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Herpes zoster (HZ) infection, also known as shingles, is associated with significant morbidity and substantial costs. There are close to a million incident cases in the United States (US) each year. Infection causes a painful, blistering rash usually isolated to one or adjoining dermatomes. In approximately 10–18% of cases, postherpetic neuralgia (PHN) occurs. This pain syndrome can last from months to years after the initial HZ rash, without very effective treatments. Other complications that can arise include bacterial skin infection, ocular complications, motor neuropathy and meningitis. HZ is caused by reactivation of latent varicella zoster virus (VZV), the virus that causes varicella (chicken pox). The incidence of HZ in the United States (US) has been increasing over the past decade, and significantly increases with age. It is estimated that the direct medical burden of HZ infection is $1000 US dollars per patient, with costs doubling for those who are immunosuppressed and quadrupling for those with PHN. This equates to greater than 1 billion dollars annually attributed to HZ in the US.
Risk factors for HZ infection primarily include increasing age and immunosuppression. Patients with inflammatory bowel disease (IBD) are one chronic disease population who routinely use immunosuppressive medications including corticosteroids, thiopurines, biologic anti-tumour necrosis factor-alpha (anti-TNF) agents and calcineurin inhibitors, and therefore may be at increased risk for HZ. In a prior study by US researchers using data from the United Kingdom (UK), Gupta et al. showed an increased risk of HZ among individuals with IBD as compared with the general population. In addition, they found that corticosteroids and thiopurines were risk factors for HZ in the IBD population. Data on biologic anti-TNF medications were not available. More recently, Zhang et al. showed a 1.2- to 2.0-fold greater risk of HZ associated with corticosteroid use, including those also on therapy with anti-TNF agents, in the older (≥age 60) population with autoimmune conditions such as rheumatoid arthritis (RA) or IBD.
Biologic anti-TNF medications, particularly the monoclonal antibodies, have been associated with an increased risk of HZ in the RA population.[7-9] To further evaluate these associations in the IBD population, we aimed to determine the risk of HZ in patients with IBD as compared with a non-IBD cohort in the United States. We also aimed to determine whether specific immunosuppressive medications, including biologic anti-TNF agents, increase the risk of HZ in patients with IBD.
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The cohort study population included 108 604 patients with IBD. Of these, 50 932 had CD, 56 403 had UC and 1269 had IBD with unknown type. The patients with IBD contributed a total of 364 533 person-years of observation time to the cohort. There were a total of 434 416 individuals in the non-IBD comparison cohort. The non-IBD patients contributed a total of 992 273 person-years of observation time to the cohort. The median length of follow-up within the non-IBD cohort was 24 months (IQR: 12–42) with a range from 1 to 138 months after the 6-month ‘screening’ period. Length of follow-up was similar for CD (34 months, IQR: 19–51) and UC populations (36 months, IQR: 21–54). Duration of follow-up was significantly less in the non-IBD comparison cohort (21 months, IQR: 10–38). Table 1 shows the characteristics of the IBD cohort as compared with the non-IBD cohort. The IBD cohort had increased health care utilisation, and immunosuppressive medication use as compared with the matched non-IBD cohort, as expected. These same factors were increased in those with CD as compared with those with UC.
