Long-term effectiveness and safety of methotrexate-tacrolimus combination therapy versus methotrexate monotherapy in reducing rheumatoid arthritis flares after TNF inhibitor discontinuation: a retrospective cohort study.

Background: This study evaluates the long-term effectiveness and safety of methotrexate-tacrolimus combination therapy compared to methotrexate monotherapy in maintaining successful tumor necrosis factor (TNF) inhibitor discontinuation in rheumatoid arthritis (RA) patients.

Methods: We retrospectively analyzed consecutive RA patients who discontinued TNF inhibitors after achieving disease control by October 2022 and received either methotrexate monotherapy or methotrexate-tacrolimus combination therapy for up to 10 years. Per-observation time-to-event analyses assessed treatment failure, treatment intensification, first disease flare, and irreversible functional deterioration. Mixed-effects Cox models, time-dependent Cox models without random effects, and Kaplan-Meier estimates with inverse probability weighting were applied. Safety assessment included treatment-limiting adverse events and renal function trends.

Results: A total of 147 treatment lines (96 methotrexate monotherapy and 51 combination therapy) in 116 patients were analyzed. The combination therapy significantly reduced treatment failure (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.24-0.72), treatment intensification with the index drugs (HR, 0.38; 95% CI, 0.22-0.67) and with biologics or Janus kinase inhibitors (HR, 0.39; 95% CI, 0.22-0.71), and first flare (HR, 0.55; 95%CI 0.36-0.84), with consistent findings across models. The benefit was most pronounced in patients with prior flares during methotrexate monotherapy after TNF inhibitor discontinuation, with HRs as low as 0.04-0.12 across outcomes. No significant differences in treatment-limiting adverse events were observed. The annual increase in serum creatinine for tacrolimus users was 0.0032 mg/dL, suggesting minimal long-term renal impact.

Conclusions: Methotrexate-tacrolimus combination therapy significantly reduces relapse risk following TNF inhibitor discontinuation without compromising safety, offering a potentially sustainable treatment alternative after achieving remission with TNF inhibitor therapy.