Recent issues in JAK inhibitor safety: perspective for the clinician

ABSTRACT

Introduction

Five jakinibs are approved for the treatment of rheumatic diseases. There has been a question of their relative safety to other medications since their approval.

Areas covered

A literature search was conducted in Pub Med for the integrated safety databases of these molecules in their clinical trial program, registries, and insurance claims data and in a prospective head-to-head study compared to tumor necrosis factor inhibitors in a high-risk population for cardiovascular and malignancy events. There were no differences found in the safety databases, registries or insurance claims data indicating jakinibs are more likely to cause major adverse cardiac events, malignancy, venous thrombotic episodes, infections, and mortality compared to other medications. The head-to-head trial found that there were numerically more of these events with the jakinib compared to tumor necrosis factor inhibitors.

Expert opinion

Cardiac events and malignancy occur more frequently in rheumatoid patients with active disease. Although the safety databases, claims data, and registries suggest that there is no difference in the risks with a jakinib versus biologics, the prospective safety study showed these events occur numerically higher in patients at the highest risk for these events. In this population, one should consider using a biologic before a jakinib.

KEYWORDS:

• Biologic DMARDs
• JAK inhibitors
• rheumatoid arthritis
• safety
• TNF inhibitors
• targeted synthetic DMARDs

Article highlights

• Active rheumatoid arthritis is associated with an increased risk of serious infections, major adverse cardiovascular events, malignancy, mortality, and venous thrombotic episodes.

• Effective treatment with conventional and biologic disease modifying drugs is associated with a marked reduction in the incidence of these adverse events in patients with rheumatoid arthritis

• Jakinibs, similar to other disease modifying anti-rheumatic drugs, have been associated with upper respiratory and urinary tract infections, but have an increased incidence rate of herpes zoster, elevation of creatinine phosphokinase, serum creatinine, hepatic enzymes, and lipids.

• Evaluation of the integrated safety data bases and registry data have suggested that there is little, if any, difference in the incidence rate of major adverse cardiovascular events, malignancy, serious infections, venous thrombotic episodes, mortality, and infections (other than herpes zoster) when comparing each of the jakinibs to biologic disease modifying drugs.

• A prospective, well-designed safety trial revealed a numerical difference in the incidence rates of major adverse cardiovascular events, malignancy, mortality, venous thrombotic episodes, and serious infections in rheumatoid arthritis patients who were a high risk for these events treated with tofacitinib compared to tumor necrosis factor inhibitors, particularly patients over the age of 65 with a history of smoking or increased risk of these events, suggesting that in these patients one should consider the use of a tumor necrosis factor inhibitor prior to the use of a jakinib.

• This study did not and could not prove that tofacitinib is associated with an increased risk of these events but rather may not decrease the risk of these events as well as tumor necrosis factor inhibitors.

Declaration of interest

R Fleischmann is a consultant for AbbVie, Amgen, BMS, Eli Lilly, Gilead, Janssen, Pfizer and UCB. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Conflict of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.