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The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study

The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory... Introduction: Zostavax, a live attenuated vaccine, has been approved in the United States for use in older individuals to reduce the risk and severity of herpes zoster (HZ), also known as shingles. The vaccine is contraindicated in individuals taking anti-tumor necrosis factor alpha (anti-TNF) therapies or other biologics commonly used to treat autoimmune diseases because of the safety concern that zoster vaccine may be associated with a short-term HZ risk. The objective of the study was to examine the use, safety (short-term HZ risk after vaccination), and effectiveness of zoster vaccine in individuals with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or inflammatory bowel diseases. Methods: We conducted a cohort study of patients aged 50 years and older with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or inflammatory bowel diseases by using administrative claims data from a nationwide health plan from January 1, 2005, to August 31, 2009. We examined the extent to which zoster vaccine was used; assessed factors associated with vaccine use (Cox proportional hazards regression); and compared the incidence rates of herpes zoster (HZ) between vaccinated and unvaccinated patients. Results: Among 44,115 patients with the autoimmune diseases, 551 (1.2%) received zoster vaccine, and 761 developed HZ. Zoster vaccine use increased continuously after approval in 2006. Younger and healthier patients, those who had an HZ infection within the past 6 months, and those who were not using anti-TNF therapies were more likely to receive the vaccine. Approximately 6% of vaccinated patients were using anti-TNF therapies at the time of vaccination. The incidence rates of HZ were similar in vaccinated and unvaccinated patients (standardized incidence ratio, 0.99; 95% confidence interval, 0.29 to 3.43). Conclusions: Use of the zoster vaccine was uncommon among older patients with autoimmune diseases, including those not exposed to immunosuppressive medications. The short-term risk of HZ did not appear to be increased in vaccinated patients, even among those using immunosuppressive therapies (for example, biologics) at the time of vaccination. However, our study was limited by the small number of vaccinated patients, and further evidence is needed to confirm the vaccine’s safety and efficacy in this population. * Correspondence: jcurtis@uab.edu Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35294, USA Full list of author information is available at the end of the article © 2011 Curtis et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 2 of 9 http://arthritis-research.com/content/13/5/R174 used the administrative claims data of a large nation- Introduction wide health plan to investigate the following aims in a Herpes zoster (HZ) infection, also known as shingles, is cohort of patients diagnosed with RA, psoriatic arthritis, caused by the reactivation of latent varicella-zoster virus psoriasis, ankylosing spondylitis, and/or inflammatory (VZV) and usually occurs decades after primary infec- bowel diseases: (a) to describe the use of zoster vaccina- tion. HZ is characterized by a painful blistering rash and tion over time; (b) to determine the extent to which zos- occurs mostly in older adults. Many patients experience ter vaccine was used in patients taking concomitant persistent pain after the rash heals, a common yet debil- immunosuppressive agents; (c) to assess patient charac- itating complication known as postherpetic neuralgia teristics associated with receipt of zoster vaccine; and (PHN) [1,2]. In the United States, the age- and sex- (d) to evaluate the incidence of HZ in patients who adjusted incidence rate (IR) of HZ is estimated to be 3.0 received and did not receive zoster vaccine. to 4.0 per 1,000 person-years [3-5]. Older age is the most important risk factor for the development of both Materials and methods HZ and PHN [3,4]. Disease risk is elevated in individuals Study population who are immune-suppressed due to human immunode- We conducted a retrospective cohort study by using ficiency virus (HIV) infection and transplantation [3,4,6]. administrative claims data from Aetna, a nationwide Recent studies reported an increased risk of HZ in health plan that provides medical coverage to more than patients with rheumatoid arthritis (RA) that is attributa- 17 million individuals in the United States, from January ble both to the disease and to treatment with anti- 1, 2006, to August 31, 2009. The cohort included tumor necrosis factor alpha (anti-TNF) therapies and patients with RA, psoriatic arthritis, psoriasis, ankylosing other immunosuppressive agents [7,8]. In addition, anti- spondylitis, and inflammatory bowel diseases, identified TNF therapies has been associated with a more severe by using the International Classification of Diseases, 9th course of HZ among patients with rheumatic diseases; revision (ICD-9) and National Drug Codes (NDC) those receiving anti-TNF therapies were 9 times more codes. Patients were included if there were (a) two ICD- likely than those not to be hospitalized for HZ [9]. 9 diagnosis codes from an outpatient physician or hospi- Zostavax, a live attenuated vaccine, was approved in tal encounter, separated by at least 7 days and occurring 2006 for use in individuals 60 years of age or older to within 365 days; or (b) one physician- or hospital- reduce the risk and severity of HZ. The Advisory Commit- encounter diagnosis code followed by a prescription for tee on Immunization Practices (ACIP) recommended that medications used to treat autoimmune diseases within all adults older than 60 years be considered for vaccina- tion, with certain exceptions [10]. Along with patients 365 days (diagnosis codes and medications listed in Additional file 1). We defined each subject’sindex date with certain malignancies and HIV/AIDS, patients receiv- (patients consist of a mix of incident and prevalent ing biologic agents such as anti-TNF therapies, some non- cases) as the date of the second diagnosis code or the biologic disease-modifying antirheumatic drugs date when the prescription was filled. Patients who met (DMARDs), such as high doses of methotrexate, and high definitions for two or more of the diseases of interest doses of glucocorticoids were also excluded. The concern were categorized into a multiple diseases category, and is that zoster vaccine, a live vaccine, could acutely trigger their index date was defined as the earliest of all dis- the development of HZ in patients with compromised ease-specific index dates. immune systems in a short time frame (for example, To ensure that we had complete medical and phar- within 4 to 6 weeks after vaccination) despite conferring a macy claims necessary to identify and characterize the longer-term protection against the development of HZ. study population, all subjects were required to have a Based on expert opinion, glucocorticoids at prednisone- “baseline period” of at least 183 continuous days during equivalent doses up to 20 mg/day, low-doses of metho- which they had medical and pharmacy benefits; subjects trexate (< 0.4 mg/kg/week, a typical dose for patients with aged 65 or older had to be enrolled in a Medicare autoimmune diseases), azathioprine (< 3.0 mg/kg/day), Advantage plan with a concomitant pharmacy benefit and 6-mercaptopurine (< 1.5 mg/kg/day) were considered administered by Aetna. Follow-up started on the later of acceptably safe so as not to require a contraindication for theindex dateor thedateonwhich thesubject hada use of zoster vaccine. Similarly, the American College of baseline period of at least 183 days. Subjects were cen- Rheumatology (ACR) 2008 guidelines for the use of biolo- sored when they lost either medical or pharmacy bene- gic and nonbiologic DMARDS did not recommend the fits, died, or for individuals aged 65 years or older, if administration of zoster vaccine to patients with RA or Aetna became the secondary payer to Medicare. Patients other rheumatic diseases treated with biologics [11]. In light of the uncertainties regarding the use, safety, were excluded if they were younger than 50 years at the and effectiveness of zoster vaccine in this population, we start of follow-up or received zoster vaccine during the Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 3 of 9 http://arthritis-research.com/content/13/5/R174 baseline period. Although the ACIP recommended the were conducted in patients who received zoster vaccine use of zoster vaccine in immune-competent individuals and were followed up for at least 30 days after aged 60 years or older [10], given the increased HZ risk vaccination. previously observed in this population, we included For Aim 3, we used Cox proportional hazards regres- those between 50 and 60 years of age in our analysis to sion models to