Review of Herpes Zoster with Immunosuppression and Autoimmune Disease Save

Researchers from the University of British Columbia reported on their systematic review and meta-analysis of risk of herpes zoster (HZ) in patients receiving biologics, DMARDs and/or corticosteroids for autoimmune diseases.

Their review included 40 randomized controlled trials (RCTs) with 20,136 patients and 19 observational studies (810,939 patients) that looked at associations between immunosuppression and risk of HZ in adults with rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), lupus (SLE) and inflammatory bowel disease (IBD).

They found an increased risk of HZ with biologic use in both RCTs (OR 1.71, 95% CI 1.11-2.64) and observational studies (OR 1.58, 95% CI 1.39-1.81). They were unable to compare individual biologic agents but did separate non-TNF blockers from TNF blockers and found an increased risk with the former (2.19, 95% CI 1.20-4.02) but not with the latter.

They also found an increased risk with non-biologic DMARDs (1.21, 95% 1.1501.28) and corticosteroids (1.73, 95% CI 1.57-1.89), but only from observational studies because too few RCTs looked at these comparisons.

Interestingly, they included tofacitinib as a nbDMARD, which may have contributed to the increased risk of HZ observed with this class. As we know, tofacitinib has an incidence of HZ nearing 40/1000 PYs (Curtis JR, et al. Ann Rheum Dis 2016; http://buff.ly/2dntqYF). This risk is 10 times that of the general population, and significantly higher than the HZ risk seen with of any of the other nbDMARDs.

As with any meta-analysis, it is limited by the reporting of HZ which is rarely reported as a separate entity and more often is reported as an adverse event. This is a common problem, as reviewed by Winthrop et al., and no consensus has previously been reached regarding what types of infections are considered “opportunistic infections” within the setting of biologic therapy (Winthrop KL, et al. Ann Rheum Dis 2015; http://buff.ly/2dnqGdO).

Does this study add to our knowledge of risk of HZ in the setting of immunosuppression? In my opinion, rheumatologists as group are already well-sensitized to the risks of HZ. Based on a large body of data we know our patients are at risk for HZ and we need to continue recommending vaccination in accordance with ACIP recommendations, at least for now.

Currently, vaccination during active use of biologic therapy is contraindicated, but it is unclear if this concern is valid. Small numbers of RA patients have received Zostavax® while on anti-TNF therapy without dissemination or developing HZ (Zhang J, et al. Arth Res Ther 2011;13(5):R174).

Toward achieving an answer for the question of safety for live HZ vaccines in the setting of biologics, the Safety and Effectiveness Study of the Live Zoster Vaccine in Anti-TNF Users (VERVE) trial is now underway (Curtis JR, https://clinicaltrials.gov/ct2/show/NCT01967316). This is a phase 2 randomized, double blind prospective study comparing Zostavax to placebo in RA patients over 50 years on anti-TNF therapy. The primary outcome is immunogenicity at 6 weeks, and secondary outcomes are clinical effectiveness, safety and adverse events.

We anxiously await the results of this study as it will have huge implications for our patients who we know are at increased risk of HZ, even at younger ages. Curtis, et al recently published a retrospective study using claims data to compare the absolute rate of HZ in younger patients with rheumatologic diseases to that of HZ in healthy adults ≥ 60 years without autoimmune disease (Yun H, et al Arth Rheumatol 2016;68(9):2328-37). They found an increased incidence of HZ in patients < 50 years with certain diseases, for example SLE patients as young as 21 years had a risk of HZ that was greater than that of healthy adults ≥ 60 years.

Bottom line: HZ is a worrisome complication for patients with immunosuppressive illnesses. Clinicians caring for such patients such as rheumatologists need to remain vigilant. Finally improved vaccine strategies and vaccines are urgently needed to protect this vulnerable patient population.