Warm AIHA can complicate several diseases. Patients with systemic lupus erythematosus (SLE) can develop warm AIHA as part of their disease complex. The initial treatment approach is the same, but data suggest that splenectomy may not be as effective.13,17 Also, many SLE patients have complex medical conditions, making surgeries riskier. For SLE patients who are refractory or cannot be weaned from steroids, rituximab may be the better choice. Babesiosis, particularly in asplenic patients, has been associated with the development of AIHA.21,22
Of the malignances associated with AIHA, chronic lymphocytic leukemia (CLL) has the strongest association.4,23 Series show that 5% to 10% of patients with CLL will have warm AIHA. AIHA can appear concurrent with CLL or develop during the course of the disease. The introduction of purine analogs such as fludarabine led to a dramatic increase in the incidence of warm AIHA in treated patients.24 It is speculated that these powerful agents reduce the number and effectiveness of T cells that hold in check the autoantibody response, leading to warm AIHA.25 However, when these purine analogs are used in com-bination with agents such as cyclophosphamide or rituximab (with their immunosuppressive effects), the rates of warm AIHA have been lower.23
The approach to patients with CLL and warm AIHA depends on the state of their CLL.23 For patients who have low-stage CLL that does not need treatment, the standard approach to warm AIHA should be steroids, splenectomy, and rituximab.24 For patients with higher-stage CLL, the treatment for the leukemia will often provide therapy for the warm AIHA. The combination of rituximab-cyclophosphamide-dexamethasone has been reported to be effective for both the AIHA and CLL components.26 The use of ibrutinib has also been reported to be effective.27
A rare but important variant of warm AIHA is Evans syndrome.28,29 This is the combination of AIHA and ITP. Approximately 1% to 3% of AIHA cases are the Evans variant. The ITP can precede, be concurrent with, or develop after the AIHA. The diagnosis of Evans syndrome should raise concern for underlying disorders. In young adults, immunodeficiency disorders such as autoimmune lymphoproliferative disease (ALPS) need to be considered. In older patients, Evans syndrome is often associated with T cell lymphomas. The sparse literature on Evans syndrome suggests that it can be more refractory to standard therapy, with response rates to splenectomy in the 50% range.28,30 In patients with lymphoma, antineoplastic therapy is crucial. There is increasing data showing that mycophenolate or sirolimus may be effective for patients with ALPS in whom splenectomy or rituximab therapy is unsuccessful.31
Warm AIHA with IgA or IgM Antibodies
In rare patients with warm AIHA, IgA or IgM is the implicated antibody. The literature suggests that patients with IgA AIHA may have more severe hemolysis.32 Patients with IgM AIHA often have a severe course with a fatal outcome.33 In such cases, the patient’s plasma may show spontaneous hemolysis and agglutination. The DAT may not be strongly positive or may show C3 reactivity only. The clinical clues are C3 reactivity with no cold agglutinins and severe hemolysis, sometimes with an intravascular component. Treatment is the same as for warm AIHA, including the use of rituximab.34
