Abstract
Objective
To determine the incidence, time trends, risk factors and severity of herpes zoster (HZ) in a population-based incidence cohort of patients with rheumatoid arthritis (RA) compared to a group of individuals without RA from the same population.
Methods
All residents of Olmsted County, MN who first fulfilled 1987 American College of Rheumatology criteria for RA between 1/1/1980 and 12/31/2007 and a cohort of similar residents without RA were assembled and followed by retrospective chart review until death, migration, or 12/31/2008.
Results
There was no difference in the presence of HZ prior to RA incidence/index date between the cohorts (p=0.85). During follow-up 84 patients with RA (rate: 12.1 per 1000 person-years) and 44 subjects without RA (rate: 5.4 per 1000 person-years) developed HZ. Patients with RA were more likely to develop HZ than those without RA (hazard ratio: 2.4; 95% confidence interval: 1.7, 3.5). Patients diagnosed with RA in 1995–2007 had a higher likelihood of developing HZ than those diagnosed in 1980–1994. Erosive disease, previous joint surgery, use of hydroxychloroquine and corticosteroids were significantly associated with the development of HZ in RA, while the use of methotrexate or biologic agents was not. Complications of HZ occurred at a similar rate in both cohorts.
Conclusion
The incidence of HZ is increased in RA and has risen in recent years. The increasing incidence of HZ in more recent years is also noted in the general population. RA disease severity is associated with development of HZ.
Keywords: rheumatoid arthritis, herpes zoster
Herpes zoster or shingles is a common cutaneous disorder caused by the reactivation of latent varicella-zoster virus dormant in the cranial nerve or dorsal root ganglia. It usually manifests as a dermatomal distribution of a vesicular eruption that can cause significant morbidity (1). Herpes zoster is known to be more frequent in patients with conditions that depress cell-mediated immunity, including malignancy, HIV, transplantation, immunosuppressive disorders and treatment with immunosuppressants (2).
The overall rate of herpes zoster in patients with rheumatoid arthritis (RA) is increased compared to the general population, with a greater risk in individuals using traditional disease modifying antirheumatic drugs (DMARDs) or biologic therapies (3). Use of prednisone in RA is an important predisposing factor for herpes zoster, and its use in conjunction with DMARDs increases the risk beyond that seen with the DMARDs alone (4). Many unanswered questions remain regarding the relationship between RA and reactivation of herpes zoster, and how RA related disease features, treatment and herpes zoster prevention measures might be addressed to avoid recurrent and complicated herpes zoster in these patients.
We performed a population-based study to assess the incidence, time trends, risk factors and severity of herpes zoster in a well defined population of patients with RA. This information should serve the eventual goal of identifying possible strategies that could be employed to minimize the risk of development of herpes zoster in patients with RA.
Patients and Methods
This retrospective, population-based cohort study was conducted in Olmsted county, MN, which is well suited for a longitudinal population-based analyses as medical records of all residents seeking medical care by any medical provider for over half a century are readily available. This task is made easier by the records linkage system of the Rochester Epidemiology Project (REP) which allows ready access to the complete records from all health care providers and hospitals for the local population. The potential of this data system for population-based research has been well established (5).
The study included an inception cohort of all cases of RA first diagnosed between January 1, 1980 and December 31, 2007 (n=813) among Olmsted County residents ≥18 years of age assembled as previously described (6). The incidence date was defined as the earliest date at which the patient fulfilled at least 4 of the 7 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 classification criteria for RA (7). A comparison cohort of subjects without RA was assembled by randomly selecting for each patient with RA, a corresponding Olmsted County resident during the same calendar year of the incident RA with similar age and sex who did not have RA. All patients in both cohorts were followed up longitudinally through their complete medical records until death, migration from Olmsted County, or 12/31/2008.
