Thromboembolic risk of JAK inhibitors in patients with autoimmune diseases：a network meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

LI Xiaoqi , HU Qiaozhi ,  XU Ting

Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

XU Ting, Email: tingx2009@163.com

Keywords：

Network meta-analysis; JAK inhibitors; Thromboembolism

DOI：

10.7507/1672-2531.202504004

Video：

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Objective To systematically review the thromboembolic risk of Janus Kinase (JAK) inhibitors. Methods We searched PubMed, Embase, Cochrane Library, and Web of Science databases from their inception until March 2025. Quality was assessed using Cochrane Risk of Bias-2. STATA 15 software was used for network meta-analysis. Results A total of 68 randomized controlled trials with a sample size of 39 059 were included. Findings did not show a significant difference between JAK inhibitors and placebo, methotrexate, tumor necrosis factor -α inhibitor, apremilast, otilimab in the risk of thromboembolism. Conclusion JAK inhibitors do not increase thromboembolism risk. To clarify the long-term safety of JAK inhibitors, future large-scale real-world studies with long-term follow-up are needed, especially in patients at risk of thromboembolism.

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16.	Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ, 2011, 343: d5928.
17.	Puhan MA, Schünemann HJ, Murad MH, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ, 2014, 349: g5630.
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19.	Wolk R, Armstrong EJ, Hansen PR, et al. Effect of tofacitinib on lipid levels and lipid-related parameters in patients with moderate to severe psoriasis. J Clin Lipidol, 2017, 11(5): 1243-1256.
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1. Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med, 2015, 278(4): 369-395.
2. Nogueira M, Puig L, Torres T. JAK inhibitors for treatment of psoriasis: focus on selective TYK2 inhibitors. Drugs, 2020, 80(4): 341-352.
3. Alunno A, Padjen I, Fanouriakis A, et al. Pathogenic and therapeutic relevance of JAK/STAT signaling in systemic lupus erythematosus: integration of distinct inflammatory pathways and the prospect of their inhibition with an oral agent. Cells, 2019, 8(8): 898.
4. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol, 2017, 13(4): 234-243.
5. Hu X, Li J, Fu M, et al. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther, 2021, 6(1): 402.
6. Alves C, Penedones A, Mendes D, et al. The risk of infections associated with JAK inhibitors in rheumatoid arthritis: a systematic review and network meta-analysis. J Clin Rheumatol, 2022, 28(2): e407-e414.
7. Markham A. Baricitinib: first global approval. Drugs, 2017, 77(6): 697-704.
8. Dhillon S, Keam S J. Filgotinib: first approva. Drugs, 2020, 80(18): 1987-1997.
9. Markham A, Keam SJ. Peficitinib: first global approval. Drugs, 2019, 79(8): 887-891.
10. Duggan S, Keam S J. Upadacitinib: first approval. Drugs, 2019, 79(16): 1819-1828.
11. FDA U. FDA approves boxed warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). 2019.
12. EMA. EMA confirms Xeljanz to be used with caution in patients at high risk of blood clots. 2020.
13. Yates M, Mootoo A, Adas M, et al. Venous thromboembolism risk with JAK inhibitors: a meta-analysis. Arthritis Rheumatol, 2021, 73(5): 779-788.
14. Maqsood MH, Weber BN, Haberman RH, et al. Cardiovascular and venous thromboembolic risk with janus kinase inhibitors in immune-mediated inflammatory diseases: a systematic review and meta-analysis of randomized trials. ACR Open Rheumatol, 2022, 4(10): 912-922.
15. Campanaro F, Zaffaroni A, Cacioppo E, et al. Venous and arterial thromboembolic risk of Janus kinase inhibitors: a systematic review with meta-analysis. Rheumatology (Oxford), 2023, 62(10): 3245-3255.
16. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ, 2011, 343: d5928.
17. Puhan MA, Schünemann HJ, Murad MH, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ, 2014, 349: g5630.
18. Damsky W, King BA. JAK inhibitors in dermatology: the promise of a new drug class. J Am Acad Dermatol, 2017, 76(4): 736-744.
19. Wolk R, Armstrong EJ, Hansen PR, et al. Effect of tofacitinib on lipid levels and lipid-related parameters in patients with moderate to severe psoriasis. J Clin Lipidol, 2017, 11(5): 1243-1256.
20. Kremer JM, Genovese MC, Keystone E, et al. Effects of baricitinib on lipid, apolipoprotein, and lipoprotein particle profiles in a phase IIb study of patients with active rheumatoid arthritis. Arthritis Rheumatol, 2017, 69(5): 943-952.
21. Rajasimhan S, Pamuk O, Katz JD. Safety of janus kinase inhibitors in older patients: a focus on the thromboembolic risk. Drugs Aging, 2020, 37(8): 551-558.
22. Miyakawa Y, Oda A, Druker B J, et al. Recombinant thrombopoietin induces rapid protein tyrosine phosphorylation of Janus kinase 2 and Shc in human blood platelets. Blood, 1995, 86(1): 23-27.
23. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med, 2022, 386(4): 316-326.
24. Mameli A, Barcellona D, Marongiu F. Rheumatoid arthritis and thrombosis. Clin Exp Rheumatol. 2009, 27(5): 846-855.
25. Alikhan R, Cohen AT, Combe S, et al. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX study. Arch Intern Med, 2004, 164(9): 963-968.
26. Setyawan J, Azimi N, Strand V, et al. Reporting of thromboembolic events with JAK inhibitors: analysis of the FAERS database 2010-2019. Drug Saf, 2021, 44(8): 889-897.
27. Conrad N, Verbeke G, Molenberghs G, et al. Autoimmune diseases and cardiovascular risk: a population-based study on 19 autoimmune diseases and 12 cardiovascular diseases in 22 million individuals in the UK. Lancet, 2022, 400(10354): 733-743.
28. Youssef J, Novosad SA, Winthrop KL. Infection risk and safety of corticosteroid use. Rheum Dis Clin North Am, 2016, 42(1): 157-176.

Chinese Journal of Evidence-Based Medicine

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