Autoimmune hemolytic anemia: New frontiers in diagnosis and therapy

Autoimmune hemolytic anemias comprise warm AIHA (wAIHA), due to IgG autoantibodies reacting at body temperatures, and cold agglutinin disease (CAD), due to IgM reacting in cold and strongly activating complement. The diagnosis, based on the direct antiglobulin test (DAT), is sometimes difficult since the DAT is performed with various methods with different sensitivity and specificity. Novel investigation includes DAT by flow-cytometry that helps the diagnosis of DAT-negative forms and in-deep bone marrow examination that aims to understand AIHA pathogenesis. Therapy is different in wAIHA and CAD: in the former, steroids represent the first-line, followed by rituximab, splenectomy and immunosuppressors, while in the latter rituximab is recommended frontline, followed by rituximab plus chemotherapy or the complement inhibitor sutimlimab. Plasmacell-directed therapies (bortezomib and daratumumab) may be administered in refractory patients. Several new therapies are under investigation, including inhibitors of Bruton's and spleen tyrosine kinases, neonatal Fc receptor, and cytokines, and bi-specific monoclonal antibodies.