What is the role of Intravenous Immunoglobulin (IVIG) in treating adult patients with Autoimmune Hemolytic Anemia (AIHA) who are refractory to first-line treatments like corticosteroids?

IVIG in Autoimmune Hemolytic Anemia

IVIG is not recommended as a primary treatment for inhibitor eradication in AIHA, but can be used as an adjunctive therapy in severe, refractory cases requiring rapid hemoglobin stabilization alongside corticosteroids and rituximab. 1, 2

First-Line Treatment Approach

Corticosteroids remain the cornerstone of initial therapy for warm AIHA, achieving clinical response in 70-85% of patients. 3, 4 The standard regimen is prednisone 1 mg/kg/day, tapered slowly over 6-12 months. 4, 5

IVIG should be reserved for specific clinical scenarios rather than routine first-line use:

• Severe, life-threatening hemolysis requiring rapid intervention while awaiting corticosteroid effect 2, 6
• Combination therapy with corticosteroids when faster hemoglobin recovery is needed 6, 5
• Patients with contraindications to corticosteroids (though this is less common in AIHA than ITP) 5

The typical IVIG dosing when used is 1 g/kg as a single dose, which may be repeated if necessary. 1

Evidence Quality and Limitations

The recommendation against IVIG for inhibitor eradication comes from acquired hemophilia A guidelines, which explicitly state: "We do not recommend use of high-dose intravenous immunoglobulin for inhibitor eradication in patients with AHA." 1 While this addresses a different autoimmune coagulopathy, the principle of IVIG's limited efficacy in autoantibody eradication applies broadly.

The evidence supporting IVIG in warm AIHA is limited to:

• Case reports showing benefit when combined with therapeutic plasma exchange and rituximab in refractory cases 6
• Expert opinion listing IVIG as an "additional therapy" rather than standard treatment 3, 4
• No randomized controlled trials demonstrating superiority over corticosteroids alone 5

Second-Line Treatment Hierarchy

For corticosteroid-refractory or relapsed AIHA, the preferred sequence is:

1. Rituximab (now the preferred second-line option, effective in 70-90% of cases) 2, 3, 4
2. Splenectomy (effective in ~70% with 20% cure rate, increasingly reserved for later lines) 2, 4
3. Immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil) 3, 4

Severe Refractory Cases

In life-threatening, treatment-resistant warm AIHA, consider this combination approach:

• High-dose corticosteroids (methylprednisolone 1g IV daily for 3 days) 2
• Therapeutic plasma exchange to rapidly remove autoantibodies 6
• Low-dose IVIG (combined with plasma exchange to prevent rebound) 6
• Rituximab (375 mg/m² weekly × 4 doses) 6, 4

This multi-modal approach showed rapid improvement in hemolysis markers in case reports of patients failing corticosteroids, IVIG, and rituximab individually. 6

Critical Pitfalls to Avoid

Do not delay corticosteroids in favor of IVIG monotherapy - corticosteroids have the strongest evidence base and highest response rates. 3, 4, 5

Do not use IVIG as maintenance therapy - unlike in ITP where IVIG has a defined role, there is no evidence supporting repeated IVIG infusions for AIHA maintenance. 5

Ensure adequate supportive care alongside any immunotherapy:

• RBC transfusions when hemoglobin is critically low despite theoretical concerns about alloimmunization 5
• Prophylactic anticoagulation for severe hemolysis (increased thrombotic risk) 2
• Recombinant erythropoietin if reticulocytopenia/inadequate marrow compensation present 2

Emerging Therapies

For multiply-refractory cases after exhausting standard options, novel agents targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and neonatal Fc receptor (nipocalimab) are in development. 2