Publications by authors named "François Maillot"

72 Publications

Symptomatic aortitis at giant cell arteritis diagnosis: a prognostic factor of aortic event.

Arthritis Res Ther 2021 01 7;23(1):14. Epub 2021 Jan 7.

Department of Internal Medicine, CHU Nantes, 1 place Alexis Ricordeau, 44093, Nantes, France.

Background: Giant cell arteritis (GCA) is frequently associated with aortic involvement that is likely to cause life-threatening structural complications (aneurysm, dissection). Few studies have investigated the occurrence of these complications, and no predictive factor has been identified so far. The aim of this study was to investigate factors associated with the risk of aortic complications in a cohort of GCA aortitis.

Methods: Data of all patients managed with aortitis (CT or 18 FDG PET) at the diagnosis of GCA in five hospitals from May 1998 and April 2019 were retrospectively collected. Clinical features were compared according to the presence of aortitis symptoms. The predictive factors of occurrence or aggravation of aortic structural abnormalities were investigated.

Results: One hundred and seventy-one patients with GCA aortitis were included; 55 patients (32%) had symptoms of aortitis (dorsal/lumbar/abdominal pain, aortic insufficiency) at diagnosis. The median follow-up was 38 months. Aortic complications occurred after a median time of 32 months. There were 19 new aortic aneurysms or complications of aneurysm and 5 dissections. Survival without aortic complication was significantly different between the symptomatic and non-symptomatic groups (Log rank, p = 0.0003). In multivariate analysis the presence of aortitis symptoms at diagnosis (HR 6.64 [1.95, 22.6] p = 0.002) and GCA relapse (HR 3.62 [1.2, 10.9] p = 0.02) were factors associated with the occurrence of aortic complications.

Conclusion: In this study, the presence of aortitis symptoms at the diagnosis of GCA aortitis and GCA relapse were independent predictive factors of occurrence of aortic complications during follow-up.
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http://dx.doi.org/10.1186/s13075-020-02396-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792092PMC
January 2021

Impact of aging on phenotype and prognosis in IgA vasculitis.

Rheumatology (Oxford) 2021 Jan 7. Epub 2021 Jan 7.

Université Paris Descartes, Paris, France.

Objectives: Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis most frequently benign in children while the disease is more severe in adults. We aimed to study the impact of age on presentation and outcome of adult IgAV.

Methods: We conducted a nationwide retrospective study including 260 IgAV patients. Patients were divided into four quartiles according to the age at IgAV diagnosis: <36; 36≤age < 52; 52≤age < 63 and ≥63 years. Comparison of presentation and outcome were performed according to age of disease onset.

Results: Mean age at diagnosis was 50.1 ± 18 years and 63% were male. IgAV diagnosed in the lowest quartile of age was associated with more frequent joint (p< 0.0001) and gastrointestinal involvement (p= 0.001). In contrast, the oldest patients had more severe purpura with necrotic lesions (p= 0.001) and more frequent renal involvement (p< 0.0001), with more frequent hematuria, renal failure, higher urine protein excretion and more frequent tubulointerstitial lesions. Patients were treated similarly in all groups of age, and clinical response and relapse rates were similar between groups. In the 127 treated patients with follow-up data for >6 months, clinical response and relapse rates were similar between the four groups. Median follow-up was of 17.2 months (9.1-38.3 months). Renal failure at the end of follow-up was significantly more frequent in the highest quartile of age (p= 0.02), but the occurrence of end-stage renal disease was similar in all groups. Last, overall and IgAV-related deaths were associated with increase age.

Conclusion: Aging negatively impacts the severity and outcome of IgAV in adults. Younger patients have more frequent joint and gastrointestinal involvement, while old patients display more frequent severe purpura and glomerulonephritis.
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http://dx.doi.org/10.1093/rheumatology/keaa921DOI Listing
January 2021

Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients.

Genes (Basel) 2020 Dec 25;12(1). Epub 2020 Dec 25.

BRAIN Laboratory (Basic Research and Advanced Investigations in Neurosciences), Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil.

Phenylketonuria (PKU) is a common inborn error of amino acid metabolism in which the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is functionally impaired due to pathogenic variants in the gene. Thirty-four Brazilian patients with a biochemical diagnosis of PKU, from 33 unrelated families, were analyzed through next-generation sequencing in the Ion Torrent PGM™ platform. Phenotype-genotype correlations were made based on the BioPKU database. Three patients required additional Sanger sequencing analyses. Twenty-six different pathogenic variants were identified. The most frequent variants were c.1315+1G>A ( = 8/66), c.473G>A ( = 6/66), and c.1162G>A ( = 6/66). One novel variant, c.524C>G (p.Pro175Arg), was found in one allele and was predicted as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG) criteria. The molecular modeling of p.Pro175Arg indicated that this substitution can affect monomers binding in the PAH tetramer, which could lead to a change in the stability and activity of this enzyme. Next-generation sequencing was a fast and effective method for diagnosing PKU and is useful for patient phenotype prediction and genetic counseling.
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http://dx.doi.org/10.3390/genes12010020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824641PMC
December 2020

New insights on IgA vasculitis with underlying solid tumor: a nationwide French study of 30 patients.

Clin Rheumatol 2020 Oct 24. Epub 2020 Oct 24.

Department of Internal Medicine and Clinical Immunology, CHRU Tours, Tours, France.

Objective: IgA vasculitis (IgAV) frequently occurs during or after a mucosal infection; it also rarely occurs in patients with cancer. We hypothesized that cancer could impact the baseline characteristics and/or outcome of vasculitis. We aimed to describe the presentation of IgAV in patients with cancer (IgAV ca+) compared to patients without cancer.

Methods: We conducted a nationwide retrospective study of adult patients in France who presented with both IgAV and cancer. Baseline characteristics were described and compared with those of the 260 patients included in a nationwide French IgAV study.