assess patient characteristics associated assess the extent to which zoster vaccine was used. with time to HZ vaccination. Subject characteristics examined were gender, type of autoimmune disease, and Assessment of vaccination status, HZ infection, and several time-varying factors including age, co-morbid- ities measured by using the Charlson co-morbidity exposure to immunosuppressive agents Zoster vaccine was covered under the health plan’s index [12], number of physician visits, hospitalization medical benefit for individuals aged 60 or older begin- (yes or no), history of HZ infection (recent, within the ning June 1, 2006, and was ascertained by using the past 6 months; remote, more than 6 months ago), his- Current Procedural Terminology (CPT) code 90736. tory of influenza and pneumococcal vaccine (within the Reimbursement of zoster vaccine for patients younger past 12 months), and use of medications listed in Aim than 60 years was made on a case-by-case basis. Cases 2. Whenever an event occurred, the time-varying char- of HZ were identified by the first HZ claim for each acteristics of interest were ascertained as of that time patient that was preceded or followed by a prescription for all patients by using claims in the preceding 6- for acyclovir, famciclovir, and valacyclovir within 30 months period, unless otherwise specified. days of the HZ claim date. Exposures to immunosup- For Aim 4, accrual of person-time began at the start pressive agents were ascertained by the days’ supply for of follow-up, and a vaccinated subject would contribute all relevant medications. To estimate cumulative gluco- both unvaccinated and vaccinated person-time. We cal- corticoid exposure as a time-varying variable, cumulative culated the crude and age- and sex-specific incidence average daily doses were calculated by summing the rates of HZ in vaccinated and unvaccinated person- total amount of oral glucocorticoids prescribed in the times. We applied the age- and sex-specific incidence preceding 6 months and then dividing the total amount rates of the unvaccinated to age- and sex-specific vacci- by 183 days. Subjects were then categorized into four nated person-time to derive the expected number of HZ groups based on their cumulative average daily predni- cases among the vaccinated and calculated the standar- sone-equivalent glucocorticoid dose: none, low (less dized incidence-rate ratio as the observed divided by the than 10 mg/day), medium (10 to 20 mg/day), and high expected number of cases [13]. (greater than 20 mg/day). Sensitivity analyses Statistical analyses Because zoster vaccine was approved for use in the Uni- To characterize use of the zoster vaccination (Aim 1), ted States in May 2006 in individuals aged 60 or older, we calculated the incidence proportion of zoster vacci- sensitivity analyses were conducted (a) in patients for nation for each 6-month interval beginning July 1, 2006, whom we had complete medical and pharmacy claims and ending August 31, 2009. For each time interval, the prior to or since June 1, 2006, to avoid misclassification denominator was the number of subjects who were of vaccination status in patients who might have been unvaccinated at the start of the interval and were under vaccinated before joining the health plan; and (b) in observation throughout the entire interval, and the patients aged 60 or older as of the start of follow-up. numerator was the number of these subjects who were BecauseHZinfectionsdiagnosed latein thecourseof vaccinated during the interval. Because we had claims the infection might not benefit from or receive antiviral up to August 31, 2009, the incidence proportion from medications, and approximately 10% to 20% of HZ cases July 1, 2009, to August 31, 2009, was multiplied by 3 to were not treated with antiviral medication, we con- approximate the incidence proportion for the 6-month ducted a sensitivity analysis that used an alternate defi- period ending December 31, 2009. nition for HZ that required only the HZ diagnosis code To characterize the immune status of patients at time to calculate incidences of HZ in vaccinated and unvacci- of vaccination (Aim 2), we described the numbers and nated patients. percentages of patients who used anti-TNF therapies The University of Alabama at Birmingham Institu- (etanercept, infliximab, adalimumab), other biologic tional Review Board approved the study and waiver of agents (abatacept, rituximab), traditional DMARDs informed consent. (methotrexate, hydroxychloroquine, sulfasalazine, azathioprine, leflunomide, mercaptopurine), and oral Results glucocorticoids 30 days before and up to 30 days after We identified 44,115 eligible subjects classified as having the administration of zoster vaccine. These analyses at least one of the autoimmune diseases of interest who Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 4 of 9 http://arthritis-research.com/content/13/5/R174 were at least 50 years old at the start of observation. At (9.3%) used oral glucocorticoids. A total of 47 patients baseline, their average age was 58.1 (standard deviation used biologics at some time within 30 days before and (SD), 6.7) years and 27,443 (62.2%) were female; 19,326 after vaccination. None of the 47 subjects developed HZ (43.8%) had RA, 867 (2.0%) had psoriatic arthritis (PsA), in the 30 days after vaccination. Their average age was 10,712 (24.3%) had psoriasis (PsO), 633 (1.4%) had AS, 60 years (standard deviation, 5); 64% were women; and 8,639 (19.6%) had IBD, and 3,938 (8.9%) had two or 70% were not exposed to oral glucocorticoids, 28% to a more of these diseases. During follow-up, 551 (1.2%) daily average dose of no more than 20 mg, and 2% to a subjects received zoster vaccine. The earliest claim for daily average dose of 20 mg or more. Patients using anti-TNF therapies were less likely to vaccination occurred in August 2006; subsequently, vac- cine use increased continuously over time (Figure 1). receive zoster vaccine than those who were not using The distribution of patients’ characteristics at baseline anti-TNF agents (hazard ratio (HR), 0.47; 95% CI, 0.33 by vaccination status is presented in Table 1. to 0.67) (Table 3). Patients who were using other biolo- Among the 551 subjects who received zoster vaccine, gics (HR, 0.52; 95% CI, 0.19 to 1.40) or high-dose oral complete claims history for at least 30 days after vacci- glucocorticoids (HR, 0.46; 95% CI, 0.15 to 1.45) were nation was available for 514 subjects. At the time of vac- only half as likely as were non-users to receive zoster cination, 32 (6.2%) subjects were using anti-TNF vaccine, but these associations did not reach statistical therapy, 34 (6.6%) were using methotrexate, and 33 significance. Patients aged 60 to 64 years were most (6.4%) were using oral glucocorticoids (Table 2). In the likely to receive zoster vaccine; those with fewer co- 30 days after vaccination, 40 (7.8%) subjects used anti- morbidities and those without hospitalization within the TNF therapy, 45 (8.8%) used methotrexate, and 48 past 6 months were more likely to receive zoster Figure 1 Incidence proportion for each 6-month period of zoster vaccination by calendar year from June 1, 2006, to December 31, 2009. The proportion is expressed as the proportion of unvaccinated individuals under observation and vaccinated in each 6-month period. It does not include individuals vaccinated in previous time periods. Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 5 of 9 http://arthritis-research.com/content/13/5/R174 Table 1 Baseline patient characteristics by vaccination gastroenterologists, or rheumatologists, both in the over- status all cohort and in patients who were exposed to biologics Vaccination status at the time of vaccination. Baseline characteristics, n (%) Vaccinated Unvaccinated During 88,354 observed person-years, 761 cases of HZ n = 551 n = 43,564 occurred (incidence rate (IR), 8.6 per 1,000 person- Age groups (years) years). The IR increased with age from 8.14 per 1,000 50 to 59 202 (36.7) 30,156 (69.2) person-years among those aged 50 to 54 years to 15.30 60 to 64 275 (49.9) 9,573 (22.0) per 1,000 person-years among those 90 years or older. 