Amandine Baptiste

Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome

The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*<20 ms, in patients with thalassemia, SCA, or MDS. Patient inclusion criteria were an accurate record of erythrocyte concentrates (ECs) received, a transfusion history >8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001). Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001). Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation.

ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis

Objectives To assess the efficacy and safety of adalimumab on uveitis in patients with early onset, chronic, juvenile idiopathic arthritis (JIA)-associated or idiopathic anterior uveitis and an inadequate response to topical steroids and methotrexate (MTX). Methods Patients aged 4 years or more with ocular inflammation quantified by laser flare photometry (LFP) ≥30 photon units/ms were double-blindly randomised (1:1) to 2 groups, one treated with placebo and one with adalimumab subcutaneously at a dose of 24 mg/m2 in patients aged <13 years, 40 mg in the others, every other week. The primary outcome was response at month 2 (M2) defined as a 30% reduction of inflammation on LFP in the assessable eye with more severe baseline inflammation and no worsening on slit lamp examination. From M2 to M12, all patients received adalimumab. Results At M2, among 31 patients included in intention-to-treat analysis, there were 9/16 responders on adalimumab and 3/15 on placebo (P=0.038, Χ2 test; relative risk=2.81, 95% CI 0.94 to 8.45; risk difference: 36.3%, 95% CI 2.1 to 60.6); there was no significant difference using the Standardised Uveitis Nomenclature classification criteria of improvement. Thirty patients continued the trial after M2 and received adalimumab (open-label phase), 29 reached M12. There were seven serious adverse events none related to study treatment. Conclusions This trial is in favour of using adalimumab in patients with early onset, chronic anterior uveitis, which is in most cases associated with JIA, in case of inadequate response to topical therapy and MTX. LFP could be a valuable tool to assess early treatment efficacy. Trial registration number NCT01385826.

Genotype-Phenotype Relationship in Patients and Relatives with SHOX Region Anomalies in the French Population

Background: The aim of our study was to describe a large population with anomalies involving the SHOX region, responsible for idiopathic short stature and Léri-Weill dyschondrosteosis (LWD), and to identify a possible genotype/phenotype correlation. Methods: We performed a retrospective multicenter study on French subjects with a SHOX region anomaly diagnosed by multiplex ligation-dependent probe amplification or Sanger sequencing. Phenotypes were collected in each of the 7 genetic laboratories practicing this technique for SHOX analysis. Results: Among 205 index cases and 100 related cases, 91.3% had LWD. For index cases, median age at evaluation was 11.7 (9.0; 15.9) years and mean height standard deviation score was -2.3 ± 1.1. A deletion of either SHOX or PAR1 or both was found in 74% of patients. Duplications and point mutations/indels affected 8 and 18% of the population, respectively. Genotype-phenotype correlation showed that deletions were more frequently associated with Madelung deformity and mesomelic shortening in girls, as well as with presence of radiologic anomalies, than duplications. Conclusions: Our results highlight genotype-phenotype relationships in the French population with a SHOX defect and provide new information showing that clinical expression is milder in cases of duplication compared to deletions.

Preoperative risk factors for intra‐operative bleeding in pediatric liver transplantation

This study analyzes the preoperative risk factors for intra‐operative bleeding in our recent series of pediatric LTs. Between November 2009 and November 2014, 84 consecutive isolated pediatric LTs were performed in 81 children. Potential preoperative predictive factors for bleeding, amount of intra‐operative transfusions, postoperative course, and outcome were recorded. Cutoff point for intra‐operative HBL was defined as intra‐operative RBC transfusions ≥1 TBV. Twenty‐six patients (31%) had intra‐operative HBL. One‐year patient survival after LT was 66.7% (CI 95%=[50.2–88.5]) in HBL patients and 83.8% (CI 95%=[74.6–94.1]) in the others (P=.054). Among 13 potential preoperative risk factors, three of them were identified as independent predictors of high intra‐operative bleeding: abdominal surgical procedure(s) prior to LT, factor V level ≤30% before transplantation, and ex situ parenchymal transsection of the liver graft. Based on these findings, we propose a simple score to predict the individual hemorrhagic risk related to each patient and graft association. This score may help to better anticipate intra‐operative bleeding and improve patients management.

Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21: A Randomized Clinical Trial

Importance Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated. Objective To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening. Design, Setting, and Participants Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening. Interventions Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing. Main Outcomes and Measures The primary outcome was number of miscarriages before 24 weeks’ gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing. Results Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of −0.03% (1-sided 95% CI, −0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%). Conclusions and Relevance Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates. Trial Registration ClinicalTrials.gov Identifier: NCT02127515

Surgery is not superior to dilation for the management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome: a multicenter comparative observational study in 131 patients

BACKGROUND: Vaginal agenesis in Mayer‐Rokitansky‐Küster‐Hauser syndrome can be managed either by various surgeries or dilation. The choice still depends on surgeon’s preferences rather than on quality comparative studies and validated protocols. OBJECTIVE: We sought to compare dilation and surgical management of vaginal agenesis in Mayer‐Rokitansky‐Küster‐Hauser syndrome, in terms of quality of life, anatomical results, and complications in a large multicenter population. STUDY DESIGN: Our multicenter study included 131 patients >18 years, at least 1 year after completing vaginal agenesis management. All had an independent gynecological evaluation including a standardized pelvic exam, and completed the World Health Organization Quality of Life instrument (general quality of life) as well as the Female Sexual Function Index and Female Sexual Distress Scale‐Revised (sexual quality of life) scales. Groups were: surgery (N = 84), dilation therapy (N = 26), and intercourse (N = 20). One patient was secondarily excluded because of incomplete surgical data. For statistics, data were compared using analysis of variance, Student, Kruskal‐Wallis, Wilcoxon, and Student exact test. RESULTS: Mean age was 26.5 ± 5.5 years at inclusion. In all groups, World Health Organization Quality of Life scores were not different between patients and the general population except for lower psychosocial health and social relationship scores (which were not different between groups). Global Female Sexual Function Index scores were significantly lower in the surgery and dilation therapy groups (median 26 range [2.8–34.8] and 24.7 [2.6–34.4], respectively) than the intercourse group (30.2 [7.8–34.8], P = .044), which had a higher score only in the satisfaction dimension (P = .004). However, the scores in the other dimensions of Female Sexual Function Index were not different between groups. The Female Sexual Distress Scale‐Revised median scores were, respectively, 17 [0–52], 20 [0–47], and 10 [10–40] in the surgery, dilation therapy, and intercourse groups (P = .38), with sexual distress in 71% of patients. Median vaginal depth was shorter in dilatation therapy group (9.6 cm [5.5–12]) compared to surgery group (11 cm [6–15]) and intercourse group (11 cm [6–12.5]) (P = .039), but remained within normal ranges. One bias in the surgery group was the high number of sigmoid vaginoplasties (57/84, 68%), but no differences were observed between surgeries. Only 4 patients achieved vaginas <6.5 cm. Delay between management and first intercourse was 6 months (not significant). Seventy patients (53%) had dyspareunia (not significant), and 17 patients all from the surgery group had an abnormal pelvic exam. In the surgery group, 34 patients (40.5%) had complications, requiring 20 secondary surgeries in 17 patients, and 35 (42%) needed postoperative dilation. In the dilation therapy group, 13 (50%) needed maintenance dilation. CONCLUSION: Surgery is not superior to therapeutic or intercourse dilation, bears complications, and should therefore be only a second‐line treatment. Psychological counseling is mandatory at diagnosis and during therapeutic management.

Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood

Background Health-related quality of life (QoL) in adult patients with congenital adrenal hyperplasia (CAH) has been variously reported. However, there is no study evaluating the impact of transition on quality of life. Methods Adult patients with classic or non-classic CAH diagnosed during childhood CAH, born between 1970 and 1990, were recruited from the registers of Pediatric departments belonging to the French reference center for endocrine rare disease. Primary end point was the QoL (WHOQOL-BREF). Results Seventy-three patients were included in the study, among them 59/73 were transferred to adult endocrinologist by their pediatricians for transition. WHOQOL-BREF scores were similar between patients with or without transition to specialist adult services, except for environment dimension score, which was slightly higher in CAH patients without transition. However, CAH patients with a regular follow-up had a better physical health, psychological health and environment score and item global QoL than the group without regular follow-up after transition. Conclusion Regular medical follow-up in adulthood is associated with the transition between pediatric and adult care and is associated with better QoL in adults with CAH.

