Nested Case-Control Study Based on a Rheumatology Immunology Longitudinal Cohort:Association Analysis of Serum Inflammatory-Metabolic Biomarkers with Structural Progression in Patients with Ankylosing Spondylitis
LI Panlong
GUO Wenyu
CHU Tianshu
Abstract：Objective To investigate the predictive value of multi-axis serum biomarkers,including inflammation,NETosis,tryptophan-kynurenine(Trp-Kyn),and sphingosine-1-phosphate-ceramide(S1 P-Cer)pathways in assessing the risk of disease progression in ankylosing spondylitis(AS),and to establish and validate a serum-based multi-index risk evaluation model.Methods A nested case-control study was conducted within rheumatology and immunology-related diseases of Henan Provincial People's Hospital(2018-2024)comprising 266 784 screened patients.A total of 1 042 confirmed AS patients were enrolled and followed for 24 months.Based on the occurrence of radiographic or functional progression at 24 months,patients were divided into a progression group(500 cases)and a non-progression group(500 cases)matched 1∶1 by age and sex.Twelve inflammation and metabolism-related serum biomarkers[interleukin-17 A(IL-17A),tumor necrosis factor-alpha(TNF-α),high-sensitivity C-reactive protein(hs-CRP),myeloperoxidase(MPO),citrullinated histone H3(H3Cit),neutrophil elastase-DNA complex(NE-DNA),indoleamine 2,3-dioxygenase 1(IDO1),kynurenine,tryptophan,sphingosine-1-phosphate(S1P),ceramide,and sphingosine kinase 1(SphKl)]were quantified.Cox proportional hazards models were used to evaluate the risk effects and dose-response relationships of individual and composite scores,to build a multi-biomarker prediction model estimating individualized 24 months progression probability.Model performance was assessed using receiver operating characteristic(ROC)curve,precision-recall curve(PR),calibration,and decision curve analyse.Results IL-17A,TNF-α,and hs-CRP,as well as NETosis-related markers such as MPO,H3Cit,and NE-DNA were all significantly associated with increased risk of structural progression(P＜0.000 1),whereas higher tryptophan levels were significantly associated with decreased risk(P＜0.000 1).Restricted cubic spline(RCS)analysis revealed nonlinear dose-response relationships for most biomarkers,with risk increases plateauing at higher concentrations.Composite scores derived from the four biological pathways(inflammation,NETosis,Trp-Kyn,and S1P-Cer)were independent predictors of AS progression.Cox regression remained significant after covariate adjustment(P＜0.05).In a 7∶3 split training and validation cohort,the multi-index predictive model demonstrated excellent performance,with area under the curve(AUC)of 0.92 and 0.89,respectively.Conclusion Serum biomarkers reflect the inflammatory and metabolic imbalance in AS and are closely correlated with disease progression.The multi-index model integrating the inflammation,NETosis,Trp-Kyn,and S1P-Cer axes effectively predicts the risk of structural progression in AS,providing a biological basis for individualized prognosis assessment and early intervention.
Keywords：ankylosing spondylitisinflammationNETosistryptophan-kynurenine pathwaysphingosine-1-phosphate-ceramidedisease progressionprediction model
Publication Date：2026-05-13
Online Publishing Date：2026-09-12(First online date of this platform, not the publication date of the document)
Pages：8( 1542-1549 )