Table 1. Characteristics of the population by inflammatory bowel disease overall, and Crohn's disease or ulcerative colitis
|Characteristics||Non-IBD cohort (n = 434 416)||IBD cohort (n = 108 604)||Crohn's disease (n = 50 932)||Ulcerative coltiis (n = 56 403)|
|n||Median (IQR) or %||n||Median (IQR) or %||n||Median (IQR) or %||n||Median (IQR) or %|
|Age|| ||43 (31–52)|| ||43 (31–52)|| ||41 (29–51)|| ||44 (33–53)|
|Gender (% female)||238 812||55.0||59 703||55.0||28 723||56.4||30 272||53.7|
|Region of the country|
|East||91 923||21.2||23 069||21.2||10 686||21.0||12 061||21.4|
|Midwest||169 043||38.9||46 232||42.6||22 155||43.5||23 614||41.9|
|South||97 829||22.5||20 350||18.7||9621||18.9||10 479||18.6|
|West||75 621||17.4||18 953||17.5||8470||16.7||10 249||18.2|
|5ASAb||552||0.1||37 609||34.6||15 974||31.4||21 195||37.6|
|Health care utilisationf|| ||1 (0–4)|| ||4 (2–9)|| ||5 (2–10)|| ||4 (1–8)|
|Diabetes mellitus||16 888||3.9||4824||4.4||2055||4.0||2705||4.8|
|Total no. of comorbiditiesg|| ||0 (0–0)|| ||0 (0–0)|| ||0 (0–0)|| ||0 (0-0)|
In the IBD population, there were a total of 2677 cases of zoster. In the non-IBD population, there were a total of 4340 cases of zoster. For patients with IBD, the overall annual incidence of HZ was 734/100 000 (95% CI: 707/100 000–763/100 000), compared with 437/100 000 (95% CI: 424/100 000–451/100 000) in the non-IBD cohort [incidence rate ratio (IRR) 1.68, 95% CI: 1.60–1.76]. The incidence of zoster in CD was somewhat higher than that in UC (Figure 1). The IBD cohort had an increased zoster risk when compared with non-IBD (IRR: 1.68, 95% CI: 1.60–1.76), as did CD vs. non-CD (IRR: 1.91, 95% CI: 1.78–2.05) and UC vs. non-UC (IRR: 1.50, 95% CI: 1.40–1.61). The incidence of HZ was then evaluated in strata of age, with increasing incidence of zoster within each strata of age, for both IBD and non-IBD populations. The highest incidence was in the 60+ age strata for those with CD (1502/100 000, 95% CI: 1236/100 000–1809/100 000), as expected (Figure 2).
Figure 1. Annual zoster incidence (per 100 000) in inflammatory bowel disease (IBD) (n = 108 604) and non-IBD populations (n = 434 416), stratified by Crohn's disease (CD) (n = 50 932) as compared with non-CD (n = 203 728) and ulcerative colitis (UC) (n = 56 403) as compared with non-UC (n = 225 612) populations. Data from IMS LifeLink® information assets-health plan claims database (1997–2009), IMS Health Incorporated.
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Figure 2. Annual zoster incidence (per 100 000) in Crohn's disease (CD) (n = 50 932) as compared with non-CD populations (n = 203 728) and ulcerative colitis (UC) (n = 56 403) as compared with non-UC populations (n = 225 612), within 10-year strata of age. Data from IMS LifeLink® information assets-health plan claims database (1997–2009), IMS Health Incorporated.
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After adjusting for comorbidities and health care utilisation on Cox analysis, zoster risk remained increased in the IBD vs. non-IBD cohort (HR: 1.49, 95% CI: 1.42–1.57). Risk was particularly increased for those with CD as compared with non-CD (HR: 1.69, 95% CI: 1.58–1.82). For UC, the adjusted risk compared with non-UC was HR 1.34, 95% CI: 1.25–1.44.
In the nested case–control study, 2659 IBD patients with HZ were matched to 10 470 IBD patients without HZ. A total of 18 IBD patients with zoster were unable to be matched to a comparison IBD patient without zoster. The characteristics of the populations are shown in Table 2. Patients with HZ had significantly more comorbidities, including cardiac conditions, diabetes, liver disease, renal disease and chronic pulmonary disease. Those with HZ also had significantly higher health care utilisation and immunosuppressive medication use. In adjusted analyses, 5-ASA use was not associated with HZ in the overall IBD population (OR: 1.08, 95% CI: 0.97–1.19). However, thiopurine use (OR: 1.85, 95% CI: 1.61–2.13), corticosteroid use (OR: 1.73, 95% CI: 1.51–1.99) and biologic anti-TNF use (OR: 1.81, 95% CI: 1.48–2.21) were independently associated with HZ in the overall IBD population. Similar risk estimates were seen when stratified by CD or UC. Crude and adjusted analyses are shown in Table 3 for specific medication use in the overall population, and by IBD subtype. In a sub-analysis, we then investigated combination use of anti-TNF and thiopurine and monotherapy of either agent as compared with no immunosuppressive medication use. Those on combination therapy had the highest risk of zoster, even after controlling for corticosteroid use, 5-ASA use, utilisation and comorbidities (OR: 3.29, 95% CI: 2.33–4.65) (Table 4).