The original and complete medical records of all subjects were reviewed longitudinally by trained nurse abstractors, supervised by the principal investigator. Information about demographics (e.g., age, sex, smoking status, body mass index), RA disease characteristics (e.g., erythrocyte sedimentation rates, rheumatoid nodules, joint erosions/destructive changes on radiographs, joint surgeries [e.g., arthroplasty, synovectomy], use of traditional DMARDs, biologic agents and systemic corticosteroids) and severe extra-articular manifestations (defined according to Malmö criteria, and included pericarditis, pleuritis, Felty’s syndrome, glomerulonephritis, vasculitis, peripheral neuropathy, scleritis, and episcleritis) were abstracted (8). The diagnostic index was also searched using International Classification of Disease (ICD) codes for herpes zoster and its complications (ICD 9 codes 053.0–053.9, 052.1). The medical records of all patients with codes for herpes zoster were reviewed to confirm the diagnosis, to ascertain the extent of the skin disease (single or multidermatomal/disseminated lesions) and to determine the outcomes of herpes zoster infection (extent of organ involvement/complications and hospitalizations). Post herpetic neuralgia was defined as documented zoster-associated pain persisting at least 90 days following the episode of herpes zoster. The diagnosis of herpes zoster was defined as the date of onset of the rash diagnosed as herpes zoster or, if the timing of the rash onset was not known, as the date of the first diagnosis of herpes zoster either at a clinic visit or by positive culture or biopsy.
Statistical methods
Descriptive statistics (means, percentages, etc.) were used to summarize the data. The cumulative incidence of herpes zoster adjusted for the competing risk of death was estimated (9). These methods are similar to Kaplan-Meier method with censoring of patients who are still alive at last follow-up. However, patients who die before experiencing herpes zoster are appropriately accounted for to avoid the overestimation of the rate of occurrence of herpes zoster, which can happen if such subjects are simply censored. Patients who were diagnosed with herpes zoster prior to the diagnosis of RA, or prior to the index date for subjects in the non-RA comparison cohort, were excluded from the analysis of cumulative incidence. Cumulative incidence comparisons between the cohorts were performed using methods described by Gray (10). Poisson regression models were used to model the rates of herpes zoster over calendar time. Smoothing splines were used to allow for non-linear time trends.
Cox proportional hazards models were used to compare the rate of development of herpes zoster between patients with RA and the non-RA comparison cohort. In addition, Cox proportional hazards models were used to assess the association of risk factors with the development of herpes zoster among patients with RA. Time-dependent covariates were used to model risk factors that developed over time. These time-dependent covariates allowed patients to be modeled as unexposed to the risk factor during the follow-up time prior to development of the risk factor, then change to exposed following development of the risk factor.
Results
The study population included 813 patients with RA and 813 subjects without RA. The average age at RA incidence (index date for the non-RA cohort) was 55.9 (standard deviation, SD 15.7) years, median age was 55.3 years (min 18, max 94), and 556 (68%) were female in each cohort. There was a significant difference in the smoking status between the RA and non RA cohorts as shown in Table 1. There was no difference in the presence of herpes zoster (p=0.85) and malignancy (p=0.22) prior to RA incidence/index date between the cohorts.
Table 1.
Characteristics of 813 patients with rheumatoid arthritis (RA) and 813 subjects without RA.
