Patients who initiated anti-TNF therapy for inflammatory diseases had no higher risk of developing herpes zoster than did those who took other disease-modifying antirheumatic drugs.
However, a large database review did find a doubling of risk among those taking at least 10 mg/day of corticosteroids, according to Dr. Kevin Winthrop and colleagues. The report is in the March 6 issue of the JAMA.
Dr. Kevin Winthrop
These findings shed important light on the current mixed-results in literature on the topic, wrote Dr. Winthrop of Oregon Health and Science University, Portland, and his coauthors. The study is more than twice as large as any other on the subject and looked at a large number of patients with elevated herpes zoster risk (JAMA 2013;309:887-95).
It comprised more than 61,000 patients: 33,324 with newly initiated anti-TNF alpha treatment for rheumatoid arthritis and 25,742 who took other nonbiologic disease modifying anti-rheumatic medications. It was a subanalysis of the ongoing Safety Assessment of Biologic Therapy, a U.S. multi-institutional project evaluating the safety of biologic therapies.
Patients were drawn from five large databases spanning 1998-2008: the National Medicaid and Medicare database; Tennessee Medicaid; New Jersey’s Pharmaceutical Assistance to the Aged and Disabled, Pennsylvania’s Pharmaceutical Assistance for the Elderly; and Kaiser Permanente of Northern California. Database selection was important in this study, the investigators said, "Because it contained a large number of Medicare and Medicaid recipients who might have had higher baseline herpes zoster risk due to comorbidities and other unknown factors."
The regression analysis was based on a propensity matching score that took into account a number of baseline factors, including demographics, markers of comorbidity and disease severity, and other potential risk factors for herpes including cancer or diabetes.
Patients were grouped according to disease: rheumatoid arthritis (36,212), inflammatory bowel disease. (10,717) and psoriasis, psoriatic arthritis, or ankylosing spondylitis (12,137). Across all of the groups, there were 470 cases of herpes zoster; 310 among those taking anti-TNF drugs (crude incidence rate of 10/1,000) and 160 among those taking other DMARDs (crude incidence rate of 11/1,000).
After the investigators adjusted for baseline corticosteroid use and the propensity matching score, they found no significant between-group differences in the risk of herpes zoster (hazard ratio of 11 for anti-TNFs; HR, 10 for DMARDs).
Daily use of at least 10 mg corticosteroids was associated with a significantly increased risk of the disease in all of the patient groups (HR, 2).
Most herpes cases (356) occurred in the rheumatoid arthritis group; the investigators analyzed this group separately. These patients were a median of 60 years old; 266 were taking the anti-TNF drugs and 90 other DMARDs. The median follow-up was almost 1 year (294 days). Herpes caused hospitalization in 16 (6%) of those using the medications and in five of the DMARD group (5.5%) – not a significant difference.
Limiting follow-up to 3-6 months did not change the results. When the researchers extended follow-up in the Medicaid/Medicare groups until the end of 2008, they found similar herpes crude incidence rates in the anti-TNF and DMARD groups, and similar disease risk (HR, 12.6 and HR, 12.4, respectively).
When the authors looked at risk in anti-TNF subgroups, they found the highest crude incidence rate among infliximab users (14/1,000) and the lowest for adalimumab users (10/1,000). However, this significant between-group difference disappeared when examined with the propensity matching score. "Furthermore," they noted, "A higher proportion of infliximab users used concomitant methotrexate at baseline and after [the] index date compared with those using etanercept or adalimumab."
The high herpes rate among patients with rheumatoid arthritis supports widespread use of the live attenuated herpes zoster vaccine in those aged 50 years and older, the authors contended.
"Currently, vaccination during active use of anti-TNF therapy is contraindicated due to theoretical safety concerns of using a live vaccine during such therapy; however, it is unclear if such concerns are valid. Our data suggest that patients who develop herpes zoster while taking anti-TNF therapy are no more likely to be hospitalized than persons with herpes zoster using nonbiologic DMARDs ... Given these findings, the potential importance of this vaccine within the rheumatoid arthritis setting and the difficulty in vaccinating patients given the widespread use of anti-TNF therapy, we believe that a trial to evaluate the safety of this live virus vaccine among current anti-TNF users is warranted."
Dr. Winthrop has consulted for Genentec, Abbott Pfizer, UCB Pharma, and Amgen, and received research grants from Pfizer. Other authors reported relationships with numerous pharmaceutical companies.