Abstract Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia, a specific clonal B-cell disorder of the bone marrow, and a monoclonal gammopathy of clinical significance. Thus, CAD should be distinguished from cold agglutinin syndrome, a more heterogeneous cold hemolytic syndrome that occurs secondary to other clinical disease. Cold agglutinins in CAD are usually of the immunoglobulin M kappa class with a heavy chain variable region encoded by the IGHV4-34 gene segment. The hemolytic anemia is entirely mediated by classical complement activation, which also explains some additional clinical features, such as fatigue and acute exacerbations. Non-complement-mediated steps in pathogenesis are also essential, such as erythrocyte agglutination and, probably, coexistent cryoglobulin activity in some patients, resulting in cold-induced circulatory symptoms. Based on this heterogeneity, different clinical phenotypes can be defined and used to guide individualized treatment. Established therapies aim at targeting the pathogenic B-cell clone or the classical complement activation pathway. Novel and investigational therapies include Bruton's tyrosine kinase inhibitors, plasma cell–directed therapies, novel complement inhibitors, and entirely new approaches such as cytokine inhibitors and, possibly, antibodies specific for the VH4-34 protein sequence. Patients with CAD requiring therapy should be considered for clinical trials.
Sigbjørn Berentsen (Fri,) studied this question.