| Characteristic | RA N = 813 | Non-RA N = 813 | p-value |
|---|---|---|---|
| Age at incidence/index, years, mean ± SD | 55.9 ± 15.7 | 55.9 ± 15.7 | 0.99 |
| Sex, female, n (%) | 556 (68%) | 556 (68%) | 1.0 |
| Length of follow-up, years, mean ± SD | 9.6 ± 6.9 | 10.9 ± 7.2 | -- |
| Smoking status at incidence/index, n (%) | |||
| Never | 364 (45%) | 435 (54%) | 0.002 |
| Current | 178 (22%) | 144 (18%) | |
| Former | 271 (33%) | 234 (29%) | |
| Body mass index at incidence/index, kg/m2, mean ± SD | 27.8 ± 6.2 | 27.8 ± 7.8 | 0.74 |
| Herpes zoster prior to incidence/index, n (%) | 58 (7%) | 60 (7%) | 0.85 |
| Any malignancy prior to incidence/index, n (%) | 53 (7%) | 66 (8%) | 0.22 |
N=number of patients, SD = standard deviation
Among patients who did not have herpes zoster prior to incidence/index date, 84 RA patients and 44 non-RA subjects developed herpes zoster during follow-up. The cumulative incidence of herpes zoster was higher in the RA patients compared to the non-RA subjects (8.9% ± 1.2% at 10 years in RA vs. 4.3% ± 0.8% in non-RA; p<0.001; Figure 1). In other words, patients with RA were more likely to develop herpes zoster during follow-up (hazard ratio [HR]: 2.4; 95% confidence interval [CI]: 1.7, 3.5 adjusted for age, sex and calendar year). The rate of development of herpes zoster was 12.1 per 1000 person-years (95% CI: 9.6, 14.9) in patients with RA and 5.4 per 1000 person-years (95% CI: 3.9, 7.2) in non-RA subjects (Figure 2).
Figure 1.
Cumulative incidence of herpes zoster in RA vs. non-RA. Solid line are patients with RA and dashed line are subjects without RA (p<0.001).
Figure 2.
The incidence of herpes zoster by calendar year of follow-up in patients with RA compared to subjects without RA. Solid line is RA and dashed line is non-RA.
The development of herpes zoster occurred more frequently in patients diagnosed with RA more recently (HR: 1.06 per year; 95% CI: 1.02, 1.10; p=0.004). Likewise, patients diagnosed with RA in 1995–2007 had a higher likelihood of developing herpes zoster than patients with RA diagnosed in 1980–1994 (HR: 1.9; 95% CI: 1.1, 3.2; p=0.013). The time trends in the non-RA subjects followed a similar pattern (HR: 2.3; 95% CI: 1.2, 4.6; p=0.016 comparing 1995–2007 to 1980–1994), reflecting an apparent increase in the incidence of herpes zoster in the general population in more recent years. There was no evidence that the increase in herpes zoster was different in patients with RA than in the subjects without RA (p=0.49 for interaction between RA/non-RA and calendar year). Furthermore, there was no statistically significant evidence that age (p=0.28) or gender (p=0.23) influenced the development of herpes zoster differently in RA than in non-RA. When seasonality of the occurrence of herpes zoster was examined there was no apparent seasonal variation in the development of herpes zoster among either the RA or the non-RA cohort (data not shown). The lack of seasonality in the occurrence of herpes zoster is in agreement with the findings from the general population (11).
Risk factors for herpes zoster in RA
Examination of RA disease characteristics and cardiovascular risk factors revealed that erosive disease, previous joint surgery, use of hydroxychloroquine and corticosteroids at any point during the follow-up were significantly associated with the development of herpes zoster in patients with RA (Table 2). There was no statistically significant association between the exposure to other antirheumatic medications, including biologic response modifiers (p=0.60), with the development of herpes zoster. When current use of antirheumatic medications was analyzed only corticosteroids were significantly associated with the occurrence of herpes zoster (HR 1.78; 95% CI 1.14, 2.76).
Table 2.
Association between rheumatoid arthritis (RA) disease characteristics and herpes zoster in patients with RA.
