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Efficacy and safety of JAK inhibitors in rheumatoid arthritis: update for the practising clinician

Nature Reviews Rheumatology volume 20, pages 101–115 (2024)Cite this article

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A Publisher Correction to this article was published on 01 February 2024

This article has been updated

Abstract

Janus kinase (JAK) inhibitors, including tofacitinib, baricitinib, upadacitinib and filgotinib, are increasingly used in the treatment of rheumatoid arthritis (RA). There has been debate about their safety, particularly following the issuance of guidance by regulatory agencies advising caution in their use in certain patients. The registrational clinical trials and registry data of JAK inhibitors did not identify a difference in the risk of major adverse cardiovascular events (MACEs), venous thromboembolism, malignancies or infections (other than herpes zoster) with a JAK inhibitor versus a biologic DMARD. In the ORAL Surveillance trial, which enrolled patients >50 years of age with ≥1 cardiovascular risk factor, tofacitinib was statistically not non-inferior to TNF inhibitors for the occurrence of MACEs and malignancy. Further post hoc analysis of the data revealed that an age of ≥65 years, a high baseline cardiovascular risk, a history of smoking, sustained inflammation, disease activity and suboptimal treatment of cardiovascular comorbidities all increase the risk of these outcomes. The guidance issued by regulatory agencies should be carefully considered to ensure appropriate and safe treatment of patients with RA without undertreatment of patients who might benefit from JAK inhibitor, as well as biologic, treatment. As always, the risks associated with the use of these agents, treatment goals, costs and patient preferences should be discussed with the patient.

Key points

  • Registrational clinical trials and registries of Janus kinase (JAK) inhibitors did not identify a difference in the risk of major adverse cardiovascular events (MACEs), venous thromboembolism, malignancies or infections versus biologic DMARDs.

  • The post-marketing ORAL Surveillance trial enrolled patients with rheumatoid arthritis (RA) >50 years of age with ≥1 cardiovascular risk factor to assess the relative risk of a JAK inhibitor versus a TNF inhibitor.

  • In ORAL Surveillance, tofacitinib was not non-inferior to TNF inhibitor therapy for the occurrence of MACEs and malignancy, although this finding does not mean that tofacitinib is inferior to TNF inhibitor therapy.

  • Post hoc analyses of the trial data revealed that an age of ≥65 years, a history or high risk of cardiovascular disease, smoking, active RA and suboptimal treatment of cardiovascular comorbidities all increased the risk of primarily MACEs and malignancies, but also venous thromboembolism and serious infections.

  • The benefit:risk ratio of JAK inhibitors strongly favours their use in the vast majority of patients.

  • Guidance from regulatory agencies and professional bodies on the use of JAK inhibitors should be considered carefully to ensure appropriate treatment of patients with RA.

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Fig. 1: Cytokine signalling through JAKs and JAK inhibitors.
Fig. 2: Involvement of JAK-dependent pathways in cardiovascular pathophysiology.

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Authors and Affiliations

  1. Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Zoltán Szekanecz & Attila Hamar

  2. Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Maya H. Buch

  3. NIHR Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    Maya H. Buch

  4. Division of Rheumatology, Department of Medicine, Harbour-University of California Los Angeles Medical Centre, Los Angeles, CA, USA

    Christina Charles-Schoeman & George A. Karpouzas

  5. Department of Inflammation Biology and Centre for Rheumatic Diseases, King’s College London, London, UK

    James Galloway

  6. The Parker Institute, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark

    Lars Erik Kristensen

  7. Division of Rheumatology, Mayo Clinic, Rochester, MN, USA

    Steven R. Ytterberg

  8. Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, TX, USA

    Roy Fleischmann

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  1. Zoltán Szekanecz
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Contributions

Z.S., A.H. and R.F. researched data for the article. All authors contributed substantially to discussion of the content. Z.S., A.H. and R.F. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Zoltán Szekanecz.

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Competing interests

Z.S. declares that he has acted as a consultant for AbbVie, Lilly and Pfizer and has received research grants from Pfizer. M.H.B. declares that she has been a consultant for AbbVie, Galapagos and Pfizer. C.C.-S. declares that she has acted as a consultant for AbbVie, Galapagos and Pfizer and has received grants from AbbVie and Pfizer. J.G. declares that he has acted as a consultant for AbbVie, Galapagos, Lilly and Pfizer. G.A.K. declares that he has received research grants from Pfizer. L.E.K. declares that he has acted as a consultant for AbbVie, Galapagos, Lilly and Pfizer. S.R.Y. declares that he has acted as a consultant for Pfizer. R.F. declares that he has acted as a consultant for AbbVie, Galapagos, Lilly and Pfizer. A.H. declares no competing interests.

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Nature Reviews Rheumatology thanks Eduardo Mysler, who co-reviewed with Ana Lizarraga, Andrea Rubbert-Roth and Yoshiya Tanaka for their contribution to the peer review of this work.

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Szekanecz, Z., Buch, M.H., Charles-Schoeman, C. et al. Efficacy and safety of JAK inhibitors in rheumatoid arthritis: update for the practising clinician. Nat Rev Rheumatol 20, 101–115 (2024). https://doi.org/10.1038/s41584-023-01062-9

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