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Background: The testing of antinuclear antibodies (ANA) has become more frequent in routine clinical practice and the interpretation of positive results may pose a significant challenge. Objective: To evaluate the current evidence on the prevalence of ANA in the general population and to discucc the clinical significance of ANA positivity in the absence of autoimmune rheumatic disease (ARD). Methodology. A literature search was conducted using the PubMed database for articles investigating antinuclear antibodies (ANA) in the general population published between 2015 and 2025. The analysis focused on large-scale population studies evaluating ANA positivity via indirect immunofluorescence (IIF) on HEp-2 cells, as well as research regarding ANA positivity of non-rheumatic origin. Furthermore, the immunological profile of ANA-positive healthy individuals is discussed. Key results: Recent data indicate an ANA prevalence ranging from 10% to 30% in the general population, significantly exceeding the estimated 2% prevalence of ARD. Studies from the US even demonstrate an increasing trend in ANA positivity over time. Immunologically, ANA-positive healthy individuals seems to exhibit a balanced, low-grade but persistent autoreactivity. Large phenome study data confirm strong associations with autoimmune diseases, Raynaud's syndrome, and alveolar fibrosing conditions, while revealing negative associations with certain non-autoimmune conditions like type 2 diabetes and viral hepatitis C. Conclusions: ANA positivity in healthy individuals may represent a persistent benign autoreactivity rather than an impending disease. Thus ANA testing without clinical suspicion of ARD is often uninformative, and may cause unnecessary patient anxiety. More studies in adherence to international guidelines (EFLM/EASI/ICAP) and the use of standardized cutoff titers (preferably ≥1:160 for pathology) as well as investigating the pathoimmunological basis of ANA-postitive healthy individuals are warranted.
References
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