Purpose
To assess whether there is a protective association between statin use and uveitis diagnosis.
Design
Retrospective, population-based case-control study.
Methods
Medical records of all patients in the Kaiser Permanente Hawaii health plan between January 1, 2006 and December 31, 2007 (N = 217 061) were searched electronically for International Classification of Diseases, 9th Revision, diagnosis codes related to uveitis. Chart review was done to confirm incident uveitis diagnosis during the study period. Two control groups were each randomly selected at a 5:1 ratio to cases, and controls were assigned an index date to match their respective case diagnosis date. One control group was selected from the general Kaiser Permanente Hawaii population that had at least 1 healthcare visit during the study period. Another control group was selected from the population of Kaiser Permanente Hawaii members who had at least 1 visit to the ophthalmology clinic during the study period. Statin use was defined as filling a prescription for statin medication in the year prior to the diagnosis or index date based on an electronic search of the Kaiser Permanente Hawaii pharmacy database for Generic Product Identification codes. A conditional logistic regression model with clinical diagnosis of uveitis as the outcome was used to assess the relationship between statin use and uveitis.
Results
One hundred eight incident cases of uveitis were identified. Nineteen percent of uveitis patients had used statin medication in the year prior to diagnosis compared to 30% of patients in the general Kaiser population control ( P = .03) and 38% of patients in the ophthalmology clinic control ( P < .001). Using the general Kaiser population control and adjusting for age, sex, race, and autoimmune diseases, the odds of a statin user developing uveitis were 48% less than the odds of a non–statin user developing uveitis (OR: 0.52, 95% CI: 0.29–0.94, P = .03). Similarly, the odds of developing uveitis were 33% less for statin users compared to non–statin users (OR: 0.67, 95% CI: 0.38–1.19, P = .17) when adjusting for these factors and using the ophthalmology clinic control group.
Conclusions
Statin use may be protective against the development of uveitis. Several anti-inflammatory and immunomodulatory mechanisms may explain this association.
Uveitis is a set of conditions defined by inflammation of the uveal tract and accounts for approximately 10% of legal blindness in the United States. The exact mechanism by which uveitis occurs is not well defined. Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors, are primarily used for decreasing low-density lipoprotein (LDL) cholesterol, as well as for reducing cardiovascular and cerebrovascular disease risk, and the side effects are generally minimal in most patients. Numerous studies have shown additional anti-inflammatory and immunomodulatory benefits of statins in a variety of systemic diseases, including multiple types of cancer, inflammatory bowel disease, and rheumatoid arthritis.
In the ophthalmology literature, several studies have investigated whether there is an association between statin use and age-related macular degeneration, as well as glaucoma, cataract, and diabetic retinopathy. While the results have been varied, some studies have shown a protective effect of this class of medications. Multiple laboratory studies have been done suggesting anti-inflammatory properties of statins in animal models with experimental autoimmune uveitis, and 1 clinical case-control study found a nonsignificant protective association between statin use and all types of ocular inflammatory disease. However, a population-based study focusing specifically on the association between statin use and uveitis is lacking.
The Pacific Ocular Inflammation study aims to elucidate details about the epidemiology of ocular inflammatory disease in the Hawaiian Islands. Kaiser Permanente Hawaii provides an optimal setting for this population-based study as it is composed of more than 15% of the general Hawaiian population with centers throughout the Hawaiian Islands. The goal of this specific case-control study was to assess whether there is a protective association between statin use and uveitis diagnosis.
Methods
Institutional Review Board and Ethics Committee approval was obtained at Kaiser Permanente Hawaii and the University of California, San Francisco, respectively. All work was HIPAA-compliant and adhered to the tenets of the Declaration of Helsinki. Detailed methods for identification of uveitis cases, including a complete list of International Classification of Diseases, 9th Revision (ICD-9) codes used, have been described previously. Briefly, all clinical encounters between January 1, 2006 and December 31, 2007 in the electronic database of Kaiser Permanente Hawaii were queried for ICD-9 diagnosis codes associated with uveitis. The medical records of patients identified by this initial search were individually reviewed by a uveitis fellowship–trained ophthalmologist to exclude patients without a confirmed diagnosis of uveitis. Additionally, incident cases were identified as patients whose first diagnosis of uveitis was within the study period based on comprehensive chart review. All patients with a confirmed incident diagnosis of uveitis were included in this study.
