After JAK inhibitor failure: to cycle or to switch, that is the question - data from the JAK-pot collaboration of registries.

The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase inhibitors (JAKi) with switching to biologic disease-modifying antirheumatic drug (bDMARD) in patients with RA after failure to the first JAKi. This is a nested cohort study within data pooled from an international collaboration of 17 national registries (JAK-pot collaboration). Data from patients with RA with JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD were prospectively collected. Differences in drug retention rates after second treatment initiation were assessed by log-rank test and Cox regression analysis adjusting for potential confounders. Change in Clinical Disease Activity Index (CDAI) over time was estimated using a linear regression model, adjusting for confounders. 365 cycling and 1635 switching patients were studied. Cyclers were older and received a higher number of previous bDMARDs. Both strategies showed similar observed retention rates after 2 years of follow-up. However, adjusted analysis revealed that cycling was associated with higher retention (p=0.04). Among cyclers, when the first JAKi was discontinued due to an adverse event (AE), it was more likely that the second JAKi would also be stopped due to an AE. Improvement in CDAI over time was similar in both strategies. After failing the first JAKi, cycling JAKi and switching to a bDMARD appear to have similar effectiveness. Caution is advised if an AE was the reason to stop the first JAKi.

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Competing interests: MP-S reports personal fees from Janssen, Merck Sharp & Dohme, Novartis and Sanofi Genzyme, outside the submitted work. CS-P has nothing to disclose. JG-R has been a consultant on advisory boards of AbbVie, Bristol Myers Squibb, Hospira, Janssen, Merck Sharp & Dohme, Pfizer, Regeneron, Roche and Sanofi Genzyme, and has received research grants from Pfizer and Roche. KL reports personal fees from Viatris, Pfizer, Celltrion and Gilead/Galapagos, outside the submitted work. DM has nothing to disclose. FI has received speaker and/or consultancy fees from AbbVie, Galapagos, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche and UCB. KP has received fees for lectures and consultations from AbbVie, Pfizer, Merck Sharp & Dohme, UCB, Eli Lilly, SOBI, Roche, Sanofi Genzyme, Celltrion, Viatris and Novartis. DCN reports speaker and consultancy fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer and UCB. NI reports grants from Roche and Pfizer, and personal fees from AbbVie, Roche, Pfizer, UCB, Novartis, Amgen, Eli Lilly and Merck Sharp & Dohme. CC has received clinical trial expenses from AbbVie, Ewopharma, Eli Lilly, Novartis and Pfizer, and speaker and consultancy fees from AbbVie, Boehringer Ingelheim, Ewopharma, Eli Lilly, Novartis, Pfizer, Sandoz and UCB. KLH has received speaker fees from AbbVie and grants from Pfizer and Bristol Myers Squibb and is also supported by the NIHR Manchester Biomedical Research Centre. DC has received consultant and speaker fees from AbbVie, Amgen, Celgene, Eli Lilly, Fresenius Kabi, Pfizer, Novartis, Sandoz and Tevapharm. AS has received speaker/honoraria from AbbVie, Celltrion, Merck Sharp & Dohme, Roche, Bristol Myers Squibb and Pfizer. BFL has received clinical trial expenses from TRB and Roche, consultancy fees from AbbVie, Amgen, Roche, Merck Sharp & Dohme, Pfizer, Celgene, Grünenthal, Kwizda, Eli Lilly, Novartis and Sandoz, and speaker fees from AbbVie, Roche, Merck Sharp & Dohme, Pfizer, Actiopharma, Boehringer Ingelheim, Kwizda, Celgene, Sandoz, Grünenthal and Eli Lilly. ZR reports speaker and consultancy fees from AbbVie, Amgen, Biogen, Pfizer, Merck Sharp & Dohme, Roche, Novartis, Sanofi Genzyme, Medis, Eli Lilly and Sandoz. AR reports personal fees from Amgen, Pfizer and AstraZeneca, outside the submitted work. EKK reports no competing interests. TKK has received fees for speaking and/or consulting from AbbVie, Amgen, Celltrion, Egis, Eva Pharma, Ewopharma, Gilead, Hikma, Janssen, Mylan, Novartis, Oktal, Pfizer, Sandoz and UCB, and received research funding to Diakonhjemmet Hospital from AbbVie, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer and UCB. OE has received clinical trial expenses from AbbVie, Pfizer, Novartis, Eli Lilly and Janssen, and speaker fees from AbbVie, Pfizer, Roche, Janssen, Eli Lilly and Novartis. GL has received consultant fees from AbbVie, BIOCAD, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer and R-PHARM. SAB received an ASPIRE grant from Pfizer. AF has received fees for speaking and/or consulting from AbbVie, AstraZeneca, Bristol Myers Squibb, Galapagos, Mylan, Novartis, Pfizer, Sandoz and UCB, and received research funding to Geneva University Hospital from AbbVie, Bristol Myers Squibb, Pfizer and Galapagos. DSC has nothing to disclose. BIOBADASER has received funding from Fundacion Española de Reumatología, the Spanish Medicines and Health Products Agency (Agencia Española del Medicamento y Productos Sanitarios) and equal grants from pharmaceutical companies (AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Samsung, Schering-Plough and UCB). The Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) database is sponsored by public and industrial support (http://scqm.ch/en/sponsoren/). Clinical work in Czech Republic was partially supported by the project from the Ministry of Health for conceptual development of research organization (MZ00023728023728) (Institute of Rheumatology). ROB-FIN is funded by AbbVie, Hospira, BMS, MSD, Pfizer, Roche and UCB. The Romanian Registry of Rheumatic Diseases (RRBR) uses unrestricted grants from AbbVie, Pfizer, Eli Lilly, Ewopharma, Novartis, MSD, Roche, UCB and BMS. The British Society for Rheumatology Biologics Register in Rheumatoid Arthritis (BSRBR-RA) is funded by a grant from the British Society for Rheumatology (BSR). The BSR currently receives funding from AbbVie, Amgen, Celltrion HC, Eli Lilly, Pfizer, Samsung Bioepis, Sanofi and Sandoz, and in the past Hospira, MSD, Roche, SOBI and UCB. This income finances a wholly separate contract between the BSR and The University of Manchester to host the BSRBR-RA. All decisions concerning study design, data capture, analyses, interpretation and publication are made autonomously of any industrial contribution. The BSRBR-RA would like to gratefully acknowledge the support of the National Institute for Health Research through the Local Clinical Research Networks in England (and equivalent organisations in the devolved nations) at participating centres and the BSRBR-RA Control Centre Consortium. Rhumadata is supported by equal unrestricted grants from AbbVie, Amgen, Celgene, Eli Lilly, Fresenius Kabi, Pfizer, Novartis, Sandoz and Tevapharm. The RABBIT register is currently supported by an unconditional grant with equal parts from AbbVie, Amgen, BMS, Celltrion, Fresenius Kabi, Galapagos, Hexal, Lilly, MSD, Viatris, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis and UCB. biorx.si has received equal grants from AbbVie, Amgen, Biogen, Pfizer, Merck Sharp & Dohme, Roche, Novartis, Mylan, Sanofi Genzyme, Medis, Eli Lilly, Sandoz and Medis. Reuma.pt has received funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis and Pfizer. NOR-DMARD has been supported with research funding to Diakonhjemmet Hospital from AbbVie, Amgen, BMS, MSD, Novartis, Pfizer and UCB.