Role of rituximab in the treatment of postpartum acquired haemophilia A: a systematic review of the literature

Acquired haemophilia A (AHA) is a rare, but often severe, haemorrhagic disorder characterised by the development of autoantibodies directed against coagulation factor VIII (FVIII:C), with an estimated incidence of approximately one case per million persons per year1–4. The age at onset of AHA is distributed in a biphasic pattern, with a small peak in young individuals, primarily postpartum women, and a major peak in those aged 68–80 years of either sex5–7. This bleeding disorder may be associated with pregnancy, malignancies, autoimmune diseases and drug exposure, but in a consistent proportion of cases, about 50%, no underlying cause can be identified at diagnosis8–11. At variance with congenital haemophilia, in which haemarthroses are the most common bleeding symptoms, haemorrhages in AHA are most frequently reported to involve soft tissues (muscle, skin). The diagnosis of AHA is based on the laboratory detection of a prolonged activated partial thromboplastin time, not corrected after mixing and incubating equal volumes of normal plasma and plasma from the patient for 2 hours at 37 °C, and a reduction of FVIII:C plasma levels with a FVIII-inhibiting activity in patients with a negative personal or family history of bleeding12,13. Prompt recognition and treatment of AHA are mandatory, as inadequate management and complications of the disease are associated with high mortality rates (up to 22%)14. The aims of the therapeutic approach are the control of bleeding, eradication of the inhibitor and, when possible, treatment and elimination of the associated disease15. While the bypassing agents activated prothrombin complex concentrates (APCC) and recombinant activated factor VII (rFVIIa) are effective therapies for the management of acute bleeding in AHA patients16–19, immunosuppression with steroids in association with cyclophosphamide is able to eradicate the inhibitor in about 70% of cases5,20. In recent years, various reports have suggested a significant role of rituximab in the treatment of patients with acquired FVIII inhibitors refractory to standard immunosuppressive regimens21,22. Rituximab is a chimeric murine/human monoclonal antibody directed against CD20 transmembrane protein expressed on the surface of premature and mature B lymphocytes. It depletes B cells from the blood, lymph nodes and bone marrow and has demonstrated efficacy in the treatment of CD20-positive lymphoproliferative diseases as well as in a variety of autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune haemolytic anaemia, autoimmune thrombocytopenic purpura and AHA23. With regards to this last indication, rituximab (at a dose of 375 mg/m2 once a week for 4 weeks), alone or in association with corticosteroids or other immunosuppressive drugs, has been used both as first-line therapy and as salvage treatment in cases refractory to conventional immunosuppressive agents with very high response rates. In particular, two systematic reviews conducted by Franchini and colleagues and Garvey found complete responses in 88% and 79% of cases, respectively22,24. However, only few cases were patients with postpartum AHA. Thus, in order to elucidate the role of rituximab in the treatment of pregnancy-associated FVIII autoantibodies, we have performed a systematic review.