Lymphoproliferative Disorders in Patients with Rheumatoid Arthritis in the Era of Widespread Use of Methotrexate: A Review of the Literature and Current Perspective

Lymphoproliferative disorders (LPD) in patients receiving methotrexate (MTX) have gained strong attention. In this article, I reviewed the basic and clinical findings of this issue. Patients with RA possess a high risk of lymphoma, but epidemiological evidence showing an association between the use of MTX and lymphoma is still limited. Rapid regression of LPD after stopping MTX in patients with RA strongly suggests that there is a causative relationship. Genetic predisposition, accumulated inflammation, impaired generation of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes, effects of MTX on the regulation of EBV genes, and low hypermethylation of apoptosis-related genes are relevant to the development of LPD and rapid regression after cessation of MTX. The clinical and histological characteristics of LPD in RA patients who are treated with MTX have been established, and recent data indicate that initial cessation of MTX and watchful waiting to observe an increase in peripheral lymphocyte counts have a therapeutic value. In advanced cases, various chemotherapy regimens are used, and consultation with hematologists is recommended to select the optimal treatment. There is no consensus on the treatment of RA after development of LPD, and long-term observation is necessary to investigate the safety of disease-modifying antirheumatic drugs in these patients.