Abstract
Introduction
A potentially elevated risk for pulmonary thrombosis with Janus kinase inhibitors (JAKinibs) was identified, as well as an increased risk for portal vein thrombosis, in ruxolitinib patients. Consequently, the objective of this investigation was to repeat a comprehensive analysis of the US FDA’s Adverse Event Reporting System (FAERS) database to assess postmarketing reporting rates of thromboembolic events (TEs) in patients treated with JAKinibs.
Methods
FAERS data (1 January 2010 to 30 September 2019) were searched for reports of all FDA-approved JAKinibs across all indications. For each drug–adverse drug reaction (ADR) pair, the reporting odds ratio (ROR) [two-sided 95% confidence interval (CI)] and empirical Bayesian geometric mean (EBGM) [one-sided 95% lower bound] were calculated to detect drug–ADR pairs with higher-than-expected reporting rates within the FAERS. Significance was declared when both lower 95% CI bounds were > 1.
Results
Significantly elevated reporting rates of pulmonary thrombosis were evident with tofacitinib (ROR 2.36 [1.69–3.31]; EBGM 2.01 [1.53]), as was pulmonary embolism with baricitinib (ROR 12.23 [8.35–17.89]; EBGM 7.72 [3.82]) and portal vein thrombosis with ruxolitinib (ROR 4.16 [2.70–6.40]; EBGM 4.52 [3.11]). Deep vein thrombosis reports were increased with baricitinib (ROR 14.84 [9.64–22.84]; EBGM 9.49 [5.91]), as was thrombosis with ruxolitinib (ROR 1.40 [1.20–1.63]; EBGM 1.72 [1.52]). The relationship between the time of treatment initiation and event occurrence indicated that time to events occurred randomly.
Conclusions
This study found significant reporting rates for TEs in patients treated with JAKinibs across brands and indications, providing additional evidence that JAKinibs may be contraindicated in patients at risk of TEs.
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An increased reporting rate of thromboembolic events for many Janus kinase inhibitors was observed. |
In clinical practice, additional consideration should be given when prescribing Janus kinase inhibitors in patients with existing risk factors for thromboembolic events. |
1 Introduction
Thromboembolic events (TEs), including venous thromboembolism (VTE), are an important cause of preventable morbidity and mortality. In the US, VTEs alone affect over 900,000 people per year, with 10–30% dying within 1 month of diagnosis [1]. VTEs are associated with a significant economic burden, with incremental total direct medical costs of between US$12,000 and US$15,000 among first-year survivors and between US$18,000 and U$23,000 per incident case, factoring in subsequent complications [2]. In total, VTEs are estimated to cost the US healthcare system US$7–12 billion dollars each year [2].
Considerable research has identified individuals at higher risk for future TEs. Patient-related risk factors include older age, obesity, and current smoking status [3]. Diseases linked to an increased risk for TEs include certain malignancies, congestive heart failure, recent myocardial infarction (MI), immobility, and immune-mediated diseases (IMDs), including inflammatory arthritis and ulcerative colitis (UC) [4,5,6]. More recently, the use of specific immunomodulatory medications, including Janus kinase inhibitors (JAKinibs), has been identified as a potential additional risk factor for TE events [7].
JAKinibs are small molecules that block the activity of one or more of the intracellular tyrosine kinases (JAK1, JAK2, JAK3, and TYK2). In blocking these cytokines, JAKinibs interfere with the JAK-STAT signaling pathway and thereby induce immunosuppression [8, 9]. Several JAKinibs have been approved by the US FDA since 2011 for a variety of indications, including rheumatoid arthritis [RA], UC, psoriasis, psoriatic arthritis, myelofibrosis, and acute graft-versus-host disease.
