Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort

Abstract

Evans syndrome (ES) is a rare autoimmune disorder whose long-term outcome is not well known. In France, a collaborative pediatric network set up via the National Rare Disease Plan now provides comprehensive clinical data in children with this disease. Patients aged less than 18 years at the initial presentation of autoimmune cytopenia have been prospectively included into a national observational cohort since 2004. The definition of ES was restricted to the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Cases were deemed secondary if associated with a primitive immunodeficiency or systemic lupus erythematosus. In December 2014, we analyzed the data pertaining to 156 children from 26 centers with ES whose diagnosis was made between 1981 and 2014. Median age (range) at the onset of cytopenia was 5.4 years (0.2–17.2). In 85 sequential cases, the time lapse between the first episodes of AIHA and ITP was 2.4 years (0.1–16.3). The follow-up period as from ES diagnosis was 6.5 years (0.1–28.8). ES was secondary, revealing another underlying disease, in 10% of cases; various associated immune manifestations (mainly lymphoproliferation, other autoimmune diseases, and hypogammaglobulinemia) were observed in 60% of cases; and ES remained primary in 30% of cases. Five-year ITP and AIHA relapse-free survival were 25 and 61%, respectively. Overall, 69% of children required one or more second-line immune treatments, and 15 patients (10%) died at the age of 14.3 years (1.7–28.1). To our knowledge, this is the first consistent long-term clinical description of this rare syndrome. It underscores the high rate of associated immune manifestations and the burden of long-term complications and treatment toxicity. Future challenges include (1) the identification of the underlying genetic defects inducing immune dysregulation and (2) the need to better characterize patient subgroups and second-line treatment strategies.

Reliable assessment of the incidence of childhood autoimmune hemolytic anemia

“…Over a 9‐year period and at a region level, the annual incidence of 0.81 cases per 100,000 children under 18 years confirms the rarity of the disease. The patients’ characteristics are consistent with the whole OBS'CEREVANCE cohort, with a shorter follow‐up: 70% of IgG/IgG + C3d DAT, 14% turn into ES, 43% are associated with a known infectious trigger, and 57% are secondary . This study using a registry‐based methodology thereby expands the severity spectrum of the disease and demonstrates a high frequency of its mild forms.…”

“…OBS'CEREVANCE is a national prospective cohort in which children with autoimmune cytopenia have been consecutively included from 2004 from all regional centers, with information on all medical data from birth to last news. It allowed descriptive studies of 265 children with AIHA and 156 children with ES . Thirty to 40 new cases per year of AIHA and AIHA/ES in children and adolescents are thought to occur in France but this incidence is likely underestimated for two main reasons: mainly the most severe forms are referred to hematological teams and the constitution of the cohort is entirely based on the dynamism of the specialists comprising the network, which may vary over time.…”

“…The pediatric literature on AIHA consisting of retrospective case series of 10-80 patients covering [15][16][17][18][19][20] year periods provided the initial clinical descriptions. [6][7][8][9][10] In Western countries, the sole estimated annual AIHA incidences previously reported are one per 80,000 residents in the adult population 11 and 0.2 per million individuals under 20 years.…”

Evans Syndrome at Childhood‐Onset Systemic Lupus Erythematosus Diagnosis: A Large Multicenter Study

“…Of note, ES recurrence or death was not observed in cSLE patients suggesting continuous complete remission, contrasting with other pediatric ES cases without associated lupus . Indeed, multicenter studies evaluating childhood cytopenias reported that approximately only one‐third of pediatric ES patients did not have recurrence and 10% of pediatric ES died at the age of 14 years . Furthermore, ES and other autoimmune cytopenias associated with ALPS seem to be a severe disease with poor outcome and increased risk of malignancy .…”

Benefits of rituximab as a second‐line treatment for autoimmune haemolytic anaemia in children: a prospective French cohort study

“…Some of these patients have already been reported in descriptive studies (Bader-Meunier et al, 2007;Aladjidi et al, 2011Aladjidi et al, , 2015. Patients with a well-defined inherited immune deficiency and those who received simultaneous disease-modifying treatment in the month before rituximab initiation were excluded.…”