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.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> 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. </entry> </row> </tbody> </tgroup> </Table>

Efficacy and safety of leflunomide with tumor necrosis factor inhibitors in psoriatic arthritis: a retrospective analysis

期刊论文
发表日期：

2026年7月31日

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İbrahim Yahya Çakır,
Emre Bilgin,
Büşra Firlatan-Yazgan,
Mustafa Ekici,
Gözde Sevgi Kart Bayram,
Erdinç Ünaldı,
Gül Sandal Uzun,
Gizem Ayan,
Zehra Özsoy,
Levent Kılıç,
Ömer Karadağ,
Ali Akdoğan,
Şule Apraş Bilgen,
Ali İhsan Ertenli,
Umut Kalyoncu,
Sedat Kiraz

摘要

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.