Background: Disease-modifying antirheumatic drugs (DMARDs) have been the main agents for treating rheumatoid arthritis (RA) unless there are serious clinical restrictions or contraindications such as comorbidities. With inefficacy of conventional synthetic DMARDs (e.g., methotrexate), biological DMARDs (bDMARDs) are now available to suppress progression of joint destruction. However, bDMARDs cannot control disease activity in some patients, so JAK inhibitors targeting different cytokines are expected to be beneficial.

Objectives: This study investigated factors associated with the efficacy and continuation of JAK inhibitor therapy in patients with refractory RA for whom disease activity was not adequately controlled even with multiple sequentially administered bDMARDs with different targets.

Methods: We obtained the number of bDMARDs used and the various reasons for discontinuing therapy in our hospital from January 2005 to December 2019. Kaplan–Meier analysis was used to obtain the therapy continuation rate, and the log-rank test was used to examine the difference in therapy continuation rate. Refractory RA was defined as RA with inefficacy with 3 or more bDMARDs with different targets (1 or more tumor necrosis factor inhibitor, a selective costimulation modulator abatacept, and an interleukin 6 receptor inhibitor tocilizumab). We then examined patients with refractory RA who had received tofacitinib (TOF) or baricitinib (BAR) therapy after discontinuation of a series of bDMARDs due to unsatisfactory response. Various statistical tests were performed to identify predictors of ≥ 6-month continuation of JAK inhibitor therapy that achieves low disease activity without increases in prednisolone (PSL) use. Explanatory variables included characteristics of patients at initiation of TOF or BAR therapy: age, sex, disease duration, number of bDMARDs previously used, concomitant methotrexate dose, concomitant PSL dose, DAS28-ESR value, presence of rheumatoid factor or anti-CCP antibodies, and MMP-3 level.

Results: A cumulative number of 782 bDMARDs were administered to 362 RA patients by December 2019. The most common reason for discontinuation was inefficacy (51.8%), followed by adverse events including deaths (30.1%), patients’ circumstances such as hospital transfer (9.2%), switch to biosimilars (5.2%), and remission (3.7%). The bDMARDs continuation rate and the number of bDMARDs used were 69.6% and 2.17 for 5 years and 53% and 2.83 for 10 years, respectively, if the switch was considered to be continuous due to insufficient effect. The 6-month continuation rates were not significantly different between TOF and BAR (60 patients [62.3%] vs. 39 patients [81.3%], respectively; P = 0.147). In patients with refractory RA, continuation rates were not significantly different between TOF and BAR (19 patients [42.1%] vs. 11 patients [54.5%], respectively; P = 0.86). Only TOF-treated patients, not BAR-treated patients, showed significant differences in disease duration (226.1 months in the continued group vs. 111.8 months in the discontinued group; P = 0.035) and concomitant PSL dose (0.71 mg vs. 4.0 mg, respectively, P = 0.045).

Conclusion: There are not a few patients with refractory rheumatoid arthritis. These findings, albeit retrospective, suggest that low concomitant PSL dose and long disease duration at the time of TOF therapy initiation were factors for TOF continuation. Therapy continuation rate was decreased in patients with refractory RA, and further study on switching therapy between different JAK inhibitors is anticipated.

REFERENCES:

[1]Souto A, Maneiro JR & Gomez-Reino JJ. Rate of diccontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care database. Rheumatology (Oxford), 55, 523-534, 2016

Disclosure of Interests: None declared