Thymic Disease, Autoimmunity, and Neuromuscular Junction Integrity in Myasthenia Gravis

Overview

The goal of this observational study is to investigate the clinical, immunological, and neuromuscular features associated with the development and progression of myasthenia gravis (MG) in adult patients with thymic abnormalities and/or MG-related antibodies, including individuals with or without clinically manifest disease. The main questions it aims to answer are: * Whether integrated clinical, serological, and histopathological profiles are associated with the presence of MG and can predict disease onset or progression * Wheter systemic immune markers are associated with disease activity, progression, and neuromuscular junction alterations Participants will: * Undergo clinical, neurological, and neurophysiological assessments at baseline and during follow-up * Provide blood samples for serological and immunological analyses * Provide thymic tissue and residual intercostal muscle samples (when undergoing clinically indicated thymectomy) for research analyses * Attend follow-up visits at 6, 12, and 18 months * Record daily symptoms using an electronic patient-reported outcome tool (for participants with MG)

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction characterized by fluctuating muscle weakness and fatigability. In most cases, the disease is associated with antibodies directed against the acetylcholine receptor (AChR) and is frequently linked to thymic abnormalities, including thymoma and thymic hyperplasia. Despite the recognized role of the thymus in MG pathogenesis, the mechanisms driving the transition from thymic autoimmunity to clinically manifest disease remain incompletely understood, and reliable biomarkers for disease prediction and monitoring are lacking. This study is a single-center, prospective, observational translational cohort designed to comprehensively characterize the clinical, neurophysiological, serological, immunological, and histopathological features of patients with thymic abnormalities and/or MG. The study adopts a multimodal approach integrating routine clinical assessments with advanced laboratory and tissue-based analyses, with the aim of identifying biological mechanisms and potential biomarkers associated with MG onset and progression. A total of 40 adult participants will be enrolled and stratified into four predefined groups: 1. patients with thymoma and MG-related antibodies, 2. patients with other thymic abnormalities and MG-related antibodies, 3. thymoma patients without MG-related antibodies (control group), and 4. patients with established MG without thymic abnormalities. This design enables comparison across different clinical and immunological phenotypes and supports exploratory evaluation of circulating and tissue-based biomarkers. At baseline, all participants will undergo standardized clinical and neurological evaluation, including validated MG-specific outcome measures, neurophysiological testing (repetitive nerve stimulation and single-fiber electromyography), and blood sampling for serological and immunological analyses. Imaging assessments, including chest CT for thymic characterization and orbital MRI for evaluation of extraocular muscle involvement, will be performed according to clinical indications. Participants will be followed longitudinally for 18 months, with scheduled evaluations at 6, 12, and 18 months. Follow-up assessments will include repeated clinical, neurophysiological, and serological measurements to capture disease evolution over time and to evaluate the relationship between biological markers and clinical outcomes. In participants undergoing thymectomy as part of standard clinical care, thymic tissue will be collected for routine diagnostic purposes, with additional samples used for research analyses. Residual intercostal muscle tissue obtained within the surgical field will also be collected, without modification of the surgical procedure or additional risk to the patient. These samples will be used to investigate structural and molecular features of the neuromuscular junction, including receptor organization and evidence of immune-mediated damage. Peripheral blood samples collected at baseline and follow-up visits will be used to characterize systemic immune profiles, including autoantibodies, cytokines, and complement activation products. These data will be integrated with clinical, neurophysiological, and histopathological findings to explore associations with MG onset, severity, and progression. In participants with established MG, longitudinal symptom monitoring will be performed using an electronic patient-reported outcome tool based on questionnaires routinely used in clinical practice. Patients will record daily symptoms across key domains (ocular, bulbar, respiratory, and limb involvement), enabling high-resolution assessment of symptom fluctuations over time. These data will be compared with clinical outcome measures collected during scheduled visits to evaluate concordance and the potential added value of continuous symptom monitoring. Overall, this study aims to provide an integrated characterization of MG across clinical, biological, and tissue levels, with the ultimate goal of identifying early predictors of disease development and progression, improving risk stratification, and supporting future strategies for personalized monitoring and intervention.