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Differential risk of herpes zoster infection with biologic agent use in rheumatoid arthritis: comment on the article by Yun et al

The study by Yun et al (1) in a recent issue of Arthritis Care & Research examining the risk of herpes zoster (HZ) in patients with rheumatoid arthritis (RA) initiated on biologic disease-modifying antirheumatic drugs revealed that the incidence of HZ was similar among the patient groups treated with the different biologic agents, which included the 5 anti–tumor necrosis factor (anti-TNF) agents, abatacept, rituximab, and tocilizumab. Our study of 20,357 veterans with RA assembled from the Department of Veterans Affairs (VA) national administrative databases (2) demonstrated a lower incidence of HZ (0.99 episodes per 100 patient-years) compared to Yun et al (1.97 episodes per 100 patient-years). Unlike Yun et al, we validated the diagnosis of HZ identified by International Classification of Diseases, Ninth Revision (ICD-9) codes by medical record review to eliminate false positives, accounting perhaps for the lower incidence in our study. In addition, our cohort was predominantly male, which may have led to a lower incidence as suggested by these same investigators previously (3). We designed our study to examine the effect of varying degrees of immunosuppression on the risk of HZ in RA. Therefore, RA patients in group 3 with severe disease treated with anti-TNF therapy had a higher incidence of HZ compared to those in group 1 with mild disease treated with hydroxychloroquine, gold, sulfasalazine, or penicillamine (10.6 versus 8.0 episodes per 1,000 patientyears). Patients in group 2 with moderate disease receiving methotrexate, leflunomide, azathioprine, cyclophosphamide, or anakinra had a higher incidence of HZ compared to those in group 1 (11.2 versus 8.0 episodes per 1,000 patient-years). There was no difference in the risk of HZ between patients in group 2 (hazard ratio [HR] 1.34, 95% confidence interval [95% CI] 1.13–1.59) and group 3 (HR 1.38, 95% CI 1.08– 1.77). Among TNF antagonists, we found a lower risk for HZ with the use of etanercept (HR 0.62, 95% CI 0.40–0.95) and adalimumab (HR 0.53, 95% CI 0.31–0.91) compared to infliximab, similar to findings by Galloway et al (4), but in contrast to those from the German biologics registry RABBIT (Rheumatoid Arthritis Observation of Biologic Therapy) (4) and the current study by Yun et al (1). One common and important risk factor for HZ in RA that emerged from all these studies was glucocorticoid use. Therefore, based on the evidence to date, the differential risk of HZ in patients with RA conferred by the biologic therapies, especially anti-TNF agents, remains unclear. It is clear, however, that the degree of immunosuppression modifies this risk including glucocorticoid use. This risk may be particularly germane to older patients, and those with significant comorbidities (2), and important to keep in mind when treating RA in such populations.