<p>The muscle weakness in patients with generalized myasthenia gravis (gMG) is often associated with the presence of autoantibodies against components of the neuromuscular junction, although some individuals are seronegative. This provides a framework for treatment options, including treatments for upstream signaling targets (ie, T cells or B cells) and downstream signaling targets (ie, at the neuromuscular junction).</p>

AChR antibody–positive gMG is B-cell mediated but T-cell dependent. It begins with abnormalities of the thymus, leading to autoreactivity and the production of anti-AChR IgG1 and IgG3 antibodies by B cells. The autoantibodies travel to the neuromuscular junction, where they cause the symptoms of muscle weakness through the following 3 mechanisms: by blocking the AChR, preventing its interaction with acetylcholine; by cross-linking the adjacent AChRs, leading to their internalization and degradation; and by activating the complement system, leading to the destruction of the muscle membrane, the further loss of AChRs, and a reduction in AChR activation.

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MuSK antibody–positive gMG is somewhat different. MuSK is a transmembrane protein that forms a complex with LRP4, which results in AChR clustering and improves transmission efficiency at the neuromuscular junction. Anti-MuSK antibodies are typically IgG4 antibodies, which do not activate complement but can block the transmembrane protein, reducing AChR clustering, transmission efficiency, and muscle contraction.

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Understanding the pathophysiologic mechanisms of gMG impacts how we think about treatment options for patients. For example, traditional therapies such as prednisone and nonsteroidal immunosuppressants such as azathioprine and mycophenolate mofetil primarily work on B cells, leading to a reduced production of pathogenic antibodies. FcRn inhibitors, plasma exchange, and intravenous immunoglobulin work for gMG that is mediated by any antibody. Complement inhibitors, however, work for AChR-positive—but not MuSK-positive—gMG because IgG4 does not activate complement. Thymectomy is an option for AChR antibody–positive gMG and seronegative gMG but not MuSK antibody–positive gMG or LRP4 antibody–positive gMG. CD20 inhibition plays a role in the management of MuSK antibody–positive gMG, but this use is off-label.

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I treat patients who are seronegative similarly to how I treat patients with AChR antibody–positive disease. Seronegative disease can behave like seropositive disease clinically, so why is it seronegative? One possibility is that patients have anti-AChR antibodies with low affinity or at low levels that are undetectable with our current tools. Another possibility is that the target of the autoantibodies has not been identified.

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With respect to the drug development pipeline for gMG, there are upstream and downstream signaling targets. Upstream targets are T cells or B cells that lead to the production of pathogenic antibodies. Downstream targets are at the level of the neuromuscular junction, with interventions reducing either the amount of pathogenic antibody or their impact. At the upstream level, I am excited about the prospect of CAR T-cell therapy and CD19 inhibition for patients with gMG. At the downstream level, proteases that cleave IgG are exciting because these agents will reduce free IgG and bound IgG, which would have the dual impact of reducing complement activation.