Two control groups were each randomly selected at a 5:1 ratio to incident uveitis cases. One control group was selected from the general Kaiser Hawaii membership who had at least 1 healthcare visit during the study period. An ophthalmology control group was selected from the population of Kaiser patients who were 18 years of age or older as of January 1, 2007, and had at least 1 visit to the Kaiser ophthalmology clinic during the study period. Each control patient was assigned an index date to match the diagnosis date for its respective case.
Statin use was determined based on an electronic search of the Kaiser Hawaii pharmacy database for all Generic Product Identification (GPI) codes corresponding to this class of medications. Patients were considered statin users if they had filled a prescription for atorvastatin, lovastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or ezetimibe-simvastatin in the year prior to the diagnosis or index date. Use of other lipid-lowering agents was based on a similar search for cholestyramine, colestipol, ezetimibe, fenofibrate, gemfibrozil, and vitamin B 3 . High-dose statin use was defined as having a prescription filled for statin medication at a dosage shown to reduce LDL cholesterol by at least 50%.
Demographic information; diagnosis of hyperlipidemia, hypertension, diabetes, or autoimmune disease; and smoking status were collected electronically for both cases and controls. Smoking status was determined based on information provided at physician visits, and each patient’s smoking status closest to the diagnosis or index date was used. Infectious uveitis was defined as having an associated diagnosis of herpes simplex virus, herpes zoster virus, histoplasmosis, toxoplasmosis, human immunodeficiency virus, Bartonella , tuberculosis, syphilis, cytomegalovirus retinitis, or Lyme disease determined by electronic ICD-9 code search or individual chart review.
Demographic data and clinical characteristics for cases and controls were compared using Fisher exact test or a 2-sample t test for categorical and continuous variables, respectively. Conditional logistic regression with diagnosis of uveitis as the outcome was used to assess the association between statin use and uveitis for each control group. Age, sex, race, diagnosis of autoimmune disease, and smoking status were used as covariates in the main regression model and sensitivity analyses to evaluate the effect of these factors on the association. A P value less than .05 was considered statistically significant.
All analyses were performed using STATA 12.0 (StataCorp, College Station, Texas, USA).
Results
The total population of Kaiser Permanente Hawaii was 217 061 people at the midpoint of the study period, January 1, 2007. Out of this population, 224 patients had a confirmed diagnosis of uveitis, and of these, 108 were confirmed incident cases. Location of inflammation, disease course, and associated diagnoses have been presented previously. A majority of incident cases were anterior (n = 88, 81%) and noninfectious (n = 82, 76%).
For both the general Kaiser Hawaii population control and the ophthalmology clinic control, 540 patients were randomly selected for comparison to the uveitis patients. Demographic data were compared between uveitis patients and control patients ( Table 1 ). Compared to both the general control group and the ophthalmology control, cases were not significantly different with respect to age and sex, with the exception that uveitis patients were significantly younger than the ophthalmology control group (mean age: 49.9 years vs 62.5 years, P < .001).
| Incident Cases | General Controls | P Value | Ophthalmology Controls | P Value | |
|---|---|---|---|---|---|
| Total | 108 | 540 | 540 | ||
| Female | 52 (48%) | 302 (56%) | .14 a | 291 (54%) | .29 a |
| Mean age (y) | 49.9 | 52.1 | .27 b | 62.5 | <.001 b |
| Current smoker | 21 (19%) | 75 (14%) | .14 a | 47 (9%) | .002 a |
| Race c | N = 82 (76%) | N = 446 (83%) | .04 a | 457 (85%) | .28 a |
| Alaskan/Native American | 1 (1%) | 10 (2%) | 5 (1%) | ||
| Asian | 39 (48%) | 166 (37%) | 211 (46%) | ||
| African American | 2 (2%) | 1 (<1%) | 6 (1%) | ||
| Pacific Islander | 18 (22%) | 134 (30%) | 97 (21%) | ||
| White | 22 (27%) | 135 (30%) | 138 (30%) |
a P value obtained by Fisher exact test.
b P value obtained by 2-sample mean comparison t test.
c Percentages for each race subgroup are listed in parentheses using the number of patients reporting race as the denominator.