Results: Thirty patients were included. The mean age was 69 ± 12 years; 80% were men. Compared to patients without underlying cancer, IgAV ca+ patients were older (69 ± 12 vs. 50 ± 18 years; p < 0.0001) and they presented more frequently with necrotic purpura (53 vs. 26%; p < 0.002) and intra-alveolar hemorrhage (10 vs. 0.5%; p < 0.0001). IgAV ca+ patients frequently had elevated serum IgA levels (79 vs. 53%; p < 0.034); most (n = 22, 73%) had adenocarcinoma or urothelial carcinoma involving the large intestines (n = 6), bladder (n = 5), and lung (n = 5). Most IgAV ca+ patients had progressive cancer (n = 21); a minority had metastatic disease (n = 2) at IgAV diagnosis. After a median follow-up of 3 months, 8 deaths were observed but none was related to IgAV.

Conclusion: Compared to their noncancer counterpart, patients with IgAV related to cancer were older and more frequently presented with necrotizing purpura, intra-alveolar hemorrhage, and elevated serum IgA levels. Adult patients with IgAV and these latter characteristics should be carefully screened for cancer. Key Points • Clinical and biological characteristics of patients presenting with IgAV are distinct depending on the underlying cause of vasculitis related to cancer. • Patients with IgAV related to cancer are older, and compared to their counterparts without IgAV, they present more frequently with necrotic purpura, alveolar hemorrhage, and elevated serum IgA levels. • All adult patients with IgAV should be screened for cancer, and there should be a focus on elderly male patients presenting with necrotic purpura and/or alveolar hemorrhage.
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http://dx.doi.org/10.1007/s10067-020-05455-zDOI Listing
October 2020

IgA Vasculitis with Underlying Liver Cirrhosis: A French Nationwide Case Series of 20 Patients.

J Rheumatol 2020 Aug 15. Epub 2020 Aug 15.

I. Elhani, MD, A. Hankard, MD, H. de Boysson, MD, A. Aouba, MD, Department of Internal Medicine, Caen, Normandie Université, UNICAEN, CHU de Caen Normandie; E. Pillebout, MD, Department of Nephrology, Hôpital Saint Louis, AP-HP, Paris; B. Terrier, MD, Université Paris Descartes, and Department of Internal Medicine, Hôpital Cochin, and National Referral Center for Systemic and Autoimmune Diseases, Hôpital Cochin, Paris; F. Vrtovsnik, MD, Department of Nephrology, Bichat- Claude Bernard Hospital, AP-HP, and Inserm U1149 - CRI, University of Paris, Paris; N. Jourde-Chiche, MD, S. Greillier, MD, Aix-Marseille Univ, C2VN, INSERM, INRA, Centre de Néphrologie et Transplantation Rénale, CHU de la Conception, AP-HM, Marseille; M. Groh, MD, Department of Internal Medicine, National Referral Center for Hypereosinophilic Syndrome (CEREO), Suresnes; N. Belfeki, MD, Department of Internal Medicine, Groupe Hospitalier Sud Ile de France, Melun; A. Bigot, MD, F. Maillot, MD, A. Audemard-Verger, MD, PhD, Department of Internal Medicine and Clinical Immunology, CHRU Tours, and University of Tours, Tours; G.P. Pageaux, MD, Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, Montpellier; L. Raffray, MD, Department of Internal Medicine, Centre Hospitalier Universitaire de la Réunion, Réunion; G. Urbanski, MD, Department of Internal Medicine, Centre Hospitalier Universitaire d'Angers, Angers; I. Ollivier, MD, Department of Hepato-Gastroenterology and Nutrition, Caen University Hospital, Caen, France. Address correspondence to Dr. A. Audemard-Verger, Department of Internal Medicine and Clinical Immunology, CHRU Tours, Tours, France, University of Tours, Tours, France. Email: Accepted for publication August 6, 2020.

Objective: Immunoglobulin A vasculitis (IgAV) and nephropathy (IgAN) share common immunological mechanisms. Liver cirrhosis is well known to be associated with IgAN. Here, we aimed to describe the presentation and outcome of IgAV patients with underlying cirrhosis.

Methods: We conducted a French nationwide retrospective study of adult patients presenting with both IgAV and cirrhosis. Baseline characteristics were compared to those of the 260 patients included in the French nationwide IgAV registry (IGAVAS).

Results: Twenty patients were included, and 7 (35%) were female. The mean ± SD age was 62.7 ± 11 years. At baseline, compared with IGAVAS patients, patients with underlying cirrhosis were older (62.7 ± 11 vs 50.1 ± 18, < 0.01) and displayed more constitutional symptoms (weight loss 25% vs 8%, = 0.03). Patients with underlying cirrhosis were also more likely to exhibit elevated serum IgA levels (5.6 g/L vs 3.6 g/L, = 0.02). Cirrhosis and IgAV were diagnosed simultaneously in 12 patients (60%). Cirrhosis was mainly related to alcohol intake (n = 15, 75%), followed by nonalcoholic steato-hepatitis (n = 2), chronic viral hepatitis (n = 1), hemochromatosis (n = 1), and autoimmune hepatitis (n = 1). During follow-up with a median of 17 months (IQR 12-84), 10/13 (77%) exhibited IgAV remission at Month 3. One patient presented a minor relapse. Six patients died, but no deaths were related to IgAV.

Conclusion: We report the first case series of IgAV patients with underlining cirrhosis, to our knowledge, which was mainly alcohol related. The liver disease did not seem to affect baseline vasculitis characteristics. Physicians should investigate the existence of liver cirrhosis at IgAV diagnosis, especially in the context of alcohol abuse.
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http://dx.doi.org/10.3899/jrheum.200293DOI Listing
August 2020

Des gangues péri-rénales.

Rev Med Interne 2020 08 19;41(8):567-568. Epub 2020 Jul 19.

Service de Médecine Interne et d'Immunologie Clinique, CHU Tours, Bretonneau, 2 Boulevard Tonnellé, 37000 Tours, France.

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http://dx.doi.org/10.1016/j.revmed.2020.04.009DOI Listing
August 2020

Understanding and managing metabolic dysfunction in Amyotrophic Lateral Sclerosis.

