JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications

Abstract

Objectives: To estimate the association of Janus kinase inhibitors (JAKi) with the incidence of malignancy, compared with placebo, tumour necrosis factor (TNF)-α inhibitors (TNFi) and methotrexate.

Methods: Systematic searches of databases were performed, to December 2022, to identify phase II/III/IV randomised clinical trials (RCTs) and long-term extension (LTE) studies of JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) compared with placebo, TNFi or methotrexate, in adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease or atopic dermatitis. Network and pairwise meta-analyses were performed to estimate incidence rate ratios (IRRs) for malignancy between JAKi and comparators. Bias was assessed using the Cochrane Risk of Bias-2 tool.

Results: In 62 eligible RCTs and 16 LTE studies, there were 82 366 person-years of exposure to JAKi, 2924 to placebo, 7909 to TNFi and 1074 to methotrexate. The overall malignancy incidence rate was 1.15 per 100 person-years in RCTs, and 1.26 per 100 person-years across combined RCT and LTE data. In network meta-analyses, the incidence of all malignancies including non-melanomatous skin cancers (NMSCs) was not significantly different between JAKi and placebo (IRR 0.71; 95% CI 0.44 to 1.15) or between JAKi and methotrexate (IRR 0.77; 95% CI 0.35 to 1.68). Compared with TNFi, however, JAKi were associated with an increased incidence of malignancy (IRR 1.50; 95% CI 1.16 to 1.94). Findings were consistent when analysing NMSC only and when analysing combined RCT/LTE data.

Conclusions: JAKi were associated with a higher incidence of malignancy compared with TNFi but not placebo or methotrexate. Cancers were rare events in all comparisons.

Prospero registration number: CRD42022362630.

Keywords: arthritis, psoriatic; arthritis, rheumatoid; biological therapy; epidemiology; spondylitis, ankylosing.

Figure 1

Network meta-analysis estimates of the risk of all malignancies including non-melanomatous skin cancers between study treatments in eligible RCTs (top panel) and combined RCT and LTE studies (bottom panel); expressed as incidence rate ratios with 95% CIs and depicted graphically as a forest plot. JAKi, Janus kinase inhibitor; LTE, long-term extension; RCT, randomised clinical trial; TNFi, tumour necrosis factor-α inhibitor.

Figure 2

Network plots, depicting the number of studies for each treatment (node size) and number of treatment comparisons (edge thickness) in eligible RCT studies (top panel) and LTE studies (bottom panel). In LTE studies without long-term comparator data, comparator data from the original RCTs were included. JAKi, Janus kinase inhibitor; LTE, long-term extension; MTX, methotrexate; RCT, randomised clinical trial; TNFi, tumour necrosis factor-α inhibitor.

Figure 3

Pairwise meta-analysis of the risk of all malignancies including non-melanomatous skin cancers between JAKi and placebo groups of eligible RCTs; expressed as incidence rate ratios with 95% CIs and depicted graphically as a forest plot. Exposure is reported in person-years. The relative weighting of each study from a random-effects model is shown. A fixed continuity correction of 0.1 was used for studies with zero events. Heterogeneity between studies was assessed using I² statistics. Further details and references for included studies are provided within online supplemental table 1. JAKi, Janus kinase inhibitor; RCTs, randomised clinical trials.

Figure 4

Pairwise meta-analysis of the risk of all malignancies including non-melanomatous skin cancers between individual JAKi medications and placebo groups of eligible RCTs; expressed as incidence rate ratios with 95% CIs and depicted graphically as a forest plot. Exposure is reported in person-years. The relative weighting of each study from a random-effects model is shown. A fixed continuity correction of 0.1 was used for studies with zero events. Heterogeneity between studies was assessed using I² statistics. Further details and references for included studies are provided within online supplemental table 1. JAKi, Janus kinase inhibitor; RCTs, randomised clinical trials.

Figure 5

Pairwise meta-analysis of the risk of all malignancies including non-melanomatous skin cancers between JAKi and TNFi groups of eligible RCTs; expressed as incidence rate ratios with 95% CIs and depicted graphically as a forest plot. Exposure is reported in person-years. The relative weighting of each study from a random-effects model is shown. A fixed continuity correction of 0.1 was used for studies with zero events. Heterogeneity between studies was assessed using I² statistics. Further details and references for included studies are provided within online supplemental table 1. JAKi, Janus kinase inhibitor; RCTs, randomised clinical trials; TNFi, tumour necrosis factor-α inhibitor.

Figure 6

Pairwise meta-analysis of the risk of all malignancies including non-melanomatous skin cancers between JAKi and methotrexate groups of eligible RCTs; expressed as incidence rate ratios with 95% CIs and depicted graphically as a forest plot. Exposure is reported in person-years. The relative weighting of each study from a random-effects model is shown. A fixed continuity correction of 0.1 was used for studies with zero events. Heterogeneity between studies was assessed using I² statistics. Further details and references for included studies are provided within online supplemental table 1. JAKi, Janus kinase inhibitor; RCTs, randomised clinical trials.