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Patients with multimorbidity increasingly impact healthcare systems, both in primary care and in hospitals. This is particularly true in Internal Medicine. This population associates with higher mortality rates, polypharmacy, hospital readmissions, post-discharge syndrome, anxiety, depression, accelerated age-related functional decline, and development of geriatric syndromes, amongst others. Internists and Hospitalists, in one of their roles as Generalists, are increasingly asked to attend to these patients, both in their own Departments as well as in surgical areas. The management of polypathology and multimorbidity, however, is often complex, and requires specific clinical skills and corresponding experience. In addition, patients' needs, health-care environment, and routines have changed, so emerging and re-emerging specific competences and approaches are required to offer the best coordinated, continuous, and comprehensive integrated care to these populations, to achieve optimal health outcomes and satisfaction of patients, their relatives, and staff. This position paper proposes a set of emerging and re-emerging competences for internal medicine specialists, which are needed to optimally address multimorbidity now and in the future.

Purpose: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults. Methods: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics. Results: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P =.0004), spleen volume (39% decrease vs 0.5% increase, P

Resume Introduction Le recours a la chirurgie bariatrique est en plein essor. Le bypass gastrique est une des techniques les plus utilisees en France, non denuee de complications a long terme. Observation Une femme de 55 ans etait hospitalisee pour un ralentissement psychomoteur, des œdemes des membres inferieurs et une eruption psoriasiforme evoluant depuis 3 mois. L’evolution a rapidement ete marquee par l’apparition d’une pancytopenie, d’une encephalopathie et d’une defaillance circulatoire menant a une defaillance multiviscerale. Retrospectivement, on documentera une encephalopathie pellagreuse, une acrodermatite, une transformation gelatineuse de la moelle d’origine multicarentielle et une probable cardiomyopathie sur carence en vitamine B1. Conclusion Une origine carentielle doit etre evoquee et traitee precocement devant tout nouveau symptome chez un patient avec antecedent de chirurgie bariatrique. Une carence en selenium doit etre evoquee devant toute insuffisance cardiaque dans ce contexte. Supplementation preventive et suivi specialise sont essentiels.

We describe a 79-year-old man with spondylodiscitis and unknown pathogen, treated with cefazolin and rifampicin. He developed a massive digestive hemorrhage. Prothrombin time was prolonged with severe vitamin-K-dependent clotting-factor deficiency. Severe bleeding can occur during cefazolin and rifampicin use. This deficiency should be assessed before prescribing cefazolin–rifampicin and prothrombin time monitored.

Fabry disease is a frequent lysosomal storage disorder secondary to the deficiency of alpha-galactosidase A enzyme. This X-linked genetic disease realizes progressive and systemic manifestations that affect both male and female. Fabry disease may present as "classical", as "late-onset" or "non-classical" forms. Symptoms and organ involvements of classical Fabry disease are acral pain crisis, cornea verticillata, hypertrophic cardiomyopathy, stroke and chronic kidney disease with proteinuria. Other common symptoms are often poorly recognized, such as gastrointestinal or ear involvements. In classical Fabry disease, symptoms first appear during childhood or during teenage years in males, but later in females. Patients with non-classical or late-onset Fabry disease have delayed manifestations or a single-organ involvement. Diagnosis is therefore difficult when classical organ involvements are missing, in paucisymptomatic patients or in late-onset forms. Recognition of Fabry disease is important because effective treatments are available. They have to be prescribed early. In male, diagnosis is made with alpha-galactosidase A enzyme activity dosage in leukocyte, that is very low or null in classical forms and under 30 percent in late-onset forms. Diagnosis is more challenging in females who may express normal residual enzyme activity. Other plasmatic biomarkers, such as lyso-globotriaosylceramide are interesting, especially in females. In this review, we aimed to summarize main clinical manifestations of Fabry disease to know when to evoke Fabry disease and propose a practical diagnosis algorithm to know how to diagnose.

