Taking Multiple Targeted Therapies for RA May Exacerbate Risk of Herpes Zoster


Patients with rheumatoid arthritis taking at least 3 targeted therapies were found to have a greater risk of developing herpes zoster.

Taking a high number of targeted therapies to treat rheumatoid arthritis (RA)—not including Janus kinase inhibitors (JAKis)—may exacerbate the risk of developing herpes zoster (HZ), according to a study published in RMD Open.

Patients who were administered at least 3 targeted therapies were found to have a greater risk of developing HZ, which is caused by reactivation of the varicella zoster virus. Among patients using JAKis, increased disease activity was noted to be an additional risk factor; however, use JAKis did not increase the risk, according to the study authors.

The researchers used data from 1147 patients with RA from a Korean cohort study. Of these patients, 223 were using JAKis and 924 were using biologic disease-modifying antirheumatic drugs (bDMARDs). Prior to being matched for sex and age, 86.9% of patients were female—mainly because RA is more common in women than men. The mean (SD) age was 55.2 (13.5) years and the average RA duration was 11.2 (8.5) years.

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

Patients using 3 or more targeted therapies before their current medication showed a greater risk of developing HZ (odds ratio [OR], 5.29; 95% CI, 1.45-19.31). 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 findings showed 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 additional conditional logistic regression analyses were performed as well as adjustments for other variables, JAKis were still not found to increase the risk of HZ, according to the study authors.

Among 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 use of at least 3 prior targeted therapies (OR, 10.12; 95% CI, 1.92-53.49).

Concomitant use of the conventional synthetic DMARD methotrexate was not associated with increased risk of HZ development, which is consistent with prior studies. However, concomitant use or dose of oral glucocorticoids was not found to be a significant risk factor, despite previous research indicating 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 study authors wrote.

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

The authors noted that these findings may not be completely generalizable, because they came from a single-institution study in Korea. They suggest further research with larger population sizes to confirm the findings.

The researchers also could not compare matched patients from the case and control groups when identifying HZ risk factors, and did not study history of HZ infection, although they said 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,” the authors wrote.


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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