<p>Most patients with generalized myasthenia gravis (gMG) have AChR antibodies, which cause gMG through multiple different mechanisms, including complement activation. Complement inhibitors are a targeted treatment option for patients with AChR antibody–positive gMG, and 3 are currently available.</p>

At least 15% of cases of MG are ocular, and up to 85% are generalized. Of those cases that are generalized, the vast majority (ie, approximately 85%) have positive AChR antibodies, which cause disease through 3 different mechanisms. One of those mechanisms is complement activation. While we have known this for quite some time, complement inhibitors did not become a therapeutic option for gMG until 2017, with the US Food and Drug Administration (FDA) approval of eculizumab. This was really a change in the paradigm of how we treat gMG because, prior to that, what we refer to as our “traditional therapies” were more broad spectrum. Eculizumab really started the new era of targeted therapy for the treatment of gMG.

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This first FDA-approved complement inhibitor for gMG was studied more in the refractory populations of AChR antibody–positive patients who were not responding to other medications. And we really saw that eculizumab works quite well for patients with AChR antibody–positive gMG. We now have a newer version of eculizumab (ie, ravulizumab) that is longer-acting (ie, intravenously every 8 weeks vs every 2 weeks), and a third complement inhibitor (ie, zilucoplan) that is injected subcutaneously daily.

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All of these agents block C5, which is the first protein in the terminal complement pathway. While these medications work well, our complement system provides very important protection against encapsulated bacteria, so our patients have to be vaccinated specifically against Neisseria meningitidis. However, vaccination guidelines have changed since the FDA approval of these complement inhibitor agents, so it is important for patients to be up to date on their immunizations as we transition to the new era of targeted therapies.

I agree with everything Dr Goyal has said. Because of the different routes and timing of administration for the currently FDA-approved complement inhibitors—intravenously every 2 or 8 weeks, or subcutaneously on a daily basis—we are beginning to have more choices for our patients with gMG, which is very critical and allows them to do what is in their own best interest.

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I cannot stress enough, as Dr Goyal discussed, that vaccination is absolutely mandatory and critical in these patients. It is a bit burdensome. It is a 6.5-month process to follow the FDA and the Advisory Committee on Immunization Practices (ACIP) guidelines, so we are trying now as a community to decide how and when patients should be vaccinated. Many are now considering vaccinating patients early against not only N meningitidis but also Streptococcus pneumoniae and other encapsulated bacteria if we think that we may need to use complement inhibitors down the road and do not want to wait a prolonged period before use. We do have the option of treating them prophylactically with an antibiotic, but, in the older population, we have concerns about antibiotic resistance, adverse effects from the antibiotic itself, and alterations to the gut microbiome. This may not make treatment with a complement inhibitor as feasible as we would like.

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There is no question that our new targeted assets, such as complement inhibitors and FcRn blockers, have been transformational in our ability to treat our patients with gMG. However, complement inhibition only works with IgG1- and IgG3-mediated disease (ie, AChR antibody–positive gMG). It will not work for the MuSK subtype of gMG, which is an IgG4-mediated disorder, and IgG4 either does not activate the complement system or does so only minimally.