Although demonstrated to be effective [10], JAKinibs have been associated with a higher risk of TE events, especially at higher doses, resulting in the FDA assigning a ‘boxed warning’ for increased risk for TE events associated with JAKinibs [11,12,13,14], and, in some cases, restricting use with regard to higher doses. This warning label applies to most of the commercially available JAKinibs, except ruxolitinib. Using real-world data from the FDA’s Adverse Event Reporting System (FAERS), Verden and colleagues found a potentially elevated risk of pulmonary thrombosis with JAKinibs, as well as a potentially increased risk of portal vein thrombosis for ruxolitinib based on available data for tofacitinib, tofacitinib extended release (XR), and ruxolitinib, from their approval dates to 31 March 2017 [7]. It should be noted that the literature remains mixed regarding the relationship between JAKinibs and increased incidence of cardiovascular (CV) events or TEs [15, The current analysis supports the growing concern regarding the increased risk of TEs in patients treated with JAKinibs across indications. Of particular concern may be patients with IMDs who are already at elevated risk for TEs [6] and who are commonly treated with JAKinibs [24]. Clinicians should carefully consider whether IMD patients have existing TE risk factors (e.g. age, obesity, and current smoking status) before adding JAKinibs, and closely monitor these patients, given that the timing of a TE from the start of therapy appears to be random. Overall, this finding converges and strengthens the results published by Verden and colleagues in 2018. Given the complex relationship between TE and JAKinibs, the results from this and the prior analysis should be validated in other real-world datasets.5 Conclusion
References
Venous thromboembolism (blood clots): data and statistics. Centers for Disease Control and Prevention. Updated 7 February 2020. http://cdc.gov/ncbddd/dvt/data.html. Accessed 11 July 2020.
Grosse SD, Nelson RE, Nyarko KA, Richardson LC, Raskob GE. The economic burden of incident venous thromboembolism in the United States: a review of estimated attributable healthcare costs. Thromb Res. 2016;137:3–10. https://doi.org/10.1016/j.thromres.2015.11.033.
Gregson J, Kaptoge S, Bolton T, Pennells L, Willeit P, Burgess S, et al. Cardiovascular risk factors associated with venous thromboembolism. JAMA Cardiol. 2019;4(2):163–73. https://doi.org/10.1001/jamacardio.2018.4537.
Dean SM, Abraham W. Venous thromboembolic disease in congestive heart failure. Congest Heart Fail. 2010;16(4):164–9. https://doi.org/10.1111/j.1751-7133.2010.00148.x.
Sejrup JK, Børvik T, Grimnes G, Isaksen T, Hindberg K, Hansen JB, et al. Myocardial infarction as a transient risk factor for incident venous thromboembolism: results from a population-based case-crossover study. Thromb Haemost. 2019;119(8):1358–64. https://doi.org/10.1055/s-0039-1692176.
Borjas-Howard JF, Leeuw K, Rutgers A, Meijer K, Tichelaar V. Risk of recurrent venous thromboembolism in autoimmune diseases: a systematic review of the literature. Semin Thromb Hemost. 2019;45(2):141–9. https://doi.org/10.1055/s-0038-1661387.
Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB. Analysis of spontaneous postmarket case reports submitted to the FDA regarding thromboembolic adverse events and JAK inhibitors. Drug Saf. 2018;41(4):357–61. https://doi.org/10.1007/s40264-017-0622-2.
O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–70. https://doi.org/10.1056/NEJMra1202117.
Danese S, Grisham M, Hodge J, Telliez JB. JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines. Am J Physiol Gastrointest Liver Physiol. 2016;310(3):G155–62. https://doi.org/10.1152/ajpgi.00311.2015.
Benamu E. Infectious risks associated with biologics targeting janus kinase-signal transducer and activator of transcription signaling and complement pathway for inflammatory diseases. Infect Dis Clin North Am. 2020;34(2):271–310. https://doi.org/10.1016/j.idc.2020.02.014.
Smolen JS, Genovese MC, Takeuchi T, Hyslop DL, Macias WL, Rooney T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol. 2019;46(1):7–18. https://doi.org/10.3899/jrheum.171361.
