New Insights in Autoimmune Hemolytic Anemia: From Pathogenesis to Therapy

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.

Autoimmune Complications in Hematologic Neoplasms

“…Additionally, 50% of patients with marginal zone lymphoma developed autoimmunity, mainly AIHA or ITP [ 12 ]. It should be noted that cold agglutinin disease (CAD), sustained by monoclonal cold reactive IgM autoantibodies, is almost invariably associated with a CD5+CD20+ B cell clone, often hardly distinguishable from other NHL [ 2 ]. Finally, in NHL some case reports of PRCA and aplastic anemia (AA) have also been described, frequently associated with previous chemotherapy, HSCT, and infections as possible triggers [ 5 ].…”

“…There is increasing awareness of autoimmune complications in hematologic malignancies. Peripheral autoimmune cytopenias (AICy) such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are well known complications of lymphoproliferative disorders (LPD) [ 1 , 2 ]. Other less investigated autoimmune diseases (AID) include various organ-specific disorders targeting endocrine glands, liver, and gut, as well as systemic AID (i.e., systemic lupus erythematosus, SLE, rheumatoid arthritis, RA, and antiphospholipid syndrome, APS).…”

“…Diagnosis of AICy may be challenging in hematologic malignancies, due to overlapping conditions like chemotherapy, bone marrow infiltration, and transfusion support. It is known that the direct antiglobulin test (DAT) or Coombs test for the diagnosis of AIHA may be negative in up to 10% of cases, and that the detection of anti-platelet and anti-neutrophil antibodies has low sensitivity [ 1 , 2 ]. Moreover, AIDs are multi-systemic conditions, frequently referred to different specialists, whose diagnosis mainly relies on a constellation of overlapping clinical/laboratory features.…”

“…Autoimmunity results from a complex interplay of genetic and environmental factors, including infections and drugs. It is known that primary immunodeficiencies have a high frequency of autoimmune disorders along with an aberrant immune response against pathogens [ 2 , 3 ]. Furthermore, autoimmune patients have a higher susceptibility to infections, possibly as a result of immunosuppressive therapy, triggering a vicious circle that further worsens immune dysregulation.…”

Epidemiology and Risk Factors of Warm and Cold Autoimmune Hemolytic Anemia

“…Infections, concurrently occurring, AIHA with thrombocytopenia (Evans syndrome), acute renal failure, and major thrombotic events (pulmonary embolism, stroke, cardiac infarction) are bad prognosis factors for AIHA patients. Recent reports stated a mortality rate of 4% in overall AIHA cases[5].…”