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Risk of Shingles with Tumor Necrosis Factor Antibodies
Abstract & Commentary
By Joseph E. Safdieh, MD, Assistant Professor of Neurology, Weill Medical College, Cornell University. Dr. Safdieh reported that he received grant/research support from the American Academy of Neurology.
Synopsis: When compared with conventional disease-modifying anti-rheumatic drugs (DMARD), tumor necrosis factor (TNF)-Alpha antibody treatment for rheumatoid arthritis (RA) may increase the risk of herpes zoster.
Source: Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA 2000;301:737-744.
Ever since they were initially approved by the U.S. Food and Drug Administration for the treatment of rheumatoid arthritis (RA), TNF-alpha receptor antibodies such as infliximab were known to induce an increased risk of bacterial infections, including tuberculosis. Much less is known about the risk of viral infections with these agents. Herpes zoster reactivation causes shingles and is more common in immune compromised patients, including those with HIV/AIDS and hematological malignancies and patients receiving chemotherapy. A causal relationship between TNF-alpha antibodies and varicella zoster virus (VZV) reactivation has never been clearly established. In this German prospective cohort study, the authors investigated whether TNF-alpha inhibitors, together as a class, or separately as either monoclonal anti-TNF-alpha antibodies (adalimumab, infliximab) or a fusion protein inhibitor (etanercept), are related to higher rates of herpes zoster in patients with RA.
The authors considered a patient as receiving anti-TNF-alpha treatment at the time of the herpes zoster infection if the treatment was ongoing or was terminated one month or less prior to the event. Incidence rates were calculated as the number of herpes zoster infections per 1,000 patient years of follow-up under specific treatment. A total of 5,040 patients were included in the analysis. Of note, patients receiving TNF-alpha agents were more likely to have worse disease severity and were more likely to be on oral corticosteroids.
The results demonstrated an incidence rate of 5.6 herpes zoster infections per 1,000 patient years in the control (DMARD) group compared to a 10.1 incidence rate in patients treated with anti TNF-alpha agents (8.9 for etanercept and 11.1 for infliximab/adalimumab). The hazard ratio for infliximab/adalimumab over DMARDs was 2.05, which reached statistical significance in univariate and multivariate analysis. Other factors which significantly increased the hazard ratio for the development of herpes zoster were advancing age (HR 1.28) and 10 mg or more of daily glucocorticoids (HR 2.52). Of note, very few patients developed post-herpetic neuralgia in any group and the rates of multidermatomal or ophthalmic zoster were increased in the TNF-alpha group, only, but the incidence rate was quite low at 2.5.
The authors conclude that treatment with monoclonal TNF-alpha antibodies may be associated with an increased risk of herpes zoster, but caution that further study is needed.
The findings of this study should be of interest to neurologists. Of course, neurologists have experience with the development of viral infections caused by monoclonal antibodies from our experience with the development of progressive multifocal leukoencephalopathy associated with natalizumab treatment in multiple sclerosis trials. Interestingly, modulation of the TNF-alpha system may actually induce or worsen demyelinating disease in some reports, suggesting that it plays a role in central nervous system inflammation as well. Neurologists are all too familiar with shingles and its frequent consequence, post herpetic neuralgia (PHN). I found it interesting that in this study, only two patients developed PHN. Perhaps the immune suppression caused by the drugs that led to the development of shingles somehow protected against PHN, a phenomenon that has been described in the past, leading to the use of prednisone in shingles by some neurologists to prevent PHN. This study did not note the development of VZV vasculopathy or encephalitis in any patient. Generally, immune-compromised patients are at increased risk of developing encephalitis and small vessel vasculopathy, so the lack of development of these complications in the patients on TNF-alpha inhibitor therapy is interesting and perhaps somewhat surprising.