International audience; Fabry disease is an X-linked lysosomal disease in which defects in the alpha-galactosidase A enzyme activity lead to the ubiquitous accumulation of glycosphingolipids. Whereas the classic disease is characterized by neuropathic pain, progressive renal failure, white matter lesions, cerebral stroke, and hypertrophic cardiomyopathy (HCM), the non-classic phenotype, also known as cardiac variant, is almost exclusively characterized by HCM. Circulating sphingosine-1-phosphate (S1P) has controversially been associated with the Fabry cardiomyopathy. We measured serum S1P levels in 41 patients of the FFABRY cohort. S1P levels were higher in patients with a non-classic phenotype compared to those with a classic phenotype (200.3 [189.6–227.9] vs. 169.4 ng/mL [121.1–203.3], p = 0.02). In a multivariate logistic regression model, elevated S1P concentration remained statistically associated with the non-classic phenotype (OR = 1.03; p < 0.02), and elevated lysoGb3 concentration with the classic phenotype (OR = 0.95; p < 0.03). S1P levels were correlated with interventricular septum thickness (r = 0.46; p = 0.02). In a logistic regression model including S1P serum levels, phenotype, and age, age remained the only variable significantly associated with the risk of HCM (OR = 1.25; p = 0.001). S1P alone was not associated with cardiac hypertrophy but with the cardiac variant. The significantly higher S1P levels in patients with the cardiac variant compared to those with classic Fabry suggest the involvement of distinct pathophysiological pathways in the two phenotypes. S1P dosage could allow the personalization of patient management.

International audience

Fluorodesoxyglucose Positron Emission Tomography (PET/CT) has never been compared to Chest-Abdomen-Pelvis CT (CAPCT) in patients with a fever of unknown origin (FUO), inflammation of unknown origin (IUO) and episodic fever of unknown origin (EFUO) through a prospective and multicentre study. In this study, we investigated the diagnostic value of PET/CT compared to CAPCT in these patients. The trial was performed between 1 May 2008 through 28 February 2013 with 7 French University Hospital centres. Patients who fulfilled the FUO, IUO or EFUO criteria were included. Diagnostic orientation (DO), diagnostic contribution (DC) and time for diagnosis of both imaging resources were evaluated. One hundred and three patients were included with 35 FUO, 35 IUO and 33 EFUO patients. PET/CT showed both a higher DO (28.2% vs. 7.8%, p < 0.001) and DC (19.4% vs. 5.8%, p < 0.001) than CAPCT and reduced the time for diagnosis in patients (3.8 vs. 17.6 months, p = 0.02). Arthralgia (OR 4.90, p = 0.0012), DO of PET/CT (OR 4.09, p = 0.016), CRP > 30 mg/L (OR 3.70, p = 0.033), and chills (OR 3.06, p = 0.0248) were associated with the achievement of a diagnosis (Se: 89.1%, Sp: 56.8%). PET/CT both orients and contributes to diagnoses at a higher rate than CAPCT, especially in patients with FUO and IUO, and reduces the time for diagnosis.

Acid sphingomyelinase deficiency (ASMD) is a rare inherited lipid storage disorder caused by a deficiency in lysosomal enzyme acid sphingomyelinase which results in the accumulation of sphingomyelin, predominantly within cells of the reticuloendothelial system located in numerous organs, such as the liver, spleen, lungs, and central nervous system. Although all patients with ASMD share the same basic metabolic defect, a wide spectrum of clinical presentations and outcomes are observed, contributing to treatment challenges. While infantile neurovisceral ASMD (also known as Niemann–Pick disease type A) is rapidly progressive and fatal in early childhood, and the more slowly progressive chronic neurovisceral (type A/B) and chronic visceral (type B) forms have varying clinical phenotypes and life expectancy. The prognosis of visceral ASMD is mainly determined by the association of hepatosplenomegaly with secondary thrombocytopenia and lung disease. Early diagnosis and appropriate management are essential to reduce the risk of complications and mortality. The accessibility of the new enzyme replacement therapy olipudase alfa, a recombinant human ASM, has been expedited for clinical use based on positive clinical data in children and adult patients, such as improved respiratory status and reduced spleen volume. The aim of this article is to share the authors experience on monitoring ASMD patients and stratifying the severity of the disease to aid in care decisions.

