FormalPara Key Points

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,

5 Conclusion

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.