Hémophilie acquise auto-immune : quelle est la place du rituximab dans la stratégie thérapeutique ? Réflexion à partir d’une série monocentrique de 8 patients et revue de la littérature

IntroductionAutoimmune acquired haemophilia is a rare autoimmune disease. The purpose of immunosuppressive therapy is to stop the production of autoantibodies that inhibit clotting factors VIII or IX. A corticosteroids-cyclophosphamide combination is recommanded as first-line therapy. From our experience at the University Hospital of Nîmes, we discuss the place of rituximab in the therapeutic arsenal.MethodsWe report a monocentric observational retrospective study. Our data are discussed in light of literature data, in particular cohorts EACH2 and SACHA.ResultsEight patients (7 with FVIII anibodies) were consecutively included from 2005. The average age was 68.5 years with a male predominance (62.5%). Bleeding manifestations were usually spontaneous and superficial. A pathology, mostly autoimmune or neoplastic, was associated in 5/8 patients. A “by-pass” haemostatic treatment was prescribed for 3/8 patients. Rituximab was prescribed for 5/8 patients, three times as first-line therapy, and always associated with corticosteroids. Three patients received a cyclophosphamid/cortisone combination, two were treated exclusively with oral corticosteroids. Remission was obtained in all patients, without subsequent relapse. The average time to obtain remission under rituximab (after the first injection) was 32.5 days (10–143). The results observed in our series of patients are consistent with the data from the literature.ConclusionsRituximab appears to be an effective and well-tolerated treatment for autoimmune acquired haemophilia. However, its place remains to be specified.     

IgG4-related disease

The term “IgG4-related disease” encompasses several disorders described many years ago under various designations depending on the organ or system involved (e.g., Mikulicz syndrome, Riedel's thyroiditis, and retroperitoneal fibrosis). The clinical presentation varies widely, as one or more organs may be affected, usually in the same region of the body and either synchronously or metachronously. The main targets are the pancreas, bile ducts, salivary glands, lachrymal glands, mediastinal lymph nodes, and retroperitoneum. IgG4-related disease is rare, with an estimated incidence of 0.2 to 1/100 000 in Japan and no available incidence data in occidental countries. Men older than 50 years are predominantly affected. Serum IgG4 levels are often greater than 1.35 g/L. Enlargement of the involved organs, which may be pseudotumoral, is due to a combination of infiltration by T cells and IgG4-expressing plasma cells, storiform fibrosis, and obliterative thrombophlebitis. Glucocorticoid therapy is effective but may be followed by relapses requiring the use of immunomodulating agents such as azathioprine, methotrexate and, more recently, rituximab. IgG4-related disease is not an autoimmune condition related to IgG4 autoantibodies, and neither does it involve immune complexes. Specific joint involvement has been reported in a very small number of patients.     

Pronase independent flow cytometry crossmatching of rituximab treated patients

ABO-incompatible (ABOi) kidney transplantation has become an established strategy to increase the number of available living donors. At our center, the conditioning protocol for ABOi patients is based on anti-A/B antibody removal and depletion of B cells with the anti-CD20 mAb rituximab (Mabthera®). It is known that even low amounts of remaining rituximab in serum of patients results in false positive B cell cross match results, masking detection of potentially harmful donor human leukocyte antigen (HLA) specific antibodies. Treatment of donor cells with high concentrations (>1?mg/mL) of pronase is currently standard procedure for elimination of rituximab (RIT) interference. It is, however, troublesome that recent reports indicate that pronase treatment per se can induce incorrect flow cytometry cross match (FCXM) results. The aim of this study was to evaluate an alternative pronase-free FCXM for crossmatching of patients treated with rituximab.FCXM with an anti-RIT monoclonal antibody (mAb) pre-blocking step were evaluated on normal human sera (NHS) and patient sera supplemented with RIT. NHS supplemented with RIT or patient sera, without donor specific antibodies (DSA), resulted in high B cell median channel shift (>200 IgG) above background. This shift was eliminated by a serum pre-blocking step with 2-fold excess of anti-RIT (clone MB2A4). Blocking with anti-RIT did not influence the T cells crossmatch results. We present data supporting proof-of-concept that blocking with anti-RIT antibody prior to XM can enable reliable detection of anti-HLA class I and II donor specific antibodies without use of pronase treated donor cells.