Getting grip on tolerance Antibodies and how to get rid of them

Inhibitor development remains the most severe and life-threatening complication of FVIII replacement therapy in persons with hemophilia A, as inhibitors are associated with increased morbidity and mortality. Therefore, inhibitor eradiation must remain the cornerstone of treatment to allow FVIII therapy, which should be attempted in every inhibitor patient unless the chances of success are very low. Until now, it has not been possible to identify patients at highest risk of ITI failure. We identified predictive clinical variables of ITI outcome, implemented in clinically applicable nomograms, which can be used to adequately inform clinicians, patients and their families in shared decision-making to choose the most appropriate treatment. In the future, we hope to extend this nomogram by integrating genetic predictive variables of ITI success, that should be identified after pooling our results with additional data obtained in other registries or cohort studies. Furthermore, to improve current ITI protocols that now achieve 70% success rate, we aimed to identify potential targets to reduce immune activation. We identified a potential role for targeting the inhibitory FcɣRIIb using a modified FVIII-specific human monoclonal antibody in inhibitor eradication. Further approaches to increase ITI success rate remain to be established. Finally, if we could identify the exact immunological mechanism underlying ITI, this will hopefully identify potential novel therapeutic targets allowing us to eradicate more inhibitors in the future.