Acid sphingomyelinase deficiency (ASMD) is an inherited lysosomal disease characterised by a diffuse accumulation of sphingomyelin that cannot be catabolised into ceramide and phosphocholine. We studied the incidence of cancer in ASMD patients. We retrospectively reviewed the medical records of the adult chronic visceral ASMD patients in our cohort. Thirty-one patients (12 females, 19 males) were included with a median age of 48.7 y. (IQ: 30.3–55.1). Five cancers were observed in 1 female (breast cancer) and 4 males (two lung cancers, one thyroid cancer and one bladder cancer), resulting in a prevalence of 16.1%. The existence of cancer was associated with a more severe ASMD characterised by a larger spleen (25 cm (22.5–25) vs. 18 cm (17–20); p = 0.042); lower diffusing capacity of the lung for carbon monoxide (DLCO; 29.5 % (17.8–43.0) vs. 58.5 % (49.8–69.5%); p = 0.01) and tobacco use (100% vs. 45%; p = 0.04). Three patients died, all from cancer (p = 0.002). The prevalence of cancer appeared to be strikingly elevated in our cohort of patients, without any specificity in the type of cancer. Systematic screening for cancer should be performed, and carcinogenic substances such as tobacco should be avoided in patients with ASMD.

International audience; Background: Fabry disease (FD) is an X-linked lysosomal disease due to a deficiency in the activity of the lysosomal α-galactosidase A (GalA), a key enzyme in the glycosphingolipid degradation pathway. FD is a complex disease with a poor genotype–phenotype correlation. FD could involve kidney, heart or central nervous system impairment that significantly decreases life expectancy. The advent of omics technologies offers the possibility of a global, integrated and systemic approach well-suited for the exploration of this complex disease. Materials and Methods: Sixty-six plasmas of FD patients from the French Fabry cohort (FFABRY) and 60 control plasmas were analyzed using liquid chromatography and mass spectrometry-based targeted metabolomics (188 metabolites) along with the determination of LysoGb3 concentration and GalA enzymatic activity. Conventional univariate analyses as well as systems biology and machine learning methods were used. Results: The analysis allowed for the identification of discriminating metabolic profiles that unambiguously separate FD patients from control subjects. The analysis identified 86 metabolites that are differentially expressed, including 62 Glycerophospholipids, 8 Acylcarnitines, 6 Sphingomyelins, 5 Aminoacids and 5 Biogenic Amines. Thirteen consensus metabolites were identified through network-based analysis, including 1 biogenic amine, 2 lysophosphatidylcholines and 10 glycerophospholipids. A predictive model using these metabolites showed an AUC-ROC of 0.992 (CI: 0.965–1.000). Conclusion: These results highlight deep metabolic remodeling in FD and confirm the potential of omics-based approaches in lysosomal diseases to reveal clinical and biological associations to generate pathophysiological hypotheses.

Fabry disease (FD) is a lysosomal storage disease responsible for cochleovestibular involvement. Exact prevalence and pathophysiological mechanisms behind ENT affections are still poorly known. Treating FD with enzyme replacement therapy (ERT) does not seem to significantly improve the ENT symptoms, while the impact of migalastat has yet to be determined. We carried out a retrospective multi-centre study on 47 patients from the FFABRY cohort who had an ENT consultation in the context of their FD. The information collected were as follows: clinical examination, videonystagmoscopy, pure-tone speech audiometry, videonystagmography or VHIT (Video Head Impulse Test). Severe hearing loss was defined as greater than 70 dB. The median age of our cohort was 52 years with a non-negligible proportion of non-classic variants and female carriers. 72.3% of the patients complained of at least one of the following symptoms: hearing loss, tinnitus or vertigo. Pure-tone audiometry was abnormal in 61.7% of the patients (29/47), while speech audiometry was abnormal for 41.7% of the patients. The age of the patients and hypertrophic cardiomyopathy were significantly associated with the existence of an anomaly in pure-tone audiometry results. Severe hearing loss (> 70 dB) was significantly more common in male patients. Hearing loss is particularly frequent in FD and is not limited to classic phenotypes. Close ENT follow-up is essential for Fabry patients to detect those who might benefit from hearing aid. Further studies are needed to define the impact of migalastat on cochleovestibular symptoms.

