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.

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.