Background Methotrexate (MTX) is used as an anchor drug for the treatment of rheumatoid arthritis (RA). Patients with RA have a modestly increased risk of developing lymphoproliferative disorders (LPD). Furthermore, although sometimes spontaneous regression occurs after withdrawal of MTX, LPD developed during the treatment with MTX is broadly defined as MTX-associated LPD (MTX-LPD).
Objectives To characterize the risk factors concerning MTX-LPD and to consider optimal treatment after occurrence of LPD in patients with RA.
Methods We retrospectively evaluated 51 RA patients with LPD from 2006 to 2015 in our institution. MTX-LPD patients were divided into two groups; regressive LPD after MTX cessation (N=27) and persistent LPD though MTX was tapered (N=24), and the clinical characteristics, pathology and treatment outcomes were compared. EBV infection and IL-6 receptor (IL-6R) expression were analyzed by in situ hybridization and immunohistochemistry.
Results There was no significant difference in disease duration, stage, disease activity of RA, the positive rate of Epstein–Barr virus-encoded small RNAs, EBERs (42.7 vs 50.0%) and treatment with TNF-inhibitors (40.7 vs 45.8%) between regressive LPD and persistent LPD. Age of LPD onset (59.1 vs 68.3), CRP (2 vs 5 mg/dl) and the weekly MTX dose (10.9 vs 8.4 mg/w) significantly differed between the groups. Of note, IL-6R was highly expressed in both group (75.0 vs 66.7%). Among regressive LPD, 3 patients developed DLBCL later. persistent LPD showed poorer prognosis and worse mortality than regressive LPD. An older age and anemia were poor prognostic factors. Of 51 patients, 41% achieved sustained low disease activity (LDA) with other DMARDs except MTX. Nine of 10 patients refractory to DMARDs were controlled by tocilizumab (TCZ) and kept LDA.
Conclusions Taken together, it seems unreasonable to be lump the persistent-group into the same category as MTX-LPD. The high expression rate of IL-6R and the high responsiveness to TCZ suggest that IL-6/IL-6R is likely to play a role in the development of LPD in patients with RA.
Disclosure of Interest K. Nakano: None declared, A. Nawata: None declared, S. Nakayamada: None declared, S. Iwata: None declared, K. Hanami: None declared, S. Kubo Speakers bureau: Bristol-Myers, I. Miyagawa: None declared, M. Yoshikawa: None declared, K. Saito: None declared, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, Eisai, Consultant for: Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Teijin, Asahi-kasei, YL Biologics, Sanofi, Janssen, Eli Lilly, GlaxoSmithKline, Speakers bureau: Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Teijin, Asahi-kasei, YL Biologics, Sanofi, Janssen, Eli Lilly, GlaxoSmithKline
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