65 and older 74 (13.4) 3,835 (8.8) Five cases of HZ occurred during vaccinated person- Women 352 (63.9) 27,091 (62.2) time (crude IR, 9.97 per 1,000 person-years), and 756 Inflammatory/Autoimmune disease HR occurred during unvaccinated person-time (crude RA 206 (37.4) 19,120 (43.9) IR, 8.61 per 1,000 person-years). The age- and sex-stan- Psoriatic arthritis 11 (2.0) 856 (2.0) dardized IR (expected IR) for the vaccinated was 10.06 Psoriasis 146 (26.5) 10,566 (24.3) per 1,000 person-years, resulting in a standardized IR Inflammatory bowel diseases 136 (24.7) 8,503 (19.5) ratio (vaccinated to unvaccinated) of 0.99 (95% CI, 0.29 Ankylosing spondylitis 8 (1.5) 625 (1.4) to 3.43). Multiple diseases 44 (8.0) 3,894 (8.9) The five cases of HZ in the vaccinated patients Medications occurred 7, 131, 201, 214, and 667 days after vaccina- TNF antagonists user 27 (4.9) 4,186 (9.6) tion. Within 90 days before vaccination, the only filled Other biologics user 0 (0) 198 (0.5) prescription for an immunosuppressive agent for the Conventional DMARDs user 92 (16.7) 9,312 (21.4) patient who developed HZ on day 7 after vaccination Oral glucocorticoids was for a 15-day supply of prednisone approximately 2 None 456 (82.8) 34,267 (78.7) months before receipt of zoster vaccination. None of the Low 86 (15.6) 8,041 (18.5) five patients was hospitalized. Medium 7 (1.3) 902 (2.1) Results from sensitivity analyses restricted to indivi- High 2 (0.4) 354 (0.8) duals under observation continuously from the time zos- Charlson comorbidity index ter vaccine was approved in 2006 had similar results 0 287 (52.1) 19,971 (45.8) (data not shown). When requiring only an HZ diagnosis 1 181 (32.9) 16,565 (38.0) code, the result was consistent, in that the crude inci- ≥ 2 83 (15.1) 7,028 (16.1) dence rates were the same between vaccinated (14.4 per Inpatient hospitalization 1,000 person-years) and unvaccinated (13.1 per 1,000 No 466 (84.6) 36,158 (83.0) person-years) patients. With Poisson regression, the Yes 45 (15.4) 7,406 (17.0) incidence rate ratio was 0.99 (95% CI, 0.35 to 2.82). Number of outpatient physician visits 0-2 83 (15.1) 8,705 (20.0) Discussion 3-5 227 (41.2) 16,843 (38.7) In this large prospective cohort study of more than 6-10 185 (33.6) 13,376 (30.7) 40,000 patients with autoimmune diseases, we showed 11 and more 54 (9.8) 4,642 (10.7) that despite their increased risk of developing HZ, only DMARDS, Disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; 551 (1.2%) received zoster vaccine. We also showed that TNF, tumor necrosis factor. Measured in the 6-month baseline period before approximately 6% of those who received the vaccine the start of observation b were currently using anti-TNF therapies, and none Cumulative average daily prednisone-equivalent glucocorticoid dose in the past 183 days: none, low (< 10 mg/day), medium (10-20 mg/day), and high (> developed HZ within 1 month after vaccination. 20 mg/day). The administration of zoster vaccine in patients exposed to biologics is in conflict with recommenda- vaccine. Patients with recent, but not remote, history of tions from ACIP and ACR. More than 80% of the vacci- HZ were more likely to be vaccinated. Finally, patients nated patients received their vaccine from their primary who had more physician visits in outpatient settings and care physicians; it is possible that they may not be those who had received influenza or pneumococcal vac- aware of their patients’ exposure to immunosuppressive cine in the past year were more likely to be vaccinated. agents or the contraindication. In patients with Results of the analysis that was restricted to individuals immune-mediated inflammatory diseases who receive aged 60 years or older were similar to the main results targeted immunosuppressive therapies (for example, (Table 3). A majority (> 80%) of the patients received anti-TNF therapy), it is currently not known whether their vaccine from family practice or internal medicine the benefits of zoster vaccine outweigh any theoretic physicians, with less than 5% from dermatologists, safety concerns, and many experts have called for Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 6 of 9 http://arthritis-research.com/content/13/5/R174 Table 2 Biologic and nonbiologic DMARDs use 30 days before and after zoster vaccination (n = 514) 30 days before vaccination Day of vaccination 30 days after vaccination n % n % n % Anti-TNF 40 7.8 32 6.2 40 7.8 Etanercept 18 3.5 12 2.3 18 3.5 Adalimumab 11 2.1 9 1.8 11 2.1 Infliximab 11 2.1 11 2.1 11 2.1 Other biologics 4 0.8 4 0.8 4 0.8 Nonbiologic DMARDs Methotrexate 52 10.1 34 6.6 45 8.8 Sulfasalazine 16 3.1 13 2.5 16 3.1 Hydroxychloroquine 26 5.1 17 3.3 25 4.9 Azathioprine 1 0.2 1 0.2 1 0.2 Leflunomide 3 0.6 3 0.6 3 0.6 Cyclosporine 7 1.4 6 1.2 7 1.4 6-Mercaptopurine 5 1.0 3 0.6 5 1.0 Oral glucocorticoid 45 8.8 33 6.4 48 9.3 DMARDS, Disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; TNF, tumor necrosis factor. The categories (columns) are not exclusive (for example, a patient who used anti-TNF therapies continuously during the 60-day period would be counted in all three categories). Abatacept, rituximab. studies to evaluate the safety and effectiveness of zoster In considering the effectiveness of the zoster vaccine vaccine in this patient population [14,15]. In pediatric in this population, we did not find any difference in the HIV patients, varicella vaccine has been administered incidence rates of HZ among the vaccinated and the safely in children with or without primary varicella unvaccinated patients. However, this and other findings infection [16,17] and is highly effective in preventing must be interpreted in light of the study’ limitations. varicella infection and subsequent HZ [18]. Moreover, The most important limitation is the small number of yellow-fever vaccine, another live attenuated vaccine, patients who received zoster vaccine (n = 551) and the was administered to 17 RA patients who were previously even fewer in whom HZ developed after vaccination (n immunized and were currently receiving infliximab; = 5). As a result, the overall IRs, and especially the age- none reported yellow-fever related symptoms after vac- and sex-specific IRs, were not so reliable. Coupled with cination [19]. a selection bias that those who were vaccinated were In our study, among 551 vaccinated subjects, HZ devel- younger, healthier, and less likely to be immune sup- oped in five after vaccination; none was hospitalized, and pressed, no conclusion could be drawn from the finding one occurred within 1 month of vaccination. Of interest, that incidence rates of HZ in vaccinated and unvacci- the patient in whom HZ developed within 1 month after nated patients were comparable. Misclassification of immunosuppressive agent use might have occurred if vaccination was not exposed to biologics, glucocorticoids, patients filled prescriptions from a pharmacy, but they or traditional DMARDs at time of vaccination. In the Shin- gles Prevention Study, seven confirmed cases of HZ were verbally told by their healthcare provider to dis- occurred within 42 days after vaccination among 19,270 continue the medications temporarily before vaccination. vaccinated subjects [20]. We observed only one such case Another limitation of the study is that we lacked medi- among 551 vaccinated patients with autoimmune diseases. cal records to confirm or evaluate the severity of HZ Taken together, our result suggests that a short-term cases identified by using the claims data. Finally, we did increase in the risk of infection might not exist, as might be not have information on race/ethnicity, a factor that has feared with a live-virus vaccine. However, although our been associated with risk of HZ [21]. results did not raise any safety concern, it is important to The underuse of zoster vaccine concerns not only note that the administration of zoster vaccine to these indi- patients with contraindications but also those who had viduals was selective. Subjects who took biologics and high no contraindication to the use of zoster vaccine. One of doses of oral glucocorticoids were less likely to be immu- the barriers is likely provider concern about inadvertent nized, whereas younger and healthier patients were more administration of the vaccine to immune-suppressed likely to be vaccinated. Our study suggested that zoster vac- patients [22]. Another possible reason is the lack of cine can be administered safely to a selected subgroup of information on the efficacy and safety of zoster vaccine patients with the autoimmune diseases studied but did not in these patients, who were not included in vaccine clin- provide definitive evidence that it is safe for all. ical trials. In addition, we found that older patients were Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 7 of 9 http://arthritis-research.com/content/13/5/R174 Table 3 Fixed and time-varying patient characteristics associated with vaccination All subjects Subjects aged 60 years or older Baseline Hazard ratio 95% Confidence interval Hazard ratio 95% Confidence interval Age groups, years 50-59 0.06 0.05-0.08 NA NA 60-64 1.00 -- - ≥ 65 0.41 0.31-0.53 0.42 0.33-0.54 Women, n (%) 1.13 0.95-1.35 1.17 0.97-1.41 Disease status Rheumatoid arthritis 1.00 -- - Psoriatic arthritis 1.58 0.86-2.91 1.27 0.63-2.59 Psoriasis 1.48 1.17-1.86 1.54 1.21-1.95 Inflammatory bowel diseases 1.71 1.36-2.14 1.64 1.29-2.09 Ankylosing spondylitis 1.45 0.71-2.97 1.23 0.54-2.79 Multiple diseases 1.00 0.72-1.39 1.01 0.71-1.43 History of herpes zoster infection None 1.00 -- - Recent 2.84 1.34-6.01 2.21 0.91-5.35 Remote 0.93 0.51-1.69 0.82 0.42-1.59 Medications (current use) TNF antagonists 0.47 0.33-0.67 0.41 0.27-0.61 Other biologics (see Additional file 1) 0.52 0.19-1.40 0.59 0.22-1.58 Conventional