Inhibitor incidence in previously untreated patients with severe haemophilia B: a systematic literature review.

http://dx.doi.org/10.1160/TH16-02-0116 Thromb Haemost 2016; 116: 201–203 Dear Sirs, Considering the high quality of replacement therapy available nowadays for haemophiliacs, the most challenging complication of haemophilia is currently the development of inhibitors, which render replacement therapy ineffective, preclude the access of patients to a safe and effective standard of care (particularly prophylaxis in children) and predispose them to a high risk of morbidity and mortality, causing moreover striking increases in healthcare costs (1–5). Although the development of activated prothrombin complex concentrate (aPCC) FEIBA first and then of recombinant activated FVII (rFVIIa) NovoSeven has dramatically improved the management of acute bleeding in patients with haemophilia complicated by inhibitory alloantibodies (6), it should, however, be recognised that both bypassing agents have lesser efficacy in the prevention and treatment of bleeding episodes in inhibitor patients, than replacement therapy with clotting factor concentrates in non-inhibitor ones (7). Alloantibodies that neutralise factor replacement therapy develop in approximately 25–30 % of patients with severe haemophilia A, while an inhibitor incidence of 1–5 % is reported in patients with severe haemophilia B (1, 8, 9). In spite of lower incidence, inhibitors in haemophilia B show the additional morbidity issues of allergic up to severe, even life-threatening, anaphylactic reactions, reported in approximately 60 % of cases (4). However, while inhibitor incidence and related risk factors have been extensively studied for haemophilia A, little is known about the true incidence of inhibitors in severely affected haemophilia B patients, probably due to the rarity of this inherited bleeding disorder. Notably, the great majority of studies or registries published so far report the overall prevalence of inhibitors in the cohorts of evaluated patients with haemophilia B, but do not clearly differentiate them on the basis of the disease severity (i. e. severe, moderate or mild haemophilia B), or between previously treated or untreated patients (PTPs or PUPs), or analyse the relationship between product type (i. e. plasma-derived vs recombinant Factor IX [FIX] concentrates) and the inhibitor risk. These aspects are, however, not insignificant considering that they have been consistently found to be strongly implicated in the development of inhibitors in haemophilia A patients (9). Thus, in order to elucidate these still unclear issues, we have conducted for the first time a systematic review of the existing literature on inhibitor development in severe haemophilia B (i. e. FIX <1 %) PUPs, who represent the most suitable model for studying this phenomenon. A computer-assisted search of the MEDLINE and SCOPUS electronic databases without time limits was conducted using different combinations of the following keywords: “haemophilia B”, “severe congenital factor IX deficiency” “inhibitor”, “alloantibody”, “previously untreated patients”, “anaphylaxis”, “factor IX concentrates”, “recombinant factor IX products”. A specific electronic search was also performed using the commercial names of licensed FIX products reported in the World Federation of Haemophilia (WFH) Registry of clotting factor concentrates (10). In addition, the reference lists of all included studies were manually searched for other potentially eligible studies. Moreover, we supplemented our search by reviewing abstract books of the most important conferences on haematological diseases. Overall, 374 studies were initially retrieved and 331 were excluded as focusing on other topics or because they were review articles. Thus, 33 potentially relevant clinical reports were identified and examined in detail. Of them, 26 were further excluded because the relevant data were unavailable, or because analysed patients were included in other published studies or because the design of the study did not permit a pooled analysis of the data. Finally, seven studies with usable information (6 prospective, 1 retrospective/prospective), published between 1996 and 2015, were included in this systematic review (11–17), as reported in ▶ Table 1. Statistical analysis was performed using the Chi-square test or the Fisher’s Exact test, as appropriate. A p-value less than 0.05 was considered statistically significant. Overall, 176 severe haemophilia B PUPs were reported in the included studies: 85 were treated with plasma-derived FIX concentrates and 91 with recombinant FIX products. Inhibitor rates between 5 % and 14 % were found, with an outlier value of 37 % in a Swedish study, consistent with previous data, probably due to the genetic background (18). Overall, inhibitors occurred in 18 patients (10.2 %). When the type of concentrate was considered, no data were available in a study reporting two inhibitor patients (15), whereas the other six studies provided a statistically significant higher inhibitor rate in patients treated with plasma-derived versus recombinant FIX products (11/72 [15.3 %] vs 5/89 [5.6 %], p=0.04). Among the 18 cases of inhibitors, seven were high responding and six low responding; in the remaining five patients, inhibitor titres were not reported. In the majority of cases with available information, inhibitors were associated with anaphylaxis (4/5, 80 %). Finally, a