What are the causes of warm autoimmune hemolytic anemia (AIHA)?

Causes of Warm Autoimmune Hemolytic Anemia (AIHA)

Warm AIHA is either primary (idiopathic, accounting for approximately 50% of cases) or secondary to lymphoproliferative disorders, autoimmune diseases, drugs, infections, immunodeficiencies, or solid tumors. 1, 2

Primary (Idiopathic) Warm AIHA

• Accounts for 50% of all warm AIHA cases, where no underlying cause can be identified despite thorough evaluation 1, 2, 3
• Results from breakdown of immunologic tolerance through mechanisms including polyclonal B-cell activation, T-cell dysfunction, and impaired immunoregulatory pathways 4

Secondary Warm AIHA

Lymphoproliferative Disorders (Most Common Secondary Cause)

• Chronic lymphocytic leukemia (CLL) is the leading cause of secondary warm AIHA, with more than 90% of autoimmune disorders in CLL caused by nonmalignant B lymphocytes producing polyclonal high-affinity IgG via T-cell-mediated mechanisms 1
• CLL tumor cells function as antigen-presenting cells, inducing formation of autoreactive T-helper cells and nonfunctional T-regulatory cells 1
• Other lymphomas including diffuse large B-cell lymphoma and follicular lymphoma are also associated with warm AIHA 1
• The autoimmune cytopenia may precede clinically apparent CLL and can be detected in monoclonal B-cell lymphocytosis 1

Drug-Induced Immune Hemolytic Anemia (DIIHA)

• Common causative drugs include:
  • Antibiotics: cephalosporins, penicillins 1
  • Antimicrobials: rifampin, dapsone 1
  • Antivirals: ribavirin, interferon 1
  • Chemotherapy: fludarabine 1
  • Anti-inflammatory: NSAIDs 1
  • Immune checkpoint inhibitors (increasingly recognized cause) 5, 2
• Drug-associated AIHA may persist for months or years after drug exposure, particularly with nitrofurantoin and minocycline 6

Autoimmune Diseases

• Systemic lupus erythematosus and other systemic autoimmune conditions 2, 3
• Organ-specific autoimmune diseases 2
• Autoimmune hepatitis (though less commonly associated with autoimmune cytopenias) 1

Infections

• Hepatitis A, hepatitis E, cytomegalovirus, and Epstein-Barr virus have been documented as precipitants 6
• Various other infectious triggers 2, 3

Other Secondary Causes

• Congenital immunodeficiencies (particularly important in pediatric cases) 2, 3
• Hematopoietic stem-cell transplantation 2
• Solid tumors 7, 2

Pathophysiologic Mechanism

• IgG-opsonized red blood cells undergo extravascular hemolysis via antibody-dependent cellular cytotoxicity, primarily through macrophage-mediated phagocytosis in the spleen and lymphoid organs 1, 7, 8
• Complement activation may occur with or without IgG binding, contributing to hemolysis 7, 8

Critical Clinical Considerations

Diagnostic Pitfalls to Avoid

• In patients with CLL-associated AIHA, distinguish immune-mediated cytopenias from bone marrow infiltration, as patients with immune mechanisms have better outcomes 1, 9
• Consider drug-induced AIHA even when patients have been taking medications for months or years, as this is atypical for standard drug-induced liver injury but characteristic of drug-related AIHA 6
• Periodically re-evaluate relapsed/refractory cases for possible evolution into myelodysplastic syndromes or bone marrow failure syndromes 7

Important Prognostic Information

• Patients with autoimmune cytopenia due to immune mechanisms in CLL have better outcomes than those with cytopenias from bone marrow infiltration 1, 9
• The incidence of autoimmune cytopenia in CLL patients treated with chemoimmunotherapy is lower than with chemotherapy alone 1