Autoantibodies against factor VIII are rare but may cause life-threatening bleeding. Up to 30% of inhibitors may resolve spontaneously, but immunosuppressive drugs with possible serious adverse effects and costly factor replacement are usually required. Rituximab (Rituxan), a humanized monoclonal antibody against CD20-positive B cells, has been reported to be beneficial in certain antibody-mediated autoimmune diseases. We describe here four consecutively treated patients whose acquired factor VIII inhibitors responded rapidly to immunosuppressive regimens that included rituximab administered at 375 mg/m² weekly for 2 to 4 weeks.
Autoantibodies against factor VIII are rare but may cause life-threateningbleeding. Up to 30% of inhibitors may resolve spontaneously, butimmunosuppressive drugs with possible serious adverse effects and costly factorreplacement are usually required. Rituximab (Rituxan), a humanized monoclonalantibody against CD20-positive B cells, has been reported to be beneficial incertain antibody-mediated autoimmune diseases. We describe here fourconsecutively treated patients whose acquired factor VIII inhibitors respondedrapidly to immunosuppressive regimens that included rituximab administered at375 mg/m² weekly for 2 to 4 weeks.
Patient 1, a 69-year-old man, presented with melena, bleeding from anarthrocentesis site, hemoglobin of 5.6 g/dL, partial thromboplastin time (PTT)of 94 seconds, factor VIII activity of 4%, and an inhibitor titer of 5 Bethesdaunits. Bleeding resolved following treatment with recombinant factor VIII,desmopressin acetate (DDAVP, Stimate), and prednisone. Weekly rituximab (fourdoses) was started on day 3. At 4 weeks, factor VIII activity was 186% andinhibitor titer 0 Bethesda units.
Patient 2, a 38-year-old man with ascites of unknown etiology, PTT of 67seconds, and factor VIII activity of less than 1% (inhibitor titer, 23 Bethesdaunits) developed a large hematoma at a venipuncture site associated with a fallin hemoglobin of 2 g/dL. One week after treatment with anti-inhibitor coagulantcomplex (Feiba VH Immuno), 1 gram of cyclophosphamide × 1, and prednisone,factor VIII activity was 3%, and treatment with weekly rituximab (four doses)was initiated. The inhibitor titer fell to 1.1 Bethesda units at 3 weeks and to0 Bethesda units with factor VIII activity of 72% at 6 weeks.
Patient 3, a 39-year-old man with congenital mild hemophilia A (baselinefactor VIII activity of 15% due to an Arg2150His mutation) developed a highinhibitor titer of 60 Bethesda units, with a fall in factor VIII level to 2% 6days postoperatively following prophylactic treatment with recombinant factorVIII during a laminectomy. After treatment with prednisone and weekly rituximab(two doses), factor VIII activity was 12% (inhibitor titer of 28 Bethesda units)at 1 week and 17% (15 Bethesda units) at 2 months, indicating resolution of theautoantibody but persistence of the alloantibody.
Patient 4, a 79-year-old woman on every-other-day prednisone and azathioprinefor polymyalgia rheumatica developed spontaneous giant ecchymoses with a PTT of58 seconds and factor VIII activity of 2% (inhibitor titer of 8 Bethesda units).Weekly rituximab (four doses) was started, azathioprine was discontinued, andprednisone continued unchanged. All bruising resolved within 1 week; factor VIIIincreased to 78% and inhibitor titer fell to 0 Bethesda units by 3 months.
CONCLUSION: Our experience with rituximab is noteworthy in several respects:(1) All four patients had complete resolution of the inhibitor; (2) theinhibitor resolved within 3 weeks in two patients, which compares favorably withreported experience; (3) one patient developed the inhibitor while onimmunosuppression with prednisone and azathioprine but responded to the additionof rituximab; and (4) no adverse reactions occurred and prednisone could betapered rapidly. We conclude that rituximab merits further evaluation in thetreatment of acquired factor VIII inhibitors.
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