New Insights in Autoimmune Hemolytic Anemia: From Pathogenesis to Therapy Stage 1

Abstract

Autoimmune hemolytic anemia (AIHA) is a highly heterogeneous disease due to increased destruction of autologous erythrocytes by autoantibodies with or without complement involvement. Other pathogenic mechanisms include hyper-activation of cellular immune effectors, cytokine dysregulation, and ineffective marrow compensation. AIHAs may be primary or associated with lymphoproliferative and autoimmune diseases, infections, immunodeficiencies, solid tumors, transplants, and drugs. The direct antiglobulin test is the cornerstone of diagnosis, allowing the distinction into warm forms (wAIHA), cold agglutinin disease (CAD), and other more rare forms. The immunologic mechanisms responsible for erythrocyte destruction in the various AIHAs are different and therefore therapy is quite dissimilar. In wAIHA, steroids represent first line therapy, followed by rituximab and splenectomy. Conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine) are now considered the third line. In CAD, steroids are useful only at high/unacceptable doses and splenectomy is uneffective. Rituximab is advised in first line therapy, followed by rituximab plus bendamustine and bortezomib. Several new drugs are under development including B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), or neonatal Fc receptor. Here, a comprehensive review of the main clinical characteristics, diagnosis, and pathogenic mechanisms of AIHA are provided, along with classic and new therapeutic approaches.

Keywords: cold agglutinin disease; complement; cytokines; direct antiglobulin test; therapies; warm autoimmune hemolytic anemia.

Figure 1

Pathogenic mechanisms of red blood cell (RBC) destruction.

Figure 2

Immunologic, environmental, and genetic factors involved in the pathogenesis of autoimmune hemolytic anemia (AIHA). CLL: chronic lymphocytic leukemia, NHL: non-Hodgkin lymphoma, PD1/-L: programmed death 1 and its ligand, CTLA-4: cytotoxic T-lymphocyte-associated protein 4.

Figure 3

Cytokine dysregulation in AIHA. IL: interleukin; TGF-β: transforming growth factor β; IFN-γ: interferon γ. Red arrows indicate stimulation black lines inhibition/block.