Rituximab for the Treatment of New-onset AChR-Myasthenia Gravis

Overview

Myasthenia gravis (MG) is the most common acquired disorder of neuromuscular junction (NMJ), the most common antibody (in 85% MG patients) being the nicotinic acetylcholine receptor (AChR). Traditional medical treatments of new-onset MG include anticholinesterase inhibitors, immunomodulating therapies such as intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) and immunosuppressive agents such as corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate and cyclophosphamide. Since a status of complete stable remission (CSR, defined as remission of MG without pharmacological treatment≥1 year) is difficult to achieve, the international consensus guidance for management of MG proposed "minimal manifestation (MM) or better status" with no greater than mild adverse events as a practical goal of MG treatment. Given the balance between efficacy and safety, a more aggressive strategy and approach for immune therapies are critical in early stage of new-onset MG. In clinical practice, biological agent monoclonal antibody rituximab (RTX), specifically targeting B-lymphocyte differentiation membrane antigen CD20, has been increasing in recent years for some immune-mediated neurological diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), and gradually represented potential advantages in immunosuppressive therapy-refractory and new-onset AChR-MG. However, up to now, the individualized regimen, optimal dosage and clinical benefit of RTX monotherapy for early stage of new-onset AChR-MG still need to be elucidated. This study was performed to assess the long-term clinical efficacy and safety of individualized low-dose 100 mg RTX monotherapy approach in new-onset AChR-MG patients.

Myasthenia gravis (MG) is the most common acquired disorder of neuromuscular junction (NMJ), in which pathogenic autoantibodies bind to components of the postsynaptic membrane in NMJ, the most common antibody (in 85% MG patients) being the nicotinic acetylcholine receptor (AChR), followed by muscle-specific kinase (MuSK) or lipoprotein related peptide 4 (LRP4), thereby making impairment of neuromuscular transmission, causing fatigable weakness and even representing a potentially life-threatening condition. Traditional medical treatments of new-onset MG include anticholinesterase inhibitors such as pyridostigmine for temporarily symptomatic relief, immunomodulating therapies such as intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) for a rapid but short-term clinical response, and immunosuppressive agents such as corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate and cyclophosphamide for long-term treatment. Moreover, accompanied with prolonged duration, approximately 20% of the generalized MG population develop to refractory progressive course even with long-time and sufficient traditional immunosuppressive agents. For all newly diagnosed MG patients, chest computed tomography (CT) scan must be performed to assess for thymoma, and thymectomy should be done immediately in those thymoma patients with IVIG or PLEX treatment 1 to 2 weeks prior to thymectomy for optimizing condition, then followed by additional medical therapy for a sustained disease control. Since a status of complete stable remission (CSR, defined as remission of MG without pharmacological treatment≥1 year) is difficult to achieve, the international consensus guidance for management of MG proposed "minimal manifestation (MM) or better status" with no greater than mild adverse events as a practical goal of MG treatment. Given the balance between efficacy and safety, a more aggressive strategy and approach for immune therapies are critical in early stage of new-onset MG. AChR-MG is an archetype for B cell-mediated autoimmune disorder, clearly implicating a principal role for B cells in the disease pathogenesis. Therefore, B lymphocytes have always been the focus of investigative interests, especially with the successful introduction of biological therapeutics that target these cells. In clinical practice, biological agent monoclonal antibody rituximab (RTX), specifically targeting B-lymphocyte differentiation membrane antigen CD20, has been increasing in recent years for some immune-mediated neurological diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), and gradually represented potential advantages in immunosuppressive therapy-refractory and new-onset AChR-MG. However, up to now, the individualized regimen, optimal dosage and clinical benefit of RTX monotherapy for early stage of new-onset AChR-MG still need to be elucidated. This study was performed to assess the long-term clinical efficacy and safety of individualized low-dose 100 mg RTX monotherapy approach in new-onset AChR-MG patients, using MG Foundation of America (MGFA)-Postintervention Status (PIS) "Minimal Manifestation (MM) or better status" as the primary outcome, changes in Quantitative Myasthenia Gravis (QMG), Manual Muscle Testing (MMT), MG-Related Activities of Daily Living (MG-ADL), and 15-item Quality-of-Life (MGQOL-15) scores as the secondary outcomes, as well as cholinesterase inhibitors reduction, peripheral CD19+B-cell percentage, AChR antibody titers and adverse effects.