Resume Introduction Le cancer du col de l’uterus represente la douzieme cause de cancer de la femme en France. Le glassy cell carcinoma est une entite histologique rare de mauvais pronostic dont l’evolution est rapidement progressive. Observation Une femme de 30 ans etait adressee dans le service de medecine interne pour des polyarthralgies febriles evoluant depuis 3 semaines. Les explorations retrouvaient un syndrome inflammatoire biologique avec au TEP-scanner des lesions osteolytiques disseminees intensement hypermetaboliques associees a un foyer pelvien droit, ainsi que des foyers ganglionnaires. L’examen gynecologique retrouvait une lesion bourgeonnante de l’endocol de 3 cm dont l’histologie retrouvait un carcinome a haut index mitotique de type glassy-cell carcinoma. L’evolution etait defavorable malgre une chimiotherapie debutee en urgence, avec deces de la patiente en trois mois. Conclusion Le glassy cell carcinoma du col de l’uterus doit etre rajoute aux causes possibles de metastases osseuses chez la femme jeune.

To study a muscle-to-muscle standardised uptake value (SUV) ratio with FDG-PET/CT (FDG-PET) as a marker for the detection of disease activity in dermatomyositis (DM). Patients with DM (n = 24) who met the European Neuro-Muscular Centre diagnostic criteria were retrospectively identified over a 3-year period through a national survey. Muscle biopsy was performed in all patients. Maximum SUV was measured in proximal muscles (SUVPROX) that had the highest radiotracer uptake on visual grading as well as in the musculus longissimus thoracis (SUVMLT), whereas mean SUV was measured for the liver (SUVLIV). Muscle-to-liver SUV ratios for either muscle group were compared and a SUVPROX/SUVMLT ratio was calculated. SUVPROX/SUVMLT of DM patients were compared with age- and sex-matched control subjects (n = 24) with melanoma who had received FDG-PET scans. DM patients presented with proximal and symmetrical muscle uptake. Differences in SUVPROX/SUVLIV and SUVMLT/SUVLIV ratios in DM subjects were significant (p

Background Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, results from mutations in SMPD1, the gene encoding acid sphingomyelinase (ASM). As a result, sphingomyelin accumulates in multiple organs including spleen, liver, lung, bone marrow, lymph nodes, and in the most severe form, in the CNS and peripheral nerves. Clinical manifestations range from rapidly progressive and fatal infantile neurovisceral disease, to less rapidly progressing chronic neurovisceral and visceral forms that are associated with significant morbidity and shorter life span due to respiratory or liver disease. Objectives To provide a contemporary guide of clinical assessments for disease monitoring and symptom management across the spectrum of ASMD phenotypes. Methods An international group of ASMD experts in various research and clinical fields used an evidence-informed consensus process to identify optimal assessments, interventions, and lifestyle modifications. Results Clinical assessment strategies for major organ system involvement, including liver, spleen, cardiovascular, pulmonary, and neurological/developmental are described, as well as symptomatic treatments, interventions, and/or life style modifications that may lessen disease impact. Conclusions There is currently no disease-specific treatment for ASMD, although enzyme replacement therapy with a recombinant human ASM (olipudase alfa) is in clinical development. Current monitoring addresses symptoms and multisystem involvement. Recommended interventions and lifestyle modifications are designed to address morbidity and disease complications and improve patient quality of life. While infantile neurovisceral ASMD is uniformly fatal in early childhood, patients with chronic visceral and chronic neurovisceral ASMD require appropriate management throughout childhood and adulthood by an interdisciplinary clinical team.

