Overall and Comparative Risk of Herpes Zoster With Pharmacotherapy for Inflammatory Bowel Diseases: A Nationwide Cohort Study

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1 Accepted Manuscript Overall and Comparative Risk of Herpes Zoster With Pharmacotherapy for Inflammatory Bowel Diseases: A Nationwide Cohort Study Nabeel Khan, Dhruvan Patel, Chinmay Trivedi, Yash Shah, Gary Lichtenstein, James Lewis, Yu-Xiao Yang PII: S (18) DOI: /j.cgh Reference: YJCGH To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 21 December 2017 Please cite this article as: Khan N, Patel D, Trivedi C, Shah Y, Lichtenstein G, Lewis J, Yang Y- X, Overall and Comparative Risk of Herpes Zoster With Pharmacotherapy for Inflammatory Bowel Diseases: A Nationwide Cohort Study, Clinical Gastroenterology and Hepatology (2018), doi: / j.cgh This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Overall and Comparative Risk of Herpes Zoster With Pharmacotherapy for Inflammatory Bowel Diseases: A Nationwide Cohort Study Short title: Herpes zoster and IBD Authors: Nabeel Khan 1, 2, Dhruvan Patel 3, Chinmay Trivedi 2, Yash Shah 2, Gary Lichtenstein 1, James Lewis 1, Yu-Xiao Yang 1, 2 1. Section of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 2. Section of Gastroenterology, VA Medical Center, Philadelphia, PA 3. Section of Gastroenterology, Drexel University College of Medicine, Philadelphia, PA Contact information for authors: Nabeel Khan, MD nabeel.khan@mail.med.upenn.edu 3900 Woodland Avenue Philadelphia, PA Dhruvan Patel, MD pateldhruvan@gmail.com 230 N Broad St, Philadelphia, PA Chinmay Trivedi, MD

3 Woodland Avenue Philadelphia, PA Yash Shah, MD Woodland Avenue Philadelphia, PA Gary Lichtenstein, MD Division of Gastroenterology GI Administration Offices 7 th Floor South, Room 753 Perelman Center One Convention Avenue Philadelphia, PA James D. Lewis, MD, MSCE lewisjd@pennmedicine.upenn.edu Center for Clinical Epidemiology and Biostatistics Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104

4 Yu-Xiao Yang, MD, MSCE Guardian Drive 722 Blockley Hall Philadelphia, PA Corresponding Author: To whom requests for reprints should be addressed: Nabeel Khan, MD Assistant Clinical Professor of Medicine Perelman School of Medicine at University of Pennsylvania Chief, Section of Gastroenterology Philadelphia VA Medical Center 3900 Woodland Avenue Philadelphia, PA Tel: Grant support This study was supported by an unrestricted research grant from Pfizer pharmaceuticals. Pfizer had no role in study concept, design, and analysis of data, critical review or drafting of the manuscript.

5 Disclaimer The study sponsor had no role in study design, analysis and interpretation of the data and in the writing of the report. The content of this report does not represent the views of the Department of Veterans Affairs or of Pfizer Pharmaceuticals. Disclosures Dr. Lewis reports having served as a consultant for Janssen, AbbVie, UCB, Pfizer, and Takeda. All other authors have no potential conflicts (financial, professional, or personal) that are relevant to this manuscript. The study was conducted and the manuscript was written and reviewed solely by the authors. Author contribution: Nabeel Khan has made substantial contribution to the study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and study supervision. Dhruvan Patel has participated in study concept and design, analysis and interpretation of data as well as drafting of the manuscript. Chinmay Trivedi and Yash Shah have participated in acquisition of data as well as interpretation of data. Gary Lichtenstein has participated in critical revision of the manuscript for important intellectual content. James Lewis has participated in study design and critical revision of the manuscript for important intellectual content. Yu- Xiao Yang has participated in study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and statistical analysis. Abstract: Background & Aims: Patients with inflammatory bowel disease (IBD) might be at increased risk for herpes zoster infection. We sought to quantify the risk of herpes zoster in patients with IBD and evaluate the effects of IBD and IBD medications on the risk of herpes zoster.

6 Methods: We conducted 2 retrospective studies of populations of Veterans, from January 2000 through June In study 1, we compared the incidence of herpes zoster among patients with IBD receiving 5-ASA alone vs matched patients without IBD. In study 2, we compared the incidence of herpes zoster among patients with IBD treated with only 5-ASA, with thiopurines, with antagonists of tumor necrosis factor (TNF), with a combination of thiopurines and TNF antagonists, and with vedolizumab. We used multivariable Cox regression to estimate the hazard ratios and 95% CIs for herpes zoster associated with IBD in study 1 and with different treatments in study 2. We also estimated the incidence rate of herpes zoster based on age and IBD medication subgroups. Results: Compared to no IBD, ulcerative colitis (UC) and Crohn s disease (CD) were each associated with significantly increased risk of herpes zoster infection. In multivariable Cox regression (compared to no IBD), UC, CD, or IBD treated with 5-ASA treatment alone was associated with significantly increased risk of herpes zoster, with adjusted HRs (AHR) of 1.81 for UC (95% CI, ), 1.56 for CD (95% CI, ), and 1.72 for treated IBD (95% CI, ). In multivariable Cox regression analysis, compared to exposure to 5-ASA alone, exposure to thiopurines (AHR, 1.47; 95% CI, ) or a combination of thiopurines and TNF antagonists (AHR, 1.65; 95% CI, ) was associated with increased risk of herpes zoster. However, exposure to TNF antagonists alone (AHR, 1.15; 95% CI, ) was not associated with increased risk of herpes zoster. The incidence rates of herpes zoster in all age groups and all IBD medication subgroups were substantially higher than that in the oldest group of patients without IBD (older than 60 years). Conclusion: In 2 retrospective studies of Veteran populations, we associated IBD and treatment with thiopurines, alone or in combination with TNF antagonists, with increased risk of herpes zoster. With the approval of a new and potentially safer vaccine for herpes zoster, the effects of immunization of patients with IBD should be investigated. KEY WORDS: opportunistic infection, varicella, thiopurine, anti-tnf Introduction: Inflammatory bowel disease (IBD), Crohn s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders involving the gastrointestinal tract of unknown etiology. The altered immune regulation seen in patients with IBD as well as medications used to treat IBD may predispose patients to systemic complications, such as an increased risk of infection. 1 Herpes zoster (HZ) results from reactivation of latent varicella zoster virus (VZV) infection. 2 The clinical presentation is characterized by a painful, unilateral vesicular eruption and is often complicated by post-

