A recent study published in Retina evaluated the association between gout and the subsequent development and progression of age-related macular degeneration (AMD).
Give me some background.
Gout is a chronic metabolic disease strongly associated with hyperuricemia that results from monosodium urate (MSU) crystal deposition in joints.
These crystals result in monocyte recruitment, triggering NOD-like receptor protein 3 (NLRP3) inflammasome and renin angiotensin system (RAS)-driven immune responses that cause joint damage.
Note: Elevated uric acid levels contribute to MSU crystal formation that could deposit in the retina.
- Consequently: MSU crystals may trigger activation of inflammatory pathways involving the NLRP3 inflammasome within the retina, potentially contributing to AMD development.
Now talk about the study.
In this retrospective cohort study, investigators utilized TriNetX, a federated collaborative health database, to identify and organize patients into two groups to assess ophthalmic outcomes:
- Gout cohort (n = 16,433, 64.3% male): Individuals with an International Classification of Diseases, Tenth Revision, (ICD-10) code for idiopathic gout and a prescription for a uric acid-lowering agent
- Control cohort (n = 16,433, 38.3% male): Propensity score matched (PSM) patients without a diagnosis of gout
Any distinctions to note about these cohorts?
Patients within the gout cohort had increased rates of systemic diseases and nicotine use as well as more members classified as obese via body mass index (BMI) compared to those in the control group.
In the gout cohort, outcomes were evaluated at 1, 3, and 5 years following the index date—defined as the first observation of concurrent age-related cataracts, gout, and a uric acid lowering agent prescription.
- Meanwhile: The index date for the control cohort was the initial observation of age-related cataracts.
Findings?
Compared to those without gout at 5 years, patients with gout had an increased risk of developing:
- Dry AMD (risk ratio [RR]: 2.73, 95% confidence interval [CI]: 2.30-3.25, P < 0.001)
- Advanced dry AMD (RR: 2.64, 95% CI: 1.32-5.28, P < 0.001)
- Wet AMD (RR: 2.48, 95% CI: 1.82-3.38, P < 0.001)
In addition: Patients with gout had an increased risk of requiring subsequent anti-vascular endothelial growth factor (VEGF) therapy (RR: 2.80, 95% CI: 2.14-3.67, P < 0.001).
Anything else?
Patients with early AMD and gout had an elevated risk for progression to advanced disease stages compared to controls.
Interestingly: Similar trends were observed among patients with early AMD and gout compared to those with early AMD without gout.
Expert opinion?
The study authors noted that drusen in AMD triggers NLRP3 inflammasome activation in retinal pigment epithelium (RPE) cells, while oxidative stress and inflammation promote RPE death and photoreceptor dysfunction in AMD pathogenesis.
“Given the shared downstream activation of inflammation and oxidative stress in both gout and AMD, shared risk factors for both diseases are present,” they explained.
Meaning: Modulation of hyperuricemia and treatment of gout may result in improved ocular outcomes in patients with gout and AMD.
Limitations?
These included:
- Potential misclassification bias by the imprecision of ICD-10 codes
- Gout with the initiation of chronic uric acid therapy was used as a proxy for hyperuricemia, as this study couldn’t directly correlate serum uric acid levels with AMD outcomes
- Controlling for smoking was difficult because the ICD-10 code for nicotine dependence may underreport actual smokers and include other nicotine products with varying risks for AMD
- TriNetX lacked specific coding for AREDS2 vitamins, leading to individual matching for each ingredient component in the supplement formulation
- The research team was unable to account for the duration of ARED2 vitamin use during the observation period
- Despite extensive PSM, residual confounding may still affect the observed association between gout and AMD
Tie it all together for me.
These findings demonstrate patients with gout had an increased risk of AMD development and progression to advanced disease stages compared to controls.
For the future: Further investigation is warranted to evaluate the association between serum uric acid levels and AMD, as well as the benefits of urate-lowering therapy, to clarify these associations.