| RA characteristic | Value | Hazard ratio (95% CI) |
|---|---|---|
| Duration of RA (per 10 year increase) | -- | 1.45 (0.92, 2.27) |
| Erythrocyte sedimentation rate at index | 24.8 ± 20.5 | 1.06 (0.96, 1.18)† |
| Rheumatoid factor positive | 537 (66%) | 1.31 (0.84, 2.06) |
| Current smoker | 178 (22%) | 1.39 (0.83, 2.31) |
| Ever smoker (current or former) | 449 (55%) | 1.25 (0.78, 1.98) |
| Time dependent characteristics | ||
| Body mass index ≥30 kg/m2 | 388 (48%) | 1.19 (0.77, 1.84) |
| Erosions/destructive changes | 433 (53%) | 1.74 (1.12, 2.71) |
| Rheumatoid nodules | 267 (33%) | 1.35 (0.85, 2.15) |
| Severe extra-articular manifestations | 90 (11%) | 1.64 (0.87, 3.11) |
| Large joint swelling | 639 (79%) | 2.01 (1.09, 3.72) |
| Joint surgery | 190 (23%) | 2.20 (1.39, 3.49) |
| Ever exposure to medications | ||
| Methotrexate | 469 (58%) | 1.34 (0.85, 2.10) |
| Hydroxychloroquine | 480 (59%) | 1.58 (1.00, 2.48) |
| Other nonbiologic DMARDs | 258 (32%) | 1.29 (0.79, 2.10) |
| Biologic agents | 137 (17%) | 1.24 (0.56, 2.74) |
| Corticosteroids | 627 (77%) | 1.72 (1.03, 2.87) |
| Cycloxygenase 2 inhibitors | 390 (48%) | 1.15 (0.71, 1.86) |
| Aspirin for RA* | 337 (41%) | 1.13 (0.67, 1.91) |
| Non steroidal anti-inflammatory drugs | 737 (91%) | 1.99 (0.80, 4.97) |
defined as ≥6 tablets of Aspirin per day (≥ 1950 mg/day) for ≥ 3 months
per 10 mm/hr increase
DMARDs: Disease modifying antirheumatic drugs
Outcomes/complications
The rates of complications of herpes zoster were similar in subjects with and without RA. Multidermatomal skin involvement occurred in 17 (20%) patients with RA and in 7 (16%) subjects without RA (p=0.69). Secondary infection of the skin and cellulitis occurred in 4 (5%) RA patients and 1 (2%) non-RA subjects (p=0.66). Thirteen (15%) patients with RA and 7 (16%) non-RA subjects were diagnosed with post-herpetic neuralgia (p=0.97). Ramsay-Hunt syndrome type II (geniculate ganglion involvement) occurred in 1 patient with RA; 1 patient with RA had disseminated herpes zoster. Hospitalization for herpes zoster was required in 11 (13%) of patients with RA and 1 (2%) of non-RA subjects (Fisher’s exact test p=0.057).
A second episode of herpes zoster occurred during follow-up in 3 patients with RA and 3 non-RA subjects (unadjusted p=0.58). Adjusting for age, sex and calendar year of the first diagnosis of herpes zoster, there was some indication that patients with RA may be less likely to experience a second episode of herpes zoster (HR: 0.17; 95% CI: 0.02, 1.60; p=0.12); however, the small number of patients with a second episode of herpes zoster limited the ability to definitively address this question. Although not reaching statistical significance, patients with RA who developed herpes zoster had a somewhat higher risk of death than patients without RA (HR: 2.1, 95% CI: 0.98, 4.4; p=0.058).
Vaccination
Some of the patients in this cohort had undergone vaccination against herpes zoster since the vaccine was introduced in 2006. We evaluated the use of vaccination in the subset of 477 patients with RA and 518 subjects with non-RA who were followed between January 1, 2006 to December 31, 2010. A total of 170 RA (rate: 6.6; 95% CI: 5.6, 7.8 per 100 person-years) and 230 non-RA subjects (rate: 8.4; 95% CI: 7.3, 9.6 per 100 person-years) were vaccinated with Zostavax® during follow-up. Patients with RA were less likely to receive the herpes zoster vaccine compared to subjects without RA (HR: 0.77, 95% CI: 0.62–0.95). There were 4 RA patients and 2 non-RA subjects with herpes zoster after the vaccination (Fisher’s exact test p-value=1.0).
Discussion
The results of this study indicate that the incidence of herpes zoster is increased in patients with RA compared to patients without RA and has risen in recent years. The increases in incidence of herpes zoster among patients with RA mirror the increases noted in the general population with the incidence of herpes zoster remaining consistently higher among patients with RA than among those without RA. Several indicators of disease severity were found to be significantly associated with the development of herpes zoster among patients with RA.
