Detección de marcadores clínicos e inmunológicos para diagnóstico y pronóstico en miastenia gravis

Abstract

Myasthenia gravis (MG) is an autoimmune disease that affects the neuromuscular junction, characterized by a wide range of clinical and pathophysiological variability. Patients can be classified into different subtypes according to the type of antibody, associated thymic pathology, age of onset, and distribution of clinical manifestations. Approximately 10-15% of patients with MG have thymoma, a subtype whose clinical and pathophysiological features have been poorly studied. This thesis aims to investigate the pathophysiological mechanisms, clinical manifestations, and prognosis in patients with thymoma-associated MG. The first article studies the role of CTLA4 in the origin of autoimmunity in patients with thymoma-associated MG. CTLA4 is a receptor present in regulatory T cells (Treg) that participate in the control of autoimmunity. Polymorphisms in the CTLA4 gene have been linked to the development of MG in the general population and specifically in patients with thymoma. Samples from 41 patients with thymoma were included, of which 23 (56. 1%) had MG. Patients with MG had fewer CTLA4-positive cells than patients with thymoma without MG: 69. 3 cells/mm2 (95% CI: 39. 6-99. 1) vs. 674. 4 cells/mm2 (95% CI: 276. 0-1024. 0), p=0. 001, and controls (200. 74 [95% CI: 57. 9-343. 6] cells/mm2; p = 0. 02). A polymorphism (rs231775) was found to be associated with lower CTLA4 expression in the thymus and an increased risk of MG, although it was not statistically significant. The second study focused on the clinical and prognostic characteristics of patients with thymoma-associated MG, using the Spanish Registry of Neuromuscular Diseases. A total of 964 patients with MG with positive anti-acetylcholine receptor antibodies were included, of which 148 (15. 4%) had thymoma. The average follow-up time was 4. 6 years. Patients with thymoma had an earlier disease onset (52. 0 vs. 60. 4 years; p < 0. 001), more severe symptoms at disease onset according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR:1. 6; 95% CI: 1. 15-2. 21 p=0. 005), as well as throughout and at the end of the follow-up. In this group, a higher rate of drug resistance (OR:2. 28; 95% CI: 1. 43-3. 63; p=0. 001) and mortality (HR: 2. 46; 95% CI: 1. 47-4. 14 p=0. 001) was found. Of the 27 patients who had a thymoma recurrence, this coincided with a worsening of myasthenic symptoms in 13. Twelve of the 15 patients with non-resectable tumor lesions had poor control of myasthenic symptoms. In conclusion, thymoma-associated MG is a subtype with specific pathophysiological and clinical features. Lower expression of CTLA4 in the thymus seems to predispose to the development of MG. This expression could have a genetic basis, although further studies with a larger number of samples are needed to confirm this. Patients with thymoma-associated MG present more severe forms of the disease and worse long-term prognosis. Within these, those with tumor recurrence or non-resectable lesions represent a subgroup with higher risk. A detailed understanding of each MG patient subtype allows for an individualized approach to each patient, as well as the development of specific therapies.

Date of Award	21 Sept 2023
Original language	Spanish
Supervisor	Eduard Gallardo Vigo (Director)