Table 2 presents the clinical characteristics of both cases and controls. Nineteen percent of uveitis patients had used statin medication in the year prior to uveitis diagnosis. This was significantly lower than both the general Kaiser population control (30%, P = .03, Table 2 ) and the ophthalmology control (38%, P < .001, Table 2 ). Use of high-dose statins or other lipid-lowering agents was not significantly different between cases and either control group. For the general population control, the proportions of cases and controls with lipid metabolism disorders, hypertension, or diabetes did not differ significantly. Patients in the ophthalmology control group had higher rates of these diseases compared to uveitis patients ( Table 2 ). After adjusting for age, lipid metabolism disorders (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 0.73–2.03, P = .45), hypertension (OR: 0.90, 95% CI: 0.54–1.50, P = 69), and diabetes (OR: 0.63, 95% CI: 0.35–1.14, P = .13) were not associated with case status.
| Incident Cases | General Controls | P Value a | Ophthalmology Controls | P Value a | |
|---|---|---|---|---|---|
| Total | 108 | 540 | 540 | ||
| Medications | |||||
| Statins | 21 (19%) | 160 (30%) | .03 | 204 (38%) | <.001 |
| High-dose statins | 2 (2%) | 17 (3%) | .75 | 14 (3%) | 1.00 |
| Other lipid-lowering agents | 4 (4%) | 25 (5%) | .80 | 17 (3%) | .77 |
| Chronic conditions | |||||
| Lipid metabolism disorder | 44 (41%) | 231 (43%) | .75 | 295 (55%) | .01 |
| Diabetes | 15 (14%) | 118 (22%) | .07 | 139 (26%) | .01 |
| Hypertension | 36 (33%) | 224 (41%) | .13 | 280 (52%) | <.001 |
| Autoimmune diseases b | 8 (7%) | 17 (3%) | .051 | 20 (4%) | .11 |
a P values obtained by Fisher exact test.
b Includes reactive arthritis, sarcoidosis, Behçet disease, multiple sclerosis, polyarteritis nodosa, granulomatosis with polyangiitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, inflammatory bowel disease, juvenile idiopathic arthritis, and systemic lupus erythematosus.
Multivariate conditional logistic regressions were used to compare uveitis patients to each control group adjusting for the effects of age, sex, race, and autoimmune disease ( Table 3 ). Using the general population control, the odds of a statin user developing uveitis were 48% less than the odds of developing uveitis for a patient not taking this class of medications (OR: 0.52, 95% CI: 0.29–0.94, P = .03, Table 3 ). Similarly, the odds of a statin user developing uveitis were 33% less than the odds for a non–statin user when using the ophthalmology clinic control (OR: 0.67, 95% CI: 0.38–1.19, P = .17, Table 3 ); however, this association was not significant.
| Cases vs General Controls | Cases vs Ophthalmology Controls | |||||
|---|---|---|---|---|---|---|
| Odds Ratio | 95% CI | P Value | Odds Ratio | 95% CI | P Value | |
| Statin use | 0.5 | 0.3–0.9 | .03 | 0.7 | 0.4–1.2 | .17 |
| Age (by decade) | 1.0 | 0.9–1.1 | .80 | 0.7 | 0.6–0.8 | <.001 |
| Female | 0.7 | 0.5–1.1 | .11 | 0.8 | 0.5–1.2 | .20 |
| Race (ref = white) | ||||||
| Alaskan/Native American | 0.6 | 0.1–4.8 | .61 | 0.5 | 0.1–5.1 | .58 |
| Asian | 1.5 | 0.8–2.7 | .17 | 1.3 | 0.7–2.4 | .41 |
| African American | 10.4 | 0.9–123.0 | .06 | 1.4 | 0.2–8.2 | .71 |
| Pacific Islander | 0.8 | 0.4–1.6 | .49 | 0.9 | 0.4–1.9 | .81 |
| Unknown | 1.5 | 0.8–2.9 | .23 | 1.1 | 0.6–2.2 | .78 |
| Autoimmune disease | 3.0 | 1.2–7.7 | .02 | 3.2 | 1.3–8.0 | .02 |
A sensitivity analysis was done to evaluate the effect of current smoking status on this association. Controlling for smoking status in addition to age, sex, race, and autoimmune disease did not affect the protective association between statin use and uveitis when using both the general population (OR: 0.52, 95% CI: 0.29–0.95, P = .03) and ophthalmology clinic control groups (OR: 0.65, 95% CI: 0.36–1.16, P = .15). Adjusting for current and prior smoking status rather than current smoking status alone also did not impact the results for either control group.
Additional sensitivity analyses were done to evaluate this association for noninfectious uveitis. Using only patients with noninfectious uveitis and their respective general population controls, the odds of developing uveitis were 56% less in statin users compared to non–statin users (OR: 0.44, 95% CI: 0.22–0.88, P = .02) when adjusting for age, sex, race, current smoking status, and autoimmune disease. A similar association, which trended toward significance, was found using the ophthalmology clinic control group and adjusting for these factors (OR: 0.52, 95% CI: 0.26–1.02, P = .057).
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