Benefit-risk analysis of upadacitinib versus adalimumab in patients with rheumatoid arthritis and higher or lower risk of cardiovascular disease.

Objectives: Evaluate the risks and benefits of upadacitinib 15 mg vs adalimumab in rheumatoid arthritis (RA) patients with an inadequate response to methotrexate based on cardiovascular (CV) risk.

Methods: In SELECT-COMPARE, patients received upadacitinib 15 mg, placebo or adalimumab 40 mg every other week, with background methotrexate. This post hoc analysis assessed patients with lower (age <65 years; no CV risk factors) and higher CV risk (age ≥65 years and/or ≥1 CV risk factor). Safety and efficacy outcomes were compared between upadacitinib and adalimumab over the short term (~6 months) and long term (5 years) based on CV risk.

Results: The study included 211 lower-risk patients (upadacitinib, n=129; adalimumab, n=82) and 767 higher-risk patients (upadacitinib, n=522; adalimumab, n=245). Rates of malignancy excluding nonmelanoma skin cancer (NMSC), major adverse cardiovascular event and venous thromboembolism were comparable between upadacitinib and adalimumab in both risk groups but numerically higher in the higher-risk group. Upadacitinib showed higher rates of herpes zoster versus adalimumab in both risk groups and numerically higher rates of serious infection and NMSC in the higher-risk group. Upadacitinib demonstrated consistently better efficacy outcomes, including 28-joint Disease Activity Score (C reactive protein) <2.6, Clinical Disease Activity Index remission and Boolean remission at 6 months, which were generally maintained through 5 years.

Conclusions: Regardless of baseline CV risk, upadacitinib demonstrated comparable safety to adalimumab, except for higher rates of herpes zoster in both CV risk groups and NMSC and serious infections in the higher-risk group. Upadacitinib consistently showed better clinical and functional outcomes than adalimumab. The benefit-risk profile of upadacitinib in RA patients was favourable, independent of CV risk category, in both short and long term.