Novel selective oral Janus activated kinase (JAK) inhibitors, tofacitinib, baricitinib, and upadicitinib, improve disease control and quality of life of patients with rheumatoid arthritis (RA), but there are also several safety concerns, including potential increased risk for infection and venous thromboembolism, according to study results published in Mayo Clinic Proceedings.

As a family of intracellular tyrosine kinases, JAKs are involved in the pathogenesis of various inflammatory and autoimmune disorders. There are 4 members in the JAK family: JAK1, JAK2, JAK3, and receptor tyrosine kinase 2 (TYK2).  Currently, there are 3 FDA-approved oral JAK inhibitors for the treatment of RA: tofacitinib, which inhibits JAK1/3 with less inhibition of JAK2 and TYK2; baricitinib, an inhibitor of JAK 1/2 with moderate activity against TYK2; and upadacitinib, which is a JAK1-selective inhibitor.

The goal of the current systematic review and meta-analysis was to compare the safety and efficacy of these 3 drugs for the treatment of RA.

The researchers performed a systematic search of MEDLINE, EMBASE, and the Cochrane Library through December 11, 2019, to identify randomized controlled trials that included adult patients with active RA, treated with tofacitinib, baricitinib, or upadicitinib. All included studies determined efficacy and safety outcomes.


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Of 116 identified clinical trials, 20 studies (8982 unique patients) with a low risk of bias were included in the analysis: 12 tofacitinib trials, 5 baricitinib studies, and 3 designed to test upadacitinib.

All JAK inhibitors were found to be effective in reducing RA disease activity, and the overall pooled analysis showed that the response rate according to American College of Rheumatology 20% (ACR) criteria was 2-fold higher than placebo (relative risk [RR], 2.03; 95% CI, 1.87-2.20; P <.001), and all treatments were associated with significant decreases in Health Assessment Questionnaire – Disability Index (HAQ-DI) (mean differences, -0.31; 95 CI, -0.34 to -0.28; P <.001).

Tofacitinib at a dose of 10 mg, twice daily, was associated with the highest response rate according to ACR20 (RR, 2.48; 95% CI, 1.97-3.14; P <.001) and the most statistically significant improvement in HAQ-DI score (mean difference, -0.38; 95% CI, -0.44 to -0.31; P <.001).

The overall incidence of adverse events was higher among patients treated with JAK inhibitors (RR, 1.09; 95% CI, 1.05-1.13; P <.001), but the frequency of serious adverse events in any of the treatment groups was not significantly different compared with placebo.

Tofacitinib given at a dose of 10 mg, twice daily, was associated with the highest risk for infection (RR, 2.75; 95% CI, 1.72-4.41), followed by upadacitinib, 15 mg, daily (RR, 1.35; 95% CI, 1.14-1.60) and baricitinib, 4 mg, daily (RR, 1.28; 95% CI, 1.12-1.45).  On the other hand, treatments with tofacitinib 5 mg, twice daily, baricitinib at a daily dose of 2 mg, or upadacitinib 30 mg daily, were not associated with an increased risk for infection.

Data on venous thromboembolism was only available from upadacitinib trials, indicating the JAK inhibitor was not associated with a significant increase in risk for venous thromboembolic disease.

The study had several limitations, including the small number of trials with baricitinib and upadacitinib, significant heterogeneity in study design, follow-up duration and treatment duration. Furthermore, in some trials patients in the placebo group switched to active treatment during the follow-up.

“Longer-term follow-up and additional trials with head-to-head comparison of tofacitinib, baricitinib, and upadacitinib, as well as additional information from ongoing trials of these and other JAK inhibitors, including peficitinib and filgotinib, will be important to further determine both efficacy and the safety profile of these agents in the management of RA,” wrote the researchers.

Reference

Wang F, Sun L, Wang S, et al. Efficacy and safety of tofacitinib, baricitinib, and upadacitinib for rheumatoid arthritis: a systematic review and meta-analysis. Mayo Clin Proc. 2020;95(7):1404-1419. doi:10.1016/j.mayocp.2020.01.039