Association of serum Sema4D and ANGPTL4 levels with disease severity and prognosis in myasthenia gravis patients

Objective To investigate the relationship of serum semaphorin 4D (Sema4D) and angiopoietin-like protein 4 (ANGPTL4) levels with disease severity and prognosis in anti–acetylcholine receptor (AChR) antibody–positive myasthenia gravis (MG) patients. Methods Between December 2023 and April 2025, 468 anti-AChR antibody–positive MG patients hospitalized at our center were prospectively enrolled and divided into good- and poor-prognosis groups according to whether they achieved minimal manifestations (MM) or better status at the 1-year follow-up. Healthy controls were also enrolled. Serum Sema4D and ANGPTL4 levels were measured by enzyme-linked immunosorbent assay (ELISA). Correlations were evaluated by Spearman’s rank correlation. Multivariable logistic regression was used to identify independent risk factors for poor prognosis. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of the two biomarkers alone and in combination, and clinical and combined models were developed to evaluate the biomarkers’ incremental predictive value. Results Serum Sema4D and ANGPTL4 levels were significantly higher in MG patients than in healthy controls (both p < 0.001). Compared with the good-prognosis group, the poor-prognosis group had higher proportions of Myasthenia Gravis Foundation of America (MGFA) class IV-V, dysphagia, and thymoma, and higher Myasthenia Gravis Quality of Life 15-item revised (MG-QoL15r) and Controlling Nutritional Status (CONUT) scores (all p < 0.05), and significantly higher levels of both biomarkers (both p < 0.05). Both Sema4D and ANGPTL4 correlated positively with MG-QoL15r and CONUT scores and with each other ( r = 0.431, p < 0.001). Multivariable logistic regression showed that MGFA class IV-V, dysphagia, thymoma, higher MG-QoL15r and CONUT scores, and elevated serum Sema4D and ANGPTL4 levels were all independent risk factors for poor prognosis (all p < 0.05). The combination of the two biomarkers yielded an area under the ROC curve (AUC) of 0.841, superior to either marker alone. Adding the biomarkers to the clinical model significantly improved prognostic discrimination, with the AUC increasing from 0.874 to 0.907 ( p = 0.0002). Conclusion Combined measurement of serum Sema4D and ANGPTL4 is associated with disease severity and poor prognosis in anti-AChR antibody–positive MG and shows good predictive value for patient prognosis.