Knowledge on rare diseases and orphan drugs

The annual incidence of AIHA is estimated at 1/35,000-1/80,000 in North America and Western Europe. Warm autoantibodies (active at temperatures between 37-40°C) cause 60-70% of cases, cold autoantibodies (active at temperatures below 30°C) account for 13-15% of cases, mixed type occurs in less than 10% of cases and the annual incidence of drug-induced AIHA is estimated at 1/1,000,000.

The disease can appear at any age and there is a slight predominance of cases in females (60%). AIHA is characterized by hemolytic anemia, which is most often revealed by an unusual weakness and fatigue with tachycardia and exertional dyspnea, and also in some cases by jaundice, dark urine and/or splenomegaly.

AIHA can be primary (idiopathic), secondary to infection or associated with diseases such as B-cell lymphomas, other systemic or organ-specific autoimmune diseases, Hodgkin's disease, hepatitis or primary immunodeficiencies, or, in the case of drug-induced AIHA, caused by a reaction to drugs. The condition may develop gradually or occur suddenly. There are different subtypes of AIHA according to the temperature reactivity of the autoantibody: warm AIHA, cold AIHA (which includes cold agglutinin disease, CAD and paroxysmal cold hemoglobinuria or PCH), mixed-type AIHA and drug-induced AIHA. Half of warm AIHA cases are idiopathic whereas almost all cold AIHA are secondary.

Diagnosis is based on clinical or laboratory evidence of hemolysis and the detection of autoantibodies by means of the direct anti-globulin test (DAT).

Biological differential diagnoses include other non-autoimmune causes of hemolytic anemia.

Treatment is dependent on correct diagnosis. Cases of drug-induced AIHA should be investigated to determine if stopping a drug will induce remission. For warm AIHAs, corticosteroids are used, followed by splenectomy if necessary. Some targeted therapies, such as rituximab (anti-CD20 monoclonal antibody), have shown promising results. Other immunosuppressive treatments may be suggested. For cold AIHA, keeping the patient warm may be sufficient, and corticosteroids and splenectomy must be avoided as they are known to be ineffective. Rituximab has been demonstrated as a relatively effective and safe option for treating patients with symptomatic chronic cold agglutinin disease. Transfusion may be necessary in cases with inadequate response to therapy and life-threatening worsening anemia. However, transfusion can be complicated because of the presence of the autoantibodies, which can, in addition, increase destruction of the donor red blood cells.

Prognosis depends on the underlying cause of the disease and whether symptoms are managed appropriately and in a timely manner, but death is a rare outcome.

Last update: August 2010 - Expert reviewer(s): Pr Marc MICHEL