The HLA-DRB1*0401 allele and the development of methotrexate-induced accelerated rheumatoid nodulosis: A follow-up study of 79 Caucasian patients with rheumatoid arthritis

In a retrospective study, HLA-DRB1, DQA1, and DQB1 alleles were ascertained in 79 Caucasian patients with rheumatoid arthritis (RA) to determine if methotrexate-induced accelerated rheumatoid nodulosis (MIARN) is related to HLA-class II gene status. These RA patients consisted of 21 patients who developed MIARN, 45 patients who received methotrexate (MTX) but did not develop MIARN, and 13 patients who never received MTX. Nodule formation induced by MTX was compared with that seen in RA and substantiated by 8 years of clinical follow-up (including 5 years after MIARN). When comparing RA patients with MIARN to those without MIARN, significant differences were noted in cumulative dose of MTX (844.3 ± 599.1 mg versus 2,121.7 ± 1,648.1 mg, p < 5.14 × 10^-6, respectively) but not in folic acid administration. Mean duration of MTX therapy was 36.4 ± 27.2 months before developing MIARN. Nodules regressed within 6.1 ± 4.5 months if MTX was discontinued but persisted for 41.2 ± 14.9 months if MTX was continued. Eighty-eight percent of MIARN occurred on the fingers (versus 34.1% in RA, p < 1.07 × 10^-4). The HLA-DRB1*0401 allele was seen in all 21 patients with MIARN (71.4% versus 17.8% in healthy controls, p < 1.57 × 10^-5). Eleven of the 45 patients without MIARN also had HLA-DRB1*0401. These 11 patients had been taking hydroxychloroquine for at least 2 years before initiating MTX or throughout MTX therapy to completion (p < 6.58 × 10^-4). When analyzing nodule formation specifically related to RA, rheumatoid nodules were noted in 61.9% of the MIARN patients (before MTX treatment) and in 57.8% of those without MIARN (p = NS). Seventy-six percent of rheumatoid nodules occurred over the olecranon (versus 30.0% in MIARN, p < 3.37 × 10^-4). Rheumatoid nodule formation was significantly associated with DR4-epi alleles when excluding DRB1*0401. Therefore, HLA typing may be a helpful marker in determining RA patients at risk for developing MIARN.