Finding Markers That Predict Response to Complement Inhibitors in Myasthenia Gravis

Anti-AChR antibodies act through three distinct mechanisms:

1. Activation of the classical complement pathway: Formation of membrane-attack complexes (MACs) results in the destruction of the postsynaptic membrane. 2. Mechanical blockade: Anti-AChR antibodies block the acetylcholine binding site on its receptor. 3. Internalization and lysosomal degradation: Bivalent IgG causes cross-linking of adjacent receptors leading to internalization and degradation of AChRs (antigenic modulation).

Patient mortality has significantly reduced due to effective treatments preventing severe exacerbations of myasthenic symptoms.

In the past five years, the FDA and EMA have approved complement inhibitors for the treatment of generalized myasthenia gravis with anti-AChR antibody positivity. Eculizumab, a humanized monoclonal antibody, binds to the complement fragment C5, inhibiting its cleavage into C5a and C5b, and preventing the formation of the terminal complement complex C5b-9 (MAC).

Currently, Eculizumab is approved in Italy for generalized myasthenia gravis associated with anti-acetylcholine receptor antibody positivity.

This class of drugs is generally more effective than conventional immunosuppressive therapies, though it comes with higher costs.

There is heterogeneity among patients in their response to complement inhibitor therapies. Currently, there is no specific evidence indicating which patients may benefit most from this class of treatments. Personalized therapy, considering the predominant pathogenic mechanisms of anti-AChR in individual patients, seems necessary. Interindividual heterogeneity in the autoantibody repertoire could underlie different responses to complement inhibitor therapies. For example, inhibition of the complement cascade in patients whose autoantibodies also block receptors might result in an unsatisfactory treatment response. Moreover, C5 gene polymorphisms could explain a lack of response to these new drugs. Investigating the immune, genetic, and cellular profile of myasthenic patients eligible for these new pharmacological therapies could be useful for identifying predictive markers of response and personalizing therapeutic choices.