Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden

Abstract

Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IMs). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS’CEREVANCE cohort. Median age at final follow-up was 18.5 (6.8–50.0) years and the median follow-up period was 11.3 (5.1–38.0) years. At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IMs increased with age: at 20 years old, 74% had at least one clinical cIM. A wide range of cIMs occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IMs. The number of cIMs was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio, 1.4; 95% confidence interval, 1.15–1.60; p = 0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 (1.7–31.5) years, and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, longterm outcomes of pES showed remission of cytopenias but frequent IMs linked to high secondline treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.

Evans syndrome in adults: an observational multicenter study

“…We found a prevalence of underlying disease of about 20%, lower than that reported in a previous French study [7] and in adult wAIHA, and much lower than that observed in recent prospective pediatric experiences [4][5][6]. This difference may be related to the greater frequency of PID in children (more than 60% of ES) [4,6] and to a possible under-diagnosis of milder adult forms, where extensive workups and immunological/molecular studies are not routinely performed. It is worth mentioning that in adults it may be more difficult to select the appropriate genetic tests a priori.…”

“…Since then, the syndrome has been further characterized, with an estimated incidence of 1 to 9 per million people year, and up to 50% of ES cases being secondary to a variety of conditions including infections, primary immunodeficiencies (PID, particularly in children), systemic autoimmune diseases (such as systemic lupus erythematosus and rheumatoid arthritis), lymphoproliferative syndromes, and hematopoietic stem cell transplant [2,3]. Whilst recent prospective studies highlighted the clinical features, including disease associations and outcome, in pediatrics [4][5][6], less is known about adult patients, with the largest series of 68 cases dating back in 2008 [7]. In this collaborative international study, we retrospectively analyzed 116 patients with ES focusing on baseline characteristics, treatment requirement, occurrence of complications and death.…”

Refractory/relapse thrombocytopenia in a patient with Evans' syndrome successfully treated with zanubrutinib

“…Despite recent therapeutic advances, responses to existing options are often temporary and durable remission remains elusive. Many patients experience a prolonged course and become relapsed/refractory to a series of different interventions [3]. In the present case, we describe the treatment of a 15-year-old Chinese girl with ES who suffered severe refractory/relapse thrombocytopenia and was treated with zanubrutinib.…”

Abatacept is useful in autoimmune cytopenia with immunopathologic manifestations caused by CTLA-4 defects

“…In 2019, a preliminary study of the French OBS'CEREVANCE cohort of children with AIC identified CTLA-4 pathway pathogenic variants in 10/80 pediatric-onset Evans syndrome (pES) cases 9 . pES is now recognized as a severe long-lasting disease : numerous IM appearing with increasing age in 78% of cases; high burden of second-line treatments to control severe bleeding or hemolytic flares or organ specific IM; mortality rate reaching 10% 10,11 . Targeted therapies are urgently warranted to improve outcome in those patients.…”

“…This was a national observational study. Of note, patients under 18 years of age with AIC are routinely included in real time in the OBS'CEREVANCE cohort, prospectively followed and screened for an underlying diagnosis of IM and PID 9,11,12 . Written informed consents are obtained from parents and patients.…”