A Distinct Immunological Signature in Late-Onset Myasthenia Gravis: Insights from an Exploratory Proteomics Study.

Objective: Approximately 80% of patients with myasthenia gravis (MG) have autoantibodies against acetylcholine receptor, and clinical characteristics may vary between early-onset (symptom onset age <50 years) and late-onset MG (EOMG and LOMG), but the pathophysiological differences between EOMG and LOMG are not well established.

Methods: We performed an exploratory in-depth proteomics analysis examining 768 inflammatory proteins utilizing the baseline serum samples from the BeatMG study (NCT02110706). We performed pathway enrichment analysis to assess the pathways involved in LOMG. A total of 15 selected proteins from the initial analysis were further examined using the UK Biobank and further quantified in a separate validation cohort.

Results: A total of 21 patients with EOMG (age 38.3 ± 12.1 years, 16 women [76.2%]) and 28 patients with LOMG (age 67.3 ± 8.6 years, 7 women [25%]) from the BeatMG study were included in the exploratory analysis. Several proteins involved in the regulation of leukocyte differentiation and myeloid leukocyte differentiation and migration pathways were more abundant in the LOMG group. Among them, 7 were significantly different in the UK Biobank cohort. A total of 80 participants (39 MG patients (age 54.33 ± 18.9 years, 17 women [43.6%]) and 41 healthy controls (age 49.56 ± 17.06 years, 21 women [66.1%]) were included in the validation cohort, and IL18R1, CXCL17, and CCL11 were validated to be specific for LOMG.

Interpretation: Growing evidence supports that LOMG has a distinct immune pathomechanism. Further prospective studies are warranted to confirm the utility of these proteins as biomarkers of LOMG, and the feasibility of using them for more precise therapeutic targets to improve patient outcomes. ANN NEUROL 2025.