Phenotypic changes in cystic fibrosis, about cystic fibrosis-related diabetes : evolution of glucose tolerance disorders, prognosis impact and screening strategy

L’amélioration de l’espérance de vie des patients atteints de mucoviscidose est associée à l’apparition de comorbidités dont le diabète est la plus fréquente. L’objectif de ce travail est de mieux déterminer l’impact pronostique du diabète et des valeurs élevées des temps précoces du test d’hyperglycémie provoquée par voie orale (HGPO). Nous présentons et discutons quatre études sur l’évolution naturelle et l’impact pronostique des troubles du métabolisme glucidique associés à la mucoviscidose. Nous présentons ensuite deux études sur l’impact du diabète dans des situations spécifiques : la grossesse et la transplantation pulmonaire. Nous retenons les éléments suivants : les variations du statut glucidique intra-individuel sont très importantes au cours du temps, et nos résultats nuancent l’impact péjoratif du diabète décrit dans la littérature, et celui des valeurs élevées de glycémie et d’insulinémie à 1 heure du test HGPO. Les perspectives de recherche sont de poursuivre l’implémentation de la cohorte GLYCONE pour gagner en effectif et durée de suivi, d’évaluer l’association entre apports alimentaires et trouble du métabolisme glucidique, d’élaborer un processus de décision médicale partagée pour l’instauration d’une insulinothérapie pour les profils de patients stables, de déterminer la consommation de soins et les coûts de prise en charge des patients diabétiques, et d’évaluer les changements épidémiologiques induits par les modulateurs du CFTR sur la prévalence et ll’âge d’apparition du diabète et son pronosticLife expectancy improvement for cystic fibrosis patients is associated with comorbidities with diabetes being the most common. The objective of this work is to better determine the prognosis impact of diabetes and high values of early times of the oral glucose tolerance test (OGTT). We present and discuss four studies on the natural evolution and prognosis impact of glucose metabolism disorders associated with cystic fibrosis. We then present two studies on the impact of diabetes in specific situations: pregnancy and lung transplantation. The following elements are important: changes in intra-individual glucose status are very important over time, and our results qualify the pejorative impact of diabetes described in the literature, and that of high blood glucose and insulin levels at one hour of the OGTT. The research perspectives are to continue the implementation of the GLYCONE cohort to increase the number of participants and the duration of follow-up, to evaluate the association between dietary intake and carbohydrate metabolism disorder, to develop a shared medical decision-making process for the introduction of insulin therapy for stable patient profiles, to determine the consumption of care and the costs of management of diabetic patients, and evaluate the epidemiological changes induced by CFTR modulators on the prevalence and the age of onset of diabetes and its prognosi

Changements phénotypiques de la mucoviscidose, à propos du diabète associé à la mucoviscidose : évolution naturelle des troubles du métabolisme glucidique, impact pronostique et stratégie de dépistage

Life expectancy improvement for cystic fibrosis patients is associated with comorbidities with diabetes being the most common. The objective of this work is to better determine the prognosis impact of diabetes and high values of early times of the oral glucose tolerance test (OGTT). We present and discuss four studies on the natural evolution and prognosis impact of glucose metabolism disorders associated with cystic fibrosis. We then present two studies on the impact of diabetes in specific situations: pregnancy and lung transplantation. The following elements are important: changes in intra-individual glucose status are very important over time, and our results qualify the pejorative impact of diabetes described in the literature, and that of high blood glucose and insulin levels at one hour of the OGTT. The research perspectives are to continue the implementation of the GLYCONE cohort to increase the number of participants and the duration of follow-up, to evaluate the association between dietary intake and carbohydrate metabolism disorder, to develop a shared medical decision-making process for the introduction of insulin therapy for stable patient profiles, to determine the consumption of care and the costs of management of diabetic patients, and evaluate the epidemiological changes induced by CFTR modulators on the prevalence and the age of onset of diabetes and its prognosisL’amélioration de l’espérance de vie des patients atteints de mucoviscidose est associée à l’apparition de comorbidités dont le diabète est la plus fréquente. L’objectif de ce travail est de mieux déterminer l’impact pronostique du diabète et des valeurs élevées des temps précoces du test d’hyperglycémie provoquée par voie orale (HGPO). Nous présentons et discutons quatre études sur l’évolution naturelle et l’impact pronostique des troubles du métabolisme glucidique associés à la mucoviscidose. Nous présentons ensuite deux études sur l’impact du diabète dans des situations spécifiques : la grossesse et la transplantation pulmonaire. Nous retenons les éléments suivants : les variations du statut glucidique intra-individuel sont très importantes au cours du temps, et nos résultats nuancent l’impact péjoratif du diabète décrit dans la littérature, et celui des valeurs élevées de glycémie et d’insulinémie à 1 heure du test HGPO. Les perspectives de recherche sont de poursuivre l’implémentation de la cohorte GLYCONE pour gagner en effectif et durée de suivi, d’évaluer l’association entre apports alimentaires et trouble du métabolisme glucidique, d’élaborer un processus de décision médicale partagée pour l’instauration d’une insulinothérapie pour les profils de patients stables, de déterminer la consommation de soins et les coûts de prise en charge des patients diabétiques, et d’évaluer les changements épidémiologiques induits par les modulateurs du CFTR sur la prévalence et ll’âge d’apparition du diabète et son pronosti

