Background/Purpose:  Lympho-proliferative disorder (LPD) developing under methotrexate (MTX) administration is a relatively rare but well known complication among rheumatoid arthritis (RA) patients. Spontaneous regression of LPD following MTX withdrawal is a singular aspect of LPD developing during MTX treatment with an incidence of 30-60%. The purpose of this study was to investigate the factors involved in spontaneous regression of LPD following MTX withdrawal.

Methods:  This was a multi center retrospective observational study. Medical chart from January 1995 to October 2015 was reviewed. Age, sex, MTX dose, and RA duration matched control patients treated with MTX for more than 6 months were randomly selected. The time of MTX cessation (equally to LPD diagnosis) was defined as week 0, and blood sample was collected at week 0, 4 and 12 for flowcytometry when it was available (7 regressive, 3 persistent, 10 controls). LPD patients were divided into regressive group or persistent group depending on the status of LPD at week 12. Epstein Barr Virus (EBV) antigen specific CD8+ T cells was detected with MHC/EBV peptide tetramer.

Results:  Forty-three RA patients complicated with LPD were identified and 76 control patients were selected. Among the 43 LPD patients, 28 were regressive and 15 were persistent. At week 0, the absolute number of peripheral lymphocytes was specifically and significantly decreased in LPD group, compared to control group. Flowcytometric analysis revealed significant decrease in absolute count of CD4+, CD8+ T cells, B cells and NK cells but not in proportion of these cell subsets. However, further subset analysis revealed that the proportion of effector memory CD8+ T cells (EM CD8+), EBV specific CD8+ and T helpler 1 (Th1) subset was specifically decreased in regressive group compared to control group. Following MTX withdrawal, a significant increase of these T cell subsets in addition to total lymphocytes was observed at week 4 and 12, only with the regressive group, but not with persistent group. Pathological category of LPD did not relate to change in lymphocytes.

Conclusion:  Our study suggested that decreased lymphocytes at the time of LPD diagnosis and restoration following MTX withdrawal may associate with pathogenesis and clinical course of regressive LPD. Proportion of Th1 cells, EM CD8+, EBV specific CD8+ was restored following MTX cessation, indicating their involvement in regression of LPD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/restoration-of-decreased-lymphocyte-counts-and-the-shift-to-th1-and-effector-memory-cd8t-cell-subsets-associate-with-spontaneous-regression-of-lympho-proliferative-disorders-developed-in-ra-patients/