THU0235 Adjuvite: A Double-Blind, Randomized, Placebo-Controlled Trial of Adalimumab in Juvenile Idiopathic Arthritis Associated Uveitis: Table 1.

Background Juvenile idiopathic arthritis (JIA) patients may develop chronic, anterior uveitis. Topical steroids and methotrexate (MTX) often lack of efficacy. Objectives To asses safety and efficacty of adalimumab in patients with JIA-associated uveitis. Methods Elligible patients had chronic, “white eyes” uveitis with inadequate response to topical steroids and MTX, no previous anti-TNF antibody therapy and at least one assessable eye with inflammation quantified by laser flare photometry ≥30 photons/ms. Double-blind randomization at Day 1 (D1) into 2 equal groups, one treated with placebo and one with adalimumab (24 mg/m2 in patients aged 4 to less than 13 years, 40 mg in patients ≥13), every other week subcutaneous injections. Primary objective: to demonstrate a higher response rate at Month 2 (M2) in the adalimumab arm versus the placebo arm. Response was defined as a 30% reduction of inflammation on laser flare photometry in the eye with the highest flare value at D1 and improvement or a stable appearance on slit lamp examination. From M2 to M12, all patients were allowed to receive adalimumab (open phase) (NCT01385826). Results 34 patients were screened and 31 received at least one injection of study treatment.Table 1. Patients characteristics at study treatment onset Ada (n=16) Placebo (n=15) All (n=31) Female, n (%) 15 (94) 13 (87) 28 (90) Age, median value, years [ranges] 10.8 [5.0–20.3] 9.2 [4.9–29.1] Active joints, median n [ranges] 0 [0–3] 0 [0–4] 0 [0–4] Uveitis median duration, years [ranges] 4.4 [0.4–18.9] 4.8 [0.6–24.2] Laser flare (ph/ms), median [ranges] 99 [23–322] 70 [36–265] Bilateral uveitis, n (%) 10 (63) 14 (93) 24 (78) Ongoing treatments at D1  Oral steroids, patients n (%) 7 (44) 3 (20) 10 (32)  Methotrexate, patients n (%) 15 (94) 11 (73) 26 (84) At M2, in intention-to-treat (Primary objective), there were 9/16 responders in the adalimumab group and 3/15 in the placebo group (p=0.038, Chi-squared test; RR=2.81, CI95%=[0.94–8.45] with log-binomial model estimation). One patient stopped the trial at D14 (adalimumab group, uveitis worsening) and one at M9 (ocular hypertony). 29 patients reached M12 on adalimumab. There were 5 serious adverse events in 4 patients, all in the placebo group, 4 during the open-label phase, none related to study treatment (investigator assessment). Conclusions Adalimumab was effective in reducing ocular inflammation within 2 months and well tolerated over 12 months in patients with JIA-associated chronic uveitis and an inadequate response to topical steroids and MTX. Laser flare photometry is a valuable tool to assess early improvement. Disclosure of Interest P. Quartier Grant/research support from: Abbvie, Novartis, Pfizer, Roche, Consultant for: Abbvie, Novartis, SOBI, Speakers bureau: Abbvie, BMS, Novartis, PfiZer, Roche, SOBI, V. Despert: None declared, S. Poignant: None declared, C. Elie: None declared, I. Kone-Paut Grant/research support from: Roche, SOBI, Consultant for: Abbvie, Chugai, Novartis, Pfizer, Roche, SOBI, A. Belot: None declared, L. Kodjikian Consultant for: Alcom, Alimera, Allergan, Bayer, Bausch&Lomb, Novartis, Thea, Speakers bureau: Alcom, Alimera, Allergan, Bayer, Bausch&Lomb, Novartis, Thea, D. Monnet: None declared, M. Weber: None declared, B. Bodaghi Consultant for: Abbvie, A. Baptiste: None declared