Expert Rev Neurother 2020 09 13;20(9):907-919. Epub 2020 Jul 13.

Unité INSERM U1253, équipe, neurogénomique et physiopathologie neuronale, Université de Tours , Tours, France.

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease that leads to death after a median survival of 36 months. The development of an effective treatment has proven to be extremely difficult due to the inadequate understanding of the pathogenesis of ALS. Energy metabolism is thoroughly involved in the disease based on the discoveries of hypermetabolism, lipid/glucose metabolism, the tricarboxylic acid (TCA) cycle, and mitochondrial impairment.

Area Covered: Many perturbed metabolites within these processes have been identified as promising therapeutic targets. However, the therapeutic strategies targeting these pathways have failed to produce clinically significant results. The authors present in this review the metabolic disturbances observed in ALS and the derived-therapeutics.

Expert Opinion: The authors suggest that this is due to the insufficient knowledge of the relationship between the metabolic targets and the type of ALS of the patient, depending on genetic and environmental factors. We must improve our understanding of the pathological mechanisms and pay attention to the subtle hidden effects of changing diet, for example, and to use this strategy in addition to other drugs or to use metabolism status to determine subgroups of patients.
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http://dx.doi.org/10.1080/14737175.2020.1788389DOI Listing
September 2020

Cornea verticillata and acroparesthesia efficiently discriminate clusters of severity in Fabry disease.

PLoS One 2020 22;15(5):e0233460. Epub 2020 May 22.

Internal Medicine Department, Reference Center for Lysosomal Storage Disorders, Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France.

Backgroud: Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity.

Methods: Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients.

Results: We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI.

Conclusion: Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244174PMC
August 2020

Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.

Neurology 2020 05 12;94(21):e2189-e2202. Epub 2020 May 12.

From the Neurology Department (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital; National Reference Centre for Wilson's Disease (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital, Paris; Hepatobiliary Centre (R.S., D.C., D.S., J.-C.D.-V.), DHU Hepatinov, UMR-1193, AP-HP, Paul Brousse Hospital, Villejuif; Service de Neurologie (W.G.M.), CHU Bordeaux; Université de Bordeaux (W.G.M.), Institut des Maladies Neurodégénératives, CNRS UMR 5393, France; Department of Medicine (W.G.M.), University of Otago and New Zealand Brain Research Institute (W.G.M.), Christchurch; Hepatology, Gastroenterology and Nutrition Department (A.-S.B., A.L.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon; National Reference Centre for Wilson's Disease (A.-S.B., E.B., C.L., L.L.-F., O.G., A.L.), Hospices Civils de Lyon; Neurology Department (E.B., C.L.), Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon; CNRS (E.B., C.L.), UMR 5229, Institut des Sciences Cognitives Marc-Jeannerod, Bron; Faculté de Médecine Lyon Sud Charles-Mérieux (E.B., C.L., A.L.), Université Claude-Bernard Lyon 1; Neurology and Paediatrics Department (L.L.-F.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron; Hepatogastroenterology Department (O.G.), Edouard Herriot Hospital, Hospices Civils de Lyon; Internal Medicine Department (F.M.), National Reference Centre for Inborn Errors of Metabolism, Université François Rabelais; Neurology Department (J.B.), CHRU Bretonneau, Tours; Surgery, Oncology and Liver Transplantation Department (E.S.), CHRU Tours; Hepatology and Gastroenterology Department (C.V.) and Surgery and Liver Transplantation Department (B.H.), CHU Besançon; Neurology and Paediatrics Department (C. Bellesme), AP-HP, Bicêtre University Hospital, Kremlin-Bicetre; Pediatric Hepatology and Pediatric Liver Transplantation Unit (U.H) and National Reference Centre for Rare Pediatric Liver Diseases (U.H), Bicêtre University Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, DHU Hepatinov, AP-HP, Le Kremlin Bicêtre; INSERM (D.H.), UMR-S1174, Hepatinov, University of Paris Sud 11, Orsay; Hepatology and Gastroenterology Department (C. Bureau) and Neurology Department (F.O.-M.), CHU Toulouse; Centre D'investigation de la Fibrose Hépatique (V.L.), Hôpital Haut-Lévêque, CHU Bordeaux; and INSERM U1053 (V.d.L.), Université de Bordeaux, France. A. Poujois is currently at Neurology Department, Rothschild Foundation Hospital, and National Reference Centre for Wilson's Disease, Rothschild Foundation Hospital, Paris.

Objective: To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.

Methods: French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.

Results: Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved ( < 0.0001 and = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved ( = 0.0007). Severe sepsis ( = 0.011) and intensive care unit admission ( = 0.001) before LT were significantly associated with death.

Conclusions: LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.

Classification Of Evidence: This study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.
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http://dx.doi.org/10.1212/WNL.0000000000009474DOI Listing
May 2020

Tryptophan metabolism in phenylketonuria: A French adult cohort study.

J Inherit Metab Dis 2020 09 4;43(5):944-951. Epub 2020 Jun 4.

Laboratoire des Maladies Héréditaires du Métabolisme, Service de Biochimie, Biologie Moléculaire, Toxicologie Environnementale, CHU de Grenoble-Alpes site Nord- Institut de Biologie et de Pathologie, La Tronche, France.

