Background/Purpose: Patients with rheumatoid arthritis (RA) have a high risk of developing lymphoproliferative disorders (LPDs). LPDs that develop in patients treated with methotrexate (MTX) are known as MTX-associated LPDs (MTX-LPDs). We previously reported that MTX is an independent risk factor for LPD onset in Japanese patients with RA. The main characteristic of MTX-LPDs is that MTX withdrawal possibly results in spontaneous regression of the LPD. However, the predictive factors of spontaneous regression of MTX-LPDs remain unclear. Some reports have suggested that Epstein-Barr virus infection and increased peripheral lymphocytes after MTX discontinuation are related to spontaneous regression of MTX-LPDs. However, evidence of the relationships between these factors and spontaneous regression of MTX-LPDs is lacking. We investigated the predictive factors for spontaneous regression of MTX-LPDs in patients with RA.

Methods: We enrolled RA patients who developed MTX-LPDs in Kagawa Prefecture, Japan from June 2010 to March 2017. Patients were diagnosed according to the American College of Rheumatology 1987 classification criteria and treated with MTX. We divided the patients into those who were followed up after discontinuation of MTX alone (MTX withdrawal group) and those who underwent chemotherapy (CTx) ≥1 month after MTX discontinuation (CTx group). The following differences between the two groups were examined: 1) change in the peripheral lymphocyte count after MTX discontinuation, 2) subset of lymphocytes in a biopsy specimen from a lesion, and 3) histological findings of biopsied lesions using immunohistochemistry (IHC).

Results: We enrolled 45 patients with MTX-LPDs. The withdrawal group comprised 30 patients, and the CTx group comprised 15 patients. Between these two groups, 32 patients underwent analysis of the change in the peripheral lymphocyte count. Additionally, 22 patients (11 in the withdrawal group and 11 in the CTx group) underwent analysis of the subset of lymphocytes, and 12 (8 in the withdrawal group and 4 in the CTx group) underwent analysis of the IHC findings with a specimen from a lesion. In the withdrawal group, the peripheral lymphocyte count was significantly elevated after MTX discontinuation. With respect to the subset of lymphocytes and IHC findings, the number of CD8-positive lymphocytes increased by more in the CTx group than withdrawal group.

Conclusion: This study showed that the change in lymphocytes before and after MTX discontinuation and low levels of CD8-positive lymphocytes in biopsy lesions are associated with spontaneous regression of MTX-LPDs. We suggest that these factors may become predictive markers for MTX-LPD treatment strategies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd8-positive-lymphocytes-in-biopsy-specimens-predict-spontaneous-regression-of-lymphoproliferative-disorders-in-patients-with-rheumatoid-arthritis-treated-with-methotrexate/