Risk of Herpes Zoster Increased With TNFi Treatment in RA Patients

Herpes zoster virus on arm
Herpes zoster virus on arm
Patients with rheumatoid arthritis receiving tumor necrosis factor inhibitors or using corticosteroids were significantly more likely to have herpes zoster.

Patients with rheumatoid arthritis (RA) receiving tumor necrosis factor inhibitors (TNFi) or using corticosteroids were significantly more likely to have herpes zoster (HZ) compared with other biologic or conventional synthetic disease-modifying antirheumatic drugs (DMARDS), according to recent research published in the Journal of Rheumatology.

Sayoko Harada, MPharm, from the division of epidemiology and pharmacoepidemiology of rheumatic diseases and Institute of Rheumatology at Tokyo Women’s Medical University in Japan, and colleagues, evaluated the rate of HZ in 1987 patients from 27 centers in the Registry of Japanese Rheumatoid Arthritis Patients on Biologics for Longterm Safety (REAL) database.

The cohort was 81.5% female and consisted of patients with a median RA disease duration of 6 years who received either biological DMARDs or conventional synthetic DMARDs during a 5-year period. Patients used biological DMARDs with TNFis  such as infliximab, adalimumab, and etanercept, as well as non-TNFis such as tocilizumab and abatacept, while other patients received methotrexate (MTX), immunosuppressive DMARDs such as leflunomide, tacrolimus, azathioprine, mizoribine, and cyclophosphamide, or oral corticosteroids.

The researchers also used a nested control case (NCC) group of 43 patients and a control group of 214 patients to estimate the relationship between immunosuppressive drugs and HZ incident rate.

“For each patient who developed HZ during the observation period (case group), the date when HZ occurred was defined as the index date,” Dr Harada said.”For a patient who developed HZ multiple times during the observation period, the first date it occurred was defined as the index date,” Dr Harada and colleagues wrote. “We randomly selected 5 control patients matched for age at index date (±3 years), sex, observation start year (ie, 2005-2007 or 2008-2011), and comorbidity (pulmonary disease, renal failure, or diabetes mellitus) at baseline who had not developed HZ until the index date of each case.”

Dr Harada and colleagues found there was a 6.66 crude incidence rate (IR) of HZ per 1000 person-years (95% CI, 4.92-8.83). In the NCC, the researchers found significant association in patients taking TNFis and oral corticosteroids, with an odds ratio (OR) of 2.28 in patients taking TNFis (95% CI, 1.09-4.76) and an OR of 1.13 (95% CI, 1.03-1.23) in patients taking oral corticosteroids per 1 mg increment of prednisolone. The researchers noted there was no elevated OR in patients taking MTX or non-TNFis.

Summary & Clinical Applicability

“We showed that TNFi use and higher corticosteroid dosage were significantly associated with the occurrence of HZ,” Dr Harada and colleagues wrote. “Our results suggest that careful monitoring for HZ is necessary in patients with RA using these drugs.”


Researchers noted 5 potential limitations to their study:

  • selection bias for patients who may have has appropriate risk management for HZ due to the low incidence in the study
  • underestimation of HZ incidence due to low reporting at other centers
  • the effect of patients lost to follow up
  • the lack of data on disease activity, structural damage, physical function, and comorbidity
  • lack of comparison data between patients taking different biological DMARDS due to low event rates


Harigai received honoraria from Mitsubishi Tanabe Pharma Co.

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Harada S, Sakai R, Hirano F, et al. Association between medications and herpes zoster in Japanese patients with rheumatoid arthritis: A 5-year prospective cohort study [published online April 15, 2017]. J Rheumatol. doi:10.3899/jrheum.161196

This article originally appeared on Rheumatology Advisor