Use of Multiple Targeted Therapies for RA Linked to Herpes Zoster Risk, Study Finds

Patients with rheumatoid arthritis (RA) who used 3 or more targeted therapies, but not Janus kinase inhibitors, were at greater risk of developing herpes zoster, according to findings from a Korean study.

A study published in RMD Open found that a higher number of targeted therapies taken for rheumatoid arthritis (RA), not including Janus kinase inhibitors (JAKis), was associated with an increased risk of developing herpes zoster (HZ).

More specifically, patients who had received at least 3 targeted therapies were at greater risk of developing HZ—a virus caused by reactivation of varicella zoster virus with symptoms including rash and severe pain. For those using JAKis, higher disease activity was found to be an additional risk factor, but JAKi use itself did not increase the risk.

A Korean cohort study collected data from 1147 patients with RA, with 223 using JAKis and 924 using biologic disease-modifying antirheumatic drugs (bDMARDs). Before matching for sex and age, most (86.9%) were female, as RA affects women more than men. The mean (SD) age was 55.2 (13.5) years and the average RA duration was 11.2 (8.5) years.

Of this general group, 61 patients were diagnosed with HZ during the observation period, which was between June 2011 or March 2017—depending on the cohort study—and May 2020. A control population of 610 people was matched for sex and age. Tofacitinib (Xeljanz) was the most commonly used targeted therapy among patients with HZ (23.0%) and a significant difference between HZ cases and controls was noted (P = .037).

Patients who used 3 or more targeted therapies before their current medication had an increased risk of developing HZ (odds ratio [OR], 5.29; 95% CI, 1.45-19.31) and RA duration was significantly shorter in patients who developed HZ (OR, 0.54; 95% CI, 0.30-0.97).

After adjusting for other risk factors, the authors found that JAKi (OR, 1.35; 95% CI, 0.70-2.61) and oral glucocorticoid (OR, 1.36; 95% CI, 0.76-2.45) use did not increase HZ risk. After the investigators performed additional conditional logistic regression analyses and adjusting for other variables, JAKis still did not increase HZ risk.

For JAKi users, higher disease activity score 28-erythrocyte sedimentation rate (OR, 1.44; 95% CI, 1.06-1.97) was found to be a risk factor, as was recipt of at least 3 previous targeted therapies (OR, 10.12; 95% CI, 1.92-53.49).

Consistent with past findings, concomitant use of the conventional synthetic DMARD methotrexate was not associated with increased risk of HZ development. However, concomitant use or dose of oral glucocorticoids was not found to be a significant risk factor in this study, despite past research suggesting that it doubles the risk of HZ in JAKi users.

“The reason for the difference might be that our study investigated glucocorticoid use on the date of data collection only, while previous studies allowed at least a month for extension to exposure,” the authors said.

Also differing from past studies, HZ vaccination did not appear to have a protective effect. The authors credit the low vaccination rate—only 18.4% among JAKi users in the study—as a potential primary reason, which was caused by general unavailability of the recombinant zoster vaccine in Korea.

The authors noted that these findings may not be completely generalizable, as they came from a single-institution study in Korea, requiring further research with larger population sizes. They also could not compare matched patients from the case and control groups when identifying HZ risk factors, nor did they study history of HZ infection, although they believe HZ history would correlate with lack of JAKi use.

“However, in the clinical setting, previous HZ infection was not a contraindication for JAKi; and other factors such as preference for oral regimen, comorbidities and disease activity could be important for the choice of JAKi or bDMARD,” they said.


Song Y, Cho S, Kim H, et al. Risk factors for herpes zoster in Korean patients with rheumatoid arthritis treated with JAK inhibitor: a nested case–control study. RMD Open. Published online January 28, 2022. doi:10.1136/rmdopen-2021-001892

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