DMARDs 0.92 0.72-1.19 0.91 0.70-1.19 Oral glucocorticoids None 1.00 -- - Low/medium 0.84 0.66-1.08 0.85 0.66-1.10 High 0.46 0.15-1.45 0.53 0.17-1.68 Charlson co-morbidity index 0 1.00 -- - 1 0.76 0.61-0.95 0.77 0.61-0.97 ≥ 2 0.57 0.42-0.78 0.57 0.42-0.79 One or more inpatient physician visit 0.53 0.40-0.72 0.50 0.37-0.69 Number of outpatient physician visits 0-2 1.00 -- - 3-5 1.68 1.32-2.14 1.70 1.31-2.19 6-10 1.80 1.39-2.34 1.80 1.37-2.38 >10 2.08 1.47-2.93 2.03 1.41-2.92 Influenza vaccine in the past year 2.25 1.87-2.71 2.05 1.69-2.49 Pneumococcal vaccine in the past year 1.79 1.45-2.21 1.81 1.45-2.26 Gender and disease status were fixed; all other characteristics were time-varying. Time-varying characteristics were ascertained by using claims in the preceding 6-month period, unless otherwise specified in the table. Sensitivity analysis restricted to individuals aged 60 and older. c d e f Reference groups were as follows: age category 60-64; RA patients; Subjects without prior zoster infection; subjects not prescribed oral glucocorticoids in the past 6 months (cumulative average daily prednisone-equivalent glucocorticoid dose: low/medium ≤20 mg/day and high (> 20 mg/day); subjects with Charlson score = 0; subject who had none to two outpatient physician encounter (s) in the past 6 months. DMARDS, disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; TNF, tumor necrosis factor. Bolded data indicates statistically significant associations. less likely to receive zoster vaccine despite the ACIP identified, with the most important being financial con- recommendations supporting its use among individuals cerns, reimbursement issues, and storage difficulties older than 60 years. This finding is consistent with [22]. In our study, zoster vaccine use increased continu- those from previous studies that showed immunization ously since it was approved in 2006. This points to lagging in older adults [23] and raises a serious concern another potential barrier to the use of the zoster vaccine because zoster vaccine appears to be underused in the (the newness of the vaccine) and suggests that programs population with the highest disease risk. A number of educating primary care physicians and specialists may barriers to the use of zoster vaccine have been help to increase the appropriate vaccine use. As Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 8 of 9 http://arthritis-research.com/content/13/5/R174 statistical analyses, and drafted the manuscript. ESD and JWB conceived the expected, more frequent physician contact and receipt of research questions and hypotheses, refined the research questions and other vaccinations, including influenza or pneumococcal hypotheses, and gave significant input to the draft of the manuscript with vaccine, was associated with a greater likelihood of regard to the interpretation of results. KW gave significant input to the draft of the manuscript with regard to the interpretation of results. FX refined the receiving zoster vaccine. These associations may reflect research questions and hypotheses, planned and performed statistical physician attentiveness and patients’ health-seeking analyses, and gave significant input to the draft of the manuscript with behaviors. regard to the interpretation of results. LC refined the research questions and hypotheses and planned and performed statistical analyses. CS, RMM, and JF assisted in acquiring data. ED planned the statistical analyses. All authors Conclusions critically reviewed and approved the final manuscript for publication. Zoster vaccine was underused in patients with autoim- Competing interests mune diseases despite their increased risk of developing ED receives research funding from Amgen; JWB is a Board Member of HZ. Contrary to clinical guidelines, a small number of Merck, is a consultant to Pfizer, and receives research funding from Pfizer; patients receiving anti-TNF therapies were vaccinated, RMM’s institution receives funding from Centocor, Bristol Myers Squibb, and Abbott; JF receives a salary from Aetna; and JRC has received research and none developed zoster infection within 30 days after grants and consulting fees from Amgen, UCB, Abbott, Genentech, Roche, vaccination. The incidence rates of HZ were similar in Centocor, BMS, and Merck. the vaccinated and unvaccinated person-times. The Received: 25 March 2011 Revised: 8 June 2011 results regarding safety and effectiveness are preliminary, Accepted: 24 October 2011 Published: 24 October 2011 and future evaluations are needed to understand better the risks and benefits associated with zoster vaccine in References patients with autoimmune disease and to help refine 1. Mueller NH, Gilden DH, Cohrs RJ, Mahalingam R, Nagel MA: Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and guidelines for the use of zoster vaccine. latency. Neurol Clin 2008, 26:675-697, viii. 2. Oxman MN: Herpes zoster pathogenesis and cell-mediated immunity and immunosenescence. J Am Osteopath Assoc 2009, 109:S13-17. Additional material 3. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS: A population-based study of the incidence and complication rates of Additional file 1: ICD9-diagnosis codes and medications used in herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007, case definitions. 82:1341-1349. 4. Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA: The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005, 20:748-753. Abbreviations 5. Mullooly JP, Riedlinger K, Chun C, Weinmann S, Houston H: Incidence of ACIP: the Advisory Committee on Immunization Practices; ACR: American herpes zoster, 1997-2002. Epidemiol Infect 2005, 133:245-253. College of Rheumatology; anti-TNF: anti-tumor necrosis factor alpha; CPT: 6. Gourishankar S, McDermid JC, Jhangri GS, Preiksaitis JK: Herpes zoster current procedural terminology; DMARDs: disease-modifying antirheumatic infection following solid organ transplantation: incidence, risk factors drugs; HIV: human immunodeficiency virus; HZ: hazard ratio; HZ: herpes and outcomes in the current immunosuppressive era. Am J Transplant th zoster; ICD-9: International Classification of Diseases, 9 edition; IR: incidence 2004, 4:108-115. rate; NDC: national drug code; PHN: postherpetic neuralgia; RA: rheumatoid 7. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, Chan KA: arthritis; SD: standard deviation; VZV: varicella zoster virus. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum 2007, Acknowledgements 57:1431-1438. This work was supported by the Agency for Healthcare Research and Quality 8. Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, Zink A: (R01HS018517) and the Doris Duke Charitable Foundation. JRC received Risk of herpes zoster in patients with rheumatoid arthritis treated with support from the National Institutes of Health (AR053351); JZ received anti-TNF-alpha agents. JAMA 2009, 301:737-744. support from the Agency for Healthcare Research and Quality 9. Garcia-Doval I, Perez-Zafrilla B, Descalzo MA, Rosello R, Hernandez MV, (T32HS013852). Gomez-Reino JJ, Carmona L: Incidence and risk of hospitalisation due to shingles and chickenpox in patients with rheumatic diseases treated Author details with TNF antagonists. Ann Rheum Dis 2010, 69:1751-1755. Department of Epidemiology, School of Public Health, University of 10. Harpaz R, Ortega-Sanchez IR, Seward JF: Prevention of herpes zoster: Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35294, USA. recommendations of the Advisory Committee on Immunization Division of Clinical Immunology and Rheumatology, School of Medicine, Practices (ACIP). MMWR Recomm Rep 2008, 57:1-30; quiz CE32-34. University of Alabama at Birmingham, 510 20th Street South, Birmingham, 11. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, AL 35294, USA. Division of Infectious Diseases, Department of Medicine, Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez University of Alabama at Birmingham and Birmingham Veteran Affairs Almazor M, Bridges SL Jr, Chatham WW, Hochberg M, MacLean C, Mikuls T, Medical Center, 1900 University Blvd., Birmingham, AL 35294, USA. Aetna Moreland LW, O’Dell J, Turkiewicz AM, Furst DE: American College of Informatics, Aetna, 980 Jolly Road, Blue Bell, PA 19422, USA. Aetna Specialty Rheumatology 2008 recommendations for the use of nonbiologic and Pharmacy, 503 Sunport Lane, Orlando, FL 32809, USA. Division of Infectious biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Diseases, Department of Medicine, Oregon Health and Science University, Arthritis Rheum 2008, 59:762-784. 3181 SW Sam Jackson Park Road L457, Portland, OR 97239, USA. 12. Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992, Authors’ contributions 45:613-619. JRC conceived the research questions and hypotheses, refined the research 13. Breslow NE, Day NE: Indirect standardization and multiplicative models questions and hypotheses, planned the statistical analyses, and gave for rates, with reference to the age adjustment of cancer incidence and significant input to the draft of the manuscript with regard to the relative frequency data. J Chronic Dis 1975, 28:289-303. interpretation of results. JZ conceived the research questions and 14. Oxman MN: Zoster vaccine: current status and future prospects. Clin hypotheses, refined the research questions and hypotheses, planned the Infect Dis 2010, 51:197-213. Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 9 of 9 http://arthritis-research.com/content/13/5/R174 15. Whitley RJ, Gnann JW Jr: Herpes zoster in the age of focused immunosuppressive therapy. JAMA 2009, 301:774-775. 16. Gershon AA, Levin MJ, Weinberg A, Song LY, LaRussa PS, Steinberg SP, Bartlett P: A phase I-II study of live attenuated varicella-zoster virus vaccine to boost immunity in human immunodeficiency virus-infected children with previous varicella. Pediatr Infect Dis J 2009, 28:653-655. 17. Wood SM, Shah SS, Steenhoff AP, Rutstein RM: Primary varicella and herpes zoster among HIV-infected children from 1989 to 2006. Pediatrics 2008, 121:e150-156. 18. Son M, Shapiro ED, LaRussa P, Neu N, Michalik DE, Meglin M, Jurgrau A, Bitar W, Vasquez M, Flynn P, Gershon AA: Effectiveness of varicella vaccine in children infected with HIV. J Infect Dis 2010, 201:1806-1810. 19. Scheinberg M, Guedes-Barbosa LS, Mangueira C, Rosseto EA, Mota L, Oliveira AC, Lima RA: Yellow fever revaccination during infliximab therapy. Arthritis Care Res (Hoboken) 2010, 62:896-898. 20. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, et al: A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005, 352:2271-2284. 21. Schmader K, George LK, Burchett BM, Hamilton JD, Pieper CF: Race and stress in the incidence of herpes zoster in older adults. J Am Geriatr Soc 1998, 46:973-977. 22. Hurley LP, Lindley MC, Harpaz R, Stokley S, Daley MF, Crane LA, Dong F, Beaty BL, Tan L, Babbel C, Dickinson LM, Kempe A: Barriers to the use of herpes zoster vaccine. Ann Intern Med 2010, 152:555-560. 23. High K: Immunizations in older adults. Clin Geriatr Med 2007, 23:669-685, viii-ix. doi:10.1186/ar3497 Cite this article as: Zhang et al.: The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study. Arthritis Research & Therapy 2011 13:R174. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arthritis Research & Therapy Springer Journals

The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study

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Springer Journals
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Copyright © 2011 by Curtis et al.; licensee BioMed Central Ltd.
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Medicine & Public Health; Rheumatology; Orthopedics
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1478-6354
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10.1186/ar3497
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22024532
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Abstract

Introduction: Zostavax, a live attenuated vaccine, has been approved in the United States for use in older individuals to reduce the risk and severity of herpes zoster (HZ), also known as shingles. The vaccine is contraindicated in individuals taking anti-tumor necrosis factor alpha (anti-TNF) therapies or other biologics commonly used to treat autoimmune diseases because of the safety concern that zoster vaccine may be associated with a short-term HZ risk. The objective of the study was to examine the use, safety (short-term HZ risk after vaccination), and effectiveness of zoster vaccine in individuals with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or inflammatory bowel diseases. Methods: We conducted a cohort study of patients aged 50 years and older with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or inflammatory bowel diseases by using administrative claims data from a nationwide health plan from January 1, 2005, to August 31, 2009. We examined the extent to which zoster vaccine was used; assessed factors associated with vaccine use (Cox proportional hazards regression); and compared the incidence rates of herpes zoster (HZ) between vaccinated and unvaccinated patients. Results: Among 44,115 patients with the autoimmune diseases, 551 (1.2%) received zoster vaccine, and 761 developed HZ. Zoster vaccine use increased continuously after approval in 2006. Younger and healthier patients, those who had an HZ infection within the past 6 months, and those who were not using anti-TNF therapies were more likely to receive the vaccine. Approximately 6% of vaccinated patients were using anti-TNF therapies at the time of vaccination. The incidence rates of HZ were similar in vaccinated and unvaccinated patients (standardized incidence ratio, 0.99; 95% confidence interval, 0.29 to 3.43). Conclusions: Use of the zoster vaccine was uncommon among older patients with autoimmune diseases, including those not exposed to immunosuppressive medications. The short-term risk of HZ did not appear to be increased in vaccinated patients, even among those using immunosuppressive therapies (for example, biologics) at the time of vaccination. However, our study was limited by the small number of vaccinated patients, and further evidence is needed to confirm the vaccine’s safety and efficacy in this population. * Correspondence: jcurtis@uab.edu Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35294, USA Full list of author information is available at the end of the article © 2011 Curtis et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 2 of 9 http://arthritis-research.com/content/13/5/R174 used the administrative claims data of a large nation- Introduction wide health plan to investigate the following aims in a Herpes zoster (HZ) infection, also known as shingles, is cohort of patients diagnosed with RA, psoriatic arthritis, caused by the reactivation of latent varicella-zoster virus psoriasis, ankylosing spondylitis, and/or inflammatory (VZV) and usually occurs decades after primary infec- bowel diseases: (a) to describe the use of zoster vaccina- tion. HZ is characterized by a painful blistering rash and tion over time; (b) to determine the extent to which zos- occurs mostly in older adults. Many patients experience ter vaccine was used in patients taking concomitant persistent pain after the rash heals, a common yet debil- immunosuppressive agents; (c) to assess patient charac- itating complication known as postherpetic neuralgia teristics associated with receipt of zoster vaccine; and (PHN) [1,2]. In the United States, the age- and sex- (d) to evaluate the incidence of HZ in patients who adjusted incidence rate (IR) of HZ is estimated to be 3.0 received and did not receive zoster vaccine. to 4.0 per 1,000 person-years [3-5]. Older age is the most important risk factor for the development of both Materials and methods HZ and PHN [3,4]. Disease risk is elevated in individuals Study population who are immune-suppressed due to human immunode- We conducted a retrospective cohort study by using ficiency virus (HIV) infection and transplantation [3,4,6]. administrative claims data from Aetna, a nationwide Recent studies reported an increased risk of HZ in health plan that provides medical coverage to more than patients with rheumatoid arthritis (RA) that is attributa- 17 million individuals in the United States, from January ble both to the disease and to treatment with anti- 1, 2006, to August 31, 2009. The cohort included tumor necrosis factor alpha (anti-TNF) therapies and patients with RA, psoriatic arthritis, psoriasis, ankylosing other immunosuppressive agents [7,8]. In addition, anti- spondylitis, and inflammatory bowel diseases, identified TNF therapies has been associated with a more severe by using the International Classification of Diseases, 9th course of HZ among patients with rheumatic diseases; revision (ICD-9) and National Drug Codes (NDC) those receiving anti-TNF therapies were 9 times more codes. Patients were included if there were (a) two ICD- likely than those not to be hospitalized for HZ [9]. 