The introduction of a new generation of products with different treatment profiles warrants the prospective collection of data in children to determine safety profiles for immunogenicity as well as for pharmacokinetics in prophylactic regimens. Another complication is the large interlaboratory variability of the inhibitor assay. Although the Nijmegen modification of the Bethesda assay was promising, recent results of external validation
studies still demonstrate up to 50% difference between the test results of a single sample [20, 21]. This has increased the demand for central testing, but equally important is that laboratory results need to be confirmed in a second SRT1720 datasheet independent sample and in the presence of reduced recovery before a diagnosis of an inhibitor can be made . The conflicting results presented in the Wight and
Paisley paper were a reason for the members of the European Pediatric Network (PedNet) to include all children diagnosed Pexidartinib cost in their centres into a prospective registry. The PedNet registry started in 2004 and is ongoing, collecting data on all reasons for exposure during the first 75 exposure days. It has now prospectively collected data on > 700 children with severe haemophilia A and B. By collecting data of complete age cohorts, patient outcomes and treatment regimens are more comparable. The number of exclusions is very small (96% of all eligible patients with severe haemophilia diagnosed in the centres were included); for the patients born between 2000 and 2009 only 4% of all data on the first 75 exposure days in severe haemophilia were missing (K. Fischer et al., personal communication). The development of an inhibitor is the result of complex interactions between the patient’s immune system and genetic and environmental factors . Much has been learned by combining treatment-related risk factors and genetic factors. Interesting work has been done to unravel the complex immune regulatory genes and their interplay . The reported
increase in inhibitor development needs critical consideration. We have demonstrated that from 2000 onward over 10% of all inhibitors are of low titre. There is an urgent need to investigate the clinical importance Uroporphyrinogen III synthase of these low-titre inhibitors; whether they need immune tolerance induction therapy or just disappear without causing problems. If it is true that the majority of these low-titre inhibitors are found only because of more frequent and more sensitive testing, having no relation to increased bleeding tendency, the definition of inhibitors might have to be reconsidered. As is well documented in many studies, different mutations in the factor VIII gene have different risk profiles for inhibitor development [3-5]. However, in a well-defined cohort of patients with severe haemophilia, almost 60% have large gene defects and therefore have comparable inhibitor risk.