Clin Rheumatol. 2026 Jul 31. doi: 10.1007/s10067-026-08325-2. Online ahead of print.
ABSTRACT
PURPOSE: The clinical benefit of combining leflunomide (LEF) with tumor necrosis factor inhibitors (TNFi) in psoriatic arthritis (PsA) remains uncertain. We aimed to evaluate the efficacy and treatment durability of LEF-TNFi compared with non-LEF regimens (predominantly methotrexate (MTX)-TNFi and TNFi monotherapy).
METHODS: This retrospective cohort included 492 biologic-naive PsA patients initiating TNFi (2003-2020): LEF-TNFi (n = 85) versus non-LEF (n = 407). Multiple imputation addressed missing data, and propensity score matching (7 covariates; caliper 0.2 standard deviations of the logit-propensity score) addressed confounding by indication. Longitudinal outcomes were analyzed using linear mixed-effects models; treatment modification was evaluated via Cox models. Reasons for treatment modification were examined descriptively using a competing risks framework.
RESULTS: Substantial baseline imbalances (23 of 36 variables with standardized mean difference > 0.10) were eliminated by propensity score matching (0 of 7 matching covariates with SMD > 0.10; 96.9% of LEF patients retained). Post-adjustment, longitudinal disease activity trajectories did not differ significantly between groups (time-by-treatment interactions: Disease Activity Score in 28 joints (DAS28), p = 0.862; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), p = 0.308). Overall treatment modification rates were similar (propensity score-matched hazard ratio (HR) = 1.16; 95% confidence interval (CI), 0.53-2.51; p = 0.709). Descriptively, LEF patients were more frequently subject to treatment modification for remission (10.6% vs. 5.9%) and less frequently for inefficacy (5.9% vs. 11.1%), although cause-specific hazard ratios did not reach statistical significance.
CONCLUSION: After propensity score adjustment, LEF-TNFi showed no detectable difference in disease activity trajectories or overall treatment persistence compared with MTX-TNFi and TNFi monotherapy. However, LEF-TNFi modifications were predominantly driven by achieved remission rather than inefficacy. Keypoints • Propensity score-adjusted analyses revealed no detectable difference in disease activity trajectories between the LEF-TNFi, MTX-TNFi, and TNFi monotherapy groups in psoriatic arthritis. • Competing risks analysis showed that LEF modifications were driven by remission rather than inefficacy, a clinical distinction obscured by standard composite endpoints. • These hypothesis-generating findings suggest that LEF may be a viable alternative to MTX as concomitant csDMARD therapy with TNFi in PsA.
PMID:42536327 | DOI:10.1007/s10067-026-08325-2
