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

Abstract

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.

Keywords: Biological therapy; Clinical remission; Recurrence; Rheumatoid arthritis; Withdrawing treatment.

Fig. 1

Longitudinal Trend of Post-TNF Inhibitor Maintenance Treatment Lines: Mono vs. Combination Therapy. Each square matrix is vertically arranged in chronological order of maintenance therapy lines after tumor necrosis factor (TNF) inhibitor discontinuation and horizontally by individual maintenance therapy regimen, with color coding. Blue is methotrexate monotherapy; orange is methotrexate and tacrolimus combination therapy. The numbers of TNF inhibitor discontinuations per subsequent maintenance therapy regimen in the square matrices and those of subsequent relapses requiring resumption of biological disease-modifying antirheumatic drugs (bDMARD) or Janus kinase inhibitors (JAKi) in the black parallelograms are displayed

Fig. 2

Impact of Combi Treatment Relative to Mono Treatment on Outcome Events. Hazard ratios for each outcome event in the Combi group relative to the Mono group according to the univariable and multivariable mixed-effects Cox proportional hazards model using all treatment lines (Mono 96, Combi 51). The multivariate results include hazard ratios calculated from the model with the lowest Bayesian Information Criterion (BIC) and no missing values, with treatment failure as the dependent variable. Additionally, pooled hazard ratios are shown by combining results from all models. Abbreviations: CI, confidence interval; DAS28, Disease Activity Score in 28 Joints; HAQ-DI, Health Assessment Questionnaire-Disability Index; JAKi, Janus kinase inhibitors; TNF, tumor necrosis factor

Fig. 3

Kaplan-Meier Curves Comparing Clinical Outcomes After TNF Inhibitor Discontinuation: Mono vs. Combi Groups. Unadjusted and IPW-adjusted Kaplan-Meier curves comparing the probability of remaining free from clinical events after TNF inhibitor discontinuation, using each patient’s earliest observation in the Mono (n = 91) and Combi (n = 44) groups. The estimated 2-year event-free probabilities in the Combi versus Mono groups were as follows: Treatment failure: 0.75 (95% CI, 0.59–0.85) vs. 0.52 (0.41–0.62) (unadjusted), 0.75 (0.56–0.86) vs. 0.51 (0.40–0.61) (IPW-adjusted). Treatment intensification with index drugs: 0.77 (0.62–0.87) vs. 0.54 (0.43–0.63) (unadjusted), 0.77 (0.58–0.88) vs. 0.52 (0.41–0.62) (IPW-adjusted). Treatment intensification with bDMARDs or JAK inhibitors: 0.82 (0.67–0.90) vs. 0.63 (0.52–0.72) (unadjusted), 0.85 (0.72–0.93) vs. 0.62 (0.50–0.71) (IPW-adjusted). First disease flare: 0.59 (0.43–0.72) vs. 0.40 (0.30–0.50) (unadjusted), 0.61 (0.43–0.75) vs. 0.40 (0.29–0.50) (IPW-adjusted). Irreversible HAQ-DI worsening: 0.95 (0.80–0.99) vs. 0.90 (0.80–0.95) (unadjusted), 0.91 (0.67–0.98) vs. 0.90 (0.80–0.95) (IPW-adjusted). Tick marks indicate censored observations. P-values were calculated using the log-rank test or IPW-adjusted log-rank test. See Supplementary Data for details on statistical methods

Fig. 4

Kaplan-Meier Curves for Treatment Outcomes Stratified by Timing of Tacrolimus Introduction After TNF Inhibitor Discontinuation. Kaplan-Meier curves comparing the time to clinical outcomes between the initial Combi group (n = 25), the subsequent Combi group (n = 19), and the Mono group (n = 91). The initial Combi group consisted of maintenance treatment episodes with methotrexate-tacrolimus combination therapy initiated after the first TNF inhibitor discontinuation, while the subsequent Combi group received combination therapy after the second or subsequent TNF inhibitor discontinuations. Tick marks indicate censored data. P-values were calculated using the log-rank test, and pairwise comparisons between the groups were performed using the Bonferroni method to adjust for multiple comparisons. Refer to the legend of Fig. 2 for abbreviations

Fig. 5

Comparison of Mono and Combi Maintenance Therapy Outcomes: Within-Patient Paired Analysis. Kaplan-Meier curves comparing the probability of not experiencing clinical outcomes during methotrexate monotherapy and methotrexate-tacrolimus combination therapy. Data from 19 patients with multiple TNF inhibitor discontinuations at different times are included, with each patient receiving either methotrexate monotherapy or methotrexate-tacrolimus combination therapy following each discontinuation. The analysis is based on within-patient comparisons across different treatment periods. Tick marks indicate censored data. The p-values were obtained using the log-rank test. Refer to the legend of Fig. 2 for abbreviations

Fig. 6

The dose and percent change of methotrexate during the treatment failure-free period after TNF inhibitor discontinuation. Methotrexate dose and mean percent change during the treatment failure-free period post-TNF inhibitor discontinuation for the Mono (left bar and blue-filled square) and Combi (right bar and orange-filled circle) groups are shown. Error bars indicate standard error. Methotrexate doses decreased over time in both groups, with a significantly higher proportion of patients receiving 6 mg/week or less in the combi group (p = 0.01 by the Fisher exact test). Missing methotrexate doses due to censoring or treatment-failure events were imputed by the last observation carried forward method. P-values in Fig. 3B for the interaction effect of adding tacrolimus on the change in methotrexate dose over time were estimated by a mixed-effects model adjusted for gender, baseline age, and methotrexate dose

Fig. 7

Serum creatinine levels over time, stratified by tacrolimus use. These scatter plots depict serum creatinine values over time for all participants stratified by tacrolimus use. For this analysis, the observations where tacrolimus had been used consecutively were consolidated: 44 lines with tacrolimus treatment (median observation period: 8.6 years; interquartile range: 5.6–10.4; 1,847 data points) and 91 lines without prior and current tacrolimus treatment (7.5; 4.8–10.3; 3,985) were compared. The baseline for the tacrolimus-treated or non-tacrolimus-treated groups was determined using the earliest time points measured immediately around the start of tacrolimus or TNF inhibitor treatment, respectively