Evans' Syndrome in Adults: An Observational Multicentre Study

Abstract

Evans' syndrome is a rare condition (estimated prevalence of 1-9 per million), characterized by the association (concomitant or not) of immune thrombocytopenia (ITP), with autoimmune hemolytic anemia (AIHA), and/or autoimmune neutropenia (AIN). Here we investigated 106 adult patients (male to female ratio 0.89, median age 50 years) followed for a median of 7.5 years in 12 European tertiary centers. Hematological data and associated conditions at diagnosis, treatments, complications, and outcome were retrospectively collected. The vast majority of patients had the combination of ITP plus AIHA, whereas 6.6% had ITP plus AIN, 2.8% AIHA plus AIN, and 8.5% had triple lineage cytopenia. At presentation, thrombocytopenia, anemia, and concomitant cytopenias were equally frequent (about 1/3 each), whilst AIN was rarer. An associated condition was present in 29% of cases, and included: a) other autoimmune diseases (11.3%), namely Hashimoto thyroiditis (N=7), anti-phospholipid syndrome (N=3), systemic lupus erythematosus (N=1), rheumatoid arthritis (N=1); b) tumors/clonal disorders (12.2%), consisting of colorectal cancers (N=3), thymoma (N=1), Ewing sarcoma (N=1), lymphoproliferative disorders (N=3), multiple myeloma (N=1), MGUS (N=3), and paroxysmal nocturnal hemoglobinuria (N=1); and c) immunodeficiencies (5.6%), including common variable immunodeficiency (N=5), and Kabuki syndrome (N=1). Laboratory values are detailed in table 1, and show a great heterogeneity depending on the predominant cytopenia. Direct antiglobulin test was positive in 93/106 cases, diagnosing 82 warm AIHA (57 IgG, 23 IgG+complement, and 2 IgA), 4 cold and 7 mixed AIHA. Anti-platelets antibodies were positive in 41/48 patients (85%), and anti-neutrophil antibodies in 10/22 (45%). Immunoglobulin levels showed high variability consistently with the underlying conditions, with hypo-IgA present in 5/49 (10%), and hypo-IgG or IgM in 9 (18%) and 8 (16%), respectively. Additionally, anti-nuclear antibodies were positive in 33/88 (37.5%), ENA in 5/63 (8%), anti-DNA in 4/66 (6%), anti-cardiolipin antibodies in 12/64 (18.7%), anti-beta2 glycoprotein antibodies in 8/50 (16%), and lupus anticoagulant in 9/60 (15%). Regarding therapies, all patients received steroids as first-line and 84% intravenous immunoglobulins (mainly for ITP). Rituximab was administered in 51.8% (7 in first, 22 in second, and 26 in subsequent lines), immunosuppressors in 49% (mycophenolate mofetil N=15, azathioprine N=14, cyclophosphamide N=12, and cyclosporine N=11), and splenectomy was performed in 20% of patients. Notably, thrombopoietin receptor analogues (TPO-RA) were given in 38% of cases, namely eltrombopag (N=24), romiplostim (N=16) or both (N=4). Additional therapies included plasma exchange (N=4), recombinant erythropoietin (EPO, N=3), GCSF (N=2), bortezomib (N=2), fostamatinib (N=1), and parsaclisib (N=1). Response rate to first line steroids+/-IVIG was 85%, however, 21 patients required further concomitant treatment (including 2 splenectomies). Response rates beyond first line therapy are difficult to evaluate given that AIHA or ITP relapses required different treatments (i.e. EPO versus TPO-RA), and that many relapses were treated with multiple concomitant treatments. On the whole, relapses were very frequent with 81/106 (76.4%) experiencing at least one, 53.7% two, and 27.3% three or more relapses. Regarding complications, bleeding was observed in 45/106 (42.4%), thrombosis in 27 (25.4%), and CTCAE >3 infections in 46 (43.3%). Death occurred in 26% of cases. In conclusion, these data highlight the clinical severity and the unmet need for therapy in adult Evans' syndrome. Moreover, the great frequency of relapses and burden of complications underline the poor clinical outcome of this condition. Disclosures Michel: Bioverativ: Consultancy; Rigel: Consultancy; Alexion Pharmaceuticals: Consultancy. McDonald:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor. Barcellini:Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Other: invited speaker , Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding.

Evans’ syndrome following vaccination with ChAdOx1 nCoV-19 in a patient with new-onset localized scleroderma

“…Regarding autoimmunity testing, almost 90% of tested subjects had a positive direct Coombs test and non-organ specific autoantibodies were detected in over 50% of cases (e.g., ANA, ENA, lupus anticoagulant). 7 LS, also referred to as morphea, is an uncommon inflammatory and fibrotic disease of the skin and subcutis. LS encompasses a wide spectrum of clinical variants ranging from solitary skin lesions with minimal discomfort to severe subtypes such as generalized or linear morphea.…”

“…Evans’ syndrome is an autoimmune condition that presents with two or more cytopenia, which usually include ITP and warm (about 37°C) AIHA which is mainly characterized by extravascular hemolysis in the spleen. 6 , 7 Warm AIHA is diagnosed in the presence of anemia, usually macrocytic and of variable intensity, reticulocytosis, and a positive direct Coombs test positive for warm anti-IgG antisera with panreactive specificity or anti-IgG plus C3 at low titer. 7 Depending on disease severity and time of evaluation, increased serum LDH and indirect bilirubin, and decreased haptoglobin are frequent findings in patients with AIHA.…”

“… 6 , 7 Warm AIHA is diagnosed in the presence of anemia, usually macrocytic and of variable intensity, reticulocytosis, and a positive direct Coombs test positive for warm anti-IgG antisera with panreactive specificity or anti-IgG plus C3 at low titer. 7 Depending on disease severity and time of evaluation, increased serum LDH and indirect bilirubin, and decreased haptoglobin are frequent findings in patients with AIHA. In the present case, normal coagulation parameters and the absence of schistocytes excluded a diagnosis of disseminated intravascular coagulation and other microangiopathies.…”

Evans Syndrome in a Jehovah’s Witness

“…This is likely attributed to the rarity of ES, especially in populations that refuse blood transfusion. The use of ESAs in isolated AIHA has been examined in greater detail; however, varying outcomes are described in small multicentric studies [ 3 ]. In a single case report, it was theorized that the mechanism of ESAs in AIHA is secondary to both stimulations of RBC production and the ability to decrease the total amount of autoantibodies present on RBCs by increasing the amount of antibody-free erythrocytes in circulation [ 8 ].…”

“…Secondary ES is usually associated with a wide array of underlying disorders, including systemic lupus erythematosus (SLE), autoimmune hepatitis, chronic lymphocytic leukemia, and autoimmune lymphoproliferative syndrome (ALPS) [ 1 , 2 ]. The exact prevalence of ES is unknown; however, rough estimates note one to nine persons per million based on small retrospective cohorts and observational studies [ 3 ]. A retrospective review in Denmark identified 242 patients diagnosed with ES from 1977 to 2017, noting a five-year mortality rate of 38% and a median survival of 1.7 years in patients with secondary ES specifically [ 4 ].…”