Cytokine Signalling Forum


A Systematic Review and Meta-Analysis of Infection Risk with Small Molecule JAK Inhibitors in Rheumatoid Arthritis

Bechman K, Subesinghe S, Norton S, Atzeni F, Galli M, Cope AP, Winthrop KL, Galloway JB. - Rheumatology (Oxford). DOI: 10.1093/rheumatology/kez087

How JAKinibs increase the risk of HZ reactivation is unclear. Roles of different JAKs in the immune response may suggest differences in safety profiles between drugs, underpinned by their differential JAK selectivity profiles. The authors undertook a systematic review and meta-analysis to evaluate SI and opportunistic indicator infections including HZ in RA Phase II/III clinic trials with JAKinibs.

A literature review of RCT of TOF (5 mg BID), BARI (4 mg OD) and UPA (15 mg OD) was conducted. A per-protocol analysis was applied, incorporating follow-up time from patients randomised to PBO who cross over into the treatment arm. Relative risk between JAKinibs and PBO was estimated and expressed as Incidence rate ratios (IRR) with 95 % CI.

The estimated IRR of SI compared to PBO in per-protocol analyses were not statistically significant with 1.22 (95% CI: 0.60, 2.45) for TOF, 0.80 (95% CI: 0.46, 1.38) for BARI and 1.14 (95% CI: 0.24, 5.43) for UPA. The IRR of HZ comparing BARI with PBO was 2.86 (95% CI: 1.26, 6.50), whereas non-significant IRRs were seen with TOF = 1.38 (95% CI: 0.66, 2.88) and UPA = 0.78 (95% CI: 0.19, 3.22).

This study did not demonstrate a significant increased risk of SI among the three JAKinibs above compared to PBO. Although higher than expected increased risk of HZ with BARI was observed, indirect comparisons between drugs did not demonstrate significant difference n risk. However, the network meta-analysis casts doubt over whether any difference between JAKinibs are of magnitude that is clinically meaningful. Active Phase III trials and post-marketing surveillance with other JAKinibs may provide new insights into the differential risk of infections with JAK inhibition, and the mechanisms behind the association with HZ.