Background Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a relatively rare but well known complication among patients under MTX treatment. Spontaneous regression of LPD after MTX withdrawal is regarded as a distinct character of MTX-LPD. Although detection of Epstein-Barr virus encoded small RNAs (EBER) in the pathological tissue is reported as a predictor of regression, although it is not necessarily specific 1).
Objectives To investigate the factors involved in spontaneous regression of LPD following MTX withdrawal.
Methods We retrospectively reviewed 43 rheumatoid arthritis (RA) patients complicated with MTX-LPD from January 2000 to October 2015 in our institution. Age, sex, RA duration matched 76 control MTX-treated patients were selected. MTX-LPD patients were divided into two groups regarding to the status of LPD after MTX cessation; regressive LPD (R group) and persistent LPD (P group), and clinical parameters were compared. Flowcytometric analysis of the whole blood was underwent in a part of the MTX-LPD patients (N=10, 7 regressive, and 3 persistent LPD) and controls (N=10). The time of MTX cessation (= time of LPD diagnosis) was defined as week 0, and whole blood sample was collected at week 0, 4 and 12. Epstein Barr Virus antigen specific CD8+ T cells (EBV specific CD8+) was defined as MHC/EBV peptide tetramer positive CD8+ T cells.
Results At the time of MTX cessation (week 0), number of peripheral lymphocytes was significantly decreased in LPD group, compared to control group. Among the LPD group, significant increase of lymphocyte number following MTX withdrawal was observed only in the R group, but not in P group while MTX dose, EBER positivity rate and pathological phenotypes did not show significant difference. Flowcytometric analysis revealed significant decrease in proportion of effector memory CD8+ T cells (EM CD8+), EBV specific CD8+ and T helpler 1 (Th1) subset in R group compared to control group. Following MTX cessation, significant increase in proportion of these subsets were observed only in the R group, but not in P group. On the other hand, proportion of CD14-CD15+ cells in lymphocyte fraction, which include myeloid derived suppressor cells 2) (MDSC) was significantly increased in LPD group at week 0, and significantly decreased following MTX cessation only in the R group, but not in P group. Proportion of CD14-CD15+ cells negatively and significantly correlated with the proportion of EM CD8+T cells.
Conclusions Our study suggested that decreased lymphocytes at the time of LPD diagnosis and restoration following MTX withdrawal are associated with pathogenesis and clinical course of “regressive” MTX-LPD. Proportion of Th1 cells, EM CD 8+, EBV specific CD8+ and CD14-CD15+ cells was restored following MTX cessation, indicating their involvement in regression of MTX-LPD.
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Disclosure of Interest S. Saito: None declared, K. Suzuki Grant/research support from: Eisai Co.,Ltd., Bristol–Myers K.K., K. Yamaoka Paid instructor for: Pfizer, Chugai Pharma, Mitsubishi-Tanabe Pharma, Takeda Industrial Pharma, GlaxoSmithKline, Nippon Shinyaku, Eli Lilly, Janssen Pharma, Eisai Pharma, Astellas Pharma and Actelion Pharmaceuticals, T. Shimizu: None declared, T. Mori Paid instructor for: Astellas Pharma,Chugai Pharma,Eisai Co.,Ltd.,Janssen Pharmaceutical K.K., S. Okamoto Grant/research support from: Astellas Pharma,Chugai Pharma,Eisai Co.,Ltd.,Bristol–Myers K.K., Takeda Pharmaceutical Co.,Pfizer, Paid instructor for: Astellas Pharma,Chugai Pharma,Eisai Co.,Ltd.,Bristol–Myers K.K.,Takeda Pharmaceutical Co., Pfizer, K. Amano: None declared, M. Tokuhira: None declared, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co.,Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Teijin Pharma Ltd., AbbVie GK, 2,Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Paid instructor for: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co.,Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Teijin Pharma Ltd., AbbVie GK, 2,Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K.,