Rituximab in the Treatment of Acquired Factor VIII Inhibitors

March 1, 2002

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.

Click here to read Dr. Bruce Cheson's commentary on this abstract.