From Traditional to Targeted Immunotherapy in Myasthenia Gravis: Prospects for Research

Abstract

Treatment of Myasthenia Gravis (MG) is still based on non-specific immunosuppression. Long-term high dose corticosteroids is still a major cause of side effects, in young as well as in elderly patients in whom comorbidities further increase the burden of chronic immunosuppression. Moreover, awareness of the limits of traditional therapies has led to the concept of “refractory MG.” The therapeutic approach to MG is therefore progressively evolving from the classic combination of corticosteroids and immunosuppressive drugs to new biological compounds targeting different immunopathological steps. Killing of B cells with Rituximab has been proposed and tested with positive results, particularly in patients with MuSK-associated MG. Therapeutic monoclonals against B cells at different stages of their maturation, or against molecules involved in B cell activation and function, represent a new area for further investigation. A differently targeted approach involved Eculizumab, a monoclonal antibody preventing the formation of C59b-induced MAC causing destruction of the neuromuscular junction. Data from clinical trials led to the approval of Eculizumab in the United States and Europe for MG. Since Eculizumab is a complement-targeted therapy, its use is limited to anti-acetylcholine receptor-associated MG, since anti-MuSK antibodies belong to IgG4 subclass and do not fix complement. Several anti-complement compounds are under investigation. An even more recent approach is the interference with the neonatal Fc receptor leading to a rapid reduction of circulating IgGs and hence of specific autoantibodies, an approach suitable for both anti-acetylcholine- and MuSK-associated MG. The investigation of compounds that selectively target the immune system will stimulate the search for specific biomarkers of disease activity and response to treatment, setting the basis for personalized medicine in MG.

Comorbidities worsen the prognosis of generalized myasthenia gravis post-thymectomy

“…Whether indications for thymectomy should be different for patients with comorbidities cannot be answered based on our study, and this should be addressed further. The impact of comorbidities on the prognosis of MuSK autoantibody-positive MG patients and those with thymoma, both groups associated with a higher risk of refractory MG [5], remain outside the scope of this study due to the low patient numbers and should be studied further.…”

“…Treatment of MG may include cholinesterase inhibitors, non-specific immunosuppression, and thymectomy in patients <70 years with AChR autoantibodies or a thymoma [5]. In many observational studies, thymectomy is associated with a reduction of immunosuppressive medication, decrease in symptoms and greater chance of complete stable remission (CSR) of also nonthymomatous MG [6,7].…”

“…The prognosis of MG is considered to be generally good and chronic symptoms can be managed with the treatments mentioned above [5]. However, CSR occurs in only 22% of AChR-positive MG patients [9].…”

Comparative Analysis of BIOCHIP Mosaic-Based Indirect Immunofluorescence with Enzyme-Linked Immunosorbent Assay for Diagnosing Myasthenia Gravis

“…Recent studies report that anti-MuSK positive patients have a worse prognosis with predominant bulbar and respiratory muscle involvement and frequent respiratory crises [3,[20][21][22]. Moreover, they respond poorly to acetylcholinesterase inhibitors, and conventional pyridostigmine doses frequently induce side effects, while they respond well to corticosteroids and to many steroid-sparing agents [23,24]. In addition, Rituximab should be considered as an early therapeutic option in patients who have an unsatisfactory response to initial immunotherapy [25,26].…”

Systems Pharmacology and Molecular Docking Reveals the Mechanisms of Nux Vomica for the Prevention of Myasthenia Gravis

“…The prevalence rate is approximately one in 5,000 worldwide, and the incidence is higher in younger women and older men [ 2 ]. Currently, patients with MG are mainly treated with corticosteroids, long-term immunosuppressive drugs, plasma exchange, or thymectomy [ 3 ]. However, their clinical application is limited due to their high costs and side effects, such as cardiac rhythm disorders and hypotension [ 4 ].…”