Immune tolerance induction in haemophilia: evidence and the way forward.

Given the inhibitor-associated morbidity resulting from limited effective treatment options, antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). First reported over 30 years ago, much of our current knowledge about ITI in haemophilia A and B was derived from small cohort studies and retrospective national and international ITI registries. More recently, prospective randomised ITI trials have been designed and initiated to answer outstanding questions related to the optimisation of current therapeutic strategy in haemophilia A. However, due to the low incidence of inhibitor development in haemophilia B compared to haemophilia A, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of FIX inhibitors. The lack of an effective strategy is particularly problematic given the even greater morbidity associated with the almost unique occurrence of allergic and anaphylactic reactions that often herald FIX antibody development, and further complicates attempts to eradicate FIX inhibitors. Ultimately, successful inhibitor prevention and eradication strategies for both diseases will emerge from the clinical translation of our evolving knowledge of immune stimulation and tolerance. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; it will also review the current consensus recommendations for ITI, as well as the emerging scientific body of immunological knowledge that may significantly impact the therapeutic and preventative strategies of the future.