Safety of Janus Kinase Inhibitors in Older Patients: A Focus on the Thromboembolic Risk

Abstract

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a membrane-to-nucleus signaling cascade that effects activation of gene transcription. JAK inhibitors have demonstrated effectiveness in autoimmune diseases such as rheumatoid arthritis. An increased risk of infection, mainly varicella-zoster reactivation, with these new agents is of concern. Comorbid conditions, along with pharmacokinetic variations in drug metabolism in the older population, further increase the risk of adverse outcomes. Newly raised concerns for potential adverse effects such as deep vein thrombosis and pulmonary embolism are essential considerations for clinicians. Older patients are at increased risk because of multiple comorbid conditions and pharmacokinetic changes related to drug metabolism and excretion. Both the US FDA and the European Medicines Agency have issued warnings regarding this risk. These warnings highlight individuals aged > 50 years with concomitant cardiovascular risk factors. Furthermore, the FDA released a black box warning for increased thromboembolic risk associated with JAK inhibitors. As the use of these drugs increases, a solid understanding of adverse effects and risks is critical to those treating older adults. Key Points Thromboembolic risk is an important and emerging consideration for clinicians who prescribe Janus kinase (JAK) inhibitors. Older patients with rheumatoid arthritis are at increased thromboembolic risk because of age and comorbid conditions. The warnings issued by the US FDA and the European Medicines Agency highlight this risk. Infectious complications, such as herpes zoster, are known and essential considerations.

Risk of Thromboembolic Events and Associated Risk Factors, Including Treatments, in Patients with Immune-mediated Diseases

“…40 Since the boxed warnings were issued, a limited number of studies based on data from clinical trials have been published to assess the tolerability of JAK inhibitors. [43][44][45] A review published in 2020 that assessed the risks of TEs in older adults with RA concluded that the tolerability of JAK inhibitors is uncertain because age and cardiovascular risk factors make it difficult to draw conclusions. 44 However, an earlier study published in 2018 based on data from the US Food and Drug Administration Adverse Event Reporting System found that although JAK inhibitors were not associated with increased rates of DVT and PE specifically, pulmonary thrombosis and portal vein thrombosis are potential risks.…”

Reporting of Thromboembolic Events with JAK Inhibitors: Analysis of the FAERS Database 2010–2019

“…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.…”

Psoas abscess during treatment with intravenous tocilizumab in a patient with rheumatoid arthritis: a case-based review

“…Therefore, in this case, a causal relationship of a psoas abscess with tocilizumab alone would be concluded hastily. Also, when considering a targeted synthetic molecule, such as a JAK inhibitor, one should assess the risk in regard to recurrent urinary tract infections and thrombosis within pre-existing coronary heart disease, as well as an increased risk of herpes zoster infection in people over 65 years of age [ 28 , 35 , 36 ].…”