›IV methylprednisolone 1 mg/kg/day if oral route unavailable
›High-dose IV methylprednisolone 1 g/day for 3 days in life-threatening cases
›Rituximab — add upfront for severe disease (Hb <4.9 mmol/l)
›Two RCTs showed doubling of long-term responses with combination steroid + rituximab
›Rituximab 375 mg/m2 IV weekly × 4 cycles
›Alternative: rituximab 1000 mg IV × 2 doses 2 weeks apart
›70–80% response rate as monotherapy second-line
›~30% relapse within 3 years after initial response
›Class IIa recommendation (ASH/AIHA expert consensus)
Second-line treatment — warm AIHA
›Rituximab (if not given first-line)
›Rituximab 375 mg/m2 IV weekly × 4 cycles
›Response onset 2–4 weeks after first dose
›Monitor for infusion reactions — premedicate with acetaminophen and diphenhydramine
›IVIG
›Indicated if no response within 7 days or as bridge therapy
›IVIG 1 g/kg/day × 2 days or 0.4 g/kg/day × 5 days
›Temporary effect (2–4 weeks); saturates Fc receptors
›Useful adjunct in Evans syndrome
›Cochrane 2021: insufficient high-quality RCT data for definitive IVIG recommendation
Third-line and refractory treatment
›Splenectomy
›~70% response rate
›Increasingly deferred due to infection and thrombosis risks
›Vaccinations required ≥2 weeks pre-operatively
›Pneumococcal, meningococcal, Haemophilus influenzae type b vaccines
›Long-term penicillin prophylaxis post-splenectomy
›Immunosuppressants
›Mycophenolate mofetil 1–1.5 g twice daily
›Response rate ~60–70%; slower onset 4–8 weeks
›Azathioprine 1–2 mg/kg/day
›Check TPMT activity before initiating
›Cyclosporine 2.5–5 mg/kg/day
›Monitor renal function and blood levels
›Cyclophosphamide — for refractory severe cases
›Higher toxicity profile
›Emerging agents (2024–2026)
›Fostamatinib — SYK inhibitor, FDA-approved for ITP; off-label in AIHA
›150 mg twice daily orally
›Rilzabrutinib — BTK inhibitor in clinical trials for warm AIHA
›Nipocalimab — anti-FcRn, reduces IgG including pathologic autoantibodies
›Sovleplenib — Phase 2/3 RCT (Lancet Haematology 2025) in warm AIHA
›Spleen tyrosine kinase inhibitor
Cold agglutinin disease treatment
›Avoid cold exposure — primary preventive measure
›Warm clothing and environmental temperature control
›Avoid cold foods and IV fluids at room temperature
›Warm all IV fluids and blood products to 37°C
›Rituximab — first-line for treatment-requiring cold agglutinin disease
›Steroids largely ineffective for long-term cold AIHA management
›Rituximab 375 mg/m2 IV weekly × 4 cycles
›Response rate ~50–60% in cold agglutinin disease
›Rituximab + bendamustine for refractory cases
›Higher response rates in clonal B-cell driven cold AIHA
›Sutimlimab (Enjaymo) — FDA-approved for hemolysis in cold agglutinin disease
›Anti-C1s complement inhibitor targeting classical complement pathway
›Sutimlimab 6.5 g IV (body weight <75 kg) or 7.5 g IV (≥75 kg) every 2 weeks
›Rapid hemolysis control within 1–3 weeks
›NEJM 2021 (Berentsen): significant reduction in hemolysis markers and transfusion need
›Approved for patients not requiring active chemotherapy
VTE prophylaxis and anticoagulation
›Prophylactic anticoagulation during active severe hemolysis
›VTE absolute risk 15–30% in warm AIHA
›LMWH enoxaparin 40 mg subcutaneously daily (standard prophylaxis)
›Higher-dose prophylaxis (enoxaparin 40 mg twice daily) if high-risk features
›Therapeutic anticoagulation if documented VTE
›LMWH or direct oral anticoagulant based on renal function
›Duration: throughout active hemolysis and initial treatment period