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Since 2011, six immune checkpoint inhibitors have been approved by the FDA and fall into three drug classes: anti-CTLA4 (ipilimumab), anti-PD1 (nivolumab, pembrolizumab, cemiplimab), and anti-PDL1 (atezolizumab, avelumab, durvalumab).
Initially approved for metastatic melanoma, they now have a range of cancer indications, both as monotherapy and in combination. These monoclonal antibodies exert their anticancer effect by releasing the normal inhibitory signals on T-cell activation. Side effects, termed immune-related adverse events, can affect any organ or tissue.
Pathophysiology
In normal immune function, PD1 and CTLA4 are inhibitors that contribute to the prevention of B-cell–mediated autoimmune disease and maintenance of self-tolerance. Polymorphisms in PD1 and CTLA4 are associated with various autoimmune conditions. As in other immune-related adverse events, the pathophysiology of immune-related MG has not been fully defined, and it is unknown how much the pathophysiology overlaps with idiopathic MG. Some proposed mechanisms for immune-related adverse events in general include the following:
Increased T-cell activity against antigens that are present in tumors and healthy tissue
Increased levels of preexisting autoantibodies
Increased inflammatory cytokines
Enhanced complement-mediated inflammation due to direct binding of an antibody against CTLA4 with CTLA4 expressed on normal tissue.
These processes may be involved in isolation or in combination, depending on the tissue, drug, and tumor type. Some patients likely have preexisting undiagnosed MG, and in some, immune-related MG is likely a de novo presentation following treatment with an immune checkpoint inhibitor.
Epidemiology: Neurologic immune-related adverse events are rare, affecting approximately 1% to 3% of patients treated with immune checkpoint inhibitors. They are variably classified and likely underdiagnosed. However, along with cardiac toxicities, they have some of the highest fatality rates of the immune related adverse events. The peripheral nervous system appears to be affected twice as often as the central nervous system. Epidemiologic data on immune-related MG are limited. Studies have been retrospective and disproportionately included patients who had ACh receptor antibody–positive MG.
While CNS complications account for 25%, neuromuscular complications account for 75%, with myopathies and MG being the most common. ICI-induced myopathies tend to arise within the first 3 months of treatment and can include necrotizing myositis, dermatomyositis, and polymyositis. Approximately 30% of ICI-induced myopathy cases also present with myocarditis, so cardiac evaluation is important in these patients.
Clinical Features: Immune-related MG resembles its idiopathic counterpart. However, early or disproportionately severe bulbar weakness or respiratory involvement, or both, may be present. It is unclear whether this is due to concurrent inflammation of bulbar and respiratory muscles or disordered neuromuscular transmission. A fatigable component to weakness may be present or absent by history and on examination. Immune-related MG can overlap with myositis, myocarditis, or thyroiditis. Symptoms typically present within one to four cycles of immune checkpoint inhibitor treatment. Fulminant symptoms may present after just one cycle, or symptoms may present more indolently.
Diagnosis: Currently, no distinct definition exists for immune-related MG. When patients present with a combination of ocular, bulbar, facial, limb, axial, and respiratory weakness after immune checkpoint inhibitor therapy, the differential diagnosis includes myositis (including orbital myositis), polyradiculoneuropathy with or without immune-mediated leptomeningeal involvement, myocarditis, and a direct effect of the cancer. The workup includes CK, ACh receptor binding and modulating panel with anti-striated muscle antibodies, antinuclear antibody, thyroid-stimulating hormone (TSH) and free T4, and troponin and ECG to screen for concurrent myocarditis. If ACh receptor binding antibodies are negative, muscle-specific tyrosine kinase and lipoprotein receptor–related protein 4 should be checked. If troponin is elevated, additional cardiac evaluation and cardiology consultation are warranted.
ICI induced ocular myopathy vs ocular MG:
Ocular weakness is the initial symptom in patientes with ICI induced myopathy which is also the predominant or sole presentation in nearly half of the patients with ICI-induced myopathy, and most commonly occurs after the second dose of ICI. Because these symptoms have overlapping features with MG, they may be mistaken as a neuromuscular junction disorder.
Although MG often has positive antibodies present, positive AChR antibodies can be present in up to 40% of patients with ICI myopathy and positive antibodies alone without clinical symptoms of fatigable weakness do not establish a definitive diagnosis of MG. A more valuable differentiating point is whether there is electrodiagnostic evidence of neuromuscular transmission abnormalities. in ICI induced myopathy, there are no positive antibodies and no evidence of neuromuscular junction defect, but patients have elevated CK and troponin, pointing toward ICI-induced myopathy.
Electrodiagnostic studies should be performed to provide further insight into the pathophysiology of the patient’s symptoms. This is important for several reasons. First, in this population, ACh receptor antibody positivity may be nonspecific. The presence of ACh receptor binding antibodies may not mean the patient has an active disorder of neuromuscular transmission, and a higher proportion of patients with immune-related MG and weakness outside of the ocular region (ie, generalized myasthenia) do not have MG-specific autoantibodies. These are features which distinguish immune-related MG from idiopathic MG. Second, overlap syndromes are common. Electrodiagnostic studies evaluate for concurrent myositis, polyneuropathy, or sensory neuronopathy. If the evaluation is unremarkable or inconclusive, single-fiber EMG and/or muscle biopsy are performed.
Treatment and Outcomes: Although several guidelines address the management of immune-related adverse events, the most recent and relevant for immune-related MG was published by the American Society of Clinical Oncology. The mainstay of treatment for immune-related adverse events and immune-related MG is holding or discontinuing immune checkpoint inhibitor therapy or adding corticosteroids, or both. In patients who have incomplete benefit or who have severe bulbar or respiratory weakness, either IVIg or plasma exchange should be quickly added or started concurrently. If patients are antibody negative and have no history of MG symptoms, corticosteroids are weaned more rapidly than in idiopathic disease, over approximately 4 to 6 weeks. If pre-existing MG is suspected or if the patient has ACh receptor antibodies, the author typically weans more slowly. While corticosteroids given afterward do not “undo” the effect of immune checkpoint inhibitor treatment, debate exists regarding whether higher or prolonged doses of corticosteroids or immunosuppressant therapies have adverse effects on the oncologic prognosis. No data exist regarding the potential for transient early steroid-associated worsening in patients with immune-related MG.
For treatment of immune-related adverse events (irAEs), the primary consideration is glucocorticoid therapy such as methylprednisolone, with symptom severity determining dosage and selection. If there is no significant improvement with glucocorticoids, IVIG or plasmapheresis should be considered. For cases where symptoms worsen or show no improvement after 2 weeks, other immunosuppressant therapies can be considered, including rituximab, TNF-alpha antagonists, or IL-6 antagonists.
In a case of ICI-induced myopathy, if there is lack of response to plasmapheresis, IVIG, IV and/or oral corticosteroids, start on rituximab 500 mg/m2 every 2 weeks for 2 doses.
A wide spectrum of severity in cases of immune-related MG exists. Some cases are mild, monophasic, and extremely steroid responsive, even if the initial presentation included notable generalized weakness. Other cases are severe, rapidly progressive, and even fatal. Patients with concurrent myositis or myocarditis appear to have a more aggressive course of immune-related MG.
Most patients do experience significant improvement in myasthenic weakness, and improvement can be rapid over days to weeks with treatment. Some patients, however, have permanent disability.
Mechanism of Myasthenia gravis (MG) caused by immune checkpoint inhibitors.
(A) T cell activation and proliferation starts 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 CTLA4 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.
Monoclonal antibody to CTLA-4;
Monoclonal antibody to PD-1;
Monoclonal antibody to PD-L1.
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