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Potential Clues to the Pathogenesis of Acquired Hemophilia
There have been several recent reports of the development of acquired hemophilia in patients who received alemtuzumab treatment for multiple sclerosis.       This monoclonal antibody is increasingly noted to be associated with secondary autoimmune disorders since its approval for use in multiple sclerosis a decade ago. Common autoimmune disorders developing after alemtuzumab therapy are thyroid diseases and immune thrombocytopenia (ITP). With the addition of acquired hemophilia to this list, it may be useful to examine whether this unusual complication may shed some light on the pathogenesis of acquired hemophilia.
Autoimmune disorders such as acquired hemophilia are characterized by the development of antibodies to self-antigens. Naturally occurring factor VIII (FVIII) antibodies are observed in individuals without hemophilia. Hu et al investigated 90 blood donors and identified a positive response for CD4+ T cells to FVIII and synthetic peptides containing FVIII domain sequences with men and older individuals having stronger responses (males and older individuals are more likely to develop acquired hemophilia). Similarly, CD4+ T cells from 11 patients with congenital hemophilia or acquired hemophilia responded to exogenous FVIII but the response was for longer periods compared with individuals without hemophilia.
Another interesting aspect worth examining is the role of regulatory T-cells. Although healthy individuals may have antibodies to FVIII, equilibrium exists between antibodies to self-antigens and regulatory T cells, which protect healthy individuals from getting autoimmune disorders. This balance is upset in older individuals, in particular those in whom the tolerance may fail and lead to an autoimmune condition like acquired hemophilia.  In the context of alemtuzumab use, the role of regulatory T cells has recently been described in an elegant model which involves both T-cells and B-cells. Alemtuzumab depletes the T-cells as part of its mechanism of action. Following the administration of this T cell suppressant, there is a lag for the development of autoimmunity which is the time taken for the T cell number to regenerate. During this period, there is a surge of hyperreactive, antibody-producing B cells which can generate autoantibodies that are not cleared by the (reduced/regenerating) regulatory T cells. It may be noted here that a combination of regenerated T-cells and hyperreactive B cells is required for the generation of autoimmunity. This “double-hit” model may account for the rarity of autoimmune disorders with alemtuzumab use and also the peak incidence 2 to 3 years after alemtuzumab administration.
How can the above model explain some of the therapeutic findings with acquired hemophilia? Spontaneous remission of acquired hemophilia has been observed in some patients that may be due to restoration of the T cell imbalance, as has been noted in other autoimmune conditions such as ITP. The above model would also support the “usefulness” of rituximab as a therapeutic agent since antibody production by hyperreactive B cells would be blocked by this B-cell-depleting drug. Timing of this therapy may, however, be crucial since early use is likely to have better outcomes. Based on a small number of acquired hemophilia patients, Aggarwal and colleagues found promising results with rituximab use in patients with high antibody titers and went on to recommend rituximab as the first-line therapy in combination with corticosteroids. Although randomized controlled trials have not been undertaken, some other studies have identified better outcomes if rituximab is administered at an early stage of the disease.
In summary, case reports linking acquired hemophilia development following alemtuzumab use stimulate interest in examining regulatory T cells' role in its pathophysiology. Some of the attractive approaches in this setting, which certainly require clinical confirmation in large studies, are the early use of rituximab, and measurement of regulatory T cells and B cell load to predict relapse.
01 March 2021 (online)
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