(Abst.) Cardiogenic shock after ocrelizumab infusion in RRMS (MS Journal)

The temporal relationship with drug administration, in combination with the reversibility of left ventricular dysfunction and the exclusion of alternative causes in a previous healthy patient, suggests a causal association with ocrelizumab, which was rated as “probable” according to the Naranjo scale. Further support for a potential role of ocrelizumab comes from the recognized cardiotoxicity of Rituximab, a chimeric anti-CD20 antibody, which has been associated with myocardial infarction, arrhythmias, and cardiogenic shock. A pharmacovigilance analysis of the US Food and Drug Administration Adverse Events Reporting System (FAERS) database in 2022 revealed an increased risk of major cardiovascular complications in patients taking ocrelizumab or ofatumumab (subcutaneously administered fully human anti-CD20 monoclonal antibody) for MS. Acute coronary syndromes and heart failure were more frequently reported with ocrelizumab, whereas atrial fibrillation was more commonly reported with ofatumumab. Since FAERS is a spontaneous reporting system, complete information on patients' cardiovascular risk factors, co-morbidities and concomitant medications is often lacking, and a causal link between the cardiac events and the drugs cannot be established. To date, no consistent or confirmed safety signals have been formally recognized by regulatory authorities (FDA and EMA).


The mechanisms behind anti-CD20-related cardiac toxicity are unknown, but a dysregulation of the immune system can be hypothesized. In our case, given the lack of systemic allergic symptoms and the gradual onset, an acute coronary syndrome in the context of a type I hypersensitivity reaction (named Kounis syndrome) can be excluded. Instead, the temporal course of symptoms suggests a delayed immune-mediated reaction. Many cardiac adverse events reported with rituximab occurred during or soon after the first infusion, likely due to cytokine release syndrome. Still, reports of heart failure with a more subacute onset (>24 hours) or after subsequent infusions also exist. Kanamori et al. described three cases of delayed and progressive reduction in left ventricular function following rituximab administration. In these patients, increased serum levels of transforming growth factor- (TGF-β) and accumulation of reticulin fiber in cardiomyocytes were observed after infusion, potentially contributing to impaired myocardial contractility and conduction. Histological analysis in our patient excluded significant interstitial myocardial fibrosis. Nonetheless, experimental studies in animal models demonstrated that B-cell depletion may up-regulate proinflammatory cytokines in the serum; in this light, it is possible that transient cytokine-mediated effects may have contributed to the reversible cardiac dysfunction observed. Additional plausible contributors include disturbances in intracellular calcium homeostasis, possibly linked to CD20 ion channel function, and increased oxidative stress, supported by experimental data showing increased ROS production and mitochondrial alterations after B-cell depletion and cytokine release.