To expand the clinical-immunological characterization of acetylcholine receptor–positive Myasthenia Gravis (AChR? MG) using an enlarged multicenter cohort of 601 patients.

This ongoing large-scale, multicenter, cross-sectional study includes prospectively recruited AChR? MG patients and biobank-derived serum samples meeting diagnostic criteria of clinical MG and anti-AChR IgG ≥0.5nM. Clinical data were correlated with total and subunit-specific anti-AChR titers, thymic histology, age, sex, and MGFA disease severity. Statistical correlations and unsupervised principal component analyses were used to define clinical–immunological associations and data clustering patterns.

The updated dataset includes 601 AChR? MG patients (49% female; median age: 65.9 years). Anti-AChR titers correlated positively with disease severity and were significantly higher in female versus male patients (median 12.7nM vs. 7.8nM, p=0.0001). Alpha and gamma subunit immunodominance maintained their sex-related patterns, with males showing greater alpha immunodominance (median α%: 23% vs. 15.3%, p=0.0209) and females showing greater gamma immunodominance (median γ%: 29% vs. 23%, p=0.0029). Gamma immunodominance was also associated with higher titers and early-onset disease. Principal component analysis confirmed the previously reported two endotypes corresponding to early-onset, gamma-immunodominant, thymic-hyperplastic disease in females (Endotype A) and predominantly late-onset, alpha-immunodominant, lower-titer disease (Endotype B).

Expanded analysis of 601 AChR? MG patients further substantiates the existence of two MG endotypes with unique clinical and immunological profiles. These findings suggest distinct underlying etiologies with potential implications for sex-dependent precision medicine, women’s health, and the development of novel therapeutic approaches for MG.