The Safety of JAK Inhibitors

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Rheumatoid arthritis patients with herpes zoster infections who are on JAK inhibitors have a low overall risk of serious infections, shows a systematic review and meta-analysis published in the April 14 issue of Rheumatology.

Biologic therapies have revolutionized the treatment of rheumatoid arthritis by selectively targeting key inflammatory factors which, if effective, can lead to remission. While not all patients respond, and some realize diminishing gains over time, Janus kinase (JAK) inhibitors have emerged as important drugs that target small-molecules down stream of cytokine production and influence the functional outcomes of receptors that are stimulated.

Tofacitinib and baricitinib are the only two JAK inhibitors currently approved for rheumatoid arthritis.

The safety profile for JAK inhibitors includes the possibility of developing opportunistic viral infections, including the reactivation of the varicella zoster virus leading to herpes zoster.

The authors of this review, which was led by Katie Bechman of the Center for Rheumatic Disease at Kings College London, sought to determine the extent of serious infectious complications with particular focus on serious infections and herpes zoster infections in rheumatoid arthritis patients. The review included 21 phase two and three randomized controlled trials of tofacitinib (5 mg), baricitinib (4 mg) and upadacitinib (15 mg).

THE REVIEW INCLUDED 21 STUDIES
• 11 on tofacitinib with 5,888 patients
• 6 on baricitinib with 3,520 patients
• 4 on upadacitinib with 1,736 patients

INFECTION RATE FOR EACH OF THREE STUDY GROUPS
• Serious infections:  1.97, 3.16 and 3.02, respectively
• Herpes zoster infections:  2.51, 3.16 and 2.41, respectively

The primary outcome was defined as the presence of a serious infection leading to death, requiring hospitalization, or requiring intravenous antibiotics. The secondary outcome was defined as the frequency of opportunistic infections.

Serious infections were identified in 40 patients who received 5 mg of tofacitinib with 2,032 patient exposure years; in 26 patients who received 4 mg baricitinib with 822 patient years and, in five patients who received 15 mg or near equivalent of upadacitinib with 166 patient years.

“The absolute serious infection rates were low. However, across JAK inhibitors, the incidence of herpes zoster was higher than expected for the population (3.23 per 100 patient years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk,” the authors wrote.

TAKE-HOME POINTS FOR CLINICIANS

Two main points can be garnered from these data:

1) The absolute rates of serious infections in rheumatoid arthritis patients on JAK inhibitors are low. This speaks to the safety of these medications.
2) Herpes zoster is more common in rheumatoid arthritis patients on JAK inhibitors.

The likely mechanism for increased risk of herpes zoster risk in rheumatoid arthritis patients on JAK inhibitors is likely complicated and rooted in disrupting immune surveillance and cell-mediated immunity leading to varicella reactivation. However, clinicians should keep in mind that there is an increasing incidence in herpes zoster with age in the general population, which may mute these findings.

Both a limitation of the study and a positive outcome, indicator opportunistic infections were too rare to provide meaningful incidence rates. This fact should reassure clinicians who prescribe JAK inhibitors for rheumatoid arthritis as well as patients with regards to safety.

While relief is paramount on the minds of patients and in turn clinicians, we must examine risk lest we throw the baby out with the bath water. Often pain and low quality of life make patients desperate for treatment. Safety is the first priority as prevention of harm precedes treatment.

REFERENCE

Katie Bechman, Sujith Subesinghe, Sam Norton, et al. "A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis," Rheumatology. April 14, 2019. http://bit.ly/2LRLR9