Many similarities between tryptophan (Trp) and phenylalanine (Phe) metabolisms exist. It is possible that a modification of Trp metabolism might be seen in phenylketonuria (PKU). As some of these metabolites have neuroactive properties, they should be consider in neurological impairment seen in this pathology and not totally explained by blood Phe concentrations. One hundred and fifty-one adult PKU patients (mean age 26.8 years) were included for this study. Plasma Trp, kynurenine (KYN), 3-hydroxykynurenic acid (3HK), and kynurenic acid (KA) were analyzed by liquid chromatography coupled with tandem mass spectrometry. KYN and 3HK were significantly lower in PKU patients compared to general population (P < .0001), and KA was significantly enhanced is this population (P = .009). Furthermore, 3HK concentration was significantly different between PKU patients underwent controlled low-Phe diet compared to PKU patients without this diet (P = .0016). In PKU patients with diet, taking AA substitute enable higher plasma 3HK concentration than without (P = .0008) but still not reaching general population level (P < .0001). Although further study has to be done, it is clear that Trp metabolism is modified in adult PKU patients. An exploration of complete Trp metabolism, and not only Trp concentration, is needed in PKU population, but also in other inborn error of metabolism treated with hypoprotidic diet.
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http://dx.doi.org/10.1002/jimd.12250DOI Listing
September 2020

Preoperative Chemerin Level Is Predictive of Inflammatory Status 1 Year After Bariatric Surgery.

Obes Surg 2020 Oct;30(10):3852-3861

Service de Médecine Interne, CHRU de Tours, université de Tours, Tours, France.

Background: Obesity is associated with chronic low-grade inflammation, which has been linked to increased morbidity. However, inflammation variably and unpredictably improves after bariatric surgery. This study aimed at (1) evaluating the relationship between amplitude of weight loss and variation of inflammatory parameters after bariatric surgery, and (2) identifying, among clinical and biological baseline parameters, predictive factors of variation in inflammatory parameters.

Methods: In a prospective cohort of patients who underwent bariatric surgery, serum concentrations of interleukin (IL)-6, IL-10, resistin, leptin, adiponectin chemerin, and C-reactive protein (CRP) were measured preoperatively and 1 year after surgery, and routine clinical and biochemical parameters were retrieved. Univariate and multivariate analyses (partial least square method) were performed to assess how parameters were associated with weight loss and to predict improvement of inflammatory parameters.

Results: Eighty-seven patients were included (mean weight ± SD 136.3 ± 3.2 kg, 35 gastric bypasses, 52 sleeve gastrectomies). In parallel with weight loss (39.5 ± 13.8 kg), pro-inflammatory markers (IL-6, CRP, leptin, resistin) significantly decreased, and anti-inflammatory markers (IL-10, adiponectin) increased. Multivariate analysis revealed a significant association between weight loss and improvement in inflammatory parameters. Among all the clinical and biological preoperative parameters, baseline chemerin level was the only parameter that was significantly associated with global improvement of the inflammatory status after surgery.

Conclusion: The amplitude of weight loss 1 year after bariatric surgery was strongly correlated with improvement of inflammatory profile, which could be predicted by baseline plasma level of chemerin. This suggests a key role of chemerin in obesity-driven inflammation, and a potential use as a biomarker.
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http://dx.doi.org/10.1007/s11695-020-04584-3DOI Listing
October 2020

Coagulation Parameters in Adult Patients With Type-1 Gaucher Disease.

J Hematol 2019 Sep 30;8(3):121-124. Epub 2019 Sep 30.

Internal Medicine Department, Tours University Hospital, University of Tours, UMR INSERM 1253, 37044 Tours, France.

Background: Gaucher disease is a rare inborn error of lysosomal metabolism, characterized by lysosomal storage of the β-glucosylceramide. Bleedings observed in type-1 Gaucher disease (GD1) are commonly attributed to a low platelet count, but they can also occur when the platelet count is normal or slightly low. Abnormal platelet function has been described and deficiencies in coagulation factors too, such as factors II, V, VII, VIII, IX, X, XI, XII, and von Willebrand factor. However, studies are few in number, involving few patients and having varying conclusions. The aim of this study was to analyze clotting factor deficiencies in a larger cohort of French patients with GD1.

Methods: This is an observational national study. The coagulation parameters were collected during routine GD1 monitoring and described retrospectively.

Results: We highlighted low levels of various coagulation factors in 46% of the patients with GD1. The most frequent coagulation abnormalities encountered were factor V, X, XI, and XII deficiencies. Deficits were usually mild and coagulation abnormalities tended to be more frequent in non-splenectomized patients.

Conclusions: In conclusion, frequent and varied coagulation abnormalities were found in a high proportion of GD1 patients.
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http://dx.doi.org/10.14740/jh543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153659PMC
September 2019

High pre-treatment neutrophil-to-lymphocyte ratio in patients with dermatomyositis/polymyositis predicts an increased risk of cancer.

Eur J Dermatol 2020 Apr 10. Epub 2020 Apr 10.

Department of Dermatology, University Hospital, Tours, UMR Inserm U1253, University of Tours, Tours, France.

Background: Neutrophil-to-lymphocyte ratio (NLR) is increased and associated with overall survival (OS) in inflammatory diseases including dermatomyositis/polymyositis (DM/PM) and many cancers. The risk of cancer is increased with DM/PM especially in adults > 50 years old.

Objectives: To determine whether high NLR is associated with an increased risk of cancer and OS in DM/PM patients.

Materials And Methods: A retrospective monocentric study was performed in a tertiary care referral centre between 2007 and 2018. Data on patient characteristics included pre-treatment NLR, visceral involvement, treatment, autoantibodies, creatine phosphokinase level, occurrence of cancer, and death. The cut-off value of NLR was determined by receiver operating characteristic curve analysis. Factors associated with risk of cancer and death were estimated by Cox proportional-hazards regression analysis.

Results: In total, 75 patients had a diagnosis of DM/PM (median age: 60 [Q1-Q3: 41.3-70.2] years and median follow-up: 3.5 [Q1-Q3: 1-5.9] years) and 16 patients had cancer. NLR ≥5.5 was associated with occurrence of cancer based on univariate analysis (HR: 3.6; 95% CI: 1.2-10.6) and multivariate analysis (HR: 3.8; 95% CI: 1.2-12.1) adjusted for age (HR: 5.0; 95% CI: 1.1-22.7), as well as corticosteroid intake (p = 0.35) before initial NLR determination.