7 herpetic neuralgia (PHN). 3 Previous studies observed that the risk of HZ is elevated by 1.2 to 1.8 times in patients with IBD as compared to patients without IBD, but these studies were either done prior to the advent of biologics, or excluded patients who were over the age of Additionally, these prior studies have not assessed the validity of the codes used to identify HZ and also did not account for the impact of vaccination. They also did not take into consideration the severity of the disease or degree of steroid exposure. To overcome these limitations and to evaluate the incidence and risk factors for HZ in a nationwide IBD population, we used a Veterans Affairs (VA) cohort for our study. The VA has predominantly older population which makes it an ideal cohort to study HZ incidence in a high-risk population. 7 Unlike insurance databases, the VA database can be validated internally and vaccination records are documented. Our aims were to determine whether patients with IBD have an increased risk of HZ independent of immunosuppressive medication use and to quantify the extent that immunosuppression increases the risk while controlling for the disease activity. Methods: We conducted two retrospective cohort studies among patients in the US national VA healthcare system using data from the VA Informatics and Computing Infrastructure (VINCI) from January 1, 2000 through June 30, We obtained inpatient and outpatient International Classification of Diseases, Version 9 & 10, Clinical Modification (ICD-9-CM, ICD-10-CM) diagnosis codes, encounters, procedures, pharmacy and demographic data for the study population. Study Population The cohort study period was from January 1, 2000, through June 30, The study population included all veterans who had an ICD-9-CM or ICD-10-CM diagnosis for inflammatory bowel disease (IBD) during the study period. IBD was defined by the presence of an inpatient or outpatient diagnosis

8 code of Crohn s Disease (556.xx), (K51.xx) and/or Ulcerative Colitis (555.xx), (K50.xx) respectively (see appendix 1). We performed a validation of the algorithm based on IBD diagnostic codes. Two members of the investigative team (YS and CT) manually reviewed the VA electronic medical records of 200 randomly selected patients who had any of the IBD diagnostic codes. The IBD diagnosis was confirmed in 189 out of 200 patients (94.5%) with 100% concordance between the two reviewers. To be included in the final cohort for this study the following criteria must have also been met: (1) 1 ICD-9 or ICD-10 diagnosis code for UC and/or CD, (2) 1 outpatient visit in VA health care system, (3) At least 1 outpatient pharmacy claim for any of the IBD medications in Group 1-5 ([1] 5-ASA only, [2] Thiopurines, [3] Anti-TNF agents, [4] a combination of thiopurines and anti-tnf, [5] Vedolizumab) (4) At least two prescriptions of one distinct medication in medication groups 1-5 (5) the censor date could not be preceded by the date of the first prescription of IBD medication/pharmacy claim. For all patients, the follow-up began at the time of the start of the first IBD medication in any of the 5 medication groups and ended at the first of any following events: (1) incident herpes zoster (HZ) diagnosis, (2) HZ vaccination (i.e., CPT code 90736), (3) death, or (4) last prescribed medication course for any of the 5 medication groups. COHORT STUDY 1: IBD vs non-ibd Exposure The exposed group (n=13,001) in this cohort study consisted of those IBD patients who were categorized in only medication group 1 (i.e., 5-ASA) and without any exposure to corticosteroids. The unexposed group consisted of a cohort of randomly selected non-ibd patients (n=35,510) from CDW who were matched with the exposed group at a ratio of up to 1:4 with respect to 1) Veterans Integrated Service Network (VISN) number which designates the geographic location of clusters of VA facilities in the same region; 2) year of first outpatient receipt of care in the VA; 3) Age (at criteria 2 visit date), and 4) gender. Outcome

9 The outcome was time to the first occurrence HZ in the follow-up period defined by relevant ICD-9-CM (053.xx), ICD-10-CM (B02.xx) codes for HZ and their complications (see appendix 3). In order to validate the coding algorithm for HZ, two members of the investigative team (YS and CT) performed manual review of the VA electronic medical records of 200 randomly selected patients who had any of the HZ diagnostic codes. HZ diagnosis was confirmed in 182 out of 200 patients (91%) with 100% concordance between the two reviewers. Statistical Analyses The baseline characteristics of the exposure groups were compared using descriptive statistics. Overall incidence rates of HZ in the respective comparison groups as well as in CD or UC subgroups were calculated as the number of events per 1000 patient-years. Multivariable Cox regression was used to estimate the HR and CI for HZ risk associated with having IBD, UC or CD and being exposed to 5-ASA versus not having IBD, adjusting for the geographical location, health care utilization defined as the number of patient visits (outpatient and inpatient), race, and the baseline comorbid medical conditions including hypertension (complicated/uncomplicated), diabetes, lymphoma, metastatic cancer, chronic pulmonary disease, congestive heart failure, renal failure, liver disease, and AIDS/HIV. CDW data was stored in Microsoft SQL Server database and extracts were created from T-SQL coding using Microsoft SQL Server Management Studio. Final dataset creation and analysis were completed using SAS Enterprise Guide 7.1 software on SAS/Grid computing environment in SAS 9.4 intelligence platform. Analyses were also performed using R software, version (R Core Team (2016). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL COHORT STUDY 2: IBD BY MEDICATION USE We conducted a second retrospective cohort study using the same national VA data in VINCI. Exposure Groups

10 The exposure of interest was use of IBD medications categorized in 5 groups: (1) 5-ASA only, (2) Thiopurines, (3) Anti-TNF agents, (4) a combination of Thiopurines and Anti-TNF medications (5) Vedolizumab (see appendix 2). Medication use information was based on all inpatient and outpatient prescription records and related procedure codes. To determine exposure status to the medication groups on any given day during follow-up, a patient is considered to be exposed to a medication or medication combination in a given medication group starting from the first day of prescription. The patient continued in that medication group until the earliest of the following events: a medication from a highernumbered medication group was prescribed, a 90-day gap was found between prescriptions, or until censoring. Regarding infusible medications which included infliximab and vedolizumab, we included 3 months after the last CPT code entry as the period of exposure. A patient could also go back to a lower group if a medication was stopped and they were still on a medication from a lower group. Ninety day gaps were considered as completion of a round of medication. A new round would start with the next prescription. The exposure was measured in a time dependent manner. Specifically, the follow-up time for each patient was divided into consecutive 60-day intervals (except for the last interval which could be <60 days). Within each interval, the exposure status was determined based on exposure to a medication group for any duration. In instances where medication group switches occurred during an interval, the exposure status was assigned according to the medication group associated with the longest duration during the interval. Outcome The outcome was time to incident HZ during the follow-up period among each medication group as defined above. Statistical Analyses Demographic and clinical characteristics were summarized with counts and percentages for categorical variables, and mean (SD) for continuous variables.

