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Across immune-mediated inflammatory diseases, Janus kinase inhibitors are consistently associated with a higher malignancy risk compared to TNF inhibitors and standard care, with meaningful absolute excess risk primarily confined to higher-risk populations. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

July 1, 2026Annals of the Rheumatic Diseases1 citationsOpen Access

Cancer risk of Janus kinase inhibitors and other advanced therapies in immune-mediated inflammatory diseases: a systematic review and Bayesian network meta-analysis of RCTs

MGMark GibsonKing's College London VAVictoria AllenKing's College London MAMaryam AdasKing's College London

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Abstract

OBJECTIVES: The Oral Rheumatoid Arthritis Trial Surveillance trial identified increased malignancy risk with tofacitinib vs tumour necrosis factor inhibitors (TNFis) in rheumatoid arthritis (RA), leading to class-wide regulatory warnings for Janus kinase inhibitors (JAKis). Comparative cancer risk vs other advanced therapies and across immune-mediated inflammatory diseases (IMIDs) remains uncertain. The objective was to estimate relative and absolute cancer risk associated with JAKi vs other advanced therapies across IMIDs. METHODS: MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception to February 2026 for phases II to IV randomised trials and long-term extension studies of licensed advanced therapies in adults with RA, psoriasis (PsO)/psoriatic arthritis (PsA), or inflammatory bowel disease (IBD) reporting malignancy outcomes. Bayesian class-level network meta-analyses using Poisson models estimated incidence rate ratios (RRs) vs standard care (placebo or methotrexate monotherapy). It includes all malignancies including nonmelanoma skin cancer. RESULTS: A total of 305 studies (164,824 participants; 264,100 person-years exposure) were included, comprising 174 studies across IMIDs, 123 in RA, 129 in PsO/PsA, and 54 in IBD. In the combined IMID network, JAKi were associated with higher malignancy risk than TNFi (RR: 1.60; 95% credible interval CrI: 1.27-2.02) and standard care (RR: 1.85; 95% CrI: 1.38-2.47). Similar directional findings were observed across RA, PsO/PsA, and IBD networks. Interleukin-6 (IL-6), Interleukin-17 (IL-17), Interleukin-23 (IL-23), Interleukin-12/23 (IL-12/23), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), B-lymphocyte antigen CD20 (CD20)-targeting therapies showed risks broadly comparable with TNFi. Absolute excess cancer risk with JAKi compared with TNFi was negligible in standard-risk populations (+0.037 cancers per 1000 person-years exposure PYE; ∼1 additional cancer per 27,000 PYE) but meaningful in higher-risk populations (+6.814 cancers per 1000 PYE; ∼1 additional cancer per 147 PYE). CONCLUSIONS: Across IMIDs, JAKi were consistently associated with higher malignancy risk relative to TNFi and standard care, extending regulatory warnings beyond RA and emphasising the need for risk-stratified treatment decisions.

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