Summary:
This prospective cohort study used data from 186,310 participants in the UK to examine whether allostatic load (AL), a measure of the cumulative effects of chronic stress, was associated with immune-mediated inflammatory diseases (IMIDs) and all-cause mortality. IMIDs are a group of chronic inflammatory conditions and include diseases such as rheumatoid arthritis, spondyloarthritis, psoriasis, inflammatory bowel disease, asthma, type 1 diabetes, autoimmune retinopathy, and myasthenia gravis. These conditions are characterised by recurring inflammation, progressive tissue damage, and can affect multiple body systems. Chronic stress is thought to influence immune function through disruption of the hypothalamic-pituitary-adrenal axis and increased activation of the sympathetic nervous system. Previous research has shown that prolonged psychological stress can alter both innate and adaptive immune responses, contributing to persistent inflammation. This study found a clear relationship between higher allostatic load and the risk of developing several IMIDs. Participants in the highest AL group had significantly greater risks of rheumatoid arthritis, spondyloarthritis, asthma, inflammatory bowel disease, type 1 diabetes, psoriasis, autoimmune retinopathy, and overall IMIDs compared with those in the lowest group. The strongest association was observed for type 1 diabetes, where risk was more than five times higher among individuals with the greatest allostatic load. Higher allostatic load was also associated with increased all-cause mortality among people with several IMIDs. The study also found that lifestyle factors modified these associations. Regular physical activity and higher intake of omega-3 polyunsaturated fatty acids were associated with a reduction in the adverse effects of allostatic load. In contrast, individuals with both high allostatic load and a high genetic predisposition to disease experienced greater risks of developing spondyloarthritis, type 1 diabetes, and psoriasis, suggesting an interaction between stress-related physiological burden and genetic susceptibility. Overall, this study suggests that chronic stress is an important predictor of both the development and progression of immune-mediated inflammatory diseases. The findings indicate that lifestyle factors such as physical activity and omega-3 intake may help reduce some of these risks, while genetic susceptibility may increase vulnerability to the harmful effects of chronic stress.
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Abstract:
Background: Allostatic load (AL)—the cumulative biological cost of lifelong stress—can disrupt immune homeostasis via hypothalamic–pituitary–adrenal-axis dysregulation and persistent sympathetic activation. Immune-mediated inflammatory diseases (IMIDs) are organ-specific chronic inflammatory disorders imposing a major public-health burden, yet their causal link with AL remains unclear. Methods: In this prospective study of 186 310 UK Biobank participants, Cox proportional-hazards models quantified dose-response associations between AL and the incidence of ten IMIDs plus all-cause mortality. Interaction models evaluated the modifying effects of physical activity, ω-3 polyunsaturated fatty acids (ω-3 PUFAs) and other lifestyle variables, and assessed gene–environment interplay using polygenic risk scores (PRS). Results: Compared with the lowest AL quartile, the highest quartile showed significantly greater incidence of rheumatoid arthritis (hazard ratios (HR) = 1.52), spondyloarthritis (HR = 2.50), asthma (HR = 1.38), inflammatory bowel disease (IBD) (HR = 1.19), type 1 diabetes (T1DM) (HR = 5.16), psoriasis (HR = 1.87), autoimmune retinopathy (HR = 1.77) and composite IMIDs (HR = 1.55) (all p < 0.05). Elevated AL also predicted dose-dependent increases in all-cause mortality among patients with rheumatoid arthritis (HR = 6.59), asthma (HR = 1.87), IBD (HR = 2.00), T1DM (HR = 2.72) and composite IMIDs (HR = 2.01). Sufficient physical activity and higher ω-3 PUFA intake partially attenuated AL-related risks, whereas high PRS synergistically amplified AL effects for spondyloarthritis (attributable proportion (AP) = 7.6%), T1DM (AP = 4.7%) and psoriasis (AP = 4.9%). Conclusions: AL is causally linked to both the development and prognosis of IMIDs, with its impact jointly modifiable by lifestyle factors and genetic susceptibility. Building AL-centred psychoneuroimmunological biomarker networks may enable refined risk stratification and precision interventions for IMIDs.
Article Publication Date: 24/01/2026
DOI: 10.1016/j.jnha.2026.100792