11 Overall incidence of HZ, the incidence by medication groups as well as by age groups at the time of HZ diagnosis (<50, 50-60, and >60 years) within each medication group were estimated as the number of events per 1000 patient-years. We performed Cox regression with time-dependent analysis to examine the risk of HZ by medication group. Medication group 5 (Vedolizumab group) was excluded from the survival analyses due to its small sample size and no observed cases of HZ in this group. Specifically, we constructed multivariable Cox regression model with robust standard errors to estimate the aggregate hazard ratios and 95% CIs by pooling the interval-specific associations between the medication exposure group status at the beginning of each 60-day interval (i.e., index date) and the risk of HZ during that interval. The model was adjusted for the following time-varying covariates updated in each interval: age at index date, intensity of prednisone use up to each index date (i.e., total amount of prednisone taken from the beginning of followup divided by the total number of days up to the index date), oral prednisone use within 30 days before index date, a proxy for disease flare up (i.e., presence of any of the following events during a 60-day interval: a hospitalization, IV corticosteroid use, abdominal and or pelvic CT, stool C. difficile toxin testing. In addition, we also included the following fixed covariates: IBD diagnosis (UC/CD), geographical location (Midwest, North Atlantic, Pacific, Southeast, Continental), health care utilization (<6, 6 to 12, 13 visits/year), race (white, black, others, unknown), gender, and the baseline comorbid medical conditions. In ascertaining comorbidities, we used ICD-9-CM, ICD-10-CM code definitions developed by Elixhauser et al. for use with administrative data. 8 We searched inpatient and outpatient diagnosis records one year prior to first medication date. An outpatient diagnosis was only kept if two distinct diagnosis records greater than 30 days apart were found. Hazard ratios (HRs) between medication groups were estimated from this model along with 95% confidence intervals (CIs). Results:

12 Cohort 1 (IBD vs non-ibd) included 13,001 eligible IBD patients (42, 510 person-years of total follow-up) who had only been exposed to 5-ASA and 35,510 randomly selected matched non-ibd patients (334,017 person-years of total follow-up) from VINCI. Table 1 presents the baseline characteristics of these two matched comparison groups. The overall crude incidence rate for HZ was 7.55 per 1000 person-years in the IBD group versus only 3.22 per 1000 person-years in the non-ibd group. IBD patients who required only 5-ASA for disease control had significantly increased risk of HZ compared to matched non-ibd patients. In multivariable Cox regression, compared to the non-ibd reference group, having either UC or CD, or any IBD (with 5-ASA treatment alone) was associated with significantly increased risk of developing HZ with adjusted HRs (AHR) of 1.81 (95 % CI: ) for UC, 1.56 (95% CI: ) for CD, 1.72 (95% CI: ) for IBD. (Table 2) Using CD as a control group, we found that UC patients did not have statistically higher risk of HZ development (AHR 1.16, 95% CI: ). Table 3 shows HZ incidence rate in IBD and non-ibd group stratified by age <50 years, years and >60 years. The IBD group had a higher incidence for HZ than the matched non-ibd group. In fact, the incidence of HZ among the youngest age group of patients with IBD (i.e., 8.62 per 1000 person-years) exceeded that of the oldest group of control patients (i.e., 3.3 per 1000 person-years). Cohort 2 (IBD by medication use) included a total of 54,919 eligible IBD patients who accumulated 243,506 person-years of at risk time. During this follow-up period, 2,007 total episodes of incident HZ were observed. A comparison of the patients who contributed at-risk time in each of the medication exposure groups with respect to total at-risk time, number of incident HZ episodes, crude HZ incident rate, and baseline characteristic is shown in Table 4. Because of the time-varying nature of the exposure variable, a patient may contribute at-risk time in more than one medication groups. Of note, there were no incident HZ events in Vedolizumab group which only included 167 patients. Therefore, Vedolizumab group was dropped from the multivariable regression analysis. In multivariable Cox regression analysis, compared to exposure to 5-ASA alone, exposure to thiopurines [AHR 1.47 (95%CI )] or a combination of thiopurines and anti-tnf agents [AHR 1.65 (95% CI )] was associated with increased risk of HZ. However, exposure to anti-tnf agents alone [AHR

13 1.15 (95% CI )] was not associated with increased risk of HZ (Table 5). Both cumulative [AHR 1.02 (95% CI )] and short term [1.27(95% CI )] exposure to prednisone were associated with an increased risk of developing HZ. As expected, increased age [1.01 (95%CI )] and disease flare [3.69 (95% CI )] as described above was also associated with an increased risk of developing HZ. Multivariate analysis of other risk factors for HZ development among IBD patients is mentioned in table 5. Table 6 shows the absolute risk of HZ across the 4 medication groups stratified by age groups. There was a clear trend of increasing risk of HZ with rising age. However, patients in the younger age group (e.g., < 50) who were exposed to immunomodulators, anti-tnf or a combination of these medications can have absolute risk of HZ comparable or higher than those over the age of 60 in patients exposed to 5-ASA only. Discussion: In this large nationwide VA cohort with IBD patients, we analyzed the incidence and risk factors for HZ and the impact of IBD medications upon them. We found that IBD itself without immunosuppressive medicine can predispose patients to develop HZ. Within the IBD cohort, older age, use of thiopurine or thiopurines and anti-tnf (combination therapy), IBD flare, higher cumulative prednisone use or prednisone use within the last 30 days were independent risk factors for HZ incidence. In multivariate analysis, after controlling for multiple confounding factors including IBD flare, anti-tnf medicine use alone was not an independent risk factor for HZ in IBD. IBD patients who were <50 years of age and on combination therapy had a higher risk of HZ than those who were >60 years of age and on mesalamine therapy alone. The highest risk was observed amongst IBD patients who were >60 years of age and on combination therapy which approached ~2% per year.

