Early-life tobacco smoke exposure and incident rheumatoid arthritis: mediated by allostatic load and joint effects...

RA is a widespread autoimmune disorder. Early-life environmental exposures may contribute to RA, and tobacco smoke represents an important modifiable factor. This study aimed to examine whether early-life tobacco smoke exposure affects incident RA risk, and to clarify the potential mediating role of allostatic load (AL) and interactive effects with genetic susceptibility.

Using questionnaire, biomarker, genetic, and linked health-record data from UK Biobank, we examined intrauterine tobacco smoke exposure (IUTSE; n = 427 037), age at tobacco use initiation (ATUI; n = 414 318) and RA cases. Cox models were used to evaluate associations between early-life tobacco exposure and RA risk. Mediation analysis quantified the mediating effect of AL. Additive and multiplicative interaction examined genetic susceptibility interactions.

IUTSE was associated with higher RA risk [hazard ratio (HR) = 1.15, 95% CI: 1.08, 1.21]. Compared with never-smokers, individuals who started tobacco smoking in childhood, adolescence, and adulthood exhibited elevated RA risk, with corresponding HRs of 1.74 (95% CI: 1.39, 2.17), 1.56 (95% CI: 1.29, 1.88) and 1.47 (95% CI: 1.22, 1.76), respectively. Mediation analyses indicated statistically significant but small indirect effects of AL. The indirect effect for IUTSE was 1.001 (95% CI: 1.001, 1.002) and the indirect effects for tobacco use during childhood, adolescence and adulthood were 1.009 (95% CI: 1.005, 1.013), 1.006 (95% CI: 1.003, 1.009) and 1.006 (95% CI: 1.003, 1.009), respectively. High genetic risk with IUTSE (HR = 1.93, 95% CI: 1.75, 2.13) or childhood initiation (HR = 2.89, 95% CI: 2.17, 3.86) increased RA risk.

Early-life tobacco smoke exposure elevates RA risk in adulthood, with limited mediation by AL and modification by genetic predisposition.