A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis

Abstract

Objectives To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors. Methods We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach. Results Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates. Conclusion The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk. Systematic review registration number Prospero 2017 CRD4201707879.

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…Baricitinib, at therapeutic dosing (either as 2 mg or 4 mg once daily) is sufficient to inhibit AAK1, thus it has been suggested to be trialed in an appropriated COVID population [6,292]. On the other hand, therapies targeting JAK complexes may interfere with normal anti-viral response including inhibition of IFN-γ activity and may potentially increase the risk of infection and/or reactivation of several viral infectious diseases [293][294][295], including a dose dependent risk for VZV observed for tofacitinib and baricitinib [296]. Thus, their usage should be carefully evaluated.…”

New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

“…The current review finally highlights the role of IFN-c in the adverse events seen with JAK inhibition. An increased risk of herpes zoster is most specifically related to the use of JAK inhibitors among patients with RA or other immune-mediated diseases [56,57]. It is also worth noting that the risk of infection with other viruses, such as cytomegalovirus and Epstein-Barr virus, has not been increased with JAK inhibition [58], suggesting a special connection between JAK-STAT pathway and immunity to VZV.…”

Functional immune mapping with deep-learning enabled phenomics applied to immunomodulatory and COVID-19 drug discovery

“…However, we observed that JAK inhibitors enhanced cellular infection of SARS-CoV-2 at higher concentrations, suggesting an effect on interferon signaling, a possible clinical liability that should be closely monitored during trials. Supporting this finding and underlining the importance of identifying diverse options to address cytokine storm, JAK inhibitors are known to increase the prevalence or severity of other viral infections including herpes zoster, JC virus, and hepatitis B [73][74][75] . This study also identified alternative mechanisms of action which have been much less deeply considered in the context of COVID-19, such as certain Syk inhibitors, c-Met inhibitors and PI3K inhibitors.…”