Navigating boundaries of autoimmunity in rare anemias: anti-erythropoietin antibody-mediated pure red cell aplasia in a patient with cold agglutinin disease

Abstract

Complement inhibitors like sutimlimab effectively control hemolysis in Cold Agglutinin Disease (CAD), although one-third of patients exhibit inadequate bone marrow compensation, requiring erythropoiesis-stimulating agents (ESAs). A rare but severe complication of such therapy is anti-erythropoietin (anti-EPO) pure red cell aplasia (PRCA), characterized by neutralizing antibodies against endogenous and exogenous EPO.
We describe the first documented case of anti-EPO PRCA in a patient with CAD receiving sutimlimab. Following an initial partial response to rituximab and subsequent remission with sutimlimab, the patient afterwards received recombinant human erythropoietin (rHuEPO) to address insufficient reticulocytosis causing persistent anemia. He subsequently developed severe and transfusion-dependent anemia in the context of a hypoproliferative phenotype with profound reticulocytopenia and normalized hemolytic markers. Diagnostic workup confirmed anti-EPO PRCA, revealing undetectable serum EPO levels and high titers of neutralizing anti-EPO antibodies. Bone marrow evaluation showed erythroid aplasia with IgG, IgM, and complement deposition. Discontinuation of rHuEPO and treatment with cyclosporine and corticosteroids failed to result in a response. Conversely, a second course of rituximab successfully controlled the B-cell clone, restoring erythropoiesis and achieving transfusion independence.
This case highlights a diagnostically challenging clinical presentation where iatrogenic aplasia may mimic refractory hemolysis. It underscores the importance of monitoring both reticulocyte kinetics and endogenous EPO levels in ESA-treated AIHA patients to promptly rule out secondary autoimmunity.