Conclusions: This is the first study to demonstrate an association between high NLR and risk of cancer in patients with DM/PM. Moreover, analysis was performed with adjustment for potential confounding factors such as corticosteroid intake. High NLR at age ≥ 60 years should prompt investigation for cancer from diagnosis of DM/PM and during follow-up.
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http://dx.doi.org/10.1684/ejd.2020.3756DOI Listing
April 2020

Pseudoaneurysmal angiolymphoid hyperplasia with eosinophilia and IgG4-related disease: A possible overlap?

Presse Med 2020 04 29;49(1):104019. Epub 2020 Mar 29.

Université François-Rabelais de Tours, 37000 Tours, France; CNRS, GICC UMR 7292, 37000 Tours, France; Service de médecine interne et maladies systémiques, hôpital Saint-Louis, 75010 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.lpm.2020.104019DOI Listing
April 2020

Gastrointestinal involvement in adult IgA vasculitis (Henoch-Schönlein purpura): updated picture from a French multicentre and retrospective series of 260 cases.

Rheumatology (Oxford) 2020 Oct;59(10):3050-3057

Department of Internal Medicine.

Objectives: To describe the clinical presentation, treatments and prognosis of gastrointestinal (GI) involvement in adult IgA vasculitis (IgAV).

Methods: Data from 260 adults with IgAV included in a French multicentre retrospective survey were analysed. Presentation and outcomes of patients with (GI+) and without (GI-) GI involvement were compared.

Results: One hundred and thirty-seven (53%) patients had GI involvement. Initial manifestations were abdominal pain in 99%, intestinal bleeding in 31%, diarrhoea in 26% and acute surgical abdomen in only 4%. Abdominal imaging revealed thickening of intestinal wall in 61%, and endoscopies revealed abnormalities in 87%, mostly mucosal ulcerations. GI+ vs GI- patients were younger (46 ± 18 vs 54 ± 18 years; P = 0.0004), had more constitutional symptoms (43% vs 23%; P = 0.0005) and joint involvement (72 vs 50%; P = 0.0002), and higher CRP levels (3.7 vs 1.9 mg/dl; P = 0.001). Clinical response and relapse rates were comparable between groups, and all causes mortality (2 vs 4%) and IgAV-related mortality (1% vs 2%) as well. GI-related deaths were due to intestinal perforation and mesenteric ischaemia.

Conclusion: GI involvement is frequent in adult IgAV. GI involvement is frequent in adult IgAV. Mortality is not uncommon but does not seem to be specifically related to GI. Immunosuppressants should not be preferred as first-line therapy for GI+ patients but may be required in case of acute surgical abdomen.
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http://dx.doi.org/10.1093/rheumatology/keaa104DOI Listing
October 2020

Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study.

EBioMedicine 2020 Jan 7;51:102623. Epub 2020 Jan 7.

University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, Nancy, France; Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Nancy, France; Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, Nancy F-54000, France.

Background: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients' ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus.

Methods: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among populations using Wright's fixation index (Fst). To estimate the molecular evolutionary history of the PAH gene, we performed phylogenetic and evolutionary analyses using whole-genome and exome-sequencing data from healthy individuals and non-PKU patients, respectively. Finally, we used exome-wide association study to decipher potential genetic loci associated with population divergence on PAH.

Findings: The study included 696 patients and revealed 132 pathogenic PAH variants. Three geographical areas showed significant enrichment for a pathogenic PAH variant: North of France (p.Arg243Leu), North-West of France (p.Leu348Val), and Mediterranean coast (p.Ala403Val). One PAH variant (p.Glu280Gln) was significantly enriched among North-Africans (OR = 23·23; 95% CI: 9·75-55·38). PAH variants exhibiting a strong genetic differentiation were significantly enriched in the 'Biopterin_H' domain (OR = 6·45; 95% CI: 1·99-20·84), suggesting a balancing selection pressure on the biopterin function of PAH. Phylogenetic and timetree analyses were consistent with population differentiation events on European-, African-, and Asian-ancestry populations. The five PAH variants most strongly associated with a high selection pressure were phylogenetically close and were located within the biopterin domain coding region of PAH or in its vicinity. Among the non-PAH loci potentially associated with population divergence, two reached exome-wide significance: SSPO (SCO-spondin) and DBH (dopamine beta-hydroxylase), involved in neuroprotection and metabolic adaptation, respectively.

Interpretation: Our data provide evidence on the combination of evolutionary and adaptive events in populations with distinct ancestries, which may explain the overdominance of some genetic variants on PAH.

Funding: French National Institute of Health and Medical Research (INSERM) UMR_S 1256.
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http://dx.doi.org/10.1016/j.ebiom.2019.102623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000351PMC
January 2020

[Monoclonal antibodies for monogenic diseases: a 2019 update].

Med Sci (Paris) 2019 Dec 6;35(12):1026-1028. Epub 2020 Jan 6.

CHRU de Tours, Service de Médecine interne;,   - Université de Tours, France.

Monogenic diseases are rare genetic diseases but they are numerous and display a highly variable degree of severity. First uses of monoclonal antibodies to treat monogenic diseases started in the 2000's and many clinical trials are ongoing. Anti-IL-1β therapies have greatly modified the outcome of auto-inflammatory diseases by modulating inflammatory response and reducing the risk of secondary amyloidosis. Anti-TNF-α are also used in such diseases. In atypical hemolytic and uremic syndrome due to deficiencies in the control of alternative complement pathway, eculizumab, an anti-C5 monoclonal antibody, has improved renal outcome in treated patients. More recently, lanadelumab, an anti-plasma kallikrein antibody, has reinforced the therapeutic arsenal in hereditary angioedema and burosumab, anti-FGF23, that of X-linked hypophosphatemia. Such examples reflect the importance of monoclonal antibody therapy of monogenic diseases, the interest of considering such an option as well as the need for future researches.
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http://dx.doi.org/10.1051/medsci/2019203DOI Listing
December 2019

Bone mineral density is within normal range in most adult phenylketonuria patients.

J Inherit Metab Dis 2020 03 6;43(2):251-258. Epub 2020 Feb 6.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC - Location AMC, Amsterdam, The Netherlands.

