Comparison of Drug Retention of TNF Inhibitors, Other Biologics and JAK Inhibitors in RA Patients who Discontinued JAK Inhibitor Therapy

Andrea Amstad; Eleftherios Papagiannoulis; Almut Scherer; Andrea Rubbert-Roth; Axel Finckh; Ruediger Mueller; Jean Dudler; Burkhard Möller; Peter M. Villiger; Martin M. P. Schulz; Diego Kyburz


Rheumatology. 2023;62(1):89-97. 

In This Article

Abstract and Introduction


Objectives: JAK Inhibitors (JAKi) are recommended DMARDs for patients with moderate-to-severe RA who failed first-line therapy with methotrexate. There is a lack of data allowing an evidence-based choice of subsequent DMARD therapy for patients who had discontinued JAKi treatment. We aimed to compare the effectiveness of TNF inhibitor (TNFi) therapy vs JAKi vs other mode of action (OMA) biologic DMARD (bDMARD) in RA patients who were previously treated with a JAKi.

Methods: RA patients who discontinued JAKi treatment within the Swiss RA registry SCQM were included for this observational prospective cohort study. The primary outcome was drug retention for either TNFi, OMA bDMARD or JAKi. The hazard ratio for treatment discontinuation was calculated adjusting for potential confounders. A descriptive analysis of the reasons for discontinuation was performed.

Results: Four hundred treatment courses of JAKi were included, with a subsequent switch to either JAKi, TNFi or OMA bDMARD. The crude overall drug retention was higher in patients switching to another JAKi as compared with TNFi and comparable to OMA. A significant difference of JAKi vs TNFi persisted after adjusting for potential confounders.

Conclusion: In a real-world population of RA patients who discontinued treatment with a JAKi, switching to another JAKi resulted in a higher drug retention than switching to a TNFi. A switch to a second JAKi seems an effective therapeutic option.


In recent years, a new class of small molecular DMARD targeting intracellular signalling molecules was approved for use in RA. These targeted synthetic DMARDs (tsDMARD) include inhibitors of Janus kinases (JAKi). In 2013 the first JAKi tofacitinib was licensed in Switzerland for RA treatment, followed 2017 by baricitinib and most recently upadacitinib in 2020. In consideration of the comparable efficacy of JAK inhibitors with biologic DMARDs (bDMARDs) licensed for use in RA in randomized controlled trials, the revised EULAR recommendations of 2019 suggest TNFi and JAKi as an equal second line therapy for patients with moderate-to-severe RA refractory to methotrexate.[1]

The efficacy of JAKi in patients with an inadequate response (IR) to methotrexate[2–4] as well as after TNF failure has been shown in phase III randomized clinical trials.[5–8] In contrast, there is a lack of data on the efficacy of TNFi, JAKi or biologics with other mode of action (OMA) in patients who have discontinued JAKi treatment.

In the SELECT-COMPARE study, RA patients were randomized to treatment with either upadacitinib or adalimumab or placebo. In a treat-to-target study design the protocol allowed an immediate switch to the alternate active treatment as a rescue in case of non-response or incomplete response until week 26. The analysis of the patients who switched from upadacitinib to adalimumab or vice versa showed improvement in both switch groups with only 5% of patients who worsened at six months post switch, suggesting that TNFi therapy after previous JAKi is an effective therapeutic option. However, the study was not powered for a direct comparison of the two populations of patients.[9]

The aim of our study was to compare the real-world effectiveness of treatment with TNFi or another JAKi or an OMA bDMARD in RA patients after the discontinuation of JAKi treatment.