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.

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).

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%).

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.