Nationwide epidemiological approach to identify associations between keratoconus and immune-mediated diseases

Background: The aetiology of keratoconus (KC) remains poorly understood. KC has typically been described as a non-inflammatory disorder of the cornea. Nonetheless, there is increasing presumptive evidence for the role of the immune system in the pathogenesis of KC. Aim: To evaluate the association between KC and immune-mediated diseases on a population level. We hypothesise that KC is immune-mediated rather than a predominantly degenerative disease. Methods: Data were obtained from the largest health insurance provider in the Netherlands. Dutch residents are obligatorily insured. The data contained all medical claims and sociodemographic characteristics from all KC patients plus all those data from a 1:6 age-matched and sex-matched control group. The primary outcome was the association between KC and immune-mediated diseases, as assessed by conditional logistic regression. Results: Based on our analysis of 2051 KC cases and 12 306 matched controls, we identified novel associations between KC and Hashimoto's thyroiditis (OR=2.89; 95% CI: 1.41 to 5.94) and inflammatory skin conditions (OR=2.20; 95% CI: 1.37 to 3.53). We confirmed known associations between KC and atopic conditions, including allergic rash (OR=3.00; 95% CI: 1.03 to 8.79), asthma and bronchial hyperresponsiveness (OR=2.51; 95% CI: 1.63 to 3.84), and allergic rhinitis (OR=2.20; 95% CI: 1.39 to 3.49). Conclusion: Keratoconus appears positively associated with multiple immune-mediated diseases, which provides a population-based argument that systemic inflammatory responses may influence its onset. The identification of these particular diseases might shed light on potential comparable pathways through which this proinflammatory state is achieved, paving the way for pharmacological treatment strategies.