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Risk of Herpes Zoster in Individuals on Biologics, Disease-Modifying Antirheumatic Drugs, And/Or Corticosteroids for Autoimmune

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Risk of Herpes Zoster in Individuals on Biologics, Disease-Modifying Antirheumatic Drugs, And/Or Corticosteroids for Autoimmune Open Forum Infectious Diseases MAJOR ARTICLE Risk of Herpes Zoster in Individuals on Biologics, Disease-Modifying Antirheumatic Drugs, and/or Corticosteroids for Autoimmune Diseases: A Systematic Downloaded from https://academic.oup.com/ofid/article-abstract/3/4/ofw205/2649125 by University of East Anglia user on 12 November 2019 Review and Meta-Analysis Fawziah Marra,1 Elaine Lo,2,3 Viktor Kalashnikov,1 and Kathryn Richardson4 1University of British Columbia, Vancouver, Canada, 2Hong Kong University, China, 3National University Hospital, Singapore, 4University of East Anglia, United Kingdom Background. Studies examining the risk of herpes zoster (HZ) associated with immunosuppressants, such as biologics, nonbio- logical disease-modifying antirheumatic drugs (nbDMARDs), or corticosteroids, have generated conflicting results. Methods. We conducted a systematic literature search from January 1946 to February 2016. Search terms related to HZ, rheu- matoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematous, or inflammatory bowel disease, biologics, nbDMARDS, and corticosteroids were used. We included randomized controlled trials (RCTs) and observational studies reporting associations between immunosuppressants and HZ outcomes in adults. For RCTs, we used the Mantel-Haenszel fixed-effects model to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for HZ risk. For observational studies, adjusted ORs were pooled sep- arately using random-effects inverse variance models. Results. Data were pooled from 40 eligible RCTs (20 136 patients) and 19 observational studies (810 939 patients). Biologics were associated with a greater risk of HZ than control (RCTs: OR = 1.71, 95% CI = 1.11–2.64; observational studies: OR = 1.58, 95% CI = 1.39–1.81). In RCTs, the OR of non-tumor necrosis factor (TNF) blockers was 2.19 (95% CI 1.20–4.02), but that of TNF blockers was not significantly different from control. Increased risks of HZ with nbDMARDs (OR = 1.21; 95% CI = 1.15–1.28) and corticosteroids (OR = 1.73; 95% CI = 1.57–1.89) were observed in observational studies, but few RCTs examined these comparisons. Conclusions. Immunocompromised patients receiving biologics were associated with an increased risk of HZ. The risk is also increased with corticosteroids and nbDMARDs. These findings raise the issue of prophylaxis with zoster vaccine in patients initiat- ing immunosuppressive therapy for autoimmune diseases. Keywords. biologics; DMARDs; herpes zoster; immunocompromised; rheumatoid arthritis. Infection with varicella zoster virus, usually during child- of treatment for HZ and PHN takes place on an outpatient basis hood, leads to the virus seeding sensory ganglia and remaining with reported rates of HZ-related hospitalization ranging widely dormant [1]. Reactivation of the virus later in life leads to herpes from 2 to 25 per 100 000 person-years [5]. The medical cost of zoster (HZ) or shingles infection [1], which is characterized by a treating HZ in the United States has been estimated to be approx- unilateral vesicular and painful rash, usually in a single dermat- imately $1.1 billion US dollars per annum [6]. ome [2]. Herpes zoster causes much morbidity including pain, Rates of HZ infection in the general population are approxi- depression, and long-term disability in the form of postherpetic mately 3 to 5 per 1000 person years, and interestingly these rates neuralgia (PHN), pain that continues after the rash has subsided are increasing over time [4, 5]. The risk of HZ seems to increase [2, 3]. More than 90% of the population has serologic evidence of with decreasing cellular immunity, which is responsible for hold- varicella infection, and approximately 1 in 3 persons will develop ing the varicella virus in check [7]. Thus, the most important risk HZ during their lifetime, leading to approximately 1 million HZ factors for developing HZ are age and decreasing immune status cases per year in the United States [1, 4]. However, the majority [1, 5]. For example, studies have shown that rates of HZ infection in those 60 years of age and over is 6–8 per 1000 person years, and rise to 8–12 per 1000 person years in persons 80 years of age Received 8 August 2016; accepted 21 September 2016. Correspondence: F. Marra, BSc (Pharm), PharmD, Professor of Pharmacy, University of British [1, 5]. Herpes zoster risk is also higher in individuals who are Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3 ([email protected]). immunocompromised