Janus kinase (JAK) inhibitors were associated with greater likelihood of developing malignancy when compared with tumor necrosis factor (TNF) inhibitors, though no significant differences were found when compared with placebo or methotrexate, according to a systematic review and meta-analysis published in Annals of the Rheumatic Disease.

Researchers examined both randomized controlled trials (RCTs) and long-term extension studies of all approved JAK inhibitors for various treatment indications to determine whether JAK inhibitors are associated with greater risk of developing malignancy, compared with placebo, TNF inhibitors, and methotrexate.

Researchers searched publication databases through December 2022 for phase 2, 3, and 4 RCTs or long-term extension studies of JAK inhibitors. Patient diagnoses included rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondylarthritis, inflammatory bowel disease, and atopic dermatitis. Incidence rate ratios (IRR) were used to estimate the risk for malignancy between JAK inhibitors and comparator treatments.

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A total of 62 RCTs and 16 long-term extension studies were examined, comprising 82,366 person-years of exposure to JAK inhibitors and 2924, 7909, and 1074 person-years of exposure to placebo, TNF inhibitors, and methotrexate, respectively. Of the eligible RCTs, 56 included placebo groups, 10 included TNF inhibitor groups, and 5 included methotrexate monotherapy groups. Additionally, 39 RCTs (62.9%) were considered to be at low risk of bias across all domains, while 16 (25.8%) included some bias and 7 (11.3%) were at high risk of bias in at least 1 domain.

Among RCTs, there were 497 malignancy events (IR, 1.15 per 100 person-years of exposure). Across both RCTs and long-term extension studies, there were 1189 malignancy events (IR, 1.26 per 100 person-years of exposure).

No significant differences in the incidence of all malignancies were found between JAK inhibitors and placebo (IRR, 0.71; 95% CI, 0.44-1.15), or between JAK inhibitors and methotrexate (IRR, 0.77; 95% CI, 0.35-1.68), in network meta-analyses of all RCTs. However, patients who took JAK inhibitors were at greater risk of developing malignancy compared with those who took TNF inhibitors (IRR, 1.50; 95% CI, 1.16-1.94).

Combined data from all studies showed that malignancy risk did not significantly differ between JAK inhibitors and placebo, including for all malignancies (IRR, 1.16; 95% CI, 0.75-1.80); all malignancies except nonmelanomatous skin cancers (IRR, 0.97; 95% CI, 0.57-1.66); and nonmelanomatous skin cancers only (IRR, 1.00; 95% CI, 0.51-1.96).

Although there were more than 80,000 person-years of exposure to JAK inhibitors, this study was limited by the much shorter duration of exposure to placebo. Additional study limitations include wide confidence intervals, potential bias, the small number of cancer-related events, and heterogeneity.

“This study might influence the choice of treatment where the decision is between a JAK inhibitor or TNF inhibitor, particularly in patients at increased risk of malignancy,” the researchers noted.

Disclosures: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the reference for a full list of authors’ disclosures.


Russell MD, Stovin C, Alveyn E, et al. JAK inhibitors and the risk of malignancy: a meta-analysis across disease indicationsAnn Rheum Dis. Published online May 29, 2023. doi:10.1136/ard-2023-224049

This article originally appeared on Rheumatology Advisor