Low bone mineral density (BMD) as a risk factor for fractures has been a long-standing concern in phenylketonuria (PKU). It is hypothesised that the disease itself or the dietary treatment might lead to a low BMD. Previous studies show conflicting results of BMD in PKU due to differences in age, techniques to assess BMD and criteria used. To assess the prevalence of low BMD and define possible risk factors in a large number of adult, early treated PKU (ETPKU) patients. European centres were invited for a survey, collecting retrospective data including results of dual-energy X-ray absorptiometry (DXA) scans of adult ETPKU patients. BMD of 183 adult ETPKU patients aged 18-46 (median age 28, all females premenopausal) years was lower than in the general population at most skeletal sites but the frequency of low BMD (Z-score <-2) was at maximum 5.5%. No risk factors for low BMD in PKU patients could be identified. Low BMD occurs only in a small subset of PKU patients. DXA scans should be considered for well controlled patients from age 35-40 years and up and on indication in those PKU patients considered to be at increased risk for fractures.
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http://dx.doi.org/10.1002/jimd.12177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078943PMC
March 2020

Rituximab-induced serum sickness is more frequent in autoimmune diseases as compared to hematological malignancies: A French nationwide study.

Eur J Intern Med 2019 Sep 3;67:59-64. Epub 2019 Jul 3.

CHRU de Tours, Centre Régional de pharmacovigilance Centre Val de Loire, Tours, France; Université de Tours, Université de Nantes, INSERM, SPHERE U1246, Tours, France.

Introduction: Rituximab induced serum sickness (RISS) is a rare delayed hypersensitivity reaction. The aim of this study was to describe the epidemiological and clinical characteristics of the RISS cases reported in France.

Method: Serum sickness cases involving rituximab were identified from the French PharmacoVigilance Database from 1998 to 2016.

Results: We analyzed 37 cases of RISS. Rituximab was prescribed for an autoimmune disease in 78% of cases. Serum sickness occurred mainly after the first injection (54%) with a median time to onset of 12 days. The most frequent manifestations were rheumatologic symptoms (92%), fever (87%), and skin lesions (78%). The incidence was significantly higher when rituximab was used for autoimmune diseases than for a hematological malignancies. Taking into account the existence of a Systemic Lupus Erythematosus (SLE) as the indication of rituximab or as a comorbidity, the incidence of RISS in patients with SLE was even higher.

Discussion: We report on the largest series of RISS studied to date and confirm that this reaction preferentially occurs in patients with autoimmune disease, especially SLE. This may be due to B-cell lysis, leading to the release of intracellular antigens into the serum and subsequent antigen-antibody complex formation, especially in patients with elevated autoantibody production. This could also explain why RISS often occurred after a single injection.

Conclusion: Patients generally recovered from RISS rapidly without obvious benefit from corticosteroid therapy. The risk of recurrence should prompt clinicians to question the use of rituximab after an episode of RISS.
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http://dx.doi.org/10.1016/j.ejim.2019.06.009DOI Listing
September 2019

Ferritin and LDL-cholesterol as biomarkers of fat-free mass loss in ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2019 08 3;20(5-6):441-444. Epub 2019 Apr 3.

c Laboratory of Biochemistry and Molecular Biology , University Hospital of Tours , Tours , France.

The availability of longitudinal clinical and biological data led us to wonder whether these parameters could be used to predict disturbances in body composition during ALS progression. Bioelectrical impedance analysis (BIA), as well as clinical and biological parameters (blood lipids and ferritin), were collected one year after diagnosis in ALS patients. The correlations were evaluated by the Spearman test. Performances to predict the evolution of BIA parameters during ALS evolution were evaluated by ROC analysis. Forty-two ALS patients were enrolled. Variations in FFM over one year were correlated to the variations in LDL-cholesterol ( = 0.53, = 0.002) and ferritin ( = -0.58, = 0.0002). To predict FFM loss, an increase in ferritin over 9 µg/L had a sensitivity of 90.0% and a specificity of 80.0% ( < 0.0001). Ferritine evolution would allow to easily follow the FFM without BIA during ALS. In addition, an adapted nutritional treatment based on this biological parameter might slow down ALS progression.
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http://dx.doi.org/10.1080/21678421.2019.1597126DOI Listing
August 2019

Betaine anhydrous in homocystinuria: results from the RoCH registry.

Orphanet J Rare Dis 2019 03 14;14(1):66. Epub 2019 Mar 14.

CHRU de Tours, Service de Médecine Interne, Université François Rabelais, Tours, France.

Background: The Registry of Adult and Paediatric Patients Treated with Cystadane® - Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year.

Results: A total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine β-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase-deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns.

Conclusions: Data from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients.
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http://dx.doi.org/10.1186/s13023-019-1036-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419445PMC
March 2019

Etiology and Outcomes of Thrombotic Microangiopathies.

Clin J Am Soc Nephrol 2019 04 12;14(4):557-566. Epub 2019 Mar 12.

Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville,

Background And Objectives: Thrombotic microangiopathies constitute a diagnostic and therapeutic challenge. Secondary thrombotic microangiopathies are less characterized than primary thrombotic microangiopathies (thrombotic thrombocytopenic purpura and atypical hemolytic and uremic syndrome). The relative frequencies and outcomes of secondary and primary thrombotic microangiopathies are unknown.

Design, Setting, Participants, & Measurements: We conducted a retrospective study in a four-hospital institution in 564 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period. We estimated the incidence of primary and secondary thrombotic microangiopathies, thrombotic microangiopathy causes, and major outcomes during hospitalization (death, dialysis, major cardiovascular events [acute coronary syndrome and/or acute heart failure], and neurologic complications [stroke, cognitive impairment, or epilepsy]).

