Abstract
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA) and has various pharmacological modes of action. Among nodular manifestations in RA, studies have suggested roles for causative contributors to the underlying pathogenesis in MTX-related nodular diseases, however, the actual mechanisms are still unclear. Histopathological diversity exists in nodules in patients with RA because of rheumatoid disease activity, MTX-induced adverse effects, and in situ reactivated Epstein-Barr virus (EBV) which often occurs in MTX-associated lymphoproliferative disorders (LPDs).
We described 3 patients with RA, whose nodules were quite different among histopathological characteristics. Although susceptibility to MTX-related nodular lesions may be related to genetic factors, one possible mechanism for the disease pertains to an MTX-induced increase in adenosine release from infiltrating monocytes, and this secreted adenosine may enhance nodule formation via ligation of adenosine A1 receptors on macrophages in susceptible patients, suggesting the presence of different pathological mechanisms and MTX susceptibilities. Thus, patients with RA may have various types of nodules, including those of rheumatoid neutrophilic dermatitis, and other types containing rheumatoid nodules, which are the most common extra-articular rheumatoid manifestation, MTX-induced accelerated rheumatoid nodulosis, and also cases of EVB-associated lymphomatoid granulomatosis and MTX-LPD.
A variety of histopathological findings in nodules in patients with RA taking MTX correlate closely with rheumatoid activity, host immune function, and modes of MTX action. Therefore, rheumatologists should carefully review histological diversity of nodular lesions. Clinical awareness of the importance in morphological diversity of nodules and prudent decisions are critical to reach accurate diagnosis and achieve timely management of cases with nodular lesions that develop after the administration of MTX.
