Association of metabolic and inflammation vulnerabilities with systemic lupus erythematosus: a prospective UK Biobank study.

Background: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease influenced by complex metabolic and inflammatory pathways, but the impact of specific metabolic and inflammatory signatures, particularly metabolic vulnerability index (MVX), inflammation vulnerability index (IVX), and metabolic malnutrition index (MMX), on the incidence of SLE remains unclear. Methods: We evaluated the association of MVX, IVX, and MMX with the risk of incident SLE using data from 398,200 participants in the UK Biobank. MVX was constructed from IVX (calculated using glycA and small HDL particles) and MMX (calculated using citrate, isoleucine, leucine, and valine). The primary outcome was SLE based on the International Classification of Diseases, 10th Revision (ICD-10) codes. Risks were estimated using Cox proportional hazards models, while restricted cubic spline (RCS) analysis was applied to identify potential non-linear trends. Subgroup analyses were performed by demographics, comorbidities, and lifestyle factors. Sensitivity analyses included a 3-year lag exclusion, landmark analyses at 5 and 10 years, additional adjustment for C-reactive protein (CRP), the use of time-dependent covariates combined with stratification, and the use of data after multiple imputation. Additionally, the Fine-Gray competing risk model was employed treating all-cause mortality and CVD-specific mortality as competing events. Results: Over a median follow-up of 13.2 years, a per standard deviation (SD) increment in MVX was associated with a 44% higher risk of SLE (HR = 1.44, 95% CI: 1.28-1.62, P < 0.01). Participants in the highest tertile (T3) of MVX had an 89% increased risk compared to those in the lowest tertile (T1) (HR = 1.89, 95% CI: 1.35-2.63, P < 0.01). Similar but attenuated associations were observed for IVX and MMX; per SD increases in IVX and MMX were associated with HRs of 1.34 (95% CI: 1.17-1.54, P < 0.01) and 1.24 (95% CI: 1.14-1.36, P < 0.01), respectively, while T3 versus T1 HRs were 1.85 (95% CI: 1.25-2.74, P < 0.01) and 1.82 (95% CI: 1.42-2.33, P < 0.01). MVX consistently demonstrated a stronger association with SLE than the sub-indices IVX and MMX. Subgroup analyses indicated that the significant association persisted across most groups, with a notable effect observed in females (HR = 1.59, 95% CI: 1.39-1.81, P < 0.01). RCS analysis confirmed a linear dose-response relationship, with risk thresholds of 36 for MVX, 40 for IVX, and 45 for MMX; beyond these thresholds, the risk of SLE increases as the index rises. Sensitivity analyses and the Fine-Gray competing risk model both confirmed the robustness of the study results, demonstrating that MVX is significantly associated with the risk of incident SLE. Conclusions: MVX serves as an independent risk factor for the development of SLE. Notably, MVX demonstrates a stronger association with SLE risk compared to its individual components, IVX and MMX. Our results suggest that MVX is valuable for risk assessment for SLE, particularly within the female population.