Autoimmune mechanisms in myasthenia gravis

n/

Differential targeting of immune-cells by Pixantrone in experimental myasthenia gravis

n/

Idiopathic Inflammatory Myopathies: A Review of Immunopathological Features and Current Models of Pathogenesis

Non

Etiology of myasthenia gravis: Innate immunity signature in pathological thymus

n/

Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis

Myasthenia Gravis (MG) is a chronic disabling autoimmune disease caused by autoantibodies to the neuromuscular junction (NMJ), characterized clinically by fluctuating weakness and early fatigability of ocular, skeletal and bulbar muscles. Despite being commonly considered a prototypic autoimmune disorder, MG is a complex and heterogeneous condition, presenting with variable clinical phenotypes, likely due to distinct pathophysiological settings related with different immunoreactivities, symptoms’ distribution, disease severity, age at onset, thymic histopathology and response to therapies. Current treatment of MG based on international consensus guidelines allows to effectively control symptoms, but most patients do not reach complete stable remission and require life-long immunosuppressive (IS) therapies. Moreover, a proportion of them is refractory to conventional IS treatment, highlighting the need for more specific and tailored strategies. Precision medicine is a new frontier of medicine that promises to greatly increase therapeutic success in several diseases, including autoimmune conditions. In MG, B cell activation, antibody recycling and NMJ damage by the complement system are crucial mechanisms, and their targeting by innovative biological drugs has been proven to be effective and safe in clinical trials. The switch from conventional IS to novel precision medicine approaches based on these drugs could prospectively and significantly improve MG care. In this review, we provide an overview of key immunopathogenetic processes underlying MG, and discuss on emerging biological drugs targeting them. We also discuss on future direction of research to address the need for patients’ stratification in endotypes according with genetic and molecular biomarkers for successful clinical decision making within precision medicine workflow

Consistent improvement with eculizumab across muscle groups in myasthenia gravis

Objective: To assess whether eculizumab, a terminal complement inhibitor, improves patient- and physician-reported outcomes (evaluated using the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale, respectively) in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis across four domains, representing ocular, bulbar, respiratory, and limb/gross motor muscle groups. Methods: Patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis were randomized 1:1 to receive either placebo or eculizumab during the REGAIN study (NCT01997229). Patients who completed REGAIN were eligible to continue into the open-label extension trial (NCT02301624) for up to 4 years. The four domain scores of each of the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale recorded throughout REGAIN and through 130 weeks of the open-label extension were analyzed. Results: Of the 125 patients who participated in REGAIN, 117 enrolled in the open-label extension; 61 had received placebo and 56 had received eculizumab during REGAIN. Patients experienced rapid improvements in total scores and all four domain scores of both the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale with eculizumab treatment. These improvements were sustained through 130 weeks of the open-label extension. Interpretation: Eculizumab treatment elicits rapid and sustained improvements in muscle strength across ocular, bulbar, respiratory, and limb/gross motor muscle groups and in associated daily activities in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis

Epstein-Barr Virus in Myasthenia Gravis: Key Contributing Factor Linking Innate Immunity with B-Cell-Mediated Autoimmunity

Epstein-Barr virus (EBV), a common human herpes virus latently infecting most of the world’s population with periodic reactivations, is the main environmental factor suspected to trigger and/or sustain autoimmunity by its ability to disrupt B-cell tolerance checkpoints. Myasthenia gravis (MG) is a prototypic autoimmune disorder, mostly caused by autoantibodies to acetylcholine receptor (AChR) of the neuromuscular junction, which cause muscle weakness and fatigability. Most patients display hyperplastic thymus, characterized by ectopic germinal center formation, chronic inflammation, exacerbated Toll-like receptor activation, and abnormal B-cell activation. After an overview on MG clinical features and intra-thymic pathogenesis, in the present chapter, we describe our main findings on EBV presence in MG thymuses, including hyperplastic and thymoma thymuses, in relationship with innate immunity activation and data from other autoimmune conditions. Our overall data strongly indicate a critical contribution of EBV to innate immune dysregulation and sustained B-cell-mediated autoimmune response in the pathological thymus of MG patients

"THE THYMUS IN MYASTHENIA GRAVIS: SITE OF ""INNATE AUTOIMMUNITY""?"

n/