men) without any episodes of MI-ILD, based on the genotyping data obtained with WAKFlow HLA typing kits (Wakunaga, Hiroshima, Japan). A significant association was found for HLA-A*31:01 (p = 8.06×10−5, corrected p [Pc]=1.93×10−3, OR 2.97, 95% CI 1.80 to 4.88, table 1). The A19 serological group (A*29–*33, and *74 alleles) was also significantly associated with increased risk of MI-ILD (p = 6.47×10−5, OR 2.59, 95% CI 1.67 to 4.01, table 1). None of the other HLA-B or C alleles was associated with MI-ILD.
Several studies have shown that HLA class I polymorphism contributes to its susceptibility to cutaneous adverse drug reactions.4–9 In these reports, each drug was associated with specific HLA class I alleles; thus, HLA-A*31:01 and B*15:02 were associated with carbamazepine, B*58:01 with allopurinol, and B*57:01 with abacavir. Our findings suggest that A*31:01 might be a multidrug hypersensitivity risk marker, and might imply presence of common pathogenic mechanisms …
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