Upadacitinib Versus Tofacitinib in Anti‐ MDA5 ‐Positive Dermatomyositis With Interstitial Lung Disease: A Multi‐Centre Cohort Study Emulating a Target Trial

ABSTRACT Background and Objective The treatment of anti‐melanoma differentiation‐associated gene 5 antibody‐positive dermatomyositis with interstitial lung disease (MDA5 + DM‐ILD) remains a significant clinical challenge. To compare the effectiveness and safety of upadacitinib (UPA) versus tofacitinib (TOFA) upon 6‐month lung transplantation‐free survival in newly diagnosed MDA5 + DM‐ILD patients. Methods This multi‐centre cohort study in China enrolled MDA5 + DM‐ILD patients treated from January 2020 to February 2025. Prevalent/incident new users and non‐inferior design along with inverse probability treatment weighting (IPTW) were implemented to emulate randomized controlled trial. Results In the eligible cohort, a total of 106 patients were treated with UPA and 328 with TOFA. The crude 6‐month lung transplantation‐free survival rates were 71.7% (76/106) in the UPA group and 67.4% (221/328) in the TOFA group. In the IPTW‐adjusted cohort, UPA showed a trend toward higher survival than TOFA ( p = 0.067), with a weighted risk difference of 10.3% (95% confidence interval −0.4% to 20.2%) meeting the non‐inferiority margin (non‐inferiority p = 0.003). Sensitivity and subgroup analyses showed consistent results, with potentially greater benefit of UPA in incident JAK inhibitor users (as first‐line treatment), monotherapy recipients (without combination with other immunosuppressants except steroid), and those with rapidly progressive ILD. Safety profiles were comparable between groups. Conclusion UPA was found to be non‐inferior to TOFA in improving 6‐month lung transplantation‐free survival among patients with MDA5 + DM‐ILD, with comparable safety.