Abstract
This cohort study uses Medicare claims data to assess the association of gout with risk of a new diagnosis of uveitis in older individuals.
Uveitis, often associated with autoimmune diseases, leads to 30 000 new cases of legal blindness annually in the United States and $243 million in health care expenses.1,2,3 Limited epidemiologic information is available from 2 US population-based studies2,4 that did not focus on older individuals (≥65 years of age), a population expected to increase to more than 70 million in 2030 in the United States. Therefore, our objective was to assess whether gout, a crystal-induced inflammatory arthritis, is associated with an increased risk of a new diagnosis of uveitis in older individuals.
Methods
We used the 5% Medicare claims data from January 1, 2005, through December 31, 2012, for this cohort study. Medicare beneficiaries enrolled in Medicare fee-for-service (Parts A and B) and not enrolled in a Medicare Advantage Plan who resided in the United States from 2006 to 2012 were included. Gout was identified by the presence of 2 claims for gout at least 4 weeks apart, with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 274.xx. Study outcome was incident uveitis, identified by 2 claims for uveitis with an ICD-9-CM code of 364.xx at least 4 weeks apart, and an absence of uveitis claims in the baseline 365-day period.5 The University of Alabama at Birmingham’s Institutional Review Board approved this study and waived the need for informed consent for this database study. All investigations were conducted in conformity with ethical principles of research. We assessed the association of gout with uveitis using multivariable-adjusted Cox proportional hazards regression analyses, controlling for several covariates or potential confounders: age; race/ethnicity; sex comorbidities, assessed using the Charlson Comorbidity Index (Romano adaptation), a validated, weighted comorbidity measure; and use of cardiovascular medications (statins, β-blockers, diuretics, and angiotensin-converting enzyme inhibitors; data from Medicare Part D) and urate-lowering medications for gout (allopurinol and febuxostat).
Results
We found 8459 incident uveitis cases in a cohort of 1 240 681 Medicare recipients, including 464 in individuals with gout and 7995 in individuals without gout (mean [SD] age, 73.4 [6.5] years; 724 307 [58.4%] female; and 1 065 536 [85.9%] white); the respective incidence rates were 179 and 93 per 100 000 person-years. The mean (SD) time from gout diagnosis to the new diagnosis of uveitis was 804 (572) days (median, 694 days; interquartile range, 329-1190 days). Compared with individuals without incident uveitis, those with uveitis were significantly more likely to be older, female, and black and have more medical comorbidities (Table 1). After multivariable adjustment, gout was associated with 1.53-fold higher hazard of uveitis (95% CI, 1.39-1.69; P < .001) (Table 2), as were older age, female sex, black or other race/ethnicity, and comorbidities, including diabetes, chronic obstructive pulmonary disease, connective tissue disease, or any tumor, leukemia, or lymphoma (Table 2). Sensitivity analysis that replaced the continuous Charlson Comorbidity Index with a categorized scale or individual comorbidities confirmed the findings from the main analyses with minimal attenuation of hazard ratios (Table 2).
Table 1. Demographic and Clinical Characteristics of Individuals With Incident Uveitisa.
| Characteristic | Entire Cohort (N = 1 240 681) | Uveitis During Follow-up | |
|---|---|---|---|
| No (n = 1 232 222) | Yes (n = 8459) | ||
| Age, mean (SD), y | 73.4 (6.5) | 73.4 (6.5) | 74.2 (6.4) |
| Sex | |||
| Male | 516 374 (41.6) | 513 158 (41.6) | 3216 (38.0) |
| Female | 724 307 (58.4) | 719 064 (58.4) | 5243 (62.0) |
| Race/ethnicity | |||
| White | 1 065 536 (85.9) | 1 058 998 (85.9) | 6538 (77.3) |
| Black | 99 864 (8.0) | 98 566 (8.0) | 1298 (15.3) |
| Other or unknown | 75 281 (6.1) | 74 658 (6.1) | 623 (7.4) |
| Charlson Comorbidity Index score, mean (SD) | 1.19 (1.94) | 1.18 (1.94) | 1.78 (2.27) |
| Charlson Comorbidity Index score | |||
| 0 | 727 854 (58.7) | 724 265 (58.8) | 3589 (42.4) |
| 1 | 140 442 (11.3) | 139 243 (11.3) | 1199 (14.2) |
| ≥2 | 372 385 (30.0) | 368 714 (29.9) | 3671 (43.4) |
| Charlson Comorbidity Index comorbidities | |||
| Myocardial infarction | 34 480 (2.8) | 34 165 (2.8) | 315 (3.7) |
| Heart failure | 101 798 (8.2) | 100 815 (8.2) | 983 (11.6) |
| Peripheral vascular disease | 103 530 (8.3) | 102 431 (8.3) | 1099 (13.0) |
| Cerebrovascular disease | 105 372 (8.5) | 104 345 (8.5) | 1027 (12.1) |
| Dementia | 18 903 (1.5) | 18 775 (1.5) | 128 (1.5) |
| Chronic obstructive pulmonary disease | 138 779 (11.2) | 137 396 (11.2) | 1383 (16.3) |
| Connective tissue disease | 31 223 (2.5) | 30 868 (2.5) | 355 (4.2) |
| Peptic ulcer disease | 15 479 (1.2) | 15 319 (1.2) | 160 (1.9) |
| Mild liver disease | 7970 (0.64) | 7885 (0.64) | 85 (1.0) |
| Diabetes | 219 306 (17.7) | 217 012 (17.6) | 2294 (27.1) |
| Diabetes with end-organ damage | 57 240 (4.6) | 56 491 (4.6) | 749 (8.9) |
| Hemiplegia | 5854 (0.47) | 5797 (0.47) | 57 (0.67) |
| Renal failure or disease | 26 365 (2.1) | 26 053 (2.1) | 312 (3.7) |
| Any tumor, leukemia, or lymphoma | 106 335 (8.6) | 105 307 (8.5) | 1028 (12.2) |
| Moderate or severe liver disease | 714 (0.06) | 710 (0.06) | 4 (0.05) |
| Metastatic cancer | 6658 (0.54) | 6580 (0.53) | 78 (0.92) |
| AIDS | 426 (0.03) | 415 (0.03) | 11 (0.13) |
| Hypertension | 566 068 (45.6) | 560 874 (45.5) | 5194 (61.4) |
| Hyperlipidemia | 454 375 (36.6) | 450 285 (36.5) | 4090 (48.4) |
| Coronary artery disease | 178 680 (14.4) | 177 014 (14.4) | 1666 (19.7) |
| Gout | 94 682 (5.5) | 94 166 (5.5) | 516 (5.3) |
Data are presented as number (percentage) of population unless otherwise indicated.