due to autoimmune diseases, solid organ Open Forum Infectious Diseases® or stem cell transplants, human immunodeficiency virus (HIV), © The Author 2016. Published by Oxford University Press on behalf of the Infectious Diseases and/or immunosuppressive medications that impair T-cell Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ immunity [8]. These medications include corticosteroids, biolog- by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any ics, such as tumor necrosis factor (TNF)-α blockers, or nonbio- medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact [email protected]. logic disease-modifying antirheumatic drugs (nbDMARDs), that DOI: 10.1093/ofid/ofw205 is, conventional synthetic DMARDs, such as methotrexate, and Risk of Herpes Zoster in Individuals on Biologics, DMARDS, and/or Corticosteroids for Autoimmune Diseases • OFID • 1 targeted synthetic DMARDs, such as tofacitinib [8]. Not only are only included the biologicals that have been approved by the elderly and immunocompromised individuals at higher risk for US Food and Drug Association and/or European Medicines HZ, but they are also more likely to develop HZ-related compli- Agency. Only RCTs and OBS, consisting of cohort studies cations. As such, studies have found the medical costs of treating and case-control studies, were eligible. We excluded SLE and HZ for immunocompromised patients to be nearly twice as high non-SLE RCTs with fewer than 15 and 50 patients in each arm, as other HZ patients, due to the higher rates of PHN and other respectively, because they were unlikely to be able to detect suf- complications in this group [5, 6]. ficient HZ events [12]. Due to the lack of randomization in OBS, There are multiple studies reporting the risk of HZ associ- eligible studies were those providing adjusted or propensity Downloaded from https://academic.oup.com/ofid/article-abstract/3/4/ofw205/2649125 by University of East Anglia user on 12 November 2019 ated with individual immunosuppressants in patients with score-matched associations. We excluded non-English, nonhu- autoimmune diseases such as rheumatoid arthritis (RA), pso- man, nonadult (ie, juvenile disease), and unpublished studies. riasis, psoriatic arthritis, systemic lupus erythematous (SLE), Finally, although individuals with HIV, solid organ transplant, and inflammatory bowel disease (IBD). However, the results are and cancer may also receive treatment with biologicals, nbD- conflicting and statistical significance is often not detected due MARDS, and/or corticosteroids, we excluded these individuals to the low incidence of HZ. We therefore conducted a system- because the mechanisms of the immunosuppression is distinct atic review and meta-analysis of published studies to assess the in each of these diseases and thus it is very likely that the back- association of biologics, nbDMARDs, corticosteroids, or com- ground risk of HZ is very different in each of these diseases. binations and risk of HZ in adults with autoimmune diseases. Data Extraction, Study Verification, and Quality Assessment METHODS Data were extracted independently by 2 authors (E. L. and V. K.) using a standardized abstraction form. Discrepancies were This systematic review and meta-analysis was reported accord- resolved through discussion with 2 other authors (F. M. and ing to the Preferred Reporting Items for Systematic Reviews K. R.). Data extracted from the studies included the author, date and Meta-Analyses (PRISMA) [9] statement for randomized of the study, baseline characteristics of patients (underlying controlled trials (RCTs) and guidelines for the reporting of autoimmune disease, age, sex), total number of subjects, study observational studies (OBS) and adverse events (AEs) [10, 11]. duration, treatment, number of patients in each medication A prespecified study protocol was developed before the litera- group, duration of treatment, person-years, HZ definition, and ture review and followed but was not registered. incidence of HZ within the different medication groups. Literature Search For RCTs, where possible, we included all AEs reporting of We conducted a systematic literature search using MEDLINE, HZ. If not recorded as such, we examined serious AEs (SAEs) of EMBASE, Google, Google Scholar, Cochrane, CAB Direct, HZ, which were generally defined as HZ that is either life-threat- CINAHL, Web of Knowledge, and PubMed for articles reporting ening, causing hospitalization, or significant disability or inca- on herpes infection in immunocompromised patients published pacity. For the OBS, we included outcome definitions of HZ between January 1946 and February 2016. Search terms, as both from either diagnostic records and/or adjunctive use of antiviral keywords and subject headings,
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