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Singh JA, Cleveland JD. Association of Gout With Uveitis in Older Individuals. JAMA Ophthalmol. 2018;136(7):835–837. doi:10.1001/jamaophthalmol.2018.1758
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.1-3 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.
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).
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).
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.
Accepted for Publication: March 23, 2018.
Corresponding Author: Jasvinder A. Singh, MBBS, MPH, University of Alabama at Birmingham, 510 20th St S, Faculty Office Tower, Ste 805B, Birmingham, AL 35294-0022 (firstname.lastname@example.org).
Published Online: May 24, 2018. doi:10.1001/jamaophthalmol.2018.1758
Author Contributions: Mr Cleveland had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Singh.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Singh.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Cleveland.
Administrative, technical, or material support: Singh.
Study supervision: Singh.
Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Singh reported receiving research grants from Takeda and Savient and consultant fees from Savient, Takeda, Regeneron, Merz, Iroko, Bioiberica, Crealta/Horizon, Allergan Pharmaceuticals, WebMD, UBM LLC, and the American College of Rheumatology; serving as the principal investigator for an investigator-initiated study funded by Horizon Pharmaceuticals through a grant to DINORA Inc, a 501(c)(3) entity; being a member of the executive board of OMERACT (Outcome Measures in Rheumatology), an organization that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; being a member of the American College of Rheumatology's (ACR’s) Annual Meeting Planning Committee; being chair of the ACR Meet-the-Professor Workshop and Study Group Subcommittee; being a member of the Veterans Affairs Rheumatology Field Advisory Committee; and being the editor and director of the University of Alabama at Birmingham Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. No other disclosures were reported.
Funding/Support: This material is the result of work supported by research funds from the Division of Rheumatology at the University of Alabama at Birmingham and the resources and use of facilities at the Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Jeffrey Curtis, MD, Division of Rheumatology, University of Alabama at Birmingham, who permitted us to reuse the 5% Medicare data. He was not compensated for his work. We thank patients at the University of Alabama gout clinic for asking us questions about comorbidities of gout and whether gout may be related to their other conditions, which prompted us to ask this question.
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