Mapping Cardiovascular and Infectious Risk of JAK inhibitors in patients with Rheumatoid Arthritis: Comparative Safety

About This Grant

PROJECT SUMMARY/ABSTRACT Janus kinase inhibitors (JAK}---including tofacitinib, baricitinib, and upadacitinib-have emerged as promising oral treatment options for patients with rheumatoid arthritis who experience an inadequate response to conventional therapies. However, major safety concerns, including increased risk of cardiovascular events, venous thromboembolism, and serious infections, have prompted FDA black box warnings and remain major barriers to widespread use. These safety concerns largely stem from potential signals in integrated analyses of premarketing studies and the ORAL Surveillance trial, which reported a dose-dependent elevated risk of cardiovascular and thromboembolic events with tofacitinib compared to tumor necrosis factor (TNF) inhibitors. However, the ORAL trial has left some critical questions unanswered-specifically, whether the observed risk elevation is attributable to a specific JAK inhibitor toxicity, a protective effect of TNF inhibitors, or both; or how the safety profile of specific JAK inhibitors may compare to approved alternatives, such as interleukin-6 inhibitors. Approved JAK inhibitors have differences in selectivity and target binding affinity, which may translate into differences in adverse health outcomes. As a pan-JAK inhibitor, tofacitinib targets multiple JAK isoforms (JAK1, JAK2, JAK3), while newer agents such as upadacitinib and baricitinib exhibit greater selectivity for JAK1. The current FDA black box warning applies to all JAK inhibitor class members, but comparisons among specific class members are lacking. Moreover, all currenUy approved JAK inhibitors are metabolized via cytochrome P450 3A4 (CYP3A4), making them susceptible to clinically significant drug-drug interactions {DDls). Co-administration with moderate or strong CYP3A4 inhibitors, such as diltiazem, can substantially increase plasma JAK inhibitor concentrations, and potentially increasing the risk of adverse events. In this R01, we propose a comprehensive examination of the safety of JAK inhibitors among patients with rheumatoid arthritis. We will use the estimand framework and target trial emulation methods to compare cardiovascular, thrombotic, and infectious risks between JAK inhibitors and other commonly used therapies, overall and by agent. We will also evaluate how co-prescribed CYP3A4 inhibitors modify these risks. Our findings will directly inform clinical guidelines and prescribing decisions for patients with rheumatoid arthritis.