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HLA-A*31:01 and methotrexate-induced interstitial lung disease in Japanese rheumatoid arthritis patients: a multidrug hypersensitivity marker?
  1. Hiroshi Furukawa1,
  2. Shomi Oka1,
  3. Kota Shimada2,3,
  4. Rheumatoid Arthritis-Interstitial Lung Disease Study Consortium,
  5. Naoyuki Tsuchiya4,
  6. Shigeto Tohma1
  1. 1Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan
  2. 2Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan
  3. 3Tokyo Metropolitan Tama Medical Center, Fuchu, Japan
  4. 4Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  1. Correspondence to Dr Hiroshi Furukawa, Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Kanagawa 252-0392, Japan; h-furukawa{at}sagamihara-hosp.gr.jp

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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.

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Table 1

HLA-A allele frequency in the RA patients

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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