Data from prior studies have shown that herpes zoster infection occurs in about 1 million individuals annually in the US (1, 12). Patients with RA are a particularly vulnerable population, as evidenced by about two-fold increase in risk of herpes zoster compared to the general population (3). Our study found that the rates of occurrence of herpes zoster in RA are elevated at 12.1 per 1000 person-years which is consistent with the estimate from the retrospective cohort study of the US Veterans of 9.96 cases per 1000 patient-years (13).
There are a number of potential explanations for the increase in incidence of herpes zoster in patients with RA, particularly in recent years (13–15). These include increasing and early use of immunosuppressive medications for management of RA, aging of the population, and increased burden of comorbidity and immunocompromised conditions. Although these factors may account for the recent incidence trend, they do not fully explain why the incidence of herpes zoster increased in both the patients with RA and the general population over the duration of the study. This recent increase in the incidence of herpes zoster in the general population has been noted by other investigators as well (16, 17).
One of the goals of our study was to explore what factors, disease or treatment related, if any, could account for the increase in incidence of herpes zoster in RA. Among RA disease characteristics, erosive disease and previous joint surgery stand out for their significant association with the development of herpes zoster, presumably as they are indicators of increased disease burden. The reasons for the lack of association of another marker of RA severity – rheumatoid factor positivity – are unclear, but this finding appears to be concordant with the previous studies (4).
Existing evidence regarding the impact of cigarette smoking on herpes zoster is inconclusive. Some population-based studies reported protective effect of current smoking on the occurrence of herpes zoster while in other more recent studies smoking has been linked to increased severity of herpes zoster (i.e. increased pain burden and risk of complications) (18, 19). Current smoking was not associated with the occurrence of herpes zoster in our study.
The impact of antirheumatic medications, in particular DMARDs and biologic response modifiers, on the risk of infections in patients with RA has been the subject of much debate in the rheumatology community. A nested case-control study by Smitten et al. (3), found the risk of herpes zoster to be elevated in patients with RA using biological DMARDs (Odds Ratio [OR]: 1.54) or traditional DMARDs (OR: 1.37), compared to individuals on no DMARD treatment. Antonelli et al. reported an increased risk of herpes zoster in patients with RA treated with low dose methotrexate compared to the general population (20). Strangfeld et al. (4) published prospective cohort data from a German biologics registry, showing an increased risk of herpes zoster in patients receiving tumor necrosis factor (TNF) inhibitors (i.e. adalimumab and infliximab) compared to those receiving traditional DMARDS. The data from the Consortium of Rheumatology Researchers of North America (CORRONA) registry showed that varicella zoster virus infection was the most frequent infection in patients who received methotrexate, TNF blockers or other DMARDs, and accounted for 44% of all cases of opportunistic infections (21).
Somewhat conversely, some studies did not find any apparent association of TNF antagonists with the risk of herpes zoster. Wolfe et al. (22) studied 10,614 patients with RA and found that cyclophosphamide, azathioprine, prednisone, leflunomide, and some nonsteroidal anti-inflammatory drugs (NSAIDs) were risk factors for herpes zoster, but that TNF antagonists and methotrexate were not. However, the use of self-administered patient questionnaires was a limitation to this study. Concordant results were obtained by McDonald et al. in a large population-based study (13). They noted no difference in herpes zoster risk for those on TNF antagonists compared to traditional DMARDs.
In our study we did not find traditional DMARDs or biologic agents to significantly increase the risk of herpes zoster. The only clear predisposing factor was the use of corticosteroids. Smitten et al. (3) also demonstrated significant association between use of corticosteroids and herpes zoster among patients with RA, with their use being a surrogate for increased RA disease activity. Decreased cell-mediated immunity associated with exposure to glucocorticoids may also contribute to this association.