9 diagnosis codes from an outpatient physician or hospi- Zostavax, a live attenuated vaccine, was approved in tal encounter, separated by at least 7 days and occurring 2006 for use in individuals 60 years of age or older to within 365 days; or (b) one physician- or hospital- reduce the risk and severity of HZ. The Advisory Commit- encounter diagnosis code followed by a prescription for tee on Immunization Practices (ACIP) recommended that medications used to treat autoimmune diseases within all adults older than 60 years be considered for vaccina- tion, with certain exceptions [10]. Along with patients 365 days (diagnosis codes and medications listed in Additional file 1). We defined each subject’sindex date with certain malignancies and HIV/AIDS, patients receiv- (patients consist of a mix of incident and prevalent ing biologic agents such as anti-TNF therapies, some non- cases) as the date of the second diagnosis code or the biologic disease-modifying antirheumatic drugs date when the prescription was filled. Patients who met (DMARDs), such as high doses of methotrexate, and high definitions for two or more of the diseases of interest doses of glucocorticoids were also excluded. The concern were categorized into a multiple diseases category, and is that zoster vaccine, a live vaccine, could acutely trigger their index date was defined as the earliest of all dis- the development of HZ in patients with compromised ease-specific index dates. immune systems in a short time frame (for example, To ensure that we had complete medical and phar- within 4 to 6 weeks after vaccination) despite conferring a macy claims necessary to identify and characterize the longer-term protection against the development of HZ. study population, all subjects were required to have a Based on expert opinion, glucocorticoids at prednisone- “baseline period” of at least 183 continuous days during equivalent doses up to 20 mg/day, low-doses of metho- which they had medical and pharmacy benefits; subjects trexate (< 0.4 mg/kg/week, a typical dose for patients with aged 65 or older had to be enrolled in a Medicare autoimmune diseases), azathioprine (< 3.0 mg/kg/day), Advantage plan with a concomitant pharmacy benefit and 6-mercaptopurine (< 1.5 mg/kg/day) were considered administered by Aetna. Follow-up started on the later of acceptably safe so as not to require a contraindication for theindex dateor thedateonwhich thesubject hada use of zoster vaccine. Similarly, the American College of baseline period of at least 183 days. Subjects were cen- Rheumatology (ACR) 2008 guidelines for the use of biolo- sored when they lost either medical or pharmacy bene- gic and nonbiologic DMARDS did not recommend the fits, died, or for individuals aged 65 years or older, if administration of zoster vaccine to patients with RA or Aetna became the secondary payer to Medicare. Patients other rheumatic diseases treated with biologics [11]. In light of the uncertainties regarding the use, safety, were excluded if they were younger than 50 years at the and effectiveness of zoster vaccine in this population, we start of follow-up or received zoster vaccine during the Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 3 of 9 http://arthritis-research.com/content/13/5/R174 baseline period. Although the ACIP recommended the were conducted in patients who received zoster vaccine use of zoster vaccine in immune-competent individuals and were followed up for at least 30 days after aged 60 years or older [10], given the increased HZ risk vaccination. previously observed in this population, we included For Aim 3, we used Cox proportional hazards regres- those between 50 and 60 years of age in our analysis to sion models to assess patient characteristics associated assess the extent to which zoster vaccine was used. with time to HZ vaccination. Subject characteristics examined were gender, type of autoimmune disease, and Assessment of vaccination status, HZ infection, and several time-varying factors including age, co-morbid- ities measured by using the Charlson co-morbidity exposure to immunosuppressive agents Zoster vaccine was covered under the health plan’s index [12], number of physician visits, hospitalization medical benefit for individuals aged 60 or older begin- (yes or no), history of HZ infection (recent, within the ning June 1, 2006, and was ascertained by using the past 6 months; remote, more than 6 months ago), his- Current Procedural Terminology (CPT) code 90736. tory of influenza and pneumococcal vaccine (within the Reimbursement of zoster vaccine for patients younger past 12 months), and use of medications listed in Aim than 60 years was made on a case-by-case basis. Cases 2. Whenever an event occurred, the time-varying char- of HZ were identified by the first HZ claim for each acteristics of interest were ascertained as of that time patient that was preceded or followed by a prescription for all patients by using claims in the preceding 6- for acyclovir, famciclovir, and valacyclovir within 30 months period, unless otherwise specified. days of the HZ claim date. Exposures to immunosup- For Aim 4, accrual of person-time began at the start pressive agents were ascertained by the days’ supply for of follow-up, and a vaccinated subject would contribute all relevant medications. To estimate cumulative gluco- both unvaccinated and vaccinated person-time. We cal- corticoid exposure as a time-varying variable, cumulative culated the crude and age- and sex-specific incidence average daily doses were calculated by summing the rates of HZ in vaccinated and unvaccinated person- total amount of oral glucocorticoids prescribed in the times. We applied the age- and sex-specific incidence preceding 6 months and then dividing the total amount rates of the unvaccinated to age- and sex-specific vacci- by 183 days. Subjects were then categorized into four nated person-time to derive the expected number of HZ groups based on their cumulative average daily predni- cases among the vaccinated and calculated the standar- sone-equivalent glucocorticoid dose: none, low (less dized incidence-rate ratio as the observed divided by the than 10 mg/day), medium (10 to 20 mg/day), and high expected number of cases [13]. (greater than 20 mg/day). Sensitivity analyses Statistical analyses Because zoster vaccine was approved for use in the Uni- To characterize use of the zoster vaccination (Aim 1), ted States in May 2006 in individuals aged 60 or older, we calculated the incidence proportion of zoster vacci- sensitivity analyses were conducted (a) in patients for nation for each 6-month interval beginning July 1, 2006, whom we had complete medical and pharmacy claims and ending August 31, 2009. For each time interval, the prior to or since June 1, 2006, to avoid misclassification denominator was the number of subjects who were of vaccination status in patients who might have been unvaccinated at the start of the interval and were under vaccinated before joining the health plan; and (b) in observation throughout the entire interval, and the patients aged 60 or older as of the start of follow-up. numerator was the number of these subjects who were BecauseHZinfectionsdiagnosed latein thecourseof vaccinated during the interval. Because we had claims the infection might not benefit from or receive antiviral up to August 31, 2009, the incidence proportion from medications, and approximately 10% to 20% of HZ cases July 1, 2009, to August 31, 2009, was multiplied by 3 to were not treated with antiviral medication, we con- approximate the incidence proportion for the 6-month ducted a sensitivity analysis that used an alternate defi- period ending December 31, 2009. nition for HZ that required only the HZ diagnosis code To characterize the immune status of patients at time to calculate incidences of HZ in vaccinated and unvacci- of vaccination (Aim 2), we described the numbers and nated patients. percentages of patients who used anti-TNF therapies The University of Alabama at Birmingham Institu- (etanercept, infliximab, adalimumab), other biologic tional Review Board approved the study and waiver of agents (abatacept, rituximab), traditional DMARDs informed consent. (methotrexate, hydroxychloroquine, sulfasalazine, azathioprine, leflunomide, mercaptopurine), and oral Results glucocorticoids 30 days before and up to 30 days after We identified 44,115 eligible subjects classified as having the administration of zoster vaccine. These analyses at least one of the autoimmune diseases of interest who Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 4 of 9 http://arthritis-research.com/content/13/5/R174 were at least 50 years old at the start of observation. At (9.3%) used oral glucocorticoids. A total of 47 patients baseline, their average age was 58.1 (standard deviation used biologics at some time within 30 days before and (SD), 6.7) years and 27,443 (62.2%) were female; 19,326 after vaccination. None of the 47 subjects developed HZ (43.8%) had RA, 867 (2.0%) had psoriatic arthritis (PsA), in the 30 days after vaccination. Their average age was 10,712 (24.3%) had psoriasis (PsO), 633 (1.4%) had AS, 60 years (standard deviation, 5); 64% were women; and 8,639 (19.6%) had IBD, and 3,938 (8.9%) had two or 70% were not exposed to oral glucocorticoids, 28% to a more of these diseases. During follow-up, 551 (1.2%) daily average dose of no more than 20 mg, and 2% to a subjects received zoster vaccine. The earliest claim for daily average dose of 20 mg or more. Patients using anti-TNF therapies were less likely to vaccination occurred in August 2006; subsequently, vac- cine use increased continuously over time (Figure 1). receive zoster vaccine than those who were not using The distribution of patients’ characteristics at baseline anti-TNF agents (hazard ratio (HR), 0.47; 95% CI, 0.33 by vaccination status is presented in Table 1. to 0.67) (Table 3). Patients who were using other biolo- Among the 551 subjects who received zoster vaccine, gics (HR, 0.52; 95% CI, 0.19 to 1.40) or high-dose oral complete claims history for at least 30 days after vacci- glucocorticoids (HR, 0.46; 95% CI, 0.15 to 1.45) were nation was available for 514 subjects. At the time of vac- only half as likely as were non-users to receive zoster cination, 32 (6.2%) subjects were using anti-TNF vaccine, but these associations did not reach statistical therapy, 34 (6.6%) were using methotrexate, and 33 significance. Patients aged 60 to 64 years were most (6.4%) were using oral glucocorticoids (Table 2). In the likely to receive zoster vaccine; those with fewer co- 30 days after vaccination, 40 (7.8%) subjects used anti- morbidities and those without hospitalization within the TNF therapy, 45 (8.8%) used methotrexate, and 48 past 6 months were more likely to receive zoster Figure 1 Incidence proportion for each 6-month period of zoster vaccination by calendar year from June 1, 2006, to December 31, 2009. The proportion is expressed as the proportion of unvaccinated individuals under observation and vaccinated in each 6-month period. It does not include individuals vaccinated in previous time periods. Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 5 of 9 http://arthritis-research.com/content/13/5/R174 Table 1 Baseline patient characteristics by vaccination gastroenterologists, or rheumatologists, both in the over- status all cohort and in patients who were exposed to biologics Vaccination status at the time of vaccination. Baseline characteristics, n (%) Vaccinated Unvaccinated During 88,354 observed person-years, 761 cases of HZ n = 551 n = 43,564 occurred (incidence rate (IR), 8.6 per 1,000 person- Age groups (years) years). The IR increased with age from 8.14 per 1,000 50 to 59 202 (36.7) 30,156 (69.2) person-years among those aged 50 to 54 years to 15.30 60 to 64 275 (49.9) 9,573 (22.0) per 1,000 person-years among those 90 years or older. 65 and older 74 (13.4) 3,835 (8.8) Five cases of HZ occurred during vaccinated person- Women 352 (63.9) 27,091 (62.2) time (crude IR, 9.97 per 1,000 person-years), and 756 Inflammatory/Autoimmune disease HR occurred during unvaccinated person-time (crude RA 206 (37.4) 19,120 (43.9) IR, 8.61 per 1,000 person-years). The age- and sex-stan- Psoriatic arthritis 11 (2.0) 856 (2.0) dardized IR (expected IR) for the vaccinated was 10.06 Psoriasis 146 (26.5) 10,566 (24.3) per 1,000 person-years, resulting in a standardized IR Inflammatory bowel diseases 136 (24.7) 8,503 (19.5) ratio (vaccinated to unvaccinated) of 0.99 (95% CI, 0.29 Ankylosing spondylitis 8 (1.5) 625 (1.4) to 3.43). Multiple diseases 44 (8.0) 3,894 (8.9) The five cases of HZ in the vaccinated patients Medications occurred 7, 131, 201, 214, and 667 days after vaccina- TNF antagonists user 27 (4.9) 4,186 (9.6) tion. Within 90 days before vaccination, the only filled Other biologics user 0 (0) 198 (0.5) prescription for an immunosuppressive agent for the Conventional DMARDs user 92 (16.7) 9,312 (21.4) patient who developed HZ on day 7 after vaccination Oral glucocorticoids was for a 15-day supply of prednisone approximately 2 None 456 (82.8) 34,267 (78.7) months before receipt of zoster vaccination. None of the Low 86 (15.6) 8,041 (18.5) five patients was hospitalized. Medium 7 (1.3) 902 (2.1) Results from sensitivity analyses restricted to indivi- High 2 (0.4) 354 (0.8) duals under observation continuously from the time zos- Charlson comorbidity index ter vaccine was approved in 2006 had similar results 0 287 (52.1) 19,971 (45.8) (data not shown). When requiring only an HZ diagnosis 1 181 (32.9) 16,565 (38.0) code, the result was consistent, in that the crude inci- ≥ 2 83 (15.1) 7,028 (16.1) dence rates were the same between vaccinated (14.4 per Inpatient hospitalization 1,000 person-years) and unvaccinated (13.1 per 1,000 No 466 (84.6) 36,158 (83.0) person-years) patients. With Poisson regression, the Yes 45 (15.4) 7,406 (17.0) incidence rate ratio was 0.99 (95% CI, 0.35 to 2.82). Number of outpatient physician visits 0-2 83 (15.1) 8,705 (20.0) Discussion 3-5 227 (41.2) 16,843 (38.7) In this large prospective cohort study of more than 6-10 185 (33.6) 13,376 (30.7) 40,000 patients with autoimmune diseases, we showed 11 and more 54 (9.8) 4,642 (10.7) that despite their increased risk of developing HZ, only DMARDS, Disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; 551 (1.2%) received zoster vaccine. We also showed that TNF, tumor necrosis factor. Measured in the 6-month baseline period before approximately 6% of those who received the vaccine the start of observation b were currently using anti-TNF therapies, and none Cumulative average daily prednisone-equivalent glucocorticoid dose in the past 183 days: none, low (< 10 mg/day), medium (10-20 mg/day), and high (> developed HZ within 1 month after vaccination. 20 mg/day). The administration of zoster vaccine in patients exposed to biologics is in conflict with recommenda- vaccine. Patients with recent, but not remote, history of tions from ACIP and ACR. More than 80% of the vacci- HZ were more likely to be vaccinated. Finally, patients nated patients received their vaccine from their primary who had more physician visits in outpatient settings and care physicians; it is possible that they may not be those who had received influenza or pneumococcal vac- aware of their patients’ exposure to immunosuppressive cine in the past year were more likely to be vaccinated. agents or the contraindication. In patients with Results of the analysis that was restricted to individuals immune-mediated inflammatory diseases who receive aged 60 years or older were similar to the main results targeted immunosuppressive therapies (for example, (Table 3). A majority (> 80%) of the patients received anti-TNF therapy), it is currently not known whether their vaccine from family practice or internal medicine the benefits of zoster vaccine outweigh any theoretic physicians, with less than 5% from dermatologists, safety concerns, and many experts have called for Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 6 of 9 http://arthritis-research.com/content/13/5/R174 Table 2 Biologic and nonbiologic DMARDs use 30 days before and after zoster vaccination (n = 514) 30 days before vaccination Day of vaccination 30 days after vaccination n % n % n % Anti-TNF 40 7.8 32 6.2 40 7.8 Etanercept 18 3.5 12 2.3 18 3.5 Adalimumab 11 2.1 9 1.8 11 2.1 Infliximab 11 2.1 11 2.1 11 2.1 Other biologics 4 0.8 4 0.8 4 0.8 Nonbiologic DMARDs Methotrexate 52 10.1 34 6.6 45 8.8 Sulfasalazine 16 3.1 13 2.5 16 3.1 Hydroxychloroquine 26 5.1 17 3.3 25 4.9 Azathioprine 1 0.2 1 0.2 1 0.2 Leflunomide 3 0.6 3 0.6 3 0.6 Cyclosporine 7 1.4 6 1.2 7 1.4 6-Mercaptopurine 5 1.0 3 0.6 5 1.0 Oral glucocorticoid 45 8.8 33 6.4 48 9.3 DMARDS, Disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; TNF, tumor necrosis factor. The categories (columns) are not exclusive (for example, a patient who used anti-TNF therapies continuously during the 60-day period would be counted in all three categories). Abatacept, rituximab. studies to evaluate the safety and effectiveness of zoster In considering the effectiveness of the zoster vaccine vaccine in this patient population [14,15]. In pediatric in this population, we did not find any difference in the HIV patients, varicella vaccine has been administered incidence rates of HZ among the vaccinated and the safely in children with or without primary varicella unvaccinated patients. However, this and other findings infection [16,17] and is highly effective in preventing must be interpreted in light of the study’ limitations. varicella infection and subsequent HZ [18]. Moreover, The most important limitation is the small number of yellow-fever vaccine, another live attenuated vaccine, patients who received zoster vaccine (n = 551) and the was administered to 17 RA patients who were previously even fewer in whom HZ developed after vaccination (n immunized and were currently receiving infliximab; = 5). As a result, the overall IRs, and especially the age- none reported yellow-fever related symptoms after vac- and sex-specific IRs, were not so reliable. Coupled with cination [19]. a selection bias that those who were vaccinated were In our study, among 551 vaccinated subjects, HZ devel- younger, healthier, and less likely to be immune sup- oped in five after vaccination; none was hospitalized, and pressed, no conclusion could be drawn from the finding one occurred within 1 month of vaccination. Of interest, that incidence rates of HZ in vaccinated and unvacci- the patient in whom HZ developed within 1 month after nated patients were comparable. Misclassification of immunosuppressive agent use might have occurred if vaccination was not exposed to biologics, glucocorticoids, patients filled prescriptions from a pharmacy, but they or traditional DMARDs at time of vaccination. In the Shin- gles Prevention Study, seven confirmed cases of HZ were verbally told by their healthcare