Disease-specific biomarker value of C-reactive protein and its composite indices in autoinflammatory diseases: an integrated study of multi-modal omics and population cohorts.

Background: Autoinflammatory diseases (AIDs) are a heterogeneous group of innate immune-driven disorders whose prevalence is rising globally, yet the lack of disease-specific biomarkers continues to hamper accurate disease activity assessment, phenotype stratification, and risk evaluation. C-reactive protein (CRP) is one of the most widely used markers of systemic inflammation, yet its disease-specific expression, clinical correlations, network connectivity, and cellular origin across both adult and pediatric AIDs have not been systematically examined. Methods: We established a single-center retrospective cohort including 11 adult and pediatric AIDs and age matched healthy controls. Baseline CRP measurements were obtained before anti-inflammatory or immunosuppressive therapy. We performed multivariate regression and subgroup analyses to examine the associations of CRP and its composite indices, the CRP to lymphocyte ratio (CLR) and CRP to albumin ratio (CAR), with different AIDs. We integrated a public serum proteomic dataset to construct CRP centered protein interaction networks in macrophage activation syndrome. We also analyzed single cell CITE seq and spatial transcriptomic data from healthy human liver to determine the cellular origin of CRP. Results: Serum CRP levels showed a disease specific distribution across AIDs, with the highest levels in hyperinflammatory conditions such as AOSD and MAS. CRP correlated with fever, rash, and arthralgia in AOSD, but showed no association with mucosal or articular phenotypes in other diseases. Both CLR and CAR showed stronger associations with disease risk than CRP alone in regression models. Proteomic network analysis positioned CRP as a prominently connected node in the MAS inflammatory interactome. Single cell and spatial transcriptomic data confirmed hepatocytes as the exclusive source of CRP transcripts in healthy human liver. Conclusions: These findings indicate a positive association of CRP and its composite indices with AIDs, suggesting their potential as disease-specific biomarkers. Yet, given the single-center retrospective design and lack of external validation, further multi-center prospective studies are required before clinical implementation.