Results: We identified primary thrombotic microangiopathies in 33 of 564 patients (6%; thrombotic thrombocytopenic purpura: 18 of 564 [3%]; atypical hemolytic and uremic syndrome: 18 of 564 [3%]). Secondary thrombotic microangiopathies were found in 531 of 564 patients (94%). A cause was identified in 500 of 564 (94%): pregnancy (35%; 11 of 1000 pregnancies), malignancies (19%), infections (33%), drugs (26%), transplantations (17%), autoimmune diseases (9%), shiga toxin due to (6%), and malignant hypertension (4%). In the 31 of 531 patients (6%) with other secondary thrombotic microangiopathies, 23% of patients had sickle cell disease, 10% had glucose-6-phosphate dehydrogenase deficiency, and 44% had folate deficiency. Multiple causes of thrombotic microangiopathies were more frequent in secondary than primary thrombotic microangiopathies (57% versus 19%; <0.001), and they were mostly infections, drugs, transplantation, and malignancies. Significant differences in clinical and biologic differences were observed among thrombotic microangiopathy causes. During the hospitalization, 84 of 564 patients (15%) were treated with dialysis, 64 of 564 patients (11%) experienced major cardiovascular events, and 25 of 564 patients (4%) had neurologic complications; 58 of 564 patients (10%) died, but the rates of complications and death varied widely by the cause of thrombotic microangiopathies.

Conclusions: Secondary thrombotic microangiopathies represent the majority of thrombotic microangiopathies. Multiple thrombotic microangiopathies causes are present in one half of secondary thrombotic microangiopathies. The risks of dialysis, neurologic and cardiac complications, and death vary by the cause of thrombotic microangiopathies.
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http://dx.doi.org/10.2215/CJN.11470918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450353PMC
April 2019

Lymphomas diagnosed in an internal medicine department compared to lymphomas diagnosed in other departments: Clinical and outcome differences.

Medicine (Baltimore) 2018 Nov;97(47):e13228

Internal Medicine Department, University Hospital Center of Tours, Université François Rabelais, France.

Lymphomas are common malignancies with highly variable clinical presentations and prognosis. Prognostic value of clinical presentation at onset is still questioned. The objective of this study was to compare the disease presentation and the outcome of lymphomas diagnosed in an Internal Medicine Department of a University Hospital to disease presentation and outcome of patients who were referred to the Hematology Department of the same institution by other departments or healthcare facilities.This retrospective monocentric observational study included 37 patients. They were matched to 73 patients, who were referred to the Hematology Department, according to age, histology, and Ann Arbor stage. The demographics, clinical and biological presentations, overall survival, and progression-free survival were compared.Patients diagnosed with lymphoma in the Internal Medicine Department were more likely to be febrile (67.5% vs 21.9%; P < .001) and have higher inflammatory markers (mean C-reactive protein 86.6 vs 56.3 mg/L; P = .02). The median overall survival of these patients was poorer (P < .001), even in the subset of patients treated with standard treatment, and remained shorter in multivariable analysis (P = .002). The specific treatment started earlier (20.2 vs 37.5 days; P = .006), but was more frequently palliative (37.8% vs 19.2%; P = .04). There was no significant difference in median progression-free survival.Lymphomas diagnosed in an Internal Medicine Department had aggressive clinical presentations and a poorer outcome, despite an early start of conventional treatment.
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http://dx.doi.org/10.1097/MD.0000000000013228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392786PMC
November 2018

Efficacy and Safety of Anti-D Immunoglobulins versus Intravenous Immunoglobulins for Immune Thrombocytopenia in Children: Systematic Review and Meta-analysis of Randomized Controlled Trials.

J Pediatr 2019 01 9;204:225-233.e8. Epub 2018 Oct 9.

Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France; CHRU de Tours, Service de Pharmacologie Clinique, Tours, France.

Objectives: To compare the efficacy and safety of intravenous immunoglobulins (IVIG) and anti-D immunoglobulin (anti-D) in pediatric immune thrombocytopenia (ITP).

Study Design: We conducted a systematic review and meta-analysis following PRISMA guidelines, including all randomized controlled trials that have assessed the efficacy and safety of anti-D and IVIG in children with ITP. We searched Medline, Embase, and Cochrane databases. Primary outcomes were the proportion of children achieving platelet count responses as defined in each study and bleeding response. Other safety outcomes included infusion reactions and hemolysis.

Results: Eleven studies with 558 children were included. Anti-D was significantly inferior to IVIG at increasing platelet counts, both for thresholds of  >20 × 10/L at 24-72 hours (response rate ratio for anti-D vs IVIG: 0.85, 95% CI 0.78-0.94) and  >50 × 10/L at 24-72 hours (response rate ratio for anti-D vs IVIG: 0.75, 95% CI 0.61-0.92). Bleeding response was assessed in 4 studies, but some heterogeneity in reporting leads to unclear conclusion. General symptoms after anti-D infusion were less frequent than after IVIG (Peto OR 0.39, 95% CI 0.25-0.62). Hemolysis was more frequent after anti-D. The overall quality of the studies was low.

Conclusions: Compared with anti-D, IVIG led to a better response in terms of platelet count and may be preferred as a first-line treatment of ITP in children with acute hemorrhagic symptoms. However, the clinical significance of IVIG superiority on platelet count remains unclear.
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http://dx.doi.org/10.1016/j.jpeds.2018.07.065DOI Listing
January 2019

Deep characterization of the anti-drug antibodies developed in Fabry disease patients, a prospective analysis from the French multicenter cohort FFABRY.

Orphanet J Rare Dis 2018 07 31;13(1):127. Epub 2018 Jul 31.

Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France.

Background: Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes.

Results: Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 μg/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p = 0.005).

Conclusion: Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.
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http://dx.doi.org/10.1186/s13023-018-0877-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069887PMC
July 2018

What is the best salivary gland ultrasonography scoring methods for the diagnosis of primary or secondary Sjögren's syndromes?

Joint Bone Spine 2019 03 24;86(2):211-217. Epub 2018 Jul 24.

Internal Medicine Department, 37000 Tours, France; François-Rabelais University of Tours, 37000 Tours, France.

