Are all JAK inhibitors for the treatment of rheumatoid arthritis equivalent? An adjusted indirect comparison of the efficacy of tofacitinib, baricitinib, upadacitinib, and filgotinib

Introduction: Comparisons of Janus kinase inhibitors (JAKi) for treatment of rheumatoid arthritis in patients with inadequate response to biologic disease-modifying anti-rheumatic drugs are lacking. We assessed the relative efficacy and safety of four JAKi (tofacitinib, baricitinib, upadacitinib, and filgotinib) in this context. Method: We performed an adjusted indirect comparison (IC) of randomized clinical trials using Bucher's method with an IC and mixed calculator. Endpoints were Disease Activity Score C-reactive protein (DAS28-CRP) and American College of Rheumatology-20 (ACR20). Equivalence was assessed using the equivalent therapeutic alternatives (ETA) guidelines. Results: We included four of 133 potentially relevant studies. IC showed no statistically significant differences between the four JAKi regarding DAS28-CRP < 3.2. Results were similar in terms of ACR20 except for tofacitinib showing lower efficacy than upadacitinib (RAR −18.4% [IC95% −33.4 to −3.5], p=0.0157). Statistically significant differences were related to the relevant difference for tofacitinib in both endpoints. Despite no statistical differences for baricitinib, we observed a probably clinically relevant difference regarding DAS28-CRP. Probably clinically relevant differences were found for tofacitinib vs. upadacitinib in both endpoints, and for baricitinib vs. upadacitinib in DAS28-CRP. Safety, drug-drug interactions, and convenience considerations did not modify the result of therapeutic equivalence assessment based on efficacy data. Conclusions: In conclusion, our results show that filgotinib and upadacitinib are ETA. Baricitinib and upadacitinib are also ETA due to a lack of clear differences and for showing superiority over placebo. The results for tofacitinib and upadacitinib show some inconsistency and more data are needed. Key Points • To date, neither a head-to-head comparison nor an indirect comparison between the Janus kinase inhibitors has been performed in patients with rheumatoid arthritis and an inadequate response to biologic disease-modifying anti-rheumatic drugs. • We performed an adjusted indirect comparison that included randomized clinical trials of tofacitinib, baricitinib, upadacitinib, and filgotinib to assess their equivalence in this scenario. • Our results show that baricitinib and filgotinib are equivalent therapeutic alternatives compared to upadacitinib. However, there is some inconsistency in the results of tofacitinib in front of upadacitinib.