Inhibitors in haemophilia B: the Italian experience

Abstract

The prevalence of inhibitors in haemophilia B is significantly lower than that of patients with haemophilia A. However, the peculiar occurrence of allergic reactions associated with the onset of inhibitor in haemophilia B (HB) may render immune tolerance a risky procedure. We have carried out a detailed survey among all the Italian Hemophilia Centers to analyse all the patients with HB and inhibitors. A total of eight patients were reported among 282 living patients (2.8%) with severe factor IX (FIX) deficiency (FIX < 1 U dL(-1)). In addition, two deceased patients were also identified. Six patients carried nonsense mutations while in four partial or complete gene deletions were detected. Three patients (one deceased) had history of allergic/anaphylactic reaction upon substitutive treatment, which in one case was recurrent and resolved after switching to plasma derived FIX. Immune tolerance was adopted in five patients and in four complete response was achieved while in the remaining it was partial. No nephrotic syndrome was observed. Our data confirm that inhibitors in HB occur in patients with null mutations or complete/partial gene deletion. Immune tolerance can be achieved also in HB patients, without allergic reactions or nephrotic syndrome upon replacement therapy.

Treatment and Prevention of Bleeds in Haemophilia Patients with Inhibitors to Factor VIII/IX

“…International groups of experts do not, therefore, recommend ITI for patients with haemophilia B with inhibitors [16,17,18,19,20,21,22,23,24]. However, data recently collected in Italy demonstrated the complete success of inhibitor eradication in four of five patients with severe haemophilia B with inhibitors treated with a low-dose ITI regimen [31]. Data on ITI in patients with non-severe haemophilia A are mostly anecdotal, and strong evidence supporting the systematic performance of ITI in such patients is therefore lacking [17,18,30,32].…”

Involvement of the IgE‐basophil system and mild complement activation in haemophilia B with anti‐factor IX neutralizing antibodies and anaphylaxis

“…Other potential tolerogenic mechanisms may be the high degree of homology between FIX and other vitamin K‐dependent clotting factors, which would confer some degree of tolerance . However, in contrast to patients with haemophilia A, those with haemophilia B complicated by inhibitors are at risk of developing hypersensitivity reactions up to anaphylaxis following FIX replacement therapy . Specific IgE antibodies, responsible for mast‐cell activation and anti‐FIX IgG1 antibodies, which activate the complement system with generation of anaphylatoxins, have been described in haemophilia B patients with inhibitor.…”

The socioeconomic burden of patients affected by hemophilia with inhibitors

“…Although some data argue for an increased consideration for low‐dose regimens, in a recent study (Immune Tolerance and Economic Retrospective ‐ ITER), the most frequently ITI regimen used in HA patients with inhibitors was 130 IU/kg daily . Furthermore, data collected in Italy demonstrated inhibitor eradication in four of five patients with severe HB and HR inhibitors treated with a low‐dose ITI regimen …”