Adherence to lumacaftor-ivacaftor therapy in patients with cystic fibrosis in France

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Iron Deficiency in Cystic Fibrosis: A Cross-Sectional Single-Centre Study in a Referral Adult Centre

Iron deficiency (ID) diagnosis in cystic fibrosis (CF) is challenging because of frequent systemic inflammation. We aimed to determine the prevalence and risk factors of ID in adult patients with CF. We conducted a single-centre prospective study in a referral centre. ID was defined by transferrin saturation ≤16% or ferritin ≤20 (women) or 30 (men) μg/L, or ≤100 μg/L in the case of systemic inflammation. Apparent exacerbation was an exclusion criterion. We included 165 patients (78 women), mean age—31.1 ± 8.9 years. ID prevalence was 44.2%. ID was significantly associated with female gender (58.9% vs. 38%), lower age (29.4 ± 8.5 vs. 32.5 ± 9.1), lower body mass index (20.5 ± 2.2 vs. 21.3 ± 2.5), and Pseudomonas aeruginosa colonization (70.8% vs. 55.1%). Diabetes mellitus, antiacid drug use and low pulmonary function were more frequent in patients with ID with no statistical significance. The use of CFTR correctors was not associated with ID. In the multivariate analysis, ID was associated with female gender (OR 2.64, CI95% 1.31–5.31), age P. aeruginosa (OR 2.09, CI95% 1.04–4.19)

A New Pathogenic Missense Variant in a Consanguineous North-African Family Responsible for a Highly Variable Aceruloplasminemia Phenotype: A Case-Report

International audienceAceruloplasminemia is a rare autosomal recessive inherited disorder. Mutations in the ceruloplasmin gene cause depressed ferroxidase activity leading to iron accumulation. The clinical phenotype is highly variable: anemia, retinopathy, diabetes mellitus, psychiatric disorders, and neurological symptoms including parkinsonian disorders and dementia are the main features of this disease. Characterized by high serum ferritin with low transferrin saturation, aceruloplasminemia uniquely combines brain, liver and systemic iron overload. We report here four new cases of aceruloplasminemia in a consanguineous North-African family. Genetic sequencing revealed a homozygous missense variant c.656T>A in exon 4 of the ceruloplasmin gene, which had been described previously as of "unknown significance" in the dbSNP database and never associated with ACP in the HGMD database. Ferroxidase activity was strongly depressed. Clinical manifestations varied among cases. The proband exhibited mild microcytic anemia, diabetes mellitus, psychosis and parkinsonism, whereas the other cases were asymptomatic or mildly anemic, although high serum ferritin and brain iron deposition were documented in all of them. Therapeutic management was complex. The proband started deferoxamine treatment when already symptomatic and he rapidly declined. In the asymptomatic cases, the treatment was associated with poor tolerance and was discontinued due to anemia requiring red blood cell transfusion. Our series illustrates the need for new therapeutic approaches to aceruloplasminemia

Clinical practice versus guidelines for the screening of cystic fibrosis-related diabetes: A French survey from the 47 centers

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The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome

International audienceObjective: To describe the clinical spectrum associated with aminoacyl-transfer RNA synthetase (ARS) autoantibodies in patients with idiopathic inflammatory myositis defined according to Peter and Bohan's criteria. Methods: Cohort studies were selected from MEDLINE and Embase up to August 2013. Two investigators independently extracted data on study design, patient characteristics, and clinical features (interstitial lung disease [ILD], fever, mechanic's hands [MH], Raynaud's phenomenon [RPh], arthralgia, sclerodactyly, cancer and dermatomyositis-specific rash) according to the presence of myositis-specific (anti-aminoacyl-transfer RNA synthetase [ARS], anti-signal recognition particle [anti-SRP] and anti-Mi2) and myositis-associated (anti-PM/Scl, anti-U1-RNP and anti-Ku) autoantibodies. Results: 27 studies (3487 patients) were included in the meta-analysis. Arthralgia (75%, CI 67-81) and IW (69%, CI 63-74) were the most prevalent clinical signs associated with anti-ARS autoantibodies. Anti-Mi2 and anti-SRP autoantibodies were associated with few extramuscular signs. ARS autoantibodies were identified in 13% of patients with cancer-associated myositis (5-25). Patients with non-anti-Jo1 ARS had greater odds of presenting fever (RR 0.63, CI 0.52-0.90) and ILD (RR 0.87, CI 0.81-0.93) compared to those with anti-Jol autoantibodies. The frequencies of myositis (RR 1.60, CI 1.38-1.85), arthralgia (RR 1.52, CI 1.32-1.76) and MH (RR 1.47, CI 1.11-1.94) were almost 50% higher in patients with anti-Jo1 compared to non-anti-Jo1 ARS autoantibodies. Patients with anti-PM/Scl differed from those with anti-ARS autoantibodies by a greater prevalence of RPh (RR 0.70, CI 0.53-0.94) and sclerodactyly (RR 0.47, Cl 025-0.89). IID was less frequent in patients with anti-Ul-RNP autoantibodies (RR 3.35, CI 1.07-10.43). No difference was observed between anti-ARS and myositis-associated autoantibodies for other outcomes. Conclusions: The presence of anti-ARS autoantibodies delimits a heterogeneous subset of patients with a high prevalence of myositis, MH, arthralgia in anti-Jo1 patients, and RPh and fever in non-anti-Jo1 patients. The clinical signs of populations positive for anti-PM/Scl and anti-ARS autoantibodies largely overlap, especially with regard to ILD, challenging the clinical delimitation of the antisynthetase syndrome