Since 2006 a live, attenuated zoster vaccine (ZostavaxR) has been available for use in immunocompetent persons aged ≥ 60 years. The vaccine was studied for three years in 38,546 individuals >60 years with a 51% reduction in shingles and a 67% reduction in postherpetic neuralgia. In the face of manufacturer recommendations contraindicating the use of this vaccine in “immunosuppressed” individuals, the Centers for Disease Control Advisory Committee on Immunization Practices recommend that patients receiving prednisone <20 mg/day, short term (<2 weeks) corticosteroids, topical or intra-articular corticosteroids, ‘low dose’ methotrexate (defined as <0.4 mg/kg/week), azathioprine (<3.0 mg/kg/day) or 6-mercaptopurine (<1.5 mg/kg/day) could be vaccinated (23). However, these guidelines do not address vaccine use when these agents are combined. Current ACR guidelines for the use of DMARDs and biologics in RA do not recommend the use of varicella-zoster vaccine in patients receiving biologics (24, 25). However, some recent findings suggest lack of increase in short-term risk of herpes zoster infection following vaccination in biologic users compared to those using only non-biologic DMARDs (26). Considering a number of contraindications for the use of varicella-zoster vaccine, it is not surprising that the diagnosis of RA was a predictor for reduced zoster vaccination rates in our cohort. There were too few patients who had herpes zoster after the vaccination in our population to draw any meaningful conclusions regarding the impact of vaccination on the occurrence and/or severity of herpes zoster in RA vs. non-RA cohort.
Because herpes zoster is caused by reactivation of the latent virus, the immunocompetence of the patient is of particular importance for the risk of development of herpes zoster and associated complications. It is thought that immunocompromised individuals have a greater likelihood of experiencing complications from herpes zoster (17) such as ocular and neurological syndromes (27). In our study, complications of herpes zoster occurred at a similar rate in patients with RA and in subjects without RA. However, patients with RA who developed herpes zoster were at somewhat higher risk of all-cause premature mortality than patients without RA.
To our knowledge, this is the first population-based study to examine the differences in the incidence and severity of herpes zoster in patients with RA compared to the general population. It has the advantage of longitudinal follow-up of a population-based RA incidence cohort with medical record confirmation of all diagnoses. With the exception of a higher proportion of the working population employed in the health care industry, and correspondingly higher education levels, on the whole, results of this study utilizing the population of Olmsted County, Minnesota are generalizable to the populations of interest elsewhere (5). As in any retrospective study, only those persons who had a medical encounter during which herpes zoster or a herpes zoster complication could be identified were included. Events of herpes zoster in persons not seeking medical care for this problem or whose diagnosis was miscoded would not be captured. Disease activity scores were not available for this cohort. Statistical power could be limited in some risk factor analyses, particularly when assessing associations between the use of biologic agents and occurrence of herpes zoster. These results should be interpreted with caution.
In conclusion, there is an apparent increase in incidence of herpes zoster in patients with RA relative to the general population. The incidence of herpes zoster in RA has further increased in recent years; similar increasing trend has been noted in subjects without RA. There was no significant difference in severity of herpes zoster in RA vs non-RA subjects. RA disease severity and the use of some antirheumatic medications (in particular, corticosteroids), have been found to be associated with occurrence of herpes zoster. Given the increasing trend of herpes zoster in patients with rheumatic diseases, a careful and thorough review of existing risk factors, risk modification with vaccination and judicious use of immunosuppressive medications would hopefully prevent recurrence and complications of herpes zoster.
Significance & Innovations.
This large population-based cohort study reports increased incidence of herpes zoster in patients with rheumatoid arthritis (RA) as compared to the general population
The occurrence of herpes zoster has risen during the recent years in both RA and non-RA subjects, but remains consistently higher in RA
RA disease severity and the use of corticosteroids appear to be associated with increased risk of herpes zoster in patients with RA
Acknowledgments
Funding: This work was funded by a grant from Pfizer. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR46849, by the National Institute on Aging of the National Institutes of Health under Award Number R01AG034676, and by Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
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