Acquired hemophilia A: is more better?

Collins and colleagues report the epidemiology, clinical course, and treatment outcomes of a 2-year observational study of all patients with acquired hemophilia A in the United Kingdom.

Acquired hemophilia A is a rare autoimmune disorder characterized by the development of IgG antibodies that neutralize coagulation factor VIII activity; these antibodies are termed inhibitors. The antibodies found in acquired hemophilia display type 2 inactivation kinetics characterized by the finding of residual factor VIII activity in plasma in the face of variable titers of antibody.¹  As a result, the patient may have severe bleeding out of proportion to that expected for the concentration of plasma factor VIII activity. A significant percentage of affected patients have an underlying diagnosis. Thus, therapeutic strategies require attention to treatment of hemorrhagic complications, treatment of any underlying disorder, and eradication of the inhibitor.

Approaches to therapy have relied on previous observational studies of patient groups referred to specialized centers²  and on reports of successful outcomes in relatively small patient groups. Collins and colleagues have provided important new knowledge regarding the incidence, clinical characteristics, and outcomes of treatment of acquired hemophilia A through complete ascertainment of all patients diagnosed in the United Kingdom in a 2-year period. Evaluation of this unbiased cohort of 172 patients revealed an incidence of 1.48 per million per year. Patients were significantly older than previously reported; mortality was more likely in older patients, but they achieved remission faster with immunosuppressive therapy. Underlying diagnoses, bleeding complications, and response to hemostatic therapy confirmed previous reports; however, bleeding symptoms were more varied, with 33% requiring no hemostatic therapy and 8% with fatal bleeding.

Collins and colleagues then analyzed the outcome of 2 basic immunosuppressive treatment regimens administered to 88 of the patients: steroids alone (n = 40; usually given as prednisolone, 1 mg/kg per day) versus steroids combined with cytotoxic therapy (n = 48; usually cyclophosphamide, 1-2 mg/kg per day). They found no differences in the proportion of patients who achieved complete remission (CR) or in the time to CR; furthermore, addition of other therapy such as intravenous immunoglobulin (IVIG) did not alter the results. The one caveat to this observation is that this was not a randomized study. Physicians were allowed to choose the immunosuppressive regimen; this led to treatment with steroids alone in patients with a lower median inhibitor titer (8 BU) than those treated with combination therapy (18 BU); P < .01. Thus, it is possible that the outcomes are biased by more intense treatment of the more severely affected group. Nevertheless, this study provides us with the best data to date from a large group of patients. Only one randomized clinical trial has been reported, a comparison of the addition of cyclophosphamide to steroid treatment versus continuation of steroids after 3 weeks; there were no differences in outcome, but the study was quite small.³ 

Collins and colleagues are to be congratulated for their major effort to identify all patients presenting with acquired hemophilia A. They have provided us with the most unbiased description of the disorder to date; in this case, more data is clearly better. The question of whether more treatment is better, either more standard therapy as described here or use of new agents such as rituximab, awaits additional well-designed clinical trials.