Autoantibodies against factor VIII(Drug information on 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(Drug information on 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.
Patient 1, a 69-year-old man, presented with melena, bleeding from an arthrocentesis 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 Bethesda units. Bleeding resolved following treatment with recombinant factor VIII, desmopressin(Drug information on desmopressin) acetate (DDAVP, Stimate), and prednisone(Drug information on prednisone). Weekly rituximab (four doses) was started on day 3. At 4 weeks, factor VIII activity was 186% and inhibitor titer 0 Bethesda units.
Patient 2, a 38-year-old man with ascites of unknown etiology, PTT of 67 seconds, and factor VIII activity of less than 1% (inhibitor titer, 23 Bethesda units) developed a large hematoma at a venipuncture site associated with a fall in hemoglobin of 2 g/dL. One week after treatment with anti-inhibitor coagulant complex (Feiba VH Immuno), 1 gram of cyclophosphamide(Drug information on 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 to 0 Bethesda units with factor VIII activity of 72% at 6 weeks.
Patient 3, a 39-year-old man with congenital mild hemophilia A (baseline factor VIII activity of 15% due to an Arg2150His mutation) developed a high inhibitor titer of 60 Bethesda units, with a fall in factor VIII level to 2% 6 days postoperatively following prophylactic treatment with recombinant factor VIII 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 the autoantibody but persistence of the alloantibody.
Patient 4, a 79-year-old woman on every-other-day prednisone and azathioprine(Drug information on azathioprine) for polymyalgia rheumatica developed spontaneous giant ecchymoses with a PTT of 58 seconds and factor VIII activity of 2% (inhibitor titer of 8 Bethesda units). Weekly rituximab (four doses) was started, azathioprine was discontinued, and prednisone continued unchanged. All bruising resolved within 1 week; factor VIII increased 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) the inhibitor resolved within 3 weeks in two patients, which compares favorably with reported experience; (3) one patient developed the inhibitor while on immunosuppression with prednisone and azathioprine but responded to the addition of rituximab; and (4) no adverse reactions occurred and prednisone could be tapered rapidly. We conclude that rituximab merits further evaluation in the treatment of acquired factor VIII inhibitors.
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