Proteomic and Machine Learning Analysis Predicts Treatment Response Signatures in Myasthenia Gravis

Myasthenia gravis (MG) is a prototypical antibody-mediated autoimmune disease with variable treatment responses with a need for biomarkers to guide therapeutic decision making. Proteomic profiling, coupled with machine learning, offers a powerful approach to identify biomarkers that may predict treatment response.

We analyzed sera collected at entry (baseline) from participants in a phase 3 trial randomized trial comparing thymectomy plus prednisone versus prednisone alone, along with matched controls using liquid chromatography-mass spectrometry. We derived disease-specific proteomic signatures and evaluated associations between baseline proteins and 6-month clinical outcomes using multiple machine-learning approaches with internal validation.

Baseline serum proteomes distinguished MG from controls, with pathway enrichment implicating complement activation, immunoglobulin production, and T-cell receptor signaling. Distinct protein panels predicted 6-month clinical improvement within each treatment arm. In the thymectomy-plus-prednisone group, models captured non-linear relationships of predictive proteins in contrast with the predominant additive patterns observed in the prednisone-alone group. Predictive proteins were enriched for T-cell signaling and leukocyte trafficking functions, providing insight into treatment-specific biology.

Baseline serum proteomics captures core disease characteristics of MG and predicts short-term clinical response in a treatment-specific manner. If validated in independent cohorts, these findings could enable biomarker-guided selection of thymectomy, refine risk stratification, and furnish mechanistic readouts for future MG trials and clinical care.