Kremer JM, Genovese MC, Keystone E, Taylor PC, Zuckerman SH, Ruotolo G, 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):943–52. https://doi.org/10.1002/art.40036.
Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13(4):234–43. https://doi.org/10.1038/nrrheum.2017.23.
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):551–8. https://doi.org/10.1007/s40266-020-00775-w.
Olivera PA, Lasa JS, Bonovas S, Danese S, Peyrin-Biroulet L. Safety of janus kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis. Gastroenterology. 2020;158(6):1554-73.e12. https://doi.org/10.1053/j.gastro.2020.01.001.
**e W, Huang Y, **ao S, Sun X, Fan Y, Zhang Z. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis. 2019;78(8):1048–54. https://doi.org/10.1136/annrheumdis-2018-214846.
Khoo JK, Barnes H, Key S, Glaspole IN, Östör AJ. Pulmonary adverse events of small molecule JAK inhibitors in autoimmune disease: systematic review and meta-analysis. Rheumatology (Oxford). 2020;59(9):2217–25. https://doi.org/10.1093/rheumatology/keaa117.
McCurdy JD, Kuenzig ME, Smith G, Spruin S, Murthy SK, Carrier M, et al. Risk of venous thromboembolism after hospital discharge in patients with inflammatory bowel disease: a population-based study. Inflamm Bowel Dis. 2020;26(11):1761–8. https://doi.org/10.1093/ibd/izaa002.
Cheng K, Faye AS. Venous thromboembolism in inflammatory bowel disease. World J Gastroenterol. 2020;26(12):1231–41. https://doi.org/10.3748/wjg.v26.i12.1231.
Chung WS, Peng CL, Lin CL, Chang YJ, Chen YF, Chiang JY, et al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Ann Rheum Dis. 2014;73(10):1774–80. https://doi.org/10.1136/annrheumdis-2013-203380.
Ungprasert P, Srivali N, Spanuchart I, Thongprayoon C, Knight EL. Risk of venous thromboembolism in patients with rheumatoid arthritis: a systematic review and meta-analysis. Clin Rheumatol. 2014;33(3):297–304. https://doi.org/10.1007/s10067-014-2492-7.
International Council for Harmonisation (ICH). 2019. https://www.ich.org/page/meddra.
Mease P, Charles-Schoeman C, Cohen S, Fallon L, Woolcott J, Yun H, et al. Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data. Ann Rheum Dis. 2020;79(11):1400–13. https://doi.org/10.1136/annrheumdis-2019-216761.
Jamilloux Y, El Jammal T, Vuitton L, Gerfaud-Valentin M, Kerever S, Sève P. JAK inhibitors for the treatment of autoimmune and inflammatory diseases. Autoimmun Rev. 2019;18(11):102390. https://doi.org/10.1016/j.autrev.2019.102390.
Acknowledgements
The authors wish to thank Jason Allaire, PhD, of Generativity Health Economics and Outcomes Research, for editorial assistance, which was funded by Arena Pharmaceuticals.
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This study was supported by Arena Pharmaceuticals.
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Juliana Setyawan is an employee of and owns stock in Arena Pharmaceuticals. Nassir Azimi, Vibeke Strand, Andres Yarur, and Moshe Fridman have received consulting fees from Arena Pharmaceuticals.
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All authors contributed to the writing and editing of this paper. JS and MF designed the study, and MF performed all analyses. All authors contributed to the interpretation of the results, and read and approved the final version submitted for publication.
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Setyawan, J., Azimi, N., Strand, V. et al. Reporting of Thromboembolic Events with JAK Inhibitors: Analysis of the FAERS Database 2010–2019. Drug Saf 44, 889–897 (2021). https://doi.org/10.1007/s40264-021-01082-y
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DOI: https://doi.org/10.1007/s40264-021-01082-y