The pathogenesis of lymphoma in patients with RA treated with methotrexate may be similar to patients receiving cyclosporine after organ transplantation. In the latter situation, emergence of a lymphoproliferative disorder is associated with an Epstein-Barr virus infection and completely regresses when immunosuppressive therapy is reduced or stopped.28–
Most lymphomas have a B-cell phenotype with either serologic evidence of active Epstein-Barr virus infection or detection of Epstein-Barr virus-specific nucleic acid sequences in biopsy specimens.29–
This process has led to the hypothesis that Epstein-Barr virus induces B lymphoproliferation with an initial reversible polyclonal stage. Although there is no consensus, this observation would suggest that the increased risk of acquiring a lymphoproliferative disorder is linked to the interplay between Epstein-Barr virus infection, immunosuppression, and an autoimmune disease, such as RA. Kamel et al30
showed that Epstein-Barr virus-associated lymphoproliferative disorder represents only a small fraction of all non-Hodgkin lymphoma in the general RA patient population. Based on this study, there was no significant difference identified between non-Hodgkin lymphoma in the RA case group and the control group without RA with respect to any variables. The test for Epstein-Barr virus was positive in only 2% of cases and 2% of control groups.30
Nevertheless, it should be noted that only 3 of the 42 patients in the case group received methotrexate. Thus, the role of methotrexate in developing lymphoproliferative disorder in patients with RA and with Epstein-Barr virus infection cannot be totally disregarded. A large case-control study to prove the association between lymphoma, methotrexate, RA, and Epstein-Barr virus infection is still needed to answer this question.