Complement inhibition by sutimlimab in cold agglutinin disease promotes red blood cell agglutination and may lead to circulatory complications, eryptosis and hemolysis.

Background: Sutimlimab, an anti-C1s monoclonal antibody, is approved for the treatment of cold agglutinin disease (CAD). It prevents hemolysis by inhibiting the classical complement pathway. One of its off-target effects may be increasing circulatory complications that have not yet been characterized. Methods: We report two patients with CAD who developed unusual widespread skin cyanosis and exacerbated acrocyanosis during sutimlimab treatment. One of the two patients additionally experienced massive intravascular hemolysis, eryptosis and acute renal failure. Serological analyses were conducted using standard techniques, and eryptosis was quantified by flow cytometry with PE-labelled Annexin V. Results: Serological assays using plasma and serum from these two patients and four additional untreated patients (n=6) with CAD were performed. They demonstrated a significant increase in red blood cell (RBC) agglutination in the presence of sutimlimab as well as in the absence of complement activation. Conclusion: The observed increase in RBC agglutination under sutimlimab treatment is likely due to a substantial reduction of C3d deposition on RBCs. This mechanism also represents the most plausible explanation for the side effects observed in some patients with CAD receiving the drug, such as aggravation of circulatory complications, including acrocyanosis, Raynaud's phenomenon, and less commonly, organ dysfunction. Inhibition of early complement components (C1-C3) may therefore not only prevent hemolysis in CAD but paradoxically also promote RBC agglutination, eryptosis, and hemolysis in certain cases. Pre-treatment serological testing with sutimlimab may help predict some of these adverse effects.