Janus Kinase Inhibitors Plus Methotrexate Not Associated With Malignancy Risk in Patients With Rheumatoid Arthritis

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Study authors assessed malignancy risk among patients with rheumatoid arthritis receiving combination therapy with Janus kinase inhibitors and methotrexate vs MTX alone.

In patients with rheumatoid arthritis (RA), combination therapy with Janus kinase inhibitors (JAKi) and methotrexate (MTX) vs MTX alone is not associated with an increased risk for malignancy and serious adverse events (SAEs) or death, according to a systematic review and meta-analysis published in Autoimmunity Highlights.

Using PubMed, Embase, and Cochrane, study authors searched randomized control trials (RCTs) that included patients with RA receiving JAKi and MTX from inception to July 2020. Primary endpoints were malignancy events, nonmelanoma skin cancer (NMSC), and malignancy excluding NMSC. Secondary endpoints were SAEs or death. 

Of the initial 659 publications screened, 13 RCTs with a total of 6911 patients were included in the analysis. Overall, 40 patients with malignancies in the JAKi plus MTX group among 3684 patient-years and 7 malignancies in the MTX-only group among 988 patient-years were reported.

No statistical difference in malignancy events was found between the combination therapy group and the MTX-only group (risk ratio [RR], 1.42; 95% CI, 0.59-3.41, P =.44). There was a relatively low level of heterogeneity across the included RCTs (χ2=5.35; P =.62; I2=0%). Using the Mantel-Haenszel random-effect method, no evidence of publication bias was observed in all comparisons.

Statistical difference remained undetectable for NMSC (RR, 1.44; 95% CI, 0.36-5.76; P =.61) and malignancies excluding NMSC (RR, 1.12; 95% CI, 0.40-3.13; P =.82), when considered separately. No statistical differences in SAEs (RR, 1.15; 95% CI, 0.90-1.47; P =.26) and deaths were detected (RR, 1.99; 95% CI, 0.75-5.27; P =.17).

Several study limitations were reported including the fact that patient-year exposure in the MTX-only group was lesser compared with the combination group, long-term extension studies were excluded, and the relatively short-follow up period of some included studies.

Study authors concluded, “These results have been consistent among all the studies included in the analysis suggesting overall acceptable safety profile of JAKi and MTX combination.”


Solipuram V, Mohan A, Patel R, Ni R. Effect of Janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. Autoimmun Highlights. 2021;12(1):8. doi:10.1186/s13317-021-00153-5