Increased Herpes Zoster Risk in Patients With RA Treated With Biologic DMARDs

Risk of stroke after herpes zoster in patients with autoimmune diseases
Risk of stroke after herpes zoster in patients with autoimmune diseases
Event and incidence rates of herpes zoster in patients with RA treated with biologic, tsDMARDs are compared.

Patients with rheumatoid arthritis (RA) treated with biologic, targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), which includes JAK inhibitors, are more than 3 times as likely to develop herpes zoster compared with patients with RA treated with conventional synthetic (cs) DMARDs, according to data from a prospective longitudinal cohort published in Annals of the Rheumatic Diseases. Older age and immunosuppressive therapy such as glucocorticoids also increased the risk for herpes zoster events, the study showed.

Investigators included patients who were registered in RABBIT, a longitudinally followed cohort of German patients with RA who were enrolled after starting a new biologic (b) DMARD or tsDMARD, or after starting a new csDMARD following at least 1 prior DMARD therapy. Demographic and clinical information was collected from patients and their rheumatologists at months 3, 6, and every 6 months thereafter, and patients are followed for up to 10 years. For this study, investigators included patients enrolled from 2007 and on with at least 1 follow-up. DMARD treatments included monoclonal anti-TNF antibodies, soluble TNF receptor fusion protein, T-cell costimulation modulator, B-cell targeted therapy, IL-6 inhibitors, and JAK inhibitors (tsDMARDs), with csDMARD treatment as the reference group.

The primary outcome was all herpes zoster events while undergoing DMARD treatment. Investigators calculated exposure-adjusted event rates (EAERs) and exposure-adjusted incidence rates (EAIRs) of herpes zoster per 1,000 patient-years. To adjust for possible confounding by indication, investigators used inverse probability weights.

There were 13,991 patients included in the final analysis, with 559 herpes zoster events reported by 533 patients. The mean age was 57.7 years, and more than 70% were women. The EAER of herpes zoster was highest for tsDMARDs at 21.5 (95% CI, 16.4-27.9), followed by B-cell targeted therapy (10.3; 95% CI, 8.0-13.0), monoclonal anti-TNF antibodies (9.3; 95% CI, 7.7-11.2), IL-6 inhibitors (8.8; 95% CI, 6.9-11.0), soluble TNF receptor fusion protein (8.6; 95% CI, 6.8-10.8), T-cell costimulation modulator (8.4; 95% CI 5.9-11.8) and csDMARDs (7.1; 95% CI, 6.0-8.3).

The event rate of serious herpes zoster adverse events over all DMARD treatments per 1000 patients years was 1.0 (95% CI, 0.7-1.2), with rates significantly higher in B-cell targeted therapy (P .0013) and JAK inhibitor (P <.0001) groups.

After adjusting for age, sex, and glucocorticoid use, and weighting with inverse probability weight, there was a significantly higher risk for herpes zoster in patients treated with JAK inhibitors (HR, 3.66; 95% CI 2.38-5.63), monoclonal anti-TNF antibodies (HR, 1.63; 95% CI 1.17-2.28), and B-cell targeted therapy (HR, 1.57; 95% CI 1.0s-2.40) compared with csDMARD treatment. A sensitivity analysis showed similar results, except B-cell targeted therapy was no longer significantly associated with herpes zoster risk compared with csDMARDs.

Older age (P <.0001), female sex (P =.0051) and glucocorticoid use in a dose-dependent manner (P <.0001) were significantly associated with an increased risk for herpes zoster before inverse probability weighting. After weighting with inverse probability weight, female sex was no longer significantly associated with increased herpes zoster risk.

The study was limited by lack of knowledge about patients’ zoster vaccination status, possibly causing an unequal distribution between the patient groups.

Investigators emphasized “the clear dose dependence with a 3.5-fold higher [herpes zoster] risk at [glucocorticoid] doses above 10 mg” for RA patients.

“In terms of risk assessment with regard to [zoster] vaccination, this suggests that especially elderly patients with higher glucocorticoid doses and patients for whom tSDMARD therapy is planned should be considered for vaccination,” the study authors wrote.

Disclosure: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.  


Redeker I, Albrecht K, Kekow J, et al. Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register. Ann Rheum Dis. Published online July 5, 2021. doi:10.1136/annrheumdis-2021-220651