Mauser-Bunschoten and colleagues [1] describe an apparent lack of association between formation of factor VIII inhibitors and long-term interferon- therapy in patients with hemophilia A and chronic hepatitis C. The study addresses two reports of acquired factor VIII inhibitors in "dissimilar" patients with and without hemophilia who received long-term interferon- treatment [2, 3]. Although the current findings are reassuring, they also raise intriguing questions about the pathogenesis of factor VIII antibodies and interferon--induced autoimmunity.

Factor VIII inhibitors may arise as alloantibodies in patients with severe hemophilia A (factor VIII level < 1%) or as autoantibodies in persons without hemophilia [2]. Immunosuppressive therapy is generally ineffective against alloantibody inhibitors but may work against autoantibody inhibitors [4]. This observation suggests that different immunologic mechanisms may be involved in the pathogenesis of the two inhibitor subtypes [5]. Furthermore, alloantibodies and autoantibodies against factor VIII are associated with different patterns of bleeding [3]. In this regard, the previous "dissimilar" cases of interferon--associated factor VIII inhibitors have a strong common feature: Both cases involved bleeding patterns typical of autoantibody inhibitors. In particular, one of the patients had mild hemophilia [3], with a baseline factor VIII level of 8%; this patient seems to have developed an autoantibody rather than an alloantibody inhibitor against factor VIII after long-term interferon- therapy.

In light of these facts, it would be important to know the number (if any) of patients with mild hemophilia in Mauser-Bunschoten and colleagues' study. If there were few or none, then the conclusion of the study should be that long-term interferon- therapy is not associated with formation of alloantibody inhibitors in patients with severe hemophilia A. A plausible explanation is that the immunopathogenesis of alloantibodies is not influenced by interferon- [5]. In contrast, the risk for development of autoantibody inhibitors in patients with mild hemophilia and persons without hemophilia who receive interferon- remains poorly defined and potentially fatal [2].