Myasthenia Gravis Activities of Daily Living Deep Phenotyping and Longitudinal

Objective. Myasthenia gravis clinical trials increasingly rely on the MG Activities of Daily Living total score to assess disease severity and treatment response. However, aggregate scores may obscure clinically meaningful changes in individual symptom domains. To determine whether item-level MG-Activities of Daily Living profiles identify distinct clinical phenotypes and whether longitudinal phenotype transitions reveal disease changes inadequately captured by aggregate scores. Methods. MG-Activities of Daily Living evaluations from seven clinical trials and observational studies (5,259 observations were analyzed using principal component analysis and K-medoids clustering with Cityblock distance. Longitudinal phenotype transitions were evaluated in the three longitudinal cohorts and compared with changes in total scores. Results. Despite low median MG-ADL scores (2.0-3.0), substantial intercohort symptom heterogeneity was observed. Clustering identified five phenotypes: mild ocular (23.7%), severe ocular-dominant (23.5%), bulbar-respiratory dominant (22.6%), severe generalized (16.0%), and proximal limb-axial weakness (14.3%). Longitudinal phenotype instability occurred in 38-49% of Explore participants, 47-49% of Promise participants, and 20-25% of MGTX participants. Importantly, clinically meaningful phenotype transitions, including shifts from ocular to bulbar predominance, frequently occurred with changes of only one point in total MG-ADL scores. Conversely, substantial total score fluctuations could occur without a change in phenotype. Interpretation. MG-ADL total scores incompletely characterize disease heterogeneity and longitudinal symptom evolution. Incorporating item-level phenotyping into clinical trials and routine care may improve interpretation of treatment response, identify clinically important deterioration overlooked by aggregate scores, and facilitate more precise assessment of disease trajectories.