Diagnosis and management of cold agglutinin disease.

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.