JAK-inhibitors and risk on serious viral infection, venous thromboembolism and cardiac events in patients with rheumatoid arthritis: A protocol for a prevalent new-user cohort study using the Danish nationwide DANBIO register

PLOS ONE STUDY PROTOCOL JAK-inhibitors and risk on serious viral infection, venous thromboembolism and cardiac events in patients with rheumatoid arthritis: A protocol for a prevalent new-user cohort study using the Danish nationwide DANBIO register a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 Maria Luisa Faquetti ID1☯, Enriqueta Vallejo-Yagüe ID1,2☯, René Cordtz3,4, Lene Dreyer ID3,4,5‡, Andrea M. Burden ID1,6‡* 1 Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland, 2 Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland, 3 Center of Rheumatic Research Aalborg, (CERRA), Aalborg University Hospital, Aalborg, Denmark, 4 DANBIO Register, Aalborg, Denmark, 5 Clinical Institute, Aalborg University, Aalborg, Denmark, 6 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada ☯ These authors contributed equally to this work. ‡ LD and AMB also contributed equally to this work. * OPEN ACCESS Citation: Faquetti ML, Vallejo-Yagüe E, Cordtz R, Dreyer L, Burden AM (2023) JAK-inhibitors and risk on serious viral infection, venous thromboembolism and cardiac events in patients with rheumatoid arthritis: A protocol for a prevalent new-user cohort study using the Danish nationwide DANBIO register. PLoS ONE 18(7): e0288757. https://doi.org/10.1371/journal. pone.0288757 Editor: Ryu Watanabe, Osaka Metropolitan University, JAPAN Received: March 30, 2023 Accepted: July 4, 2023 Published: July 27, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0288757 Copyright: © 2023 Faquetti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Janus Kinase inhibitors (JAKis) are targeted synthetic disease-modifying antirheumatic drugs and represent an important alternative to treat patients with moderate to high rheumatoid arthritis (RA) disease activity. Safety concerns associated with increased risk for venous thromboembolism (VTE), serious viral infection, and, more recently, major adverse cardiovascular events (MACE) in JAKi users have emerged worldwide. However, as the exact mechanisms to explain these safety concerns remain unclear, the increased risk of VTE, MACE, and serious viral infection in JAKi users is heavily debated. In light of the need to enrich the safety profile of JAKis in real-world data, we aim to quantify the incidence and risk of MACE, VTE, and serious viral infections in RA patients registered in the Danish DANBIO registry, a nationwide registry of biological therapies used in rheumatology. Therefore, we will conduct a population-based cohort study using a prevalent new-user design. We will identify all RA patients in the DANBIO, � 18 years old, receiving a JAKi or a tumor necrosis factor α inhibitor (TNF-αi) from January 2017 to December 2022. Prevalent and new users of JAKis will be matched to TNF-αi comparators with similar exposure history using time-conditional propensity scores (TCPS). We will describe the cumulative incidence of the outcomes (VTE, MACE, serious viral infection) in each exposure group (JAKi users; TNF-αi users), stratified by outcome type. Additionally, the Aalen-Johansen method will be used to estimate the time-to-event survival function stratified by outcome type. We will also estimate the hazard ratio (HR) with 95% confidence interval (CI) of each outcome in both exposure groups using the time-dependent Cox proportional hazards model. Results will enrich the safety profile of JAKis in real-world data. PLOS ONE | https://doi.org/10.1371/journal.pone.0288757 July 27, 2023 1 / 15 PLOS ONE Data Availability Statement: Due to restrictions imposed by the data provider, Statistics Denmark, the authors are not permitted to share the deidentified data. Data requests for future use will be handled by Statistics Denmark, (https://www. dst.dk/en). Additionally, further information on how to access the DANBIO data is available on their website (https://danbio-online.dk/front-page). Funding: The author(s) received no specific funding for this work. Competing interests: RC has received a consultant fee from Galapagos and is employed by IQVIA outside of the present work. LD has received research grant (paid to her institution) from BMS outside the current manuscript. LD is a member of the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owners and funding from pharmaceutical companies. MLF, EVY, AMB declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. JAK-inhibitors and risk on adverse events: A protocol for a prevalent new-user cohort study using the DANBIO Introduction Janus Kinase inhibitor (JAKi) drugs are novel targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) and represent an important alternative to treat patients with moderate-to-serious rheumatoid arthritis (RA) disease [1]. The JAKis target kinases of the JAK family (JAK1, JAK2, JAK3, and non-receptor tyrosine-protein kinase TYK2), inhibiting the production of multiple pro-inflammatory cytokines, such as interleukin (IL)-6, IL-10, and interferon IFN-γ [2, 3]. For the treatment of RA, JAKi drugs with different affinities for one or more JAK enzymes have been approved worldwide, such as tofacitinib, baricitinib, and updacitinib. While tofacitinib, for example, preferentially inhibits JAK1 and JAK3, baricitinib is designed to target JAK1 and JAK2, and upadacitinib is selective for JAK1 [3–5]. However, safety concerns on the increased risk of serious viral infections, venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) associated with JAKis have emerged worldwide, regardless of their selectivity [6–12]. Patients with rheumatoid arthritis (RA) have increased risk of serious infection, thrombosis and cardiovascular risk factors [13–15]. An increasing amount of literature suggests that the use of JAKi drug may further increase the risk of cardiovascular diseases (e.g., increased serum lipid levels) and, thus, potentially increased the risk of MACE [11, 16–18]. Nevertheless, the underlying mechanism of cardiovascular outcomes due to JAKis use is not fully understood. Recent analyses of thromboembolic events as suspected adverse drug reactions for JAKis using real-world data support the need to investigate further this potential safety issue on different drugs of this class [8, 19]. While, conversely, integrated analyses of randomized clinical trials (RCTs) of JAKis did not reveal (...truncated)