Objective: To evaluate the performance of salivary gland ultrasonography for the diagnosis of primary and secondary Sjögren's syndromes (pSS and sSS).

Method: Multicenter cross-sectional study on 97 patients with clinical sicca symptoms. The pSS (n = 22) met the American-European Consensus Group (AECG) classification criteria. The control patients (n = 36) with sicca symptoms did not fulfill the AECG criteria. Four scores were used to evaluate the 4 major salivary gland echostructure: the Salaffi score (0-16), Jousse-Joulin score (0-4), Hocevar score (0-48) and Milic score (0-12).

Results: The medians of ultrasonographic (US) scores were higher in the pSS and sSS groups than in the control group (P < 0.001). The receiver-operating characteristic (ROC) curves and the positive likelihood ratio (LR+) of the four scores showed a good diagnostic performance for the US diagnosis of pSS and sSS. Respectively, for pSS and sSS, the AUC were 0.891 (95%CI 0.812-0.970) and 0.824 (95%CI 0.695-0.954) for Hocevar score, 0.885 (95%CI 0.804-0.965) and 0.808 (95%CI 0.673-0.943) for Milic score, 0.915 (95%CI 0.848-0.982) and 0.844 (95%CI 0.724-0.965) for Salaffi score, 0.897 (95%CI 0.821-0.973) and 0.851 (95%CI 0.735-0.968) for Jousse-Joulin score. This study showed an interesting inter-observer reproducibility (kappa = 0.714 ± 0.131) of the US evaluation with 85.7% agreement between reader to determine the pathological character of the salivary glands.

Conclusion: Salivary gland US is a simple, non-invasive and performant imaging procedure for the diagnosis of pSS and sSS, with Salaffi, Milic and Jousse-Joulin scores.
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http://dx.doi.org/10.1016/j.jbspin.2018.06.014DOI Listing
March 2019

Effect of Glyburide vs Subcutaneous Insulin on Perinatal Complications Among Women With Gestational Diabetes: A Randomized Clinical Trial.

JAMA 2018 05;319(17):1773-1780

Centre for Research in Epidemiology and Population Health, Université Paris-Saclay, Université Paris-Sud, Université de Versailles Saint-Quentin-en-Yvelines, INSERM, Villejuif, France.

Importance: Randomized trials have not focused on neonatal complications of glyburide for women with gestational diabetes.

Objective: To compare oral glyburide vs subcutaneous insulin in prevention of perinatal complications in newborns of women with gestational diabetes.

Design, Settings, And Participants: The Insulin Daonil trial (INDAO), a multicenter noninferiority randomized trial conducted between May 2012 and November 2016 (end of participant follow-up) in 13 tertiary care university hospitals in France including 914 women with singleton pregnancies and gestational diabetes diagnosed between 24 and 34 weeks of gestation.

Interventions: Women who required pharmacologic treatment after 10 days of dietary intervention were randomly assigned to receive glyburide (n=460) or insulin (n=454). The starting dosage for glyburide was 2.5 mg orally once per day and could be increased if necessary 4 days later by 2.5 mg and thereafter by 5 mg every 4 days in 2 morning and evening doses, up to a maximum of 20 mg/d. The starting dosage for insulin was 4 IU to 20 IU given subcutaneously 1 to 4 times per day as necessary and increased according to self-measured blood glucose concentrations.

Main Outcomes And Measures: The primary outcome was a composite criterion including macrosomia, neonatal hypoglycemia, and hyperbilirubinemia. The noninferiority margin was set at 7% based on a 1-sided 97.5% confidence interval.

Results: Among the 914 patients who were randomized (mean age, 32.8 [SD, 5.2] years), 98% completed the trial. In a per-protocol analysis, 367 and 442 women and their neonates were analyzed in the glyburide and insulin groups, respectively. The frequency of the primary outcome was 27.6% in the glyburide group and 23.4% in the insulin group, a difference of 4.2% (1-sided 97.5% CI, -∞ to 10.5%; P=.19).

Conclusion And Relevance: This study of women with gestational diabetes failed to show that use of glyburide compared with subcutaneous insulin does not result in a greater frequency of perinatal complications. These findings do not justify the use of glyburide as a first-line treatment.

Trial Registration: clinicaltrials.gov Identifier: NCT01731431.
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http://dx.doi.org/10.1001/jama.2018.4072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583037PMC
May 2018

Liver involvement in urea cycle disorders: a review of the literature.

J Inherit Metab Dis 2017 11 12;40(6):757-769. Epub 2017 Sep 12.

CHRU de Tours, service médecine interne, Tours, France.

Urea cycle disorders (UCDs) are inborn errors of metabolism of the nitrogen detoxification pathway and encompass six principal enzymatic deficiencies. The aging of UCD patients leads to a better knowledge of the long-term natural history of the condition and to the reporting of previously unnoticed manifestations. Despite historical evidence of liver involvement in UCDs, little attention has been paid to this organ until recently. Hence, we reviewed the available scientific evidence on acute and chronic liver dysfunction and liver carcinogenesis in UCDs and discuss their pathophysiology. Overall, liver involvement, such as acute liver failure or steatotic-like disease, which may evolve toward cirrhosis, has been reported in all six main UCDs. Excessive glycogen storage is also a prominent histologic feature, and hypoglycemia has been reported in citrin deficiency. Hepatocarcinomas seem frequent in some UCDs, such as in citrin deficiency, and can sometimes occur in non-cirrhotic patients. UCDs may differ in liver involvement according to the enzymatic deficiency. Ornithine transcarbamylase deficiency may be associated more with acute liver failure and argininosuccinic aciduria with chronic liver failure and cirrhosis. Direct toxicity of metabolites, downstream metabolic deficiencies, impaired tricarboxylic acid cycle, oxidative stress, mitochondrial dysfunction, energy deficit, and putative toxicity of therapies combine in various ways to cause the different liver diseases reported.
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http://dx.doi.org/10.1007/s10545-017-0088-5DOI Listing
November 2017