14 Patients with IBD have been previously shown to have an increased risk of HZ compared to general population in prior studies. 4-6 In our study, we compared IBD patients who were only on mesalamine therapy to matched control group who had no IBD and we found that patients with both UC and CD have significantly higher chance of developing HZ. The incidence of HZ was slightly higher in UC patients (7.98 per 1000 PYs) compared to CD patients (6.83 per 1000 PYs) in our cohort but it was not statistically significant. This is in contrast with previous case-control studies which showed that patients with CD had higher risk of HZ than patients with UC. 4, 5 Unlike those studies, in our case-control analysis we excluded IBD patients who were on prednisone as well as immunosuppressant medicines because we wanted to study the effect of the disease process in the absence of medication-induced systemic immunosuppression on HZ development. Our aim was to ascertain whether the immune dysregulation associated with IBD is in itself a factor that predisposes patients to an increased risk of herpes zoster while removing the impact of known pharmacological risk factors such as corticosteroids which have been extensively studied. Additionally, we censored our IBD cohort as well as non-ibd cohort for HZ vaccination which other prior studies did not. Our result proposes that innate immune dysregulation in IBD itself may play an important role in HZ development. Because of higher risk of HZ in IBD population, it is important to understand the HZ risk factors which predispose IBD patients to develop HZ. In our cohort, use of thiopurine alone [AHR 1.47 (95%CI )] and combination therapy [AHR 1.65 (95% CI )] were independently associated with the increased risk of HZ after adjusting for other confounding factors. Previous studies that have evaluated the risk of HZ in IBD found a similar result of increased HZ risk with the use of thiopurine and combination therapy. 4-6, 9 Interestingly, the use of anti-tnf alone [AHR 1.15 (95% CI )] was not an independent risk factor of HZ incidence after controlling for all possible confounding variables, most importantly for IBD flare. This is in contrast with existing literatures which states that anti-tnf use increases the risk of HZ incidence in IBD. 4-6, 9 However, none of these previous studies have evaluated IBD flare as one of the confounders which could have overestimated the risk of HZ incidence in patients taking anti-tnf medicines. Although it is difficult to accurately capture all flares in a retrospective study we feel that the criteria we devised would capture the majority of the flares. As suspected, IBD flare had

15 the strongest association with the development of HZ (HR 3.69, 95%CI ). Further studies are warranted to support our findings. Cumulative exposure of prednisone over the course of the disease and current use of prednisone could serve as a proxy of disease severity and associated with increased HZ risk. While performing timedependent analysis and including two additional time-dependent covariates designed to capture both chronic (i.e., cumulative prednisone use per unit follow-up time) and current (i.e., presence of events specific for IBD flare) disease activity, we found that intensity of cumulative prednisone exposure ( HR 1.02, 95% CI ) and prednisone use within 30 days of index date (HR 1.27, 95% CI ) were both independent risk factors for HZ incidence after controlling for confounding factors. The result is in keeping with previous studies which have identified that longer duration and higher dose of glucocorticoids use confer a greater risk of HZ in IBD as demonstrated by Winthrop et al. 10 In addition to the use of immunosuppressive medicine, we found that advancing age (HR 1.01, 95% CI ) is another independent risk factor for development of HZ in IBD population. A novel aspect of this study was the assessment of the combined effect of older age and medication use on HZ incidence in an IBD population. We found that IBD patients who were >60 years of age and on combination therapy had the highest risk of HZ development which approached almost 2% per year. Advancement has been made in the field of vaccination against herpes zoster. Recently a new recombinant subunit vaccine for HZ was developed by GlaxoSmithKline and in clinical trials it has shown 97.2% efficacy in patients >50 years of age. 11 Current ACG (American College of Gastroenterology) guidelines have recommended vaccination among patients over the age of 50 in patients with IBD. 12 The high herpes zoster rates observed in patients with <50 years of age and on combination therapy or with immunomodulatory therapy in our study raises the question of whether younger patients with IBD should also be vaccinated for the prevention of HZ. Further studies should be conducted on universal vaccination among IBD population to assess the efficacy and feasibility of this new vaccination.

16 The major strength of this study was that data was captured form a nationwide cohort and had one of the longest follow up duration spanning a 16-year period. As we evaluated IBD patients long after the advent of anti-tnf medicines, we were able to capture a large number of patients on anti-tnf and thiopurines unlike previous studies focused on the same hypothesis. 4-6, 9 The older population in VA system also makes it an ideal cohort to study the incidence and risk factors for HZ in this high-risk group unlike one of the previous studies which excluded patients who were >64 years of age. 5 HZ vaccination record is widely available in the VA system and ours was the first study that accounted for the use of zostavax. Additionally, we internally validated ICD-9 and ICD-10 codes for both IBD and HZ diagnosis. Our validation demonstrates that the diagnosis of HZ and IBD in our data is accurate with positive predictive value of 91% for HZ and 94.5% for IBD diagnosis. Another strength of our study is that we controlled for additional measure of disease activity/severity (cumulative prednisone exposure as well as prednisone exposure within 30 days and the first study to control for IBD flare) which would help minimize the effect of confounding by indication. Lastly, we used other surrogate measures as a mechanism for evaluating disease flare and controlled for this as well. There are certain limitations in our study. The VA population is a selected cohort not only due to the male predominance but this is also an older population, and thus our results may not be generalizable to a general population. However, none of the previous studies have shown that gender as a risk factor for HZ infection in IBD population. Moreover, the size of the population still allowed us to perform meaningful age-specific subgroup analyses. Because we used the VA pharmacy database to estimate medication exposure rates, prescriptions filled outside the VA were not captured by our analysis. We do not anticipate this has created any bias as previous reports have shown that veterans have very good adherence in using the VA pharmacy We employed a time-varying analytical approach and estimated the incidence of HZ risk for the respective medication groups based on the total person-time of exposure to a particular medication group and the number of HZ events that occurred during such person-time of exposure. Based on the known pharmacological effects of the IBD medications, we expected that any impact of IBD medications on herpes zoster (HZ) risk would primarily be limited to the period of exposure to the respective medication groups. To the extent that this assumption might not

17 precisely reflect the true induction periods between exposure to the various groups IBD medications and HZ risk, our effect estimates could potentially contain some degree of error. A better understanding of the mechanism(s) mediating the effect of IBD medications on HZ risk would allow future studies to more accurately define the etiologically relevant exposure window and minimize such error. In conclusion, using a large nationwide VA database we found that IBD itself and treatment with thiopurines alone or in combination with anti-tnf agents, cumulative and recent use of prednisone within 30 days were independently associated with a higher risk of HZV. The highest risk of HZ was observed in IBD patients who were >60 years of age and on combination therapy. IBD patients younger than 50 years who were on combination therapy had higher risk of HZ compared to IBD patients older than 60 years of age who were not on immunosuppressive therapy. With the approval of the new HZ vaccine further studies into its efficacy and expansion of use among the IBD population should be undertaken. References: 1. Irving PM, Gibson PR. Infections and IBD. Nature Clinical Practice Gastroenterology & Hepatology. 2008;5(1): Cohen JI. Herpes zoster. New England Journal of Medicine. 2013;369(3): Sampathkumar P, Drage LA, Martin DP, editors. Herpes zoster (shingles) and postherpetic neuralgia. Mayo Clinic Proceedings; 2009: Elsevier. 4. Gupta G, Lautenbach E, Lewis JD. Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology. 2006;4(12): Long MD, Martin C, Sandler RS, et al. Increased risk of herpes zoster among patients with inflammatory bowel disease. Alimentary pharmacology & therapeutics. 2013;37(4):420-9.

18 6. Marehbian J, Arrighi HM, Hass S, et al. Adverse events associated with common therapy regimens for moderate-to-severe Crohn's disease. The American journal of gastroenterology. 2009;104(10): ; Available from: 8. Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9- CM and ICD-10 administrative data. Medical care. 2005: Osterman MT, Haynes K, Delzell E, et al. Effectiveness and Safety of Immunomodulators With Anti Tumor Necrosis Factor Therapy in Crohn s Disease. Clinical Gastroenterology and Hepatology. 2015;13(7): e Winthrop KL, Baddley JW, Chen L, et al. Association between the initiation of anti tumor necrosis factor therapy and the risk of Herpes Zoster. Jama. 2013;309(9): Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. New England Journal of Medicine. 2015;372(22): Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: preventive care in inflammatory bowel disease. The American journal of gastroenterology. 2017;112(2): Klein R, Stockford D. Data on the Socioeconomic Status of Veterans and on VA Program Usage. Office of the Actuary, Veterans Health Administration U.S. Government Accountability Office Report VHC. Use of VA Services by Medicare-Eligible Veterans. Washington, DC Wolinsky FD, Miller TR, An H, et al. Dual use of Medicare and the Veterans Health Administration: are there adverse health outcomes? BMC Health Services Research. 2006;6(1):131.

19 Table 1. Baseline characteristics of IBD patients receiving only 5-ASA and matched non-ibd patients IBD patients on 5-ASA therapy only Variable Non-IBD match IBD CD UC All (%) 35,510 13, (35.63) 8369 (64.37) Gender, no. (%) Female 2486 (7.5) 826 (6.35) 311 (6.71) 515 (6.15) Male 33,024 (92.5) 12,175 (93.65) 4321 (93.29) 7854 (93.85) Race, no. (%) African American 4566 (12.86) 1146 (8.81) 393 (8.48) 753 (9) Caucasian 28,433 (80.07) 11,283 (86.79) 4039 (87.2) 7244 (86.56) Others 648 (1.82) 204 (1.57) 57 (1.23) 147 (1.76) Unknown 1863 (5.25) 368 (2.83) 143 (3.09) 225 (2.69) District, no. (%) Continental 4355 (12.26) 1539 (11.84) 538 (11.61) 1001 (11.96) Mid-West 6487 (18.27) 2689 (20.68) 994 (21.46) 1695 (20.25) North Atlantic 13,791 (38.84) 4595 (35.34) 1673 (36.12) 2922 (34.91) Pacific 3337 (9.4) 1401 (10.78) 459 (9.91) 942 (11.26) Southeast 7540 (21.23) 2777 (21.36) 968 (20.9) 1809 (21.62) Age, no. (%) <50 years 4322 (12.17) 2088 (16.06) 750 (16.19) 1338 (15.99) years 4001 (11.27) 1902 (14.63) 720 (15.54) 1182 (14.12) >60 years (76.56) 9011 (69.31) 3162 (68.26) 5849 (69.89) Age, mean (SD) years All 70 (15.73) (15.85) (15.85) (115.85) HZ diagnosis 70 (12.49) (13.77) (12.75) (14.27)

20 Utilization, mean (SD) visits/year <6 11,512 (32.42) 2954 (22.72) 1053 (22.73) 1901 (22.71) ,541 (38.13) 5193 (39.94) 1835 (39.62) 3358 (40.12) >13 10,457 (29.45) 4854 (37.34) 1744 (37.65) 3110 (37.16) Follow-up [mean (SD), median] All 9.41 (4.41), (3.98), (4.04), (3.95), 2.76 HZ diagnosis 6.38 (3.93), (3.37), (3.43), (3.34), 2.58 End of follow up reason, no. (%) Last recorded date 24,559 (69.16) (78.04) 3636 (78.5) 6510 (77.79) HZ diagnosis date 1076 (3.03) 321 (2.47) 109 (2.35) 212 (2.53) HZ vaccination date 4970 (14) 1612 (12.4) 554 (11.96) 1058 (12.64) Death 4905 (13.81) 922 (7.09) 333 (7.19) 589 (7.04) Comorbidities, no. (%) Hypertension 66 (0.19) 101 (0.78) 29 (0.63) 72 (0.86) Complicated Hypertension Uncomplicated 10,167 (28.63) 4974 (38.26) 1751 (37.8) 3223 (38.51) Diabetes Complicated 39 (0.11) 271 (2.08) 99 (2.14) 172 (2.06) Diabetes Uncomplicated 293 (0.83) 1505 (11.58) 518 (11.18) 987 (11.79) Lymphoma 46 (0.13) 37 (0.28) 15 (0.32) 22 (0.26) Metastatic Cancer 31 (0.09) 22 (0.17) 7 (0.15) 15 (0.18) Chronic Pulmonary Disease 1073 (3.02) 850 (6.54) 289 (6.24) 561 (6.7)

21 Congestive Heart Failure 600 (1.69) 319 (2.45) 107 (2.31) 212 (2.53) Renal Failure 217 (0.61) 230 (1.77) 87 (1.88) 143 (1.71) Liver Disease 185 (0.52) 201 (1.55) 67 (1.45) 134 (1.6) HIV 63 (0.18) 54 (0.42) 12 (0.26) 42 (0.5) None of the above 24,286 (68.39) 7025 (54.03) 2553 (55.12) 4472 (53.44) IBD, Irritable Bowel Disease; UC, Ulcerative Colitis; CD, Crohn s Disease; HZ, Herpes Zoster; SD, standard deviation; District, geographical VA district recorded at first outpatient visit in the VA; Age, calculated at end of follow up date ; Last recorded date, last prescription date for IBD or last visit date for non-ibd; Comorbidities, diagnosed in the year prior to group time

22 Table 2. Association between IBD and IBD subtype status and the risk of HZ* Adjusted Hazard 95% CI Ratio** Comparison groups IBD (5-ASA treatment only) 1.72 (1.51, 1.96) UC only 1.81 (1.56, 2.11) CD only 1.56 (1.28, 1.91) Non-IBD group Reference Reference * the comparison groups of overall IBD (5-ASA treatment only) group and non-ibd group were matched on age, sex, calendar year of start of follow-up, VISN. **this analysis adjusted geographic region, intensity of VA healthcare utilization, race, and baseline comorbidity status (i.e., Hypertension (controlled and uncontrolled), diabetes mellitus, lymphoma, metastatic cancer, Chronic Pulmonary Disease, Congestive heart failure, renal failure, liver disease, AIDS.)

23 Table 3: Episodes of herpes zoster (HZ incidence) by cohort IBD case cohort Non-IBD match cohort Episodes of HZ per 1000 person Age<50 years Age years Age>60 years years No. of patients Patient-years Episodes of HZ per 1000 person years No. of patients Patient-years

24 Table 4. Comparison of characteristics of IBD medication groups Medication Group* Variable All (n=5491 9) 5-ASA alone (n=5096 2) Thiopur ines (n=1317 4) IBD CD UC Age, mean (SD) years Male gender, no. (%) Race, no. (%) Caucasian African American Other (38.57) (61.43) 63.8 (14.83) (93.3) (85.98) 5124 (9.33) 983 (1.79) (36.21) (63.79) 65.7 (14.18) (93.52) (86.07) 4753 (9.33) 918 (1.8) 7015 (53.25) 6159 (46.75) 59.3 (14.93) (92.01) (84.45) 1358 (10.31) 247 (1.87) Unknown (2.9) (2.8) (3.37) Anti-TNF Thiopurines agents and anti-tnfs Vedolizuma (n=6653) (n=2534) b (n=167) 4143 (62.27) 2510 (37.73) 52.4 (14.47) 5889 (88.52) 5490 (82.52) 1655 (65.31) 95 (56.89) 879 (34.69) 72 (43.11) (52.7) 51.8 (14.99) 2239 (88.36) 149 (89.22) 2081 (82.12) 145 (86.83) 321 (12.67) 14 (8.38) 844 (12.69) 132 (1.98) 55 (2.17) 4 (2.4) 187 (2.81) 77 (3.04) 4 (2.4) Geographical region Continental 7965 (14.5) 7391 (14.5) 2073 (15.74) 1036 (15.57) 461 (18.19) 27 (16.17)

25 Mid-West (23.54) (23.3) 3057 (23.2) 1516 (22.79) 537 (21.19) 35 (20.96) North Atlantic 582 (22.97) 39 (23.35) (26.67) (26.77) (25.7) (23.72) Pacific 520 (20.52) 39 (23.35) (16.07) (16.01) (17.09) (18.83) Southeast 434 (17.13) 27 (16.17) (19.21) (19.42) (18.26) (19.09) Episodes of HZ, no Patient-years Episodes per 1000 patientyears Comorbidities Hypertension complicated Hypertension uncomplicated Diabetes Complicated Diabetes Uncomplicated Lymphoma (0.54) (32.12) 795 (1.45) 4439 (8.08) 270 (0.53) (32.76) 743 (1.46) 4140 (8.12) 43 (0.33) 3192 (24.23) 130 (0.99) 763 (5.79) 20 (0.3) 6 (0.24) 1 (0.6) 1443 (21.69) 498 (19.65) 37 (22.16) 73 (1.1) 22 (0.87). (.) 441 (6.63) 137 (5.41) 10 (5.99) 7 (0.11) 1 (0.04) 0 (0) (0.21) (0.22) (0.14) Metastatic Cancer 56 (0.1) 55 (0.11) 4 (0.03) 2 (0.03) 0 (0) 0 (0)

26 Chronic Pulmonary Disease 3553 (6.47) 3358 (6.59) 563 (4.27) 244 (3.67) 80 (3.16) 6 (3.59) Congestive Heart Failure Renal Failure Liver Disease HIV None of the above 1185 (2.16) 807 (1.47) 810 (1.47) 138 (0.25) (61.13) 1118 (2.19) 729 (1.43) 736 (1.44) 135 (0.26) (60.48) 191 (1.45) 139 (1.06) 182 (1.38) 12 (0.09) 9299 (70.59) 58 (0.87) 27 (1.07) 2 (1.2) 48 (0.72) 11 (0.43) 2 (1.2) 72 (1.08) 26 (1.03) 2 (1.2) 11 (0.17) 3 (0.12) 0 (0) 4886 (73.44) 1925 (75.97) 126 (75.45) * Because of the time-varying nature of the exposure variable, a patient may contribute at-risk time in more than one medication groups. This table presents a comparison of the patient who contributed at-risk time in each of the medication group. Therefore, a patient may be included in more than one exposure group. The baseline characteristics reflect status at the beginning of the total follow-up for each patient and were not time-updating. IBD, Irritable Bowel Disease; UC, Ulcerative Colitis; CD, Crohn s Disease; HZ, Herpes Zoster; SD, standard deviation; Comorbidities, diagnosed in the year prior to group time

27 Table 5. Multivariate Analysis for HZ Risk Factors Among IBD Patients Adjusted Hazard Variable Ratio* Medication Group 95% CI p value 5-ASA alone Reference Reference Thiopurines 1.47 (1.31, 1.65) <0.001 Anti-TNF agents 1.15 (0.96, 1.38) Thiopurines and 1.65 (1.22, 2.23) anti-tnf agents Age at index date 1.01 (1.01, 1.02) <0.001 Prednisone 1.02 (1.01, 1.03) cumulative (mg/day) Prednisone within (1.10, 1.48) days before index date Disease flare 3.69 (3.22, 4.23) <0.001 IBD Diagnosis CD Reference Reference Reference UC 1.01 ( 0.92, 1.11) District Continental Reference Reference Reference Midwest 1.01 ( 0.87, 1.18) 0.848

28 North Atlantic 0.98 ( 0.84, 1.13) Pacific 1.15 ( 0.99, 1.35) Southeast 1.01 ( 0.87, 1.17) Race Black Reference Reference Reference White 1.17 ( 0.99, 1.37) Other 1.33 ( 0.95, 1.88) Unknown 1.33 ( 0.91, 1.94) Gender Female Reference Reference Reference Male 1.01 ( 0.83, 1.22) Health Care Utilization <6 Reference Reference Reference 6 to ( 1.25, 1.97) <0.001 > ( 1.85, 2.90) <0.001 Baseline comorbid medical conditions Complicated Hypertension Uncomplicated Hypertension 1.41 ( 0.68, 2.95) ( 0.92, 1.13) Diabetes mellitus 0.55 ( 0.32, 0.95) 0.031

29 Lymphoma 0.99 ( 0.31, 3.14) Metastatic Cancer 1.61 ( 0.37, 6.95) Chronic Pulmonary Disease Congestive Heart Failure 1.13 ( 0.94, 1.37) ( 0.77, 1.46) Renal failure 1.02 ( 0.63, 1.68) Liver disease 1.40 ( 1.01, 1.96) AIDS 1.31 ( 0.47, 3.62) * adjusting for IBD type, age at index date, cumulative prednisone, prednisone use within 30 days prior to the index date, disease flare, geographic region, intensity of VA healthcare utilization, race, gender, and baseline comorbidity status ( i.e., Hypertension (controlled and uncontrolled), diabetes mellitus, lymphoma, metastatic cancer, Chronic Pulmonary Disease, Congestive heart failure, renal failure, liver disease, AIDS.)

30 Table 6: Absolute risk of HZ across the medication groups stratified by age 5-ASA Thiopurines Anti-TNF agents Combination Age Age<50 years years Rate of HZ per 1000 personyears Number of patients Age>60 years Patient-years Rate of HZ per 1000 personyears Number of patients Patient-years Rate of HZ per 1000 personyears Number of patients (Thiopurines + Patient-years Rate of HZ per 1000 person years Anti-TNF) Number of patients

31 Patient-years Rate of HZ per Vedolizumab 1000 personyears Number of patients Patient-years

32 Supplementary materials for review: Appendix 1. IBD Cohort Diagnosis List icd9code Description 555 REGIONAL ENTERITIS OF SMALL INTESTINE REGIONAL ENTERITIS OF LARGE INTESTINE REGIONAL ENTERITIS OF SMALL INTESTINE WITH LARGE INTESTINE REGIONAL ENTERITIS OF UNSPECIFIED SITE 556 ULCERATIVE ENTEROCOLITIS ULCERATIVE ILEOCOLITIS ULCERATIVE PROCTITIS ULCERATIVE PROCTOSIGMOIDITIS PSEUDOPOLYPOSIS OF COLON LEFT-SIDED ULCERATIVE COLITIS UNIVERSAL ULCERATIVE COLITIS OTHER ULCERATIVE COLITIS ULCERATIVE COLITIS, UNSPECIFIED icd10code Description K50.00 CROHN'S DISEASE OF SMALL INTESTINE WITHOUT COMPLICATIONS K CROHN'S DISEASE OF SMALL INTESTINE WITH RECTAL BLEEDING K CROHN'S DISEASE OF SMALL INTESTINE WITH INTESTINAL OBSTRUCTION K CROHN'S DISEASE OF SMALL INTESTINE WITH FISTULA K CROHN'S DISEASE OF SMALL INTESTINE WITH ABSCESS K CROHN'S DISEASE OF SMALL INTESTINE WITH OTHER COMPLICATION K CROHN'S DISEASE OF SMALL INTESTINE WITH UNSPECIFIED COMPLICATIONS K50.10 CROHN'S DISEASE OF LARGE INTESTINE WITHOUT COMPLICATIONS

33 K CROHN'S DISEASE OF LARGE INTESTINE WITH RECTAL BLEEDING K CROHN'S DISEASE OF LARGE INTESTINE WITH INTESTINAL OBSTRUCTION K CROHN'S DISEASE OF LARGE INTESTINE WITH FISTULA K CROHN'S DISEASE OF LARGE INTESTINE WITH ABSCESS K CROHN'S DISEASE OF LARGE INTESTINE WITH OTHER COMPLICATION K CROHN'S DISEASE OF LARGE INTESTINE WITH UNSPECIFIED COMPLICATIONS K50.80 CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITHOUT COMPLICATIONS K CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH RECTAL BLEEDING CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH INTESTINAL K OBSTRUCTION K CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH FISTULA K CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH ABSCESS K CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH OTHER COMPLICATION CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH UNSPECIFIED K COMPLICATIONS K50.90 CROHN'S DISEASE, UNSPECIFIED, WITHOUT COMPLICATIONS K CROHN'S DISEASE, UNSPECIFIED, WITH RECTAL BLEEDING K CROHN'S DISEASE, UNSPECIFIED, WITH INTESTINAL OBSTRUCTION K CROHN'S DISEASE, UNSPECIFIED, WITH FISTULA K CROHN'S DISEASE, UNSPECIFIED, WITH ABSCESS K CROHN'S DISEASE, UNSPECIFIED, WITH OTHER COMPLICATION K CROHN'S DISEASE, UNSPECIFIED, WITH UNSPECIFIED COMPLICATIONS K51.00 ULCERATIVE (CHRONIC) PANCOLITIS WITHOUT COMPLICATIONS K ULCERATIVE (CHRONIC) PANCOLITIS WITH RECTAL BLEEDING K ULCERATIVE (CHRONIC) PANCOLITIS WITH INTESTINAL OBSTRUCTION K ULCERATIVE (CHRONIC) PANCOLITIS WITH FISTULA K ULCERATIVE (CHRONIC) PANCOLITIS WITH ABSCESS K ULCERATIVE (CHRONIC) PANCOLITIS WITH OTHER COMPLICATION

34 K ULCERATIVE (CHRONIC) PANCOLITIS WITH UNSPECIFIED COMPLICATIONS K51.20 ULCERATIVE (CHRONIC) PROCTITIS WITHOUT COMPLICATIONS K ULCERATIVE (CHRONIC) PROCTITIS WITH RECTAL BLEEDING K ULCERATIVE (CHRONIC) PROCTITIS WITH INTESTINAL OBSTRUCTION K ULCERATIVE (CHRONIC) PROCTITIS WITH FISTULA K ULCERATIVE (CHRONIC) PROCTITIS WITH ABSCESS K ULCERATIVE (CHRONIC) PROCTITIS WITH OTHER COMPLICATION K ULCERATIVE (CHRONIC) PROCTITIS WITH UNSPECIFIED COMPLICATIONS K51.30 ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITHOUT COMPLICATIONS K ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH RECTAL BLEEDING K ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH INTESTINAL OBSTRUCTION K ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH FISTULA K ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH ABSCESS K ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH OTHER COMPLICATION K ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH UNSPECIFIED COMPLICATIONS K51.40 INFLAMMATORY POLYPS OF COLON WITHOUT COMPLICATIONS K INFLAMMATORY POLYPS OF COLON WITH RECTAL BLEEDING K INFLAMMATORY POLYPS OF COLON WITH INTESTINAL OBSTRUCTION K INFLAMMATORY POLYPS OF COLON WITH FISTULA K INFLAMMATORY POLYPS OF COLON WITH ABSCESS K INFLAMMATORY POLYPS OF COLON WITH OTHER COMPLICATION K INFLAMMATORY POLYPS OF COLON WITH UNSPECIFIED COMPLICATIONS K51.50 LEFT SIDED COLITIS WITHOUT COMPLICATIONS K LEFT SIDED COLITIS WITH RECTAL BLEEDING K LEFT SIDED COLITIS WITH INTESTINAL OBSTRUCTION K LEFT SIDED COLITIS WITH FISTULA K LEFT SIDED COLITIS WITH ABSCESS K LEFT SIDED COLITIS WITH OTHER COMPLICATION

35 K LEFT SIDED COLITIS WITH UNSPECIFIED COMPLICATIONS K51.80 OTHER ULCERATIVE COLITIS WITHOUT COMPLICATIONS K OTHER ULCERATIVE COLITIS WITH RECTAL BLEEDING K OTHER ULCERATIVE COLITIS WITH INTESTINAL OBSTRUCTION K OTHER ULCERATIVE COLITIS WITH FISTULA K OTHER ULCERATIVE COLITIS WITH ABSCESS K OTHER ULCERATIVE COLITIS WITH OTHER COMPLICATION K OTHER ULCERATIVE COLITIS WITH UNSPECIFIED COMPLICATIONS K51.90 ULCERATIVE COLITIS, UNSPECIFIED, WITHOUT COMPLICATIONS K ULCERATIVE COLITIS, UNSPECIFIED WITH RECTAL BLEEDING K ULCERATIVE COLITIS, UNSPECIFIED WITH INTESTINAL OBSTRUCTION K ULCERATIVE COLITIS, UNSPECIFIED WITH FISTULA K ULCERATIVE COLITIS, UNSPECIFIED WITH ABSCESS K ULCERATIVE COLITIS, UNSPECIFIED WITH OTHER COMPLICATION K ULCERATIVE COLITIS, UNSPECIFIED WITH UNSPECIFIED COMPLICATIONS Appendix 2. Medication Group (by hierarchy) Drug Name Without Dose 5 VEDOLIZUMAB BALSALAZIDE 1 OLSALAZINE SULFASALAZINE AZATHIOPRINE 2 MERCAPTOPURINE 3 ADALIMUMAB CERTOLIZUMAB

36 GOLIMUMAB INFLIXIMAB 4 Group 2 and 3 medications concurrently Appendix 3. ICD9Code Description 053 HERPES ZOSTER WITH MENINGITIS ICD10Code HERPES ZOSTER WITH UNSPECIFIED NERVOUS SYSTEM COMPLICATION GENICULATE HERPES ZOSTER POSTHERPETIC TRIGEMINAL NEURALGIA POSTHERPETIC POLYNEUROPATHY HERPES ZOSTER MYELITIS HERPES ZOSTER WITH OTHER NERVOUS SYSTEM COMPLICATIONS HERPES ZOSTER DERMATITIS OF EYELID HERPES ZOSTER KERATOCONJUNCTIVITIS HERPES ZOSTER IRIDOCYCLITIS HERPES ZOSTER WITH OTHER OPHTHALMIC COMPLICATIONS OTITIS EXTERNA DUE TO HERPES ZOSTER HERPES ZOSTER WITH OTHER SPECIFIED COMPLICATIONS HERPES ZOSTER WITH UNSPECIFIED COMPLICATION HERPES ZOSTER WITHOUT MENTION OF COMPLICATION Description B02.0 ZOSTER ENCEPHALITIS B02.1 ZOSTER MENINGITIS B02.30 ZOSTER OCULAR DISEASE, UNSPECIFIED