Table 2. Association of Gout and Other Risk Factors With Incident Uveitis.
| Characteristic | Multivariable Adjusted Analysisa | |||||
|---|---|---|---|---|---|---|
| Model 1b | Model 2b | Model 3b | ||||
| HR (95% CI) | P Value | HR (95% CI) | P Value | HR (95% CI) | P Value | |
| Age, y | ||||||
| 65 to <75 | 1 [Reference] | NA | 1 [Reference] | NA | 1 [Reference] | NA |
| 75 to <85 | 1.21 (1.16-1.27) | <.001 | 1.19 (1.14-1.25) | <.001 | 1.19 (1.13-1.24) | <.001 |
| ≥85 | 1.16 (1.06-1.27) | .001 | 1.14 (1.05-1.24) | .003 | 1.20 (1.10-1.31) | <.001 |
| Sex | ||||||
| Male | 1 [Reference] | NA | 1 [Reference] | NA | 1 [Reference] | |
| Female | 1.16 (1.11-1.21) | <.001 | 1.15 (1.10-1.21) | <.001 | 1.12 (1.07-1.18) | <.001 |
| Race | ||||||
| White | 1 [Reference] | 1 [Reference] | 1 [Reference] | |||
| Black | 2.05 (1.93-2.17) | <.001 | 2.07 (1.95-2.20) | <.001 | 2.05 (1.93-2.18) | <.001 |
| Other | 1.35 (1.24-1.46) | <.001 | 1.38 (1.27-1.49) | <.001 | 1.37 (1.27-1.49) | <.001 |
| Charlson Comorbidity Index score, per unit change | 1.11 (1.11-1.12) | <.001 | NA | NA | NA | NA |
| Charlson Comorbidity Index score | ||||||
| 0 | NA | NA | 1 [Reference] | NA | NA | NA |
| 1 | NA | NA | 1.69 (1.58-1.80) | <.001 | NA | NA |
| ≥2 | NA | NA | 1.93 (1.84-2.02) | <.001 | NA | NA |
| Select Charlson Comorbidity Index comorbiditiesc | ||||||
| Diabetes | NA | NA | NA | NA | 1.21 (1.15-1.29) | <.001 |
| Chronic obstructive pulmonary disease | NA | NA | NA | NA | 1.26 (1.19-1.34) | <.001 |
| Any tumor, leukemia, or lymphoma | NA | NA | NA | NA | 1.26 (1.18-1.35) | <.001 |
| Connective tissue disease | NA | NA | NA | NA | 1.35 (1.21-1.51) | <.001 |
| Allopurinol | 0.75 (0.62-0.91) | .003 | 0.77 (0.63-0.93) | .006 | 0.78 (0.64-0.95) | .01 |
| Febuxostat | 1.74 (0.72-4.17) | .22 | 1.79 (0.74-4.30) | .19 | 1.78 (0.74-4.29) | .20 |
| Gout | 1.53 (1.39-1.69) | <.001 | 1.51 (1.37-1.66) | <.001 | 1.39 (1.26-1.54) | <.001 |
Abbreviations: HR, hazard ratio; NA, not applicable.
The proportional hazards assumption was verified for the main study exposure.
Model 1 included Charlson Comorbidity Index (Romano adaptation) score as a continuous variable; model 2 replaced it with a categorized Charlson Comorbidity Index (Romano adaptation) score; and model 3 replaced it with each of the 17 Charlson Comorbidity Index (Romano adaptation) comorbidities and also included hypertension, hyperlipidemia, and coronary artery disease. All models were also adjusted for medications for cardiovascular diseases and for urate-lowering therapies for gout.
Select Charlson Comorbidity Index (Romano adaptation) comorbidities from a list of 17 comorbidities, suspected to be risk factors for uveitis.
Discussion
Gout was independently associated with a 1.5-fold higher risk of uveitis in the older individuals after adjustment for demographics, comorbidities, and medications, and the risk could be 1.4- to 1.9-fold higher. Proinflammatory cytokines, including tumor necrosis factor α and interleukins 1 and 6, are induced by exposure to monosodium urate crystals and released by monocytes in individuals with gout; elevated intraocular levels of these proinflammatory cytokines and systemic levels of C-reactive protein (inflammatory marker) are also seen in patients with uveitis.6 Inflammation might explain the association and the increased risk of uveitis in individuals with gout, a hypothesis that should be tested. Hyperuricemia, oxidative stress, and other disease processes may also contribute to this association. A confirmation of this study finding and temporal association studies are needed for greater confidence in this finding, which is at risk of residual confounding bias or could be attributable to chance. We were unable to assess the effect of gout duration on the observed association, which needs further exploration. A clinically relevant implication of our finding is whether reduction of chronic inflammation in gout can reduce or eliminate this increased risk of uveitis in older adults.
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