Background: Gaucher disease is a rare inborn error of lysosomal metabolism, characterized by lysosomal storage of the beta-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. J Hematol. 2019;8(3):121-124 doi: https://doi.org/10.14740/jh543

International audience; Background: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD.Methods and findings: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial.Conclusion: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Fabry disease. Fabry disease is an X-linked disorder in which lysosomal alpha-galactosidase A is lacking, leading to enzyme-substrate accumulation and tissues dysfunction. Acroparesthesia, angiokeratoma, familial nephropathy or hypertrophic cardiomyopathy should suggest Fabry disease. Enzymatic assay allows diagnosis in men but genetic assay is needed for women. Enzyme replacement therapy is available since 2001 and a pharmacologic chaperone since 2016.Maladie de Fabry. La maladie de Fabry est une maladie rare, monogénique, liée à l’X, où un déficit enzymatique en alpha-galactosidase A lysosomale provoque l’accumulation intracellulaire de son substrat à l’origine de dysfonctions d’organe. On doit l’évoquer aussi bien chez l’homme que chez la femme, en particulier devant des acroparesthésies à électropyogramme normal, des angiokératomes, une insuffisance rénale familiale ou une cardiopathie hypertrophique possiblement isolée et sans obstacle à l’éjection. Le diagnostic se fait par dosage enzymatique chez l’homme et par analyse génétique chez la femme. Trois traitements sont disponibles : deux enzymothérapies substitutives depuis 2001, une molécule chaperon depuis 2016.

BACKGROUND Fabry disease (FD) is the second most common lysosomal storage disorder, carrying a large morbidity and mortality. It has been recently reported that lysosomal storage disorders could cause inflammation and, subsequently, AA amyloidosis (AAA). Our aim was to describe AAA cases occurring in the course of FD. PATIENTS AND METHODS We described two patients displaying both AAA and FD and an additional case from the literature. RESULTS Three female patients originating from Europe (n = 2) and Algeria (n = 1) harboured heterozygous GLA mutations. The median age at AAA diagnosis was 61 years old. The diagnosis of Fabry was made before the diagnosis of AAA (n = 1) or concomitantly (n = 2). At AAA diagnosis, two patients displayed a nephrotic syndrome; all had inflammation. CONCLUSION Fabry disease can be associated with AAA, suggesting that an inflammatory component could exist in this genetic disease.

Background Acid sphingomyelinase deficiency (ASMD) also known as Niemann-Pick disease, is a rare lysosomal storage disorder with a diverse disease spectrum that includes slowly progressive, chronic visceral (type B) and neurovisceral forms (intermediate type A/B), in addition to infantile, rapidly progressive fatal neurovisceral disease (type A). Purpose and methods We review the published evidence on the relevance of splenomegaly and reduced lung diffusion capacity to the clinical burden of chronic forms of ASMD. Targeted literature searches were conducted to identify relevant ASMD and non-ASMD studies for associations between diffusing capacity of the lungs for carbon monoxide (DLCO) and splenomegaly, with clinical parameters and outcome measures. Results Respiratory disease and organomegaly are primary and independent contributors to mortality, disease burden, and morbidity for patients with chronic ASMD. The degree of splenomegaly correlates with short stature, atherogenic lipid profile, and degree of abnormality of hematologic parameters, and thus may be considered a surrogate marker for bleeding risk, abnormal lipid profiles and possibly, liver fibrosis. Progressive lung disease is a prevalent clinical feature of chronic ASMD, contributing to a decreased quality of life (QoL) and an increased disease burden. In addition, respiratory-related complications are a major cause of mortality in ASMD. Conclusions The reviewed evidence from ASMD natural history and observational studies supports the use of lung function and spleen volume as clinically meaningful endpoints in ASMD trials that translate into important measures of disease burden for patients.

International audience; 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

Objectives The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. Design and setting Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists’ free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. Results A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. Conclusions PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised., Instituto de Estudios Inmunológicos y Fisiopatológicos

Introