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

Thomas Pincez, Helder Fernandes, Thierry Leblanc, Gérard Michel, Vincent Barlogis, Yves Bertrand, Bénédicte Neven, Wadih Abou Chahla, Marlène Pasquet, Corinne Guitton, Aude Marie-Cardine, Isabelle Pellier, Corinne Armari-Alla, Joy Benadiba, Pascale Blouin, Eric Jeziorski, Frédéric Millot, Catherine Paillard, Caroline Thomas, Nathalie Cheikh, Sophie Bayart, Fanny Fouyssac, Christophe Piguet, Marianna Deparis, Claire Briandet, Eric Dore, Capucine Picard, Frédéric Rieux-Laucat, Judith Landman-Parker, Guy Leverger, Nathalie Aladjidi, Thomas Pincez, Helder Fernandes, Thierry Leblanc, Gérard Michel, Vincent Barlogis, Yves Bertrand, Bénédicte Neven, Wadih Abou Chahla, Marlène Pasquet, Corinne Guitton, Aude Marie-Cardine, Isabelle Pellier, Corinne Armari-Alla, Joy Benadiba, Pascale Blouin, Eric Jeziorski, Frédéric Millot, Catherine Paillard, Caroline Thomas, Nathalie Cheikh, Sophie Bayart, Fanny Fouyssac, Christophe Piguet, Marianna Deparis, Claire Briandet, Eric Dore, Capucine Picard, Frédéric Rieux-Laucat, Judith Landman-Parker, Guy Leverger, Nathalie Aladjidi

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 (IM). 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 years (range, 6.8-50.0 years) and the median follow-up period was 11.3 years (range, 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 IM increased with age: at the age of 20 years, 74% had at least one clinical IM (cIM). A wide range of cIM occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IM. The number of cIM 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 years (range, 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, long-term outcomes of pES showed remission of cytopenias but frequent IM linked to high second-line treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.

Figures

Figure 1.
Figure 1.
Hematological outcomes. (A) Cumulative incidence of patients achieving a sustained complete remission (CR). Among the 23 patients without sustained CR for autoimmune hemolytic anemia (AIHA), four (17%) had achieved sustained CR for immune thrombocytopenic purpura (ITP). Conversely, among the 32 patients without sustained CR for ITP, 13 (40%) had achieved sustained CR for AIHA. (B) Percentage of patients with a sustained complete remission according to age.
Figure 2.
Figure 2.
Immunopathological manifestations. (A) Age at first clinical immunopathological manifestation (cIM) diagnosis and at first cytopenia. Pearson correlation coefficient r=0.42, P<0.0001. There was no difference in the median age at first cIM and at first cytopenia in terms of the number of cIM (data not shown). (B) Cumulative incidence of cIM according to age. Half of the patients had developed a cIM by the age of 13.5 years and a second IM by the age of 27 years. (C) Cumulative incidence of any biological IM (bIM), as well as each category. Half of the patients had at least one bIM diagnosed by 13.2 years of age. The biological workup was not standardized and was made at the clinician’s discretion. SLE: systemic lupus erythematosus; ALPS: autoimmune lymphoproliferative syndrome.
Figure 3.
Figure 3.
Immunopathological manifestations and other associated manifestations. Individual occurrence of autoimmune neutropenia, clinical immunopathological manifestations (cIM), biological IM (bIM), atopy, severe or recurrent infections, and malignancies. Each column represents a patient. The patients are ordered according to their cIM, from the most (lymphoproliferation) to the least (hematological, other) frequent. Hypoγ: hypogammaglobulinemia; SLE: systemic lupus erythematosus; ALPS: autoimmune lymphoproliferative syndrome.
Figure 4.
Figure 4.
Second-line treatments. (A) Total number of second-line treatments received according to the age. (B) Number of second-line treatments ongoing according to age.
Figure 5.
Figure 5.
Long-term survival. (A) Survival estimate of patients in terms of time from first cytopenia. At 10-year follow- up, survival rates among patients with chronic immune thrombocytopenic purpura (ITP) alone, autoimmune hemolytic anemia (AIHA) alone and pediatric-onset Evans syndrome (pES) were 100%, 99% and 92%, respectively. (B) Mortality is shown in terms of time from first cytopenia, as well as age. Individual values are shown as dots with medians and interquartile ranges shown as lines. (C) Hematological status at death. CR: complete remission; PR: partial remission; NR: no remission.

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