Cold Agglutinin Disease: Improved Understanding of Pathogenesis Helps Define Targets for Therapy

Abstract

The last 2 decades have seen great progress in understanding the pathogenesis of cold agglutinin disease (CAD) and development of effective therapies. Cold agglutinins can cause hemolytic anemia as well as peripheral circulatory symptoms such as acrocyanosis. We distinguish CAD, a well-defined clinicopathologic entity, from secondary cold agglutinin syndrome. This review addresses the histopathologic, immune phenotypic, and molecular features that allow CAD to be classified as a distinct clonal lymphoproliferative disorder of the bone marrow, recently recognized in the WHO classification. We discuss recent data on the possible overlap or distinction between CAD and Waldenström’s macroglobulinemia. Two major steps in the pathogenesis of CAD are identified: clonal B-cell lymphoproliferation (leading to monoclonal IgM production) and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. Established as well as novel and experimental therapies are reviewed.

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

“…Cold agglutinin disease (CAD) is a type of autoimmune hemolytic anemia (AIHA) caused by a bone marrow lymphoproliferative disorder that creates cold agglutinin autoantibodies ( Berentsen, 2021 ; Berentsen et al., 2022 ; Chonat and Stowell, 2022 ). CAD is sometimes distinguished from cold agglutinin syndrome (CAS), a similar type of AIHA that can be caused by infections (e.g.…”

“…Mycoplasma pneumoniae, Epstein-Barr virus infection) and malignancies (e.g. B cell lymphoma) ( Berentsen et al., 2022 ). It is most often caused by anti-I IgM antibody and rarely by antibodies with other specificities ( Berentsen, 2018 ).…”

The choice of new treatments in autoimmune hemolytic anemia: how to pick from the basket?

“…Binding of cold agglutinin to its cell surface antigen results in agglutination of erythrocytes, leading to complement-mediated hemolysis and, often, circulatory symptoms such as acrocyanosis and Raynaud-like phenomena ( 16 , 61 ). Of note, the agglutination and circulatory symptoms are not complement-mediated.…”

“…Until the turn of the millennium, treatment was mostly based on theoretical considerations, clinical experience, and expert opinion, but during the last two decades, several prospective studies have been conducted ( 1 , 12 – 14 ). Currently, several new therapies have appeared and quite a few clinical trials are running ( 15 , 16 ). Furthermore, not only the treatment options but also the clinical landscape of AIHA have changed over time ( 17 , 18 ).…”

Sutimlimab for the Treatment of Cold Agglutinin Disease

“…3,5,32 The 2 major steps in pathogenesis, clonal B-cell lymphoproliferation and classical complement activation, are logical and feasible targets for therapy. 18 This review will primarily address the complement C1s inhibitor sutimlimab as an extensively studied and recently established therapy option.…”