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Complement C5 inhibition in generalized myasthenia gravis is associated with improved survival and increased
Carl Vahldieck1,2,3, Benedikt Fels2,3
1Department of Anesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein, Luebeck, Germany.
Insights
Complement C5 inhibitors improve survival in generalized myasthenia gravis (MG) but increase cardiovascular and thromboembolic risks. Ravulizumab showed a lower risk of major adverse cardiovascular events compared to eculizumab.
Area of Science:
- Neurology
- Immunology
- Cardiovascular Medicine
Background:
- Acetylcholine receptor antibody-positive generalized myasthenia gravis (MG) is treated with complement C5 inhibitors.
- Cardiovascular safety of C5 inhibitors requires dedicated evaluation due to prolonged use.
- Systematic assessment of cardiovascular and thromboembolic risk, including drug-specific differences, is needed.
Purpose of the Study:
- To evaluate the cardiovascular and thromboembolic safety of C5 inhibitors in generalized MG.
- To compare the safety profiles of ravulizumab and eculizumab in MG patients.
Main Methods:
- Retrospective cohort study using the TriNetX electronic health record network.
- Propensity score-matched cohorts compared C5 inhibitor users with controls and ravulizumab with eculizumab.
- Outcomes included major adverse cardiovascular events (MACE), thrombotic disorders, AKI, arrhythmias, and mortality over 365 days.
Main Results:
- C5 inhibition increased the risk of AKI and thrombotic disorders but lowered all-cause mortality.
- MACE occurred more frequently with C5 inhibition, with a trend toward higher hazard over time.
- Ravulizumab was associated with a lower hazard of MACE compared to eculizumab, with similar risks for other outcomes.
Conclusions:
- C5 inhibition in generalized MG improves survival but increases cardiovascular and thromboembolic risk.
- This analysis suggests heterogeneity in cardiovascular risk within the C5 inhibitor class.
- Longitudinal cardiovascular monitoring is crucial for MG patients receiving complement inhibition.
Background:
Complement C5 inhibitors are effective disease-modifying therapies for acetylcholine receptor antibody-positive generalized myasthenia gravis (MG), but cardiovascular safety has not been evaluated as a dedicated outcome domain. With increasing and prolonged use, systematic assessment of cardiovascular and thromboembolic risk - including potential differences between individual C5 inhibitors - is needed.
Methods:
We performed a retrospective cohort study using the TriNetX federated electronic health record network, including adults with generalized MG. Propensity score-matched cohorts compared patients treated with C5 inhibitors with untreated controls (N = 1,094 vs. 1,094), and ravulizumab with eculizumab (N = 330 vs. 330). Outcomes included major adverse cardiovascular events (MACE), thrombotic disorders, acute kidney injury (AKI), arrhythmias, and all-cause mortality over 365 days. Associations were evaluated using risk ratios (RR) and Cox proportional hazards models.
Results:
After matching, C5 inhibition was associated with increased risk of AKI (6.1% vs 3.2%, p<0.01; RR 1.70) and thrombotic disorders (5.1% vs 2.6%, p=0.002; RR 1.74) compared to no C5-inhibition treatment. All-cause mortality was significantly lower among C5-treated patients after one year (RR 0.54; p=0.045). MACE occurred more frequently with C5 inhibition (8.3% vs 5.5%; p=0.009), with a trend toward higher hazard over time. In agent-specific analyses (ravulizumab vs. eculizumab), ravulizumab was associated with a significantly lower hazard of MACE compared with eculizumab (6.6% vs 11.1%, p=0.041; HR 0.58, while hazards for mortality, thrombotic events, and other cardiovascular outcomes were similar.
Conclusions:
C5 inhibition in generalized MG is associated with improved survival but increased cardiovascular and thromboembolic risk. Although limited by its retrospective design, this analysis highlights a clinically relevant safety signal and suggests heterogeneity within the C5 inhibitor class. As use of complement inhibition expands, careful longitudinal cardiovascular monitoring will become increasingly important for clinicians managing patients with MG.
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