Thymic Disease, Autoimmunity, and Neuromuscular Junction Integrity in Myasthenia Gravis: An Observational Prospective Translational Cohort Study
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Qualitative assessment of neuromuscular junction structural abnormalities in intercostal muscle samples
研究概览
简要总结
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)
详细描述
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:
- patients with thymoma and MG-related antibodies,
- patients with other thymic abnormalities and MG-related antibodies,
- thymoma patients without MG-related antibodies (control group), and
- 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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years at the time of informed consent
- •Ability to provide written informed consent and comply with study procedures
- •Availability of a serum sample for testing MG-related antibodies
- •Availability of chest imaging (CT and/or MRI) to classify thymic status
- •Participants must also meet the criteria for at least one of the following study groups:
- •Cohort 1: Thymoma with MG-related antibodies
- •Histologically or radiologically confirmed thymoma
- •Presence of at least one pathogenic MG-related antibody (AChR)
- •Presence or absence of clinically manifest myasthenia gravis
- •Cohort 2: Other thymic abnormalities with MG-related antibodies
- •Imaging or histological evidence of non-thymomatous thymic pathology (e.g., thymic hyperplasia)
- •Presence of at least one pathogenic MG-related antibody (AChR)
- •Presence or absence of clinically manifest myasthenia gravis
- •Cohort 3: Thymoma without MG-related antibodies
- •Histologically or radiologically confirmed thymoma
- •Negative for pathogenic MG-related antibodies (AChR)
- •No clinical diagnosis or symptoms suggestive of myasthenia gravis
- •Cohort 4: Myasthenia gravis without thymic abnormalities
- •Established clinical diagnosis of myasthenia gravis with consistent clinical features, supported by at least one of the following:
- •Seropositivity for MG-related antibodies (AChR, MuSK, or LRP4), or
- •Abnormal neuromuscular transmission demonstrated by SFEMG or RNS, or
- •Improvement of MG signs with treatment such as oral acetylcholinesterase inhibitors, plasma exchange, IVIg, or corticosteroids
- •Absence of thymic abnormalities on CT or MRI
排除标准
- •Inability to provide informed consent
- •Other neuromuscular diseases that could interfere with interpretation of clinical or neurophysiological findings
- •Severe uncontrolled systemic illness that, in the investigator's judgment, may limit participation or confound study outcomes
- •Any medical or psychiatric condition, or history of substance abuse, that may compromise adherence to study procedures
- •Pregnancy or breastfeeding
研究组 & 干预措施
Patients with established MG without thymic abnormalities
Patients with an established diagnosis of myasthenia gravis based on clinical, serological, and/or neurophysiological criteria, and no evidence of thymic abnormalities.
Patients with thymoma and MG-related antibodies
Patients with histologically or radiologically confirmed thymoma and presence of MG-related antibodies (AChR), with or without clinically manifest myasthenia gravis.
Patients with other thymic abnormalities and MG-related antibodies
Patients with non-thymomatous thymic pathology (e.g., thymic hyperplasia) and presence of MG-related antibodies (AChR), with or without clinically manifest myasthenia gravis.
Thymoma patients without MG-related antibodies
Patients with confirmed thymoma, negative for MG-related antibodies, and without clinical signs or diagnosis of myasthenia gravis.
结局指标
主要结局
Qualitative assessment of neuromuscular junction structural abnormalities in intercostal muscle samples
时间窗: At the time of thymectomy (baseline)
The primary outcome is the qualitative assessment of neuromuscular junction structural abnormalities in residual intercostal muscle samples collected from participants undergoing clinically indicated thymectomy. Neuromuscular junction integrity will be evaluated using histological, immunofluorescence, and ultrastructural analyses, including assessment of acetylcholine receptor clustering, IgG and complement deposition, postsynaptic fold morphology, and features of synaptic remodeling or immune-mediated injury. Structural abnormalities will be described in terms of presence or absence and, where applicable, semi-quantitative grading. Findings will be compared across participant groups according to thymic pathology, MG-related antibody status, and the presence or absence of clinically manifest myasthenia gravis.
次要结局
- Qualitative assessment of thymic histopathological features(At the time of thymectomy (baseline))
- Change in Myasthenia Gravis Activities of Daily Living (MG-ADL) score(Baseline, 6, 12, and 18 months)
- Change in Quantitative Myasthenia Gravis (QMG) score(Baseline, 6, 12, and 18 months)
- Change in serum MG-related autoantibody levels over time(Baseline, 6, 12, and 18 months)
- Change in plasma and serum levels of complement activation products(Baseline, 6, 12, and 18 months)
- Change in mean daily composite MG symptom questionnaire score (electronically collected)(Baseline and up to 18 months)
研究者
Stefano Previtali
Principal Investigator, Head Neuromuscular Repair Research Unit
IRCCS San Raffaele