Characteristics at diagnosis of autoimmune hemolytic anemias in adults: First results from a prospective, multicenter cohort of 413 patients included in the carmen-France registry

Abstract

Abstract Autoimmune hemolytic anemias (AIHA) encompass with three main different subtypes based on the properties of the autoantibody: warm AIHA (wAIHA), cold agglutinin disease/syndrome (CAD/CAS; i.e., primary/secondary AIHA with exclusively cold antibodies, respectively), and mixed AIHA (mAIHA). The epidemiology of AIHA has been assessed using retrospective cohort studies including up to 308 patients, or cohorts based on claims databases that often lack detailed clinical and biological data. This study aimed to describe the clinical and biological characteristics at diagnosis of AIHA by subtypes, in a multicenter, prospective cohort in France. The data source was the Carmen-France Registry, that includes prospectively all adults with AIHA in the 50 participating centers. We selected the patients included between January 2015 and February 2025. AIHA diagnosis was based on international consensus criteria. The clinical and biological characteristics of patients at AIHA onset were described, as well as the causes of secondary AIHA, and the treatments used within the first week following the diagnosis. During the study period, 413 AIHA patients were included in the registry: 283 (68.5%) had wAIHA, 64 had CAD/CAS (15.5%), and 66 (16.0%) had mAIHA. The median age at diagnosis was 69 years (Q1-Q3: 56-79) and was similar between AIHA subtypes. There was a slight male predominance among wAIHA patients (148 males, 52.3%), and a female predominance among CAD/CAS (42 females, 65.6%) and mAIHA patients (38 females, 57.6%). A Charlson Comorbidity Index median score ≥1 was more frequent among the patients with wAIHA and mAIHA than CAD/CAS (respectively, 49.8%, 60.6% and 39.1%). Before AIHA diagnosis, 225 (54.5%) patients had cardiovascular risk factors: 150 (36.3%) had hypertension, 66 (16.0%) had dyslipidemia, 58 (14.0%) had diabetes, and 45 (10.9%) patients had active or recent cessation of smoking. In total, 51 (12.3%) patients had a history of arterial thrombosis, and 42 (10.2%) of venous thrombosis. At AIHA onset, 40 (62.5%) patients had symptoms of anemia in CAD/CAS versus 212 (74.9%) and 48 (72.7%) in wAIHA and mAIHA, respectively. In wAIHA, 123 (43.5%) had jaundice versus 18 (28.1%) and 19 (28.8%) in CAD/CAS and mAIHA, respectively. Clinical splenomegaly was present in 21.2% of wAIHA (primary: 14.0%; secondary: 30.2%) and 22.7% of mAIHA. Cardiac failure was present in 3.9% of patients and coronary insufficiency in 1.2%. The hemoglobin level was 71 g/L (Q1-Q3: 59-85) in wAIHA, 77 g/L (Q1-Q3: 66-94) in mAIHA, and 87 g/L (Q1-Q3: 76-99) in CAD/CAS. The levels of hemolytic markers were similar between groups. In the overall population, the lactate dehydrogenase level was 450 U/L (Q1-Q3: 338-666), the total bilirubinemia level was 38 µmol/L (Q1-Q3: 22-60), and the total haptoglobin level was 0.08 g/L (Q1-Q3: 0.00-0.10). We identified 126 secondary wAIHA (44.5% of wAIHA), 27 CAS (42.2% in CAD/CAS group), and 20 secondary mAIHA (30.3% of mAIHA). B cell clonal lymphoproliferative diseases were predominant in all AIHA subtypes (wAIHA: 55.6%; CAS: 44.4%; mAIHA 70.0%). In secondary wAIHA, the most frequent cause was chronic lymphocytic leukemia (23.0%) followed by marginal zone lymphoma (12.7%). Other autoimmune diseases were found in up to 25.4 % of wAIHA. Infections were the second causes of CAS (33.3%) including 5 (18.5%) patients with Mycoplasma pneumoniae infection. In secondary wAIHA, 10.3% of patients had systemic lupus erythematosus and 6.3% had antiphospholipid syndrome. Drug-induced wAIHA concerned 12 patients (n=5 immune checkpoint inhibitors; n=3 antibiotics). During the first week after AIHA diagnosis, wAIHA patients mostly received corticosteroids: 226 (80.0%) versus 28 (42.4%) and 10 (15.6%) in mAIHA and CAD/CAS, respectively. Red blood cell transfusion was required in 99 (35.0%) wAIHA patients, 20 (31.3%) CAD/CAS patients, and 16 (24.2%) mAIHA patients. During this early period, rituximab was introduced in 34 (12.0%) wAIHA patients, 6 (9.1%) mAIHA patients, and 3 (4.7%) CAD/CAS patients. Erythropoietin was scarcely used in all subtypes (wAIHA: 6.0%; CAD/CAS: 7.8%; mAIHA: 9.1%).In conclusion, age at AIHA diagnosis was similar between subtypes. AIHA was a severe disease with red blood cell transfusion requested at diagnosis in one quarter to one third of patients. The hemoglobin level was higher in cAIHA than in wAIHA and mAIHA. Rituximab was used early after wAIHA diagnosis in 12% of patients.