HOMA indices as screening tests for cystic fibrosis-related diabetes

International audienceIntroduction Intervention in the preschool period is currently recommended for autism spectrum disorder. Therapies delivered by parents are particularly suitable for young children. Preschool Autism Communication Trial (PACT) is a parent-mediated therapy that has shown a significant and sustained impact on autism symptom reduction. However, access to such evidence-based therapies for families is limited due to autism centres located in large urban areas. Using videoconferencing to deliver PACT training to parents may improve accessibility for families living in underserved areas. Methods and analysis This single-blind randomised controlled trial, involving six sites in France, will investigate the efficacy of a telehealth, videoconferencing-based, parent-mediated PACT therapy on autism symptoms, over a 12-month period. It will compare PACT plus treatment as usual (TAU) against TAU only in a cohort of 238 toddlers (119 per group) aged 18–36 months at inclusion and living with their families more than 40 min away from the specialist centres for autism. Primary outcome will include change of overall autism score on the Autism Diagnostic Observation Scale (ADOS) at 12 months. Secondary outcomes will measure change in child skills, child functioning, impact on parents (stress, health, priorities) and implementation characteristics. Repeated measures analyses will be used to test the effect of PACT intervention on the overall ADOS module 1 score over the 12-month study period. Linear mixed models will be used with time, treatment allocation and the interaction between treatment and time as fixed effects and individual variation as random effect. Ethics and dissemination This protocol (V.5, date: 25 October 2019) is approved by the French National Review Board (reference no 2018-A02516-49). The results will be disseminated via peer-reviewed journals Trial registration number NCT04244721

Treatment of idiopathic inflammatory myositis associated interstitial lung disease: A systematic review and meta-analysis

International audienceObjective: Interstitial lung disease (ILD) is the most severe complication of idiopathic inflammatory myositis (IIM), resulting in significant increase in morbidity and mortality and for which the best treatment remains controversial. We conducted a meta-analysis to evaluate the efficacy of therapies used for the management of IIM-related ILD.Methods: Studies were selected from MEDLINE up to July 2017. Two investigators independently extracted data on study design, patient characteristics, clinical features, treatment, follow-up and outcomes. Global survival rates and objectively confirmed lung function improvements were extracted as the main outcome for rapidly progressive IIM-related ILD (RP-ILD) and chronic forms of ILD (C-ILD), respectively, and pooled using the weighted mean proportion with fixed or random-effects models in case of significant heterogeneity (I-2 > 50%).Results: Twenty-seven studies encompassing 553 patients (male: 30.5%, age: 53.5 +/- 5.5 years) were included in the meta-analysis. Globally, retrieved studies were of limited methodological quality (no controlled studies and only 2 prospective studies). Dermatomyositis (40%) and anti-tRNA synthetase syndrome (45%) were the most represented IIM subtypes. In C-ILD, functional improvement rates were 89.2% (95%CI 82.5-93.6; 7 studies, n = 124) for corticosteroids alone, 80.7% (95%CI 49.6-94; 6 studies, n = 38) for cyclosporine A, 64.1% (95%CI 46.3-78.7; 4 studies, n = 32) for azathioprine, 86.2% (95%CI 61.5-96; 2 studies, n = 23) for tacrolimus, 56.4% (95%CI 44-68.0; 8 studies, n = 71) for cyclophosphamide, and 76.6% (95%CI 50.4-96.0; 2 studies, n = 20) for rituximab. In RP-ILD, survival rates at 3 months were 51.7% (95%CI 24.2-78.1; 2 studies, n = 11) for corticosteroids alone, 69.2% (95%CI 55.0-80.5; 8 studies, n = 146) for cyclosporine A and 72.4% (95%CI 6.4-99.0, 2 studies, n = 16) for cyclophosphamide.Conclusion: Despite aggressive immunosuppressive therapies, the short-term mortality of RP-ILD remains high. While immunosuppressive therapies are associated with significant functional improvements in most patients with C-ILD, substantial uncertainty remains about the best treatment strategy in the absence of good quality evidence