Practical Management for Use of Eculizumab in the Treatment of Severe, Refractory, Non-Thymomatous, AChR + Generalized Myasthenia Gravis: A Systematic Review

Abstract

Myasthenia gravis (MG) is a rare autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. MG is classified by the antigen specificity of these antibodies. Acetylcholine receptor (AChR) antibodies are the most common type (74-88%), followed by anti-muscle specific kinase (MuSK) and other antibodies. While all these antibodies lead to neuromuscular transmission failure, the immuno-pathogenic mechanisms are distinct. Complement activation is a primary driver of AChR antibody-positive MG (AChR+ MG) pathogenesis. This leads to the formation of the membrane attack complex and destruction of AChR receptors and the postsynaptic membrane resulting in impaired neurotransmission and muscle weakness characteristic of MG. Broad-based immune-suppressants like corticosteroids are effective in controlling MG; however, their long-term use can be associated with significant adverse effects. Advances in translational research have led to the development of more directed therapeutic agents that are likely to alter the future of MG treatment. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and is approved for use in generalized MG. In this review, we discuss the pathophysiology of MG; the therapeutic efficacy and tolerability of eculizumab, as well as the practical guidelines for its use in MG; future studies exploring the role of eculizumab in different stages and subtypes of MG subtypes; the optimal duration of therapy and its discontinuation; the characterization of non-responder patients; and the use of biomarkers for monitoring therapy are highlighted. Based on the pathophysiologic mechanisms, emerging therapies and new therapeutic targets are also reviewed.

Keywords: autoantibodies; complement; eculizumab; myasthenia gravis; pathophysiology.

Figure 1

Complement and its role in MG. This figure shows different pathways and associated regulatory proteins involved in the successful formation of MAC, including factors B and D (FB, FD), properdin (P), and mannan-binding lectin serine protease 1 (MASP-1).

Figure 2

Pathogenesis of MG – The potential cascade of events in AChR+ and MuSK+ MG: (A) Normal Immune tolerance in thymus. (B and C) Thymic pathology, including thymic hyperplasia and thymoma in AChR+ MG. In thymic hyperplasia, a potential sequence of events leading to tertiary lymphoid genesis has been discovered which is initiated by an inciting event, such as a viral infection in a susceptible environment, leading to the creation of a suitable environment for autoimmune pathology. Altered properties of neoplastic epithelial cells in thymoma favor autoimmunity. (D) Sensitization to the AChR and germinal center formation. (E) Peripheral spread of the thymus-initiated autoimmune process. (F and G) B-cell- and T-cell-mediated factors contributing to the pathogenesis of MG. (H) Mode of action of AChR-specific autoantibodies. (I and J) Activation and physiologic functions of MuSK. (K) Safety factor and neuromuscular transmission failure. (L) Additional MG-associated antibodies. (M) FcRn blockers. Red square – AIRE; Yellow oval– folded AChR; Blue oval – unfolded AChR.

Figure 3

Vaccination for Neisseria meningitidis.