What are the treatment differences between cold and warm Autoimmune Hemolytic Anemia (AIHA)?

Treatment Differences Between Cold and Warm AIHA

Warm AIHA requires corticosteroids as first-line therapy, while cold agglutinin disease (CAD) should be treated with rituximab as first-line therapy—this fundamental difference stems from their distinct pathophysiology and antibody characteristics. 1, 2, 3

Warm AIHA Treatment Algorithm

First-Line Therapy

• Initiate prednisone 1-2 mg/kg/day orally for moderate cases, or intravenous methylprednisolone 1-2 mg/kg/day for severe presentations, with expected response rates of 70-85% within 3 weeks 1, 4, 5
• Add folic acid 1 mg daily to support increased erythropoiesis 1
• Monitor hemoglobin weekly until steroid tapering is complete 1
• Taper corticosteroids slowly over 6-12 months once response is achieved 5

Second-Line Therapy for Refractory/Relapsed Cases

• Rituximab is now the preferred second-line option with 70-90% response rates and potential for long-lasting complete remission, increasingly chosen before splenectomy due to lower morbidity 4, 2, 3
• Splenectomy remains effective in approximately 70% of cases with a 20% cure rate, but carries surgical risks and long-term infection susceptibility 4, 3

Third-Line Options

• Immunosuppressive agents including azathioprine, cyclophosphamide, cyclosporine, or mycophenolate mofetil for cases failing both corticosteroids and rituximab 1, 3, 6
• Last resort options include alemtuzumab, high-dose cyclophosphamide, or plasma exchange 3, 6

Cold Agglutinin Disease (CAD) Treatment Algorithm

First-Line Therapy

• Rituximab is recommended as first-line treatment for CAD, not corticosteroids 2, 3, 6, 5
• The European Society for Medical Oncology suggests rituximab combined with glucocorticoids for severe manifestations 2
• Avoidance of cold exposure is a critical supportive measure 2

Key Distinction

• Splenectomy is characteristically NOT used for CAD, unlike warm AIHA where it serves as an effective second-line option 2
• This difference exists because cold agglutinins cause complement-mediated intravascular hemolysis rather than splenic extravascular destruction 7

Pathophysiologic Basis for Treatment Differences

Warm AIHA Mechanism

• IgG antibodies (>90% of cases) opsonize red blood cells, leading to extravascular hemolysis via antibody-dependent cellular cytotoxicity primarily in the spleen 2
• Direct antiglobulin test (DAT) is positive for IgG with or without complement 2
• This splenic-predominant destruction explains why splenectomy is effective in warm AIHA 2

Cold AIHA Mechanism

• IgM antibodies (typically specific to Ii blood group system) activate complement, causing intravascular hemolysis 7
• DAT is positive only for C3d, not IgG 2, 7
• The complement-mediated pathophysiology explains why rituximab (targeting B-cells producing IgM) is more effective than splenectomy 2, 7

Common Pitfalls to Avoid

• Do not use corticosteroids as first-line monotherapy for CAD—they are ineffective compared to rituximab 3, 6, 5
• Do not perform splenectomy for CAD—it lacks efficacy in complement-mediated hemolysis 2
• Delaying treatment in severe cases of either type increases morbidity and mortality 1
• Monitor patients on long-term corticosteroids (warm AIHA) for hyperglycemia, hypertension, mood changes, insomnia, and fluid retention 1
• Perform DAT before initiating treatment to distinguish warm (IgG positive) from cold (C3d only positive) AIHA 1, 2

Secondary AIHA Considerations

• For CLL-associated AIHA not responding to conventional autoimmune therapy, treat the underlying CLL 1, 2
• Drug-induced AIHA (from cephalosporins, penicillins, NSAIDs, fludarabine, ribavirin) may resolve after discontinuing the offending agent 1