Drugs That Induce or Cause Deterioration of Myasthenia Gravis: An Update

Abstract

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder which is characterized by presence of antibodies against acetylcholine receptors (AChRs) or other proteins of the postsynaptic membrane resulting in damage to postsynaptic membrane, decreased number of AChRs or blocking of the receptors by autoantibodies. A number of drugs such as immune checkpoint inhibitors, penicillamine, tyrosine kinase inhibitors and interferons may induce de novo MG by altering the immune homeostasis mechanisms which prevent emergence of autoimmune diseases such as MG. Other drugs, especially certain antibiotics, antiarrhythmics, anesthetics and neuromuscular blockers, have deleterious effects on neuromuscular transmission, resulting in increased weakness in MG or MG-like symptoms in patients who do not have MG, with the latter usually being under medical circumstances such as kidney failure. This review summarizes the drugs which can cause de novo MG, MG exacerbation or MG-like symptoms in nonmyasthenic patients.

Keywords: aminoglycoside; anesthesia; antibiotics; checkpoint inhibitor; corticosteroid; fluoroquinolone; macrolide; myasthenia gravis; sugammadex; tyrosine kinase inhibitor.

Figure 1

Proposed mechanisms of effects of drugs on neuromuscular junction.

Figure 2

Mechanism of Myasthenia gravis (MG) caused by immune checkpoint inhibitors. (A) T cell activation and proliferation start with antigen presentation to T-cells by antigen-presenting-cells (APCs); also involved in this process are major histocompatibility complex, T-cell receptors, and a costimulatory signal involving interaction between B7 (B7.1 and B7.2) on APCs and CD28 on T-cells. CTLA-4 is induced in T-cells at the time of their initial response to antigen. Activated T-cells upregulate PD-1 and inflammatory signals in the tissue induce the expression of PD1-L1. (B) B7.1 binds to CTLA-4 with greater affinity than to CD28, resulting in T-cell inactivation; the PD-1/PD-L1 signaling suppresses the activity of effector T cells in later stages of tissue inflammation. CTLA-4 and PD1/PD-L1 signaling promote self-tolerance and prevent autoimmunity. These pathways are also used by tumor cells to evade the immune response. (C) Monoclonal antibodies that block CTLA-4 or PD1/PD1-L1 pathways increase T-cell activation and proliferation which then lead to autoantibody production and increased levels of proinflammatory cytokines, causing immune-related adverse effects (irAEs) mediated by cytotoxic T cells or autoantibodies, such as myositis or MG. 1: Monoclonal antibody to CTLA-4; 2: monoclonal antibody to PD-1; 3: monoclonal antibody to PD-L1.