[Cold agglutinin disease (CAD)]

Cold agglutinin disease (CAD) is a rare but clinically impressive disease with a high level of disease burden and a risk of severe thromboembolic complications.

This review article provides a concise, clinically oriented summary of the current knowledge on the disease and the treatment options.

The diagnosis requires the detection of a chronic hemolysis with demonstration of C3d in a monospecific direct Coombs or antiglobulin test (DAT), the detection of cold agglutinins with a titer ≥ 1:64 at 4 °C and the exclusion of a malignant disease or relevant infection. Treatment options are so far the avoidance of low temperatures, adequate hydration in hemolytic crises, thrombosis prophylaxis as well as immunosuppressive treatment with rituximab and/or cytostatic agents. The only approved treatment is complement inhibition with sutimlimab. The hemolysis responds to inhibition of the classical complement pathway with the anti-C1s antibody sutimlimab within a few days with a decrease of hemolysis parameters and an improvement of fatigue. The treatment requires a comprehensive vaccination against capsulated bacteria and if necessary, a bridging antibiotic prophylaxis until this has been achieved. Supplementary treatment, such as administration of folic acid, vitamin B12 and iron in cases of deficiency or also a combination with other treatment strategies should be considered when necessary. Data on the use of sutimlimab in secondary cold agglutinin syndrome (CAS) are not yet available.

Knowledge of the specific clinical and laboratory hallmark changes of CAD with the early initiation of specific and targeted therapy or also referral to specialized centers has significantly improved the prognosis of the disease in recent years and reduced the suffering of patients.