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Pediatric-onset Evans syndrome outcomes
(median 4.8 years [range, 3–7 years]).1,3–7 However, although the trends reported here are clear, some factors may also influence the estimates. The loss to follow-up mainly concerned AYA and few patients were followed after the age of 20 years. As well, the CEREVANCE group recommends clinical and biological follow-up at least every 6-12 months but local practice or patients’ pheno- type (such as the presence of cIM) may have influenced biological testing.
Sustained CR was eventually achieved for both types of cytopenia in the vast majority of patients, although this often took many years, especially for ITP (>10 years for one-third of our patients). Because active treatments are used to treat most AYA (notably because of cIM), hemato- logical CR may be drug induced and it is impossible to determine whether an underlying hematological autoim- munity is still present. The higher rate of sustained CR in ITP among patients with pES compared to patients with cITP alone may be due to more patients with pES receiv- ing treatment.18
One of the most striking findings in this study was the progressive increase in the frequency and number of IM. A range of cIM, affecting almost every organ, were identi- fied and developed independently of cytopenias. These findings clearly show that pES is a marker for a more gen- eral tendency toward immunodeficiencies while we can- not exclude a contribution of the second-line treatments received to some IM. The underlying etiology is not com- pletely understood and may vary among patients, with both genetic and environmental factors being important. Consequently, pES may be considered a composite syn- drome with several overlapping subgroups of secondary pES. One of these subgroups includes patients with PID. Classically, ALPS has been associated with pES.12 In this study, only 4% of patients were diagnosed with ALPS based on well-defined criteria, despite evocative biological “ALPS-like” abnormalities in a larger proportion of patients.17 This observation is consistent with our previ- ous study,13 which showed that more immune-response genes are potentially involved in pES than initially sus- pected.13,19–21 However, pES rarely comports as a Mendelian disease,1 and some of these variants may be predisposing rather than disease-causing alleles. Even in patients carrying a variant in a monogenic PID gene (e.g., TNFRFS6 or CTLA4),13,22 the altered genes show incom- plete penetrance.23,24 We were unable to evaluate the pro- portion of patients who met common variable immunod- eficiency disorders diagnostic criteria,25 as vaccine responses were not evaluable in all cases due to second- line treatments received. A second subgroup includes patients with SLE, although the prevalence of this sub- group is controversial.11,26,27 Our cohort suggests that SLE eventually occurs almost exclusively within the known at- risk population of female adolescents and is frequent in this subgroup, as it developed in seven of 15 (47%) of the females >12 years old.26 Despite its heterogeneity, the course of pES, in terms of age-related changes and trends, was similar for the majority of patients. The spectrum of IM described here is probably influenced by the underly- ing etiology, and further analyses are needed to under- stand the determinant of IM. The long-term follow-up of the present study confirms that the subgroup of patients with identified PID had more cIM.13
Most patients required second-line treatments. These treatments reflect local practices and we cannot draw con-
clusions regarding their efficacy. We were unable to inves- tigate the risk associated to specific treatments given the high heterogeneity in second-line treatment combinations and duration as well as the changes in management prac- tices since the cohort onset in 2004. The rapid initial increase in second-line treatments is partly due to the high rate of early relapse and the current practice of administer- ing steroid-sparing agents to treat pES.28 However, the presence of cytopenia is not the only reason for using these drugs and first- and second-line treatments were also used after CR of both cytopenias. cIM are important in determining the number of second-line treatments used, but bIM may also play a role, particularly in patients with SLE biomarkers, who are frequently given hydroxy- chloroquine. Nevertheless, second-line treatments are rarely selected based on a single factor. Patients with pES often have bIM and cIM, and the whole clinical picture needs to be assessed before selecting a treatment strategy. As previously reported,13 approximately one-third of patients may carry alterations in genes that are potentially accessible to targeted therapy.29–31 Given the high burden of second-line treatments and their association with infec- tions and mortality, the CEREVANCE network has pro- posed implementing genetic analyses for all patients with pES to limit the use of immunosuppressive and toxic drugs.
Comprehensively, the pES clinical picture changes as patients age. From 10 to 20 years of age, cytopenia tends to be controlled but IM are more prevalent, and active sec- ond-line treatments are used in more than two-thirds of patients during the pediatric-to-adult transition. Overall, as patients age, the illness becomes more severe and the risk of mortality increases. Both IM and treatment burden contribute to the infection-related mortality peak observed at the end of the second decade. The patients who died had received more second-line treatments, including splenectomy. Because these two parameters are correlated (r=0.60; P<0.0001), the number of deaths was too low to determine whether splenectomy alone was a risk factor of mortality per se or a marker of severity.
In conclusion, pES must now be considered a complex multi-systemic disease in which cytopenias frequently present fewer challenges than IM and infections in long- term follow-up. Adult patients with pES form a specific subgroup, distinct from older adults with ES.32 Multidisciplinary follow-up of patients with pES is needed and must focus on IM screening, genetic diagnosis, infec- tions prevention, patient-tailored drugs development, and AYA management. Specifically, the infection burden may be reduced by ensuring up-to-date vaccinations, eradicat- ing chronic infections, and using adequate antimicrobial prophylaxis or immunoglobulin replacements. As in sever- al chronic pediatric diseases,33 dedicated child-to-adult transition programs are warranted to improve outcomes in patients with pES.
Disclosures
No conflicts of interest to disclose.
Contributions
TP, HF, TL, GL and NA designed the study, analyzed the data and drafted the paper; TP and HF performed statistical analyses; CP and FR-L performed genetic analyses. All of the authors participated to prospective data collection and interpreta- tion and revised the manuscript for critical content.
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