provider to dis- occurred within 42 days after vaccination among 19,270 continue the medications temporarily before vaccination. vaccinated subjects [20]. We observed only one such case Another limitation of the study is that we lacked medi- among 551 vaccinated patients with autoimmune diseases. cal records to confirm or evaluate the severity of HZ Taken together, our result suggests that a short-term cases identified by using the claims data. Finally, we did increase in the risk of infection might not exist, as might be not have information on race/ethnicity, a factor that has feared with a live-virus vaccine. However, although our been associated with risk of HZ [21]. results did not raise any safety concern, it is important to The underuse of zoster vaccine concerns not only note that the administration of zoster vaccine to these indi- patients with contraindications but also those who had viduals was selective. Subjects who took biologics and high no contraindication to the use of zoster vaccine. One of doses of oral glucocorticoids were less likely to be immu- the barriers is likely provider concern about inadvertent nized, whereas younger and healthier patients were more administration of the vaccine to immune-suppressed likely to be vaccinated. Our study suggested that zoster vac- patients [22]. Another possible reason is the lack of cine can be administered safely to a selected subgroup of information on the efficacy and safety of zoster vaccine patients with the autoimmune diseases studied but did not in these patients, who were not included in vaccine clin- provide definitive evidence that it is safe for all. ical trials. In addition, we found that older patients were Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 7 of 9 http://arthritis-research.com/content/13/5/R174 Table 3 Fixed and time-varying patient characteristics associated with vaccination All subjects Subjects aged 60 years or older Baseline Hazard ratio 95% Confidence interval Hazard ratio 95% Confidence interval Age groups, years 50-59 0.06 0.05-0.08 NA NA 60-64 1.00 -- - ≥ 65 0.41 0.31-0.53 0.42 0.33-0.54 Women, n (%) 1.13 0.95-1.35 1.17 0.97-1.41 Disease status Rheumatoid arthritis 1.00 -- - Psoriatic arthritis 1.58 0.86-2.91 1.27 0.63-2.59 Psoriasis 1.48 1.17-1.86 1.54 1.21-1.95 Inflammatory bowel diseases 1.71 1.36-2.14 1.64 1.29-2.09 Ankylosing spondylitis 1.45 0.71-2.97 1.23 0.54-2.79 Multiple diseases 1.00 0.72-1.39 1.01 0.71-1.43 History of herpes zoster infection None 1.00 -- - Recent 2.84 1.34-6.01 2.21 0.91-5.35 Remote 0.93 0.51-1.69 0.82 0.42-1.59 Medications (current use) TNF antagonists 0.47 0.33-0.67 0.41 0.27-0.61 Other biologics (see Additional file 1) 0.52 0.19-1.40 0.59 0.22-1.58 Conventional DMARDs 0.92 0.72-1.19 0.91 0.70-1.19 Oral glucocorticoids None 1.00 -- - Low/medium 0.84 0.66-1.08 0.85 0.66-1.10 High 0.46 0.15-1.45 0.53 0.17-1.68 Charlson co-morbidity index 0 1.00 -- - 1 0.76 0.61-0.95 0.77 0.61-0.97 ≥ 2 0.57 0.42-0.78 0.57 0.42-0.79 One or more inpatient physician visit 0.53 0.40-0.72 0.50 0.37-0.69 Number of outpatient physician visits 0-2 1.00 -- - 3-5 1.68 1.32-2.14 1.70 1.31-2.19 6-10 1.80 1.39-2.34 1.80 1.37-2.38 >10 2.08 1.47-2.93 2.03 1.41-2.92 Influenza vaccine in the past year 2.25 1.87-2.71 2.05 1.69-2.49 Pneumococcal vaccine in the past year 1.79 1.45-2.21 1.81 1.45-2.26 Gender and disease status were fixed; all other characteristics were time-varying. Time-varying characteristics were ascertained by using claims in the preceding 6-month period, unless otherwise specified in the table. Sensitivity analysis restricted to individuals aged 60 and older. c d e f Reference groups were as follows: age category 60-64; RA patients; Subjects without prior zoster infection; subjects not prescribed oral glucocorticoids in the past 6 months (cumulative average daily prednisone-equivalent glucocorticoid dose: low/medium ≤20 mg/day and high (> 20 mg/day); subjects with Charlson score = 0; subject who had none to two outpatient physician encounter (s) in the past 6 months. DMARDS, disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; TNF, tumor necrosis factor. Bolded data indicates statistically significant associations. less likely to receive zoster vaccine despite the ACIP identified, with the most important being financial con- recommendations supporting its use among individuals cerns, reimbursement issues, and storage difficulties older than 60 years. This finding is consistent with [22]. In our study, zoster vaccine use increased continu- those from previous studies that showed immunization ously since it was approved in 2006. This points to lagging in older adults [23] and raises a serious concern another potential barrier to the use of the zoster vaccine because zoster vaccine appears to be underused in the (the newness of the vaccine) and suggests that programs population with the highest disease risk. A number of educating primary care physicians and specialists may barriers to the use of zoster vaccine have been help to increase the appropriate vaccine use. As Zhang et al. Arthritis Research & Therapy 2011, 13:R174 Page 8 of 9 http://arthritis-research.com/content/13/5/R174 statistical analyses, and drafted the manuscript. ESD and JWB conceived the expected, more frequent physician contact and receipt of research questions and hypotheses, refined the research questions and other vaccinations, including influenza or pneumococcal hypotheses, and gave significant input to the draft of the manuscript with vaccine, was associated with a greater likelihood of regard to the interpretation of results. KW gave significant input to the draft of the manuscript with regard to the interpretation of results. FX refined the receiving zoster vaccine. These associations may reflect research questions and hypotheses, planned and performed statistical physician attentiveness and patients’ health-seeking analyses, and gave significant input to the draft of the manuscript with behaviors. regard to the interpretation of results. LC refined the research questions and hypotheses and planned and performed statistical analyses. CS, RMM, and JF assisted in acquiring data. ED planned the statistical analyses. All authors Conclusions critically reviewed and approved the final manuscript for publication. Zoster vaccine was underused in patients with autoim- Competing interests mune diseases despite their increased risk of developing ED receives research funding from Amgen; JWB is a Board Member of HZ. Contrary to clinical guidelines, a small number of Merck, is a consultant to Pfizer, and receives research funding from Pfizer; patients receiving anti-TNF therapies were vaccinated, RMM’s institution receives funding from Centocor, Bristol Myers Squibb, and Abbott; JF receives a salary from Aetna; and JRC has received research and none developed zoster infection within 30 days after grants and consulting fees from Amgen, UCB, Abbott, Genentech, Roche, vaccination. The incidence rates of HZ were similar in Centocor, BMS, and Merck. the vaccinated and unvaccinated person-times. The Received: 25 March 2011 Revised: 8 June 2011 results regarding safety and effectiveness are preliminary, Accepted: 24 October 2011 Published: 24 October 2011 and future evaluations are needed to understand better the risks and benefits associated with zoster vaccine in References patients with autoimmune disease and to help refine 1. Mueller NH, Gilden DH, Cohrs RJ, Mahalingam R, Nagel MA: Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and guidelines for the use of zoster vaccine. latency. Neurol Clin 2008, 26:675-697, viii. 2. Oxman MN: Herpes zoster pathogenesis and cell-mediated immunity and immunosenescence. J Am Osteopath Assoc 2009, 109:S13-17. Additional material 3. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS: A population-based study of the incidence and complication rates of Additional file 1: ICD9-diagnosis codes and medications used in herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007, case definitions. 82:1341-1349. 4. Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA: The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005, 20:748-753. Abbreviations 5. Mullooly JP, Riedlinger K, Chun C, Weinmann S, Houston H: Incidence of ACIP: the Advisory Committee on Immunization Practices; ACR: American herpes zoster, 1997-2002. Epidemiol Infect 2005, 133:245-253. College of Rheumatology; anti-TNF: anti-tumor necrosis factor alpha; CPT: 6. 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Ann Intern Med 2010, 152:555-560. 23. High K: Immunizations in older adults. Clin Geriatr Med 2007, 23:669-685, viii-ix. doi:10.1186/ar3497 Cite this article as: Zhang et al.: The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study. Arthritis Research & Therapy 2011 13:R174. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

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Published: Oct 24, 2011

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