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Impact of Janus Kinase Inhibitors on Risk of Cardiovascular Events in Patients with Rheumatoid Arthritis: Systematic Review and Meta-Analysis of Randomised Controlled Trials

Xie W, Huang Y, Xiao S, Sun X, Fan Y, Zhang Z. - Ann Rheum Dis. 2019 Aug;78(8):1048-1054.

Existing evidence from RCTs indicated no significant change in CV risk for JAK inhibitor (JAKinib) treated RA patients in a short-term perspective compared to placebo.

Patients with RA have an elevated risk of CV morbidity and mortality, which cannot be fully explained by traditional CV risk factors. Reaching remission or LDA in order to reduce CV events (CVE) is encouraged in the current EULAR recommendations. JAKinibs and their roles in the modulation of CV risk remain undetermined. This study sets out to explore the association between JAKinib therapies and CVEs in adult RA patients.

PubMed, Embase and the Cochrane library were searched from inception through October 2018 for RCTs reporting safety issues in RA patients receiving JAKinibs. The primary and secondary outcomes were relationships between JAKinibs and all CVEs, MACEs or VTEs. Two kinds of comparisons were made for both primary and secondary outcomes: 1) all or individual JAKinib vs placebo; 2) comparisons of different dosage (TOF 5 vs 10 mg; BARI 2 vs 4 mg; UPA 15 vs 30 mg). Odds ratio (OR) and 95% CI were calculated using the Mantel-Haenszel
fixed-effect method.

Comparisons of JAKinibs against placebo indicated no statistically significant differences in all CVE risk (OR=1.04). Considered separately, statistical differences for all CVEs remained undetectable for TOF (OR=0.63), BARI (OR=1.21), UPA (OR=3.29), PEF (OR=0.43) and DEC (OR=1.12). Likewise, there was no statistically significant difference for JAKinib treatment overall regarding occurrence of MACEs (OR=0.80) or VTEs (OR=1.16) compared with placebo. No dose-dependent impact of TOF and UPA on the risk of all CVEs, MACEs and VTEs was also observed. However, BARI 4 mg seem to be associated with a higher occurrence of CVEs compared to 2 mg dose (OR=0.19).

The meta-analysis indicates that neither individual nor all JAKinibs considered as a group significantly influence CV outcomes in adult RA patients. Post-marketing data are crucial to ascertain CV safety, especially at higher dose of JAKinibs. Recent FDA and EMEA cautions have indicated that there may be a risk of thromboembolism events for TOF and BARI - these observations require further examination and confirmation. Newer JAKinibs will require close attention in this regard.