Table 2. Characteristics of the IBD population by zoster (matched characteristics include age, IBD type, gender, region)
|Characteristics||No Zoster (n = 10 470)||Zoster (n = 2659)||P-valuea|
| n ||% or median (IQR)|| n ||% or median (IQR)|
|Ageb||10 470||49 (37–56)||2659||49 (38–56)||0.11|
|Gender (% Male)||3883||37.1||991||37.3||0.86|
|Ulcerative colitis||5095||48.7||1290||48.5|| |
|Utilisationc||10 470||4 (1–9)||2659||9 (5–16)||<0.01|
|No. of comorbiditiesd||10 470||0 (0–0)||2659||0 (0–1)||<0.01|
Table 3. Crude and multivariate adjustedb estimates (odds ratios and 95% CI) of medication use and zoster in patients with IBD, overall and by CD or UC
|Medication||IBD overall (n = 13 129)||Crohn's disease (n = 6688)||Ulcerative colitis (n = 6381)|
|Crude OR, 95% CI||Adjusted OR, 95% CI||Crude OR, 95% CI||Adjusted OR, 95% CI||Crude OR, 95% CI||Adjusted OR, 95% CI|
|Any use in prior 120 daysa|
|5-ASA||1.20 (1.09–1.32)||1.08 (0.97–1.19)||1.27 (1.10–1.46)||1.09 (0.94–1.27)||1.14 (1.00–1.31)||1.07 (0.93–1.24)|
|Biologic||2.57 (2.13–3.10)||1.81 (1.48–2.21)||2.37 (1.92–2.92)||1.72 (1.38–2.15)||3.85 (2.47–6.00)||2.36 (1.47–3.79)|
|Thiopurine||2.28 (2.00–2.60)||1.85 (1.61–2.13)||2.31 (1.98–2.70)||1.93 (1.63–2.28)||2.20 (1.73–2.78)||1.68 (1.30–2.16)|
|Corticosteroid||2.53 (2.22–2.87)||1.73 (1.51–1.99)||2.28 (1.91–2.72)||1.54 (1.27–1.86)||2.83 (2.34–3.43)||1.96 (1.60–2.40)|
Table 4. Multivariate adjustedd estimates (odds ratios and 95% CI) of immunosuppressive medication combinations and zoster in patients with IBD, overall and by CD or UC
|Medication||IBD overall (n = 13 129)||Crohn's disease (n = 6688)||Ulcerative colitis (n = 6381)|
|adjusted OR, 95% CI||adjusted OR, 95% CI||adjusted OR, 95% CI|
|Any use in prior 120 days|
|Thiopurinea||1.86 (1.61–2.15)||1.96 (1.64–2.34)||1.65 (1.27–2.14)|
|Biologicb||1.83 (1.44–2.31)||1.78 (1.37–2.32)||2.22 (1.30–3.80)|
|Combinationc||3.29 (2.33–4.65)||3.13 (2.16–4.55)||4.79 (1.84–12.45)|
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Herpes zoster is an important cause of increased morbidity and mortality in the United States, with approximately 1 million cases annually. Incidence of HZ in the general population is 340/100 000, but is strongly affected by age, with the highest incidence in those >80 years at 1100/100 000.
The lifetime risk of developing HZ is approximately 30%. The course of the unilateral, painful rash is generally 2–4 weeks. There can be significant complications from HZ including: postherpetic neuralgia, ophthalmological, neurological (encephalitis) and dermatological (secondary skin infection) involvement or complications. Understanding the incidence and risk factors for HZ in an IBD population is important to guide prevention efforts. As HZ is associated with substantial morbidity and costs, this emphasis upon prevention is warranted.
In our large administrative study of HZ infection in IBD patients, we demonstrated a significantly increased risk of HZ when compared with the general population; with particularly increased risk among those on immunosuppression. As with the general population, we showed increasing HZ risk with advancing age. The aetiology of the increased HZ risk in IBD is likely multifactorial; immunosuppressive medications, age-related changes in immune function and the innate immune dysregulation associated with IBD itself.
Other populations receiving immunosuppression are also at increased risk for HZ. For example, in individuals with RA, the incidence of HZ has been found to be 996 per 100 000 patient-years. Risk factors for HZ in this population of Veterans included advancing age, corticosteroid use, immunosuppressive medications used in moderate RA (such as thiopurines, calcineurin inhibitors or methotrexate) and severe RA (biologic anti-TNF agents), malignancy and comorbid conditions such as chronic lung disease, renal failure or liver disease. A separate study of anti-TNF use in RA patients found increased risk associated with the monoclonal anti-TNF antibodies (HR: 1.82, 95% CI: 1.05–3.15). Increased risk has also been demonstrated in the solid organ transplant (SOT) population. The incidence of HZ is 2222 per 100 000 person-years in the SOT population, with increasing risk associated with increasing levels of immunosuppression (the highest absolute risk is among heart transplant recipients) and increasing age.
The IBD population has been previously shown to have an increased risk of HZ. Gupta et al. evaluated data from the UK and found an increased relative risk of HZ for both CD and UC (IRR: 1.61, 95% CI: 1.35–1.92 and IRR: 1.21, 95% CI: 1.05–1.40 respectively). We found similar risks in our population, with unadjusted IRRs of 1.9 for CD and 1.5 for UC. Similar to Gupta et al., we found increasing risk with advancing age. The overall incidence in our population was 734/100 000 (95% CI: 707/100 000–763/100 000) person-years, and overall age-specific risks in 10-year strata were similar to those risks found by Gupta et al. We also found an increased risk of HZ associated with increasing numbers of comorbidities, as has been reported in the other populations. In a recent study by Zhang et al. of older individuals (age ≥60 years) with autoimmune conditions such as RA or IBD, the incidence of HZ in those with prior shingles vaccination was 780/100 000 and 1160/100 000 in those not previously receiving vaccination. These effect estimates are slightly higher than overall estimates found in our study, but similar to those in our older age strata.
In our nested case–control study, we investigated the independent effects of various classes of medications used in the treatment of IBD. We found that immunosuppressive medications, including anti-TNF agents (OR: 1.81, 95% CI: 1.48–2.21), corticosteroids (OR: 1.73, 95% CI: 1.51–1.99) and thiopurines (OR: 1.85, 95% CI: 1.61–2.13) were each independently associated with increased HZ risk. The study by Gupta et al. predated use of anti-TNF agents, but did estimate the risk of corticosteroids and thiopurines in IBD. Their adjusted odds ratio for corticosteroid use was OR: 1.5, 95% CI: 1.1–2.2; whereas for thiopurines, the risk was greater (adjusted odds ratio: 3.1; 95% CI: 1.7–5.6). We found similar levels of increased risk, albeit somewhat lower for thiopurines. We found no risk associated with 5-ASA use, which served as a negative control, demonstrating that the mechanism of increased risk is driven by immunosuppression and/or severity of underlying IBD. Finally, we investigated the risk associated with combination therapy (anti-TNF and thiopurine), controlling for comorbidities, utilisation and other medication use, and found the highest overall odds ratio of 3.3. This demonstrates that there are potentially additive risks of HZ with >1 immunosuppressive agent.
There are strengths to this large study of HZ incidence and risk factors. Primarily, we studied a very large and geographically diverse population from throughout the United States. Due to this diversity, the sample is broadly generalisable to the commercially insured US population. Secondly, we utilised complete data on all billed out-patient prescriptions to capture medication exposures, without relying on patient recall. Thirdly, were also able to account for both health care utilisation and potentially confounding comorbidities. To do so, we used a validated comorbidity index for administrative data.[18, 19]
There are also several limitations to this study that utilised administrative claims data. As with all studies of claims data, there is the possibility of misclassification of exposure and outcome related to the lack of clinical detail. However, we used an established IBD exposure definition[10, 11] that requires multiple health contacts and/or IBD-related prescriptions. A similar, but even less specific, administrative case definition has been validated by Herrinton et al. with a sensitivity exceeding 90% and a PPV exceeding 80% for overall IBD. We used an outcome definition of HZ consisting of any ICD-9 code (053.xx). This administrative definition has been validated, with a sensitivity of 98% and a positive predictive value of 93%. In a separate validation, ICD-9 code 053.xx for HZ correlated extremely well with HZ diagnosis from chart review (kappa = 0.92). In addition, as risk of HZ is known to increase with age, it is a limitation that the elderly (>age 65) were not represented in our population. This lack of older persons in our study population does not affect the validity of the relative risks we presented in the context of the under 65 population. In spite of controlling for both health care utilisation and comorbidities (including malignancy) within our study, and excluding those with HIV, there are other potential risk factors associated with HZ that may not have been accounted for. For example, we were unable to capture race, and there are some data to suggest that age at diagnosis of HZ may be associated with race. However, to be a confounder, a factor must be associated with both the exposure and the outcome. Race may or may not be associated with our exposures of IBD (in the cohort study) and immunosuppressive medication use (in the nested case–control study). In fact, the incidence of IBD among African Americans now approaches that of Caucasians in the US. Among studies that have shown differences in immunosuppressive medication use by race, many quote access to care and socioeconomic factors as a potential cause. In our study, all patients have health insurance, thereby alleviating many of the socioeconomic factors. Finally, we could not utilise the potentially ideal study design of a cohort study with time varying medication exposures due to the inability to account for the precise timing of initiation and discontinuation of medications. This is particularly true for corticosteroids, which are often written for use ‘as directed’. For this reason, we designed the nested case–control study and accounted for any medication use over a 120-day window. We were also unable to assess the role of the shingles vaccination in our population, as this vaccination is often not covered by insurers in those <age 60, and our data do not extend beyond age 64 due to medicare dual eligibility.
In conclusion, understanding the medication-specific risks of HZ is important, particularly as practice patterns in IBD management change. For example, there is now an emphasis upon early, aggressive management of CD. As biologic anti-TNF and other immunosuppressant use in IBD becomes more prevalent, this increased utilisation may account for a further increase in the incidence of HZ. A new vaccine against varicella zoster virus (shingles), Zostavax® (Merck & Co. Inc., Whitehouse Station, NJ, USA), became commercially available in 2006. The vaccine contains the same strain used in the varicella (chicken pox) vaccine, but is 14 times more potent. The shingles vaccine is effective, decreasing zoster incidence by >50%. This vaccine is currently recommended by the Advisory Committee on Immunization Practices (ACIP) in individuals ≥age 60 without contraindications. As the vaccine is live, it is contraindicated in individuals already on immunosuppression [corticosteroids (≥20 mg/day for greater than 2 weeks), biologic anti-TNF agents, chemotherapy]. In its most recent Guide to Vaccine Contraindications and Precautions, the Centers for Disease Control (CDC) determined that the vaccine could be offered to individuals on low doses of immunosuppression [defined as methotrexate (≤0.4 mg/kg/week), azathioprine (≤3.0 mg/kg/day) or mercaptopurine (≤1.5 mg/Kg/day)]. However, the ideal time to dose this vaccine may be prior to initiation of immunosuppression. The vaccine has not specifically been tested in younger populations or in populations with immune dysfunction such as IBD. Zhang et al. recently found a reduced incidence of HZ in older individuals (≥age 60) with autoimmune conditions and prior receipt of vaccination as compared with a similar group with no prior vaccination, including those exposed to biologics. Importantly, overall rates of HZ vaccination in older individuals with autoimmune conditions remain quite low; 1.2% in one US population. Therefore, this represents a potential missed opportunity for prevention. Future studies will need to determine the role, safety and timing of this vaccination in patients of all ages with IBD. As HZ and its complications are potentially preventable, optimising the delivery and timing of vaccination in IBD patients will be important in years to come.