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: S1542-3565(18)30012-0
DOI: 10.1016/j.cgh.2017.12.052
Reference: YJCGH 55638

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: 10.1016/
j.cgh.2017.12.052.

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 ACCEPTED MANUSCRIPT

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

Short title: Herpes zoster and IBD

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1, 2 3 2 2 1
Authors: Nabeel Khan , Dhruvan Patel , Chinmay Trivedi , Yash Shah , Gary Lichtenstein , James

Lewis1, Yu-Xiao Yang1, 2

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1. Section of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia,

PA

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2. Section of Gastroenterology, VA Medical Center, Philadelphia, PA

3. Section of Gastroenterology, Drexel University College of Medicine, Philadelphia, PA

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Contact information for authors:
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Nabeel Khan, MD

Email: nabeel.khan@mail.med.upenn.edu
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3900 Woodland Avenue

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Philadelphia, PA 19104
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Dhruvan Patel, MD
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Email: pateldhruvan@gmail.com
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230 N Broad St,

Philadelphia, PA 19102

Chinmay Trivedi, MD
 ACCEPTED MANUSCRIPT

Email: Chinmay.Trivedi@va.gov

3900 Woodland Avenue

Philadelphia, PA 19104

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Yash Shah, MD

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Email: yash.shah@va.gov

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3900 Woodland Avenue

Philadelphia, PA 19104

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Gary Lichtenstein, MD
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Email: gary.lichtenstein@uphs.upenn.edu

Division of Gastroenterology
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GI Administration Offices
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th
7 Floor South, Room 753

Perelman Center
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One Convention Avenue

Philadelphia, PA 19104
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James D. Lewis, MD, MSCE

Email: lewisjd@pennmedicine.upenn.edu

Center for Clinical Epidemiology and Biostatistics

Perelman School of Medicine at the University of Pennsylvania,

Philadelphia, PA 19104
 ACCEPTED MANUSCRIPT

Yu-Xiao Yang, MD, MSCE

Email: yangy@mail.med.upenn.edu

423 Guardian Drive

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722 Blockley Hall

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Philadelphia, PA 19104

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Corresponding Author: To whom requests for reprints should be addressed:

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Nabeel Khan, MD
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Assistant Clinical Professor of Medicine

Perelman School of Medicine at University of Pennsylvania

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Chief, Section of Gastroenterology

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Philadelphia VA Medical Center

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3900 Woodland Avenue

Philadelphia, PA 19104
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Tel: 215-823-4451
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Email: nabeelk@mail.med.upenn.edu
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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.
 ACCEPTED MANUSCRIPT

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.

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Disclosures

Dr. Lewis reports having served as a consultant for Janssen, AbbVie, UCB, Pfizer, and Takeda. All other

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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

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authors.
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Author contribution:
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Nabeel Khan has made substantial contribution to the study concept and design, acquisition of data,
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analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for
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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
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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
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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
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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.
 ACCEPTED MANUSCRIPT

Methods: We conducted 2 retrospective studies of populations of Veterans, from January 2000

through June 2016. 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

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in study 2. We also estimated the incidence rate of herpes zoster based on age and IBD
medication subgroups.

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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

SC
associated with significantly increased risk of herpes zoster, with adjusted HRs (AHR) of 1.81
for UC (95% CI, 1.56–2.11), 1.56 for CD (95% CI, 1.28–1.91), and 1.72 for treated IBD (95%
CI, 1.51–1.96). In multivariable Cox regression analysis, compared to exposure to 5-ASA alone,
exposure to thiopurines (AHR, 1.47; 95% CI, 1.31–1.65) or a combination of thiopurines and

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TNF antagonists (AHR, 1.65; 95% CI, 1.22–2.23) was associated with increased risk of herpes
zoster. However, exposure to TNF antagonists alone (AHR, 1.15; 95% CI, 0.96–1.38) was not
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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).
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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
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immunization of patients with IBD should be investigated.

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KEY WORDS: opportunistic infection, varicella, thiopurine, anti-TNF

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Introduction:
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Inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are chronic
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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
1
systemic complications, such as an increased risk of infection.

2
Herpes zoster (HZ) results from reactivation of latent varicella zoster virus (VZV) infection. The clinical

presentation is characterized by a painful, unilateral vesicular eruption and is often complicated by post-
 ACCEPTED MANUSCRIPT

3
herpetic neuralgia (PHN). 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
4-6
advent of biologics, or excluded patients who were over the age of 64. 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

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vaccination. They also did not take into consideration the severity of the disease or degree of steroid

exposure.

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To overcome these limitations and to evaluate the incidence and risk factors for HZ in a nationwide IBD

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population, we used a Veterans’ Affairs (VA) cohort for our study. The VA has predominantly older
7
population which makes it an ideal cohort to study HZ incidence in a high-risk population. Unlike

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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
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independent of immunosuppressive medication use and to quantify the extent that immunosuppression

increases the risk while controlling for the disease activity.

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Methods:
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We conducted two retrospective cohort studies among patients in the US national VA healthcare system
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using data from the VA Informatics and Computing Infrastructure (VINCI) from January 1, 2000 through

June 30, 2016. We obtained inpatient and outpatient International Classification of Diseases, Version 9 &
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10, Clinical Modification (ICD-9-CM, ICD-10-CM) diagnosis codes, encounters, procedures, pharmacy
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and demographic data for the study population.

Study Population

The cohort study period was from January 1, 2000, through June 30, 2016. 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
 ACCEPTED MANUSCRIPT

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

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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

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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

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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

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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
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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.
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COHORT STUDY 1: IBD vs non-IBD

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Exposure
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The exposed group (n=13,001) in this cohort study consisted of those IBD patients who were categorized
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in only medication group 1 (i.e., 5-ASA) and without any exposure to corticosteroids. The unexposed
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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
 ACCEPTED MANUSCRIPT

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

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diagnostic codes. HZ diagnosis was confirmed in 182 out of 200 patients (91%) with 100% concordance

between the two reviewers.

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Statistical Analyses

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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

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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
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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
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including hypertension (complicated/uncomplicated), diabetes, lymphoma, metastatic cancer, chronic

pulmonary disease, congestive heart failure, renal failure, liver disease, and AIDS/HIV. CDW data was
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stored in Microsoft SQL Server database and extracts were created from T-SQL coding using Microsoft
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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.
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Analyses were also performed using R software, version 3.3.1 (R Core Team (2016). R: A language and

environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL
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https://www.R-project.org/).
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COHORT STUDY 2: IBD BY MEDICATION USE

We conducted a second retrospective cohort study using the same national VA data in VINCI.

Exposure Groups
 ACCEPTED MANUSCRIPT

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

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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

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continued in that medication group until the earliest of the following events: a medication from a higher-

numbered medication group was prescribed, a 90-day gap was found between prescriptions, or until

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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

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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
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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
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<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
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exposure status was assigned according to the medication group associated with the longest duration
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during the interval.

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Outcome

The outcome was time to incident HZ during the follow-up period among each medication group as
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defined above.
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Statistical Analyses

Demographic and clinical characteristics were summarized with counts and percentages for categorical

variables, and mean (SD) for continuous variables.

 ACCEPTED MANUSCRIPT

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.

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We performed Cox regression with time-dependent analysis to examine the risk of HZ by medication

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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

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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

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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
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prednisone use up to each index date (i.e., total amount of prednisone taken from the beginning of follow-

up divided by the total number of days up to the index date), oral prednisone use within 30 days before
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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.
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In addition, we also included the following fixed covariates: IBD diagnosis (UC/CD), geographical location
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(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.
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In ascertaining comorbidities, we used ICD-9-CM, ICD-10-CM code definitions developed by Elixhauser

8
et al. for use with administrative data. We searched inpatient and outpatient diagnosis records one year
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prior to first medication date. An outpatient diagnosis was only kept if two distinct diagnosis records
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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:
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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

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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

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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

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developing HZ with adjusted HRs (AHR) of 1.81 (95 % CI: 1.56-2.11) for UC, 1.56 (95% CI: 1.28-1.91) for

CD, 1.72 (95% CI: 1.51-1.96) for IBD. (Table 2) Using CD as a control group, we found that UC patients

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did not have statistically higher risk of HZ development (AHR 1.16, 95% CI: 0.92-1.47).
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Table 3 shows HZ incidence rate in IBD and non-IBD group stratified by age <50 years, 50-60 years and

>60 years. The IBD group had a higher incidence for HZ than the matched non-IBD group. In fact, the
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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).
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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
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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
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variable, a patient may contribute at-risk time in more than one medication groups. Of note, there were
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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 1.31-1.65)] or a combination of thiopurines and anti-TNF agents [AHR 1.65 (95% CI

1.22-2.23)] was associated with increased risk of HZ. However, exposure to anti-TNF agents alone [AHR
 ACCEPTED MANUSCRIPT

1.15 (95% CI 0.96-1.38)] was not associated with increased risk of HZ (Table 5). Both cumulative [AHR

1.02 (95% CI 1.01-1.03)] and short term [1.27(95% CI 1.10-1.48)] exposure to prednisone were

associated with an increased risk of developing HZ. As expected, increased age [1.01 (95%CI 1.01-1.02)]

and disease flare [3.69 (95% CI 3.22-3.43)] as described above was also associated with an increased

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risk of developing HZ. Multivariate analysis of other risk factors for HZ development among IBD patients

is mentioned in table 5.

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Table 6 shows the absolute risk of HZ across the 4 medication groups stratified by age groups. There

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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

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can have absolute risk of HZ comparable or higher than those over the age of 60 in patients exposed to

5-ASA only.
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Discussion:
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In this large nationwide VA cohort with IBD patients, we analyzed the incidence and risk factors for HZ
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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
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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
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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
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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.

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Patients with IBD have been previously shown to have an increased risk of HZ compared to general
4-6
population in prior studies. 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

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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

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4, 5
higher risk of HZ than patients with UC. 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

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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

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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
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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
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itself may play an important role in HZ development.

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Because of higher risk of HZ in IBD population, it is important to understand the HZ risk factors which
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predispose IBD patients to develop HZ. In our cohort, use of thiopurine alone [AHR 1.47 (95%CI 1.31-

1.65)] and combination therapy [AHR 1.65 (95% CI 1.22-2.23)] were independently associated with the
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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
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4-6, 9
therapy. Interestingly, the use of anti-TNF alone [AHR 1.15 (95% CI 0.96-1.38)] was not an
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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
4-6, 9
increases the risk of HZ incidence in IBD. 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
 ACCEPTED MANUSCRIPT

the strongest association with the development of HZ (HR 3.69, 95%CI 3.22-4.23). Further studies are

warranted to support our findings.

Cumulative exposure of prednisone over the course of the disease and current use of prednisone could

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serve as a proxy of disease severity and associated with increased HZ risk. While performing time-

dependent analysis and including two additional time-dependent covariates designed to capture both

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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

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1.02, 95% CI 1.01-1.03) and prednisone use within 30 days of index date (HR 1.27, 95% CI 1.10-1.48)

were both independent risk factors for HZ incidence after controlling for confounding factors. The result is

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in keeping with previous studies which have identified that longer duration and higher dose of
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glucocorticoids use confer a greater risk of HZ in IBD as demonstrated by Winthrop et al.
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In addition to the use of immunosuppressive medicine, we found that advancing age (HR 1.01, 95% CI
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1.01-1.02) 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
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an IBD population. We found that IBD patients who were >60 years of age and on combination therapy
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had the highest risk of HZ development which approached almost 2% per year.
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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
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11
97.2% efficacy in patients >50 years of age. Current ACG (American College of Gastroenterology)
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12
guidelines have recommended vaccination among patients over the age of 50 in patients with IBD. 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.
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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
4-6, 9
unlike previous studies focused on the same hypothesis. The older population in VA system also

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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

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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

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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

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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
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of confounding by indication. Lastly, we used other surrogate measures as a mechanism for evaluating

disease flare and controlled for this as well.

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There are certain limitations in our study. The VA population is a selected cohort not only due to the male
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predominance but this is also an older population, and thus our results may not be generalizable to a
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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
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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
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anticipate this has created any bias as previous reports have shown that veterans have very good
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13-15
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
 ACCEPTED MANUSCRIPT

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.

PT
RI
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

SC
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

U
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
AN
studies into its efficacy and expansion of use among the IBD population should be undertaken.
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References:
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1. Irving PM, Gibson PR. Infections and IBD. Nature Clinical Practice Gastroenterology &

Hepatology. 2008;5(1):18-27.
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2. Cohen JI. Herpes zoster. New England Journal of Medicine. 2013;369(3):255-63.

3. Sampathkumar P, Drage LA, Martin DP, editors. Herpes zoster (shingles) and postherpetic
C

neuralgia. Mayo Clinic Proceedings; 2009: Elsevier.

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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):1483-90.

5. Long MD, Martin C, Sandler RS, et al. Increased risk of herpes zoster among 108 604 patients

with inflammatory bowel disease. Alimentary pharmacology & therapeutics. 2013;37(4):420-9.

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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):2524-33.

7. ; Available from: https://www.va.gov/vetdata/docs/SpecialReports/Profile_of_Veterans_2011.pdf.

PT
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. 2005:1130-9.

RI
9. 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.

SC
2015;13(7):1293-301. e5.

10. Winthrop KL, Baddley JW, Chen L, et al. Association between the initiation of anti–tumor necrosis

U
factor therapy and the risk of Herpes Zoster. Jama. 2013;309(9):887-95.

11. Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit
AN
vaccine in older adults. New England Journal of Medicine. 2015;372(22):2087-96.

12. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: preventive care in
M

inflammatory bowel disease. The American journal of gastroenterology. 2017;112(2):241-58.

13. Klein R, Stockford D. Data on the Socioeconomic Status of Veterans and on VA Program Usage.
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Office of the Actuary, Veterans Health Administration. 2001. 2013.

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14. U.S. Government Accountability Office Report VHC. Use of VA Services by Medicare-Eligible

Veterans. Washington, DC. 2013 2013.

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15. 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.
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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

PT
All (%) 35,510 13,001 4632 (35.63) 8369 (64.37)

Gender, no. (%)

RI
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)

SC
Race, no. (%)

African American 4566 (12.86) 1146 (8.81) 393 (8.48) 753 (9)

Caucasian 28,433 (80.07)

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11,283 (86.79) 4039 (87.2) 7244 (86.56)
AN
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)

M

District, no. (%)

Continental 4355 (12.26) 1539 (11.84) 538 (11.61) 1001 (11.96)

D

Mid-West 6487 (18.27) 2689 (20.68) 994 (21.46) 1695 (20.25)

TE

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)

EP

Southeast 7540 (21.23) 2777 (21.36) 968 (20.9) 1809 (21.62)

Age, no. (%)

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<50 years 4322 (12.17) 2088 (16.06) 750 (16.19) 1338 (15.99)
AC

50-60 years 4001 (11.27) 1902 (14.63) 720 (15.54) 1182 (14.12)

>60 years 27187 (76.56) 9011 (69.31) 3162 (68.26) 5849 (69.89)

Age, mean (SD) years

All 70 (15.73) 65.93 (15.85) 65.62 (15.85) 66.09 (115.85)

HZ diagnosis 70 (12.49) 66.69 (13.77) 65.60 (12.75) 67.25 (14.27)

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Utilization, mean (SD)

visits/year

<6 11,512 (32.42) 2954 (22.72) 1053 (22.73) 1901 (22.71)

6-12 13,541 (38.13) 5193 (39.94) 1835 (39.62) 3358 (40.12)

PT
>13 10,457 (29.45) 4854 (37.34) 1744 (37.65) 3110 (37.16)

Follow-up [mean (SD),

RI
median]

All 9.41 (4.41), 10 4.24 (3.98), 2.87 4.40 (4.04), 3.06 4.15 (3.95), 2.76

SC
HZ diagnosis 6.38 (3.93), 5.96 3.71 (3.37), 2.71 4.00 (3.43), 2.90 3.56 (3.34), 2.58

End of follow up reason,

U
no. (%)
AN
Last recorded date 24,559 (69.16) 10146 (78.04) 3636 (78.5) 6510 (77.79)

HZ diagnosis date 1076 (3.03) 321 (2.47) 109 (2.35) 212 (2.53)
M

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)

D

Comorbidities, no. (%)

TE

Hypertension
66 (0.19) 101 (0.78) 29 (0.63) 72 (0.86)
Complicated

Hypertension
EP

10,167 (28.63) 4974 (38.26) 1751 (37.8) 3223 (38.51)

Uncomplicated

Diabetes Complicated 39 (0.11) 271 (2.08) 99 (2.14) 172 (2.06)

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Diabetes
AC

293 (0.83) 1505 (11.58) 518 (11.18) 987 (11.79)

Uncomplicated

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
1073 (3.02) 850 (6.54) 289 (6.24) 561 (6.7)
Disease
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Congestive Heart
600 (1.69) 319 (2.45) 107 (2.31) 212 (2.53)
Failure

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)

PT
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)

RI
IBD, Irritable Bowel Disease; UC, Ulcerative Colitis; CD, Crohn’s Disease; HZ, Herpes Zoster; SD,

SC
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

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non-IBD; Comorbidities, diagnosed in the year prior to group time
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Table 2. Association between IBD and IBD subtype status and the risk of HZ*

Adjusted Hazard 95% CI

Ratio**

Comparison groups

PT
IBD (5-ASA treatment only) 1.72 (1.51, 1.96)

UC only 1.81 (1.56, 2.11)

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CD only 1.56 (1.28, 1.91)

Non-IBD group Reference Reference

SC
* the comparison groups of overall IBD (5-ASA treatment only) group and non-IBD group were matched

U
on age, sex, calendar year of start of follow-up, VISN.
AN
**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,
M

AIDS.)
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Table 3: Episodes of herpes zoster (HZ incidence) by cohort

Age<50 years Age 50-60 years Age>60 years

Episodes of HZ

PT
per 1000 person 8.62 9.03 7.15

years

RI
IBD case cohort
No. of patients 35 53 233

SC
Patient-years 4062.56 5866.16 32582.06

Episodes of HZ

per 1000 person

U2.41 3.36 3.30

AN
Non-IBD match years

cohort
No. of patients 77 131 868
M

Patient-years 32015.73 39038.93 262962.5

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Table 4. Comparison of characteristics of IBD medication groups

Medication Group*

5-ASA Thiopur

All alone ines Anti-TNF Thiopurines

PT
(n=5491 (n=5096 (n=1317 agents and anti-TNFs Vedolizuma

Variable 9) 2) 4) (n=6653) (n=2534) b (n=167)

RI
IBD

21184 18454 7015 4143

SC
CD 1655 (65.31) 95 (56.89)
(38.57) (36.21) (53.25) (62.27)

33735 32508 6159 2510

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UC 879 (34.69) 72 (43.11)
(61.43) (63.79) (46.75) (37.73)
AN
63.8 65.7 59.3 52.4
Age, mean (SD) years 13.67 (52.7) 51.8 (14.99)
(14.83) (14.18) (14.93) (14.47)
M

51238 47660 12121 5889

Male gender, no. (%) 2239 (88.36) 149 (89.22)
(93.3) (93.52) (92.01) (88.52)
D

Race, no. (%)

TE

47222 43862 11125 5490

Caucasian 2081 (82.12) 145 (86.83)
(85.98) (86.07) (84.45) (82.52)
EP

5124 4753 1358 844

African American 321 (12.67) 14 (8.38)
(9.33) (9.33) (10.31) (12.69)
C

983 918 247

Other 132 (1.98) 55 (2.17) 4 (2.4)
(1.79) (1.8) (1.87)
AC

1590 1429 444

Unknown 187 (2.81) 77 (3.04) 4 (2.4)
(2.9) (2.8) (3.37)

Geographical region

7965 7391 2073 1036

Continental 461 (18.19) 27 (16.17)
(14.5) (14.5) (15.74) (15.57)
 ACCEPTED MANUSCRIPT

12928 11872 3057 1516

Mid-West 537 (21.19) 35 (20.96)
(23.54) (23.3) (23.2) (22.79)

14646 13645 3386 1578

North Atlantic 582 (22.97) 39 (23.35)
(26.67) (26.77) (25.7) (23.72)

PT
8828 8159 2252 1253
Pacific 520 (20.52) 39 (23.35)
(16.07) (16.01) (17.09) (18.83)

RI
10552 9895 2406 1270
Southeast 434 (17.13) 27 (16.17)
(19.21) (19.42) (18.26) (19.09)

SC
Episodes of HZ, no. 2007 1372 437 152 46 0

243506. 188652. 37240.1

Patient-years 14578.28 2964.81 70.43

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10 43 4
AN
Episodes per

1000 patient- 8.24 7.27 11.73 10.43 15.52 0

years
M

Comorbidities
D

Hypertension 295 270 43

20 (0.3) 6 (0.24) 1 (0.6)
complicated (0.54) (0.53) (0.33)
TE

Hypertension 17642 16693 3192 1443

498 (19.65) 37 (22.16)
uncomplicated (32.12) (32.76) (24.23) (21.69)
EP

Diabetes 795 743 130

73 (1.1) 22 (0.87) . (.)
Complicated (1.45) (1.46) (0.99)
C

Diabetes 4439 4140 763

441 (6.63) 137 (5.41) 10 (5.99)
AC

Uncomplicated (8.08) (8.12) (5.79)

116 111 18
Lymphoma 7 (0.11) 1 (0.04) 0 (0)
(0.21) (0.22) (0.14)

55
Metastatic Cancer 56 (0.1) 4 (0.03) 2 (0.03) 0 (0) 0 (0)
(0.11)
 ACCEPTED MANUSCRIPT

Chronic
3553 3358 563
Pulmonary 244 (3.67) 80 (3.16) 6 (3.59)
(6.47) (6.59) (4.27)
Disease

Congestive Heart 1185 1118 191

58 (0.87) 27 (1.07) 2 (1.2)

PT
Failure (2.16) (2.19) (1.45)

807 729 139

Renal Failure 48 (0.72) 11 (0.43) 2 (1.2)

RI
(1.47) (1.43) (1.06)

810 736 182

Liver Disease 72 (1.08) 26 (1.03) 2 (1.2)

SC
(1.47) (1.44) (1.38)

138 135 12
HIV 11 (0.17) 3 (0.12) 0 (0)

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(0.25) (0.26) (0.09)
AN
None of the 33574 30820 9299 4886
1925 (75.97) 126 (75.45)
above (61.13) (60.48) (70.59) (73.44)
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* Because of the time-varying nature of the exposure variable, a patient may contribute at-risk time in
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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
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group. The baseline characteristics reflect status at the beginning of the total follow-up for each patient

and were not time-updating.

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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

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Table 5. Multivariate Analysis for HZ Risk Factors Among IBD Patients

Adjusted Hazard
Variable 95% CI p value
Ratio*

PT
Medication Group

5-ASA alone Reference Reference

RI
Thiopurines 1.47 (1.31, 1.65) <0.001

SC
Anti-TNF agents 1.15 (0.96, 1.38) 0.132

Thiopurines and

U
1.65 (1.22, 2.23) 0.001
anti-TNF agents
AN
Age at index date 1.01 (1.01, 1.02) <0.001
M

Prednisone
1.02 (1.01, 1.03) 0.002
cumulative (mg/day)
D

Prednisone within 30
TE

1.27 (1.10, 1.48) 0.002

days before index date

Disease flare 3.69 (3.22, 4.23) <0.001

EP

IBD Diagnosis
C

CD Reference Reference Reference

AC

UC 1.01 ( 0.92, 1.11) 0.862

District

Continental Reference Reference Reference

Midwest 1.01 ( 0.87, 1.18) 0.848

 ACCEPTED MANUSCRIPT

North Atlantic 0.98 ( 0.84, 1.13) 0.753

Pacific 1.15 ( 0.99, 1.35) 0.070

Southeast 1.01 ( 0.87, 1.17) 0.916

PT
Race

Black Reference Reference Reference

RI
White 1.17 ( 0.99, 1.37) 0.062

SC
Other 1.33 ( 0.95, 1.88) 0.097

Unknown 1.33 ( 0.91, 1.94) 0.141

Gender
U
AN
Female Reference Reference Reference

Male 1.01 ( 0.83, 1.22) 0.942

M

Health Care Utilization

D

<6 Reference Reference Reference

TE

6 to 12 1.57 ( 1.25, 1.97) <0.001

EP

>13 2.31 ( 1.85, 2.90) <0.001

Baseline comorbid
C

medical conditions
AC

Complicated
1.41 ( 0.68, 2.95) 0.355
Hypertension

Uncomplicated
1.02 ( 0.92, 1.13) 0.698
Hypertension

Diabetes mellitus 0.55 ( 0.32, 0.95) 0.031

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Lymphoma 0.99 ( 0.31, 3.14) 0.983

Metastatic Cancer 1.61 ( 0.37, 6.95) 0.523

Chronic

PT
Pulmonary 1.13 ( 0.94, 1.37) 0.183

Disease

RI
Congestive Heart
1.06 ( 0.77, 1.46) 0.707
Failure

SC
Renal failure 1.02 ( 0.63, 1.68) 0.923

Liver disease 1.40 ( 1.01, 1.96) 0.046

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AN
AIDS 1.31 ( 0.47, 3.62) 0.601
M

* 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
D

baseline comorbidity status ( i.e., Hypertension (controlled and uncontrolled), diabetes mellitus,
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lymphoma, metastatic cancer, Chronic Pulmonary Disease, Congestive heart failure, renal failure, liver

disease, AIDS.)
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Table 6: Absolute risk of HZ across the medication groups stratified by age

Age 50-60
Age<50 years Age>60 years
years

PT
Rate of HZ per

1000 person- 5.5 7.6 7.6

RI
years
5-ASA
Number of
145 275 952

SC
patients

Patient-years 26333.12 36256.4 126062.91

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Rate of HZ per
AN
1000 person- 8.2 11.0 13.9

years
Thiopurines
M

Number of
79 97 261
patients
D

Patient-years 9663.16 8799.21 18777.77

TE

Rate of HZ per

1000 person- 6.2 14.2 13.0

years
EP

Anti-TNF
Number of
agents
38 50 64
patients
C

Patient-years 6132.69 3515.23 4930.37

AC

Rate of HZ per

Combination 1000 person- 10.9 20.1 17.5

(Thiopurines + years

Anti-TNF) Number of
13 16 17
patients
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Patient-years 1196.62 797.37 970.82

Rate of HZ per

1000 person- 0 0 0

years
Vedolizumab

PT
Number of
0 0 0
patients

RI
Patient-years 34.51 11.45 24.47

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Supplementary materials for review:

Appendix 1.

IBD Cohort Diagnosis List

PT
icd9code Description

555 REGIONAL ENTERITIS OF SMALL INTESTINE

RI
555.1 REGIONAL ENTERITIS OF LARGE INTESTINE

555.2 REGIONAL ENTERITIS OF SMALL INTESTINE WITH LARGE INTESTINE

SC
555.9 REGIONAL ENTERITIS OF UNSPECIFIED SITE

556 ULCERATIVE ENTEROCOLITIS

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556.1 ULCERATIVE ILEOCOLITIS
AN
556.2 ULCERATIVE PROCTITIS

556.3 ULCERATIVE PROCTOSIGMOIDITIS

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556.4 PSEUDOPOLYPOSIS OF COLON

556.5 LEFT-SIDED ULCERATIVE COLITIS

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556.6 UNIVERSAL ULCERATIVE COLITIS

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556.8 OTHER ULCERATIVE COLITIS

556.9 ULCERATIVE COLITIS, UNSPECIFIED

icd10code Description
EP

K50.00 CROHN'S DISEASE OF SMALL INTESTINE WITHOUT COMPLICATIONS

K50.011 CROHN'S DISEASE OF SMALL INTESTINE WITH RECTAL BLEEDING

C

K50.012 CROHN'S DISEASE OF SMALL INTESTINE WITH INTESTINAL OBSTRUCTION

AC

K50.013 CROHN'S DISEASE OF SMALL INTESTINE WITH FISTULA

K50.014 CROHN'S DISEASE OF SMALL INTESTINE WITH ABSCESS

K50.018 CROHN'S DISEASE OF SMALL INTESTINE WITH OTHER COMPLICATION

K50.019 CROHN'S DISEASE OF SMALL INTESTINE WITH UNSPECIFIED COMPLICATIONS

K50.10 CROHN'S DISEASE OF LARGE INTESTINE WITHOUT COMPLICATIONS

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K50.111 CROHN'S DISEASE OF LARGE INTESTINE WITH RECTAL BLEEDING

K50.112 CROHN'S DISEASE OF LARGE INTESTINE WITH INTESTINAL OBSTRUCTION

K50.113 CROHN'S DISEASE OF LARGE INTESTINE WITH FISTULA

K50.114 CROHN'S DISEASE OF LARGE INTESTINE WITH ABSCESS

PT
K50.118 CROHN'S DISEASE OF LARGE INTESTINE WITH OTHER COMPLICATION

K50.119 CROHN'S DISEASE OF LARGE INTESTINE WITH UNSPECIFIED COMPLICATIONS

RI
K50.80 CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITHOUT COMPLICATIONS

K50.811 CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH RECTAL BLEEDING

SC
CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH INTESTINAL

K50.812 OBSTRUCTION

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K50.813 CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH FISTULA

K50.814 CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH ABSCESS
AN
K50.818 CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH OTHER COMPLICATION

CROHN'S DISEASE OF BOTH SMALL AND LARGE INTESTINE WITH UNSPECIFIED

M

K50.819 COMPLICATIONS

K50.90 CROHN'S DISEASE, UNSPECIFIED, WITHOUT COMPLICATIONS

D

K50.911 CROHN'S DISEASE, UNSPECIFIED, WITH RECTAL BLEEDING

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K50.912 CROHN'S DISEASE, UNSPECIFIED, WITH INTESTINAL OBSTRUCTION

K50.913 CROHN'S DISEASE, UNSPECIFIED, WITH FISTULA

EP

K50.914 CROHN'S DISEASE, UNSPECIFIED, WITH ABSCESS

K50.918 CROHN'S DISEASE, UNSPECIFIED, WITH OTHER COMPLICATION

C

K50.919 CROHN'S DISEASE, UNSPECIFIED, WITH UNSPECIFIED COMPLICATIONS

AC

K51.00 ULCERATIVE (CHRONIC) PANCOLITIS WITHOUT COMPLICATIONS

K51.011 ULCERATIVE (CHRONIC) PANCOLITIS WITH RECTAL BLEEDING

K51.012 ULCERATIVE (CHRONIC) PANCOLITIS WITH INTESTINAL OBSTRUCTION

K51.013 ULCERATIVE (CHRONIC) PANCOLITIS WITH FISTULA

K51.014 ULCERATIVE (CHRONIC) PANCOLITIS WITH ABSCESS

K51.018 ULCERATIVE (CHRONIC) PANCOLITIS WITH OTHER COMPLICATION

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K51.019 ULCERATIVE (CHRONIC) PANCOLITIS WITH UNSPECIFIED COMPLICATIONS

K51.20 ULCERATIVE (CHRONIC) PROCTITIS WITHOUT COMPLICATIONS

K51.211 ULCERATIVE (CHRONIC) PROCTITIS WITH RECTAL BLEEDING

K51.212 ULCERATIVE (CHRONIC) PROCTITIS WITH INTESTINAL OBSTRUCTION

PT
K51.213 ULCERATIVE (CHRONIC) PROCTITIS WITH FISTULA

K51.214 ULCERATIVE (CHRONIC) PROCTITIS WITH ABSCESS

RI
K51.218 ULCERATIVE (CHRONIC) PROCTITIS WITH OTHER COMPLICATION

K51.219 ULCERATIVE (CHRONIC) PROCTITIS WITH UNSPECIFIED COMPLICATIONS

SC
K51.30 ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITHOUT COMPLICATIONS

K51.311 ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH RECTAL BLEEDING

U
K51.312 ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH INTESTINAL OBSTRUCTION

K51.313 ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH FISTULA

AN
K51.314 ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH ABSCESS

K51.318 ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH OTHER COMPLICATION

M

K51.319 ULCERATIVE (CHRONIC) RECTOSIGMOIDITIS WITH UNSPECIFIED COMPLICATIONS

K51.40 INFLAMMATORY POLYPS OF COLON WITHOUT COMPLICATIONS

D

K51.411 INFLAMMATORY POLYPS OF COLON WITH RECTAL BLEEDING

TE

K51.412 INFLAMMATORY POLYPS OF COLON WITH INTESTINAL OBSTRUCTION

K51.413 INFLAMMATORY POLYPS OF COLON WITH FISTULA

EP

K51.414 INFLAMMATORY POLYPS OF COLON WITH ABSCESS

K51.418 INFLAMMATORY POLYPS OF COLON WITH OTHER COMPLICATION

C

K51.419 INFLAMMATORY POLYPS OF COLON WITH UNSPECIFIED COMPLICATIONS

AC

K51.50 LEFT SIDED COLITIS WITHOUT COMPLICATIONS

K51.511 LEFT SIDED COLITIS WITH RECTAL BLEEDING

K51.512 LEFT SIDED COLITIS WITH INTESTINAL OBSTRUCTION

K51.513 LEFT SIDED COLITIS WITH FISTULA

K51.514 LEFT SIDED COLITIS WITH ABSCESS

K51.518 LEFT SIDED COLITIS WITH OTHER COMPLICATION

 ACCEPTED MANUSCRIPT

K51.519 LEFT SIDED COLITIS WITH UNSPECIFIED COMPLICATIONS

K51.80 OTHER ULCERATIVE COLITIS WITHOUT COMPLICATIONS

K51.811 OTHER ULCERATIVE COLITIS WITH RECTAL BLEEDING

K51.812 OTHER ULCERATIVE COLITIS WITH INTESTINAL OBSTRUCTION

PT
K51.813 OTHER ULCERATIVE COLITIS WITH FISTULA

K51.814 OTHER ULCERATIVE COLITIS WITH ABSCESS

RI
K51.818 OTHER ULCERATIVE COLITIS WITH OTHER COMPLICATION

K51.819 OTHER ULCERATIVE COLITIS WITH UNSPECIFIED COMPLICATIONS

SC
K51.90 ULCERATIVE COLITIS, UNSPECIFIED, WITHOUT COMPLICATIONS

K51.911 ULCERATIVE COLITIS, UNSPECIFIED WITH RECTAL BLEEDING

U
K51.912 ULCERATIVE COLITIS, UNSPECIFIED WITH INTESTINAL OBSTRUCTION

K51.913 ULCERATIVE COLITIS, UNSPECIFIED WITH FISTULA

AN
K51.914 ULCERATIVE COLITIS, UNSPECIFIED WITH ABSCESS

K51.918 ULCERATIVE COLITIS, UNSPECIFIED WITH OTHER COMPLICATION

M

K51.919 ULCERATIVE COLITIS, UNSPECIFIED WITH UNSPECIFIED COMPLICATIONS

D
TE

Appendix 2.

Medication Group
EP

(by hierarchy) Drug Name Without Dose

5 VEDOLIZUMAB
C

BALSALAZIDE
AC

1 OLSALAZINE

SULFASALAZINE

AZATHIOPRINE
2
MERCAPTOPURINE

ADALIMUMAB
3
CERTOLIZUMAB
 ACCEPTED MANUSCRIPT

GOLIMUMAB

INFLIXIMAB

4 Group 2 and 3 medications concurrently

PT
Appendix 3.

RI
ICD9Code Description

053 HERPES ZOSTER WITH MENINGITIS

SC
HERPES ZOSTER WITH UNSPECIFIED NERVOUS SYSTEM

053.1 COMPLICATION

U
053.11 GENICULATE HERPES ZOSTER

053.12 POSTHERPETIC TRIGEMINAL NEURALGIA

AN
053.13 POSTHERPETIC POLYNEUROPATHY

053.14 HERPES ZOSTER MYELITIS

M

HERPES ZOSTER WITH OTHER NERVOUS SYSTEM

053.19 COMPLICATIONS
D

053.2 HERPES ZOSTER DERMATITIS OF EYELID

TE

053.21 HERPES ZOSTER KERATOCONJUNCTIVITIS

053.22 HERPES ZOSTER IRIDOCYCLITIS

EP

053.29 HERPES ZOSTER WITH OTHER OPHTHALMIC COMPLICATIONS

053.71 OTITIS EXTERNA DUE TO HERPES ZOSTER

C

053.79 HERPES ZOSTER WITH OTHER SPECIFIED COMPLICATIONS

AC

053.8 HERPES ZOSTER WITH UNSPECIFIED COMPLICATION

053.9 HERPES ZOSTER WITHOUT MENTION OF COMPLICATION

ICD10Code Description

B02.0 ZOSTER ENCEPHALITIS

B02.1 ZOSTER MENINGITIS

B02.30 ZOSTER OCULAR DISEASE, UNSPECIFIED

 ACCEPTED MANUSCRIPT

B02.31 ZOSTER CONJUNCTIVITIS

B02.32 ZOSTER IRIDOCYCLITIS

B02.33 ZOSTER KERATITIS

B02.34 ZOSTER SCLERITIS

PT
B02.39 OTHER HERPES ZOSTER EYE DISEASE

B02.7 DISSEMINATED ZOSTER

RI
B02.8 ZOSTER WITH OTHER COMPLICATIONS

B02.9 ZOSTER WITHOUT COMPLICATIONS

SC
CPT code Description

ZOSTER (SHINGLES) VACCINE, LIVE, FOR SUBCUTANEOUS

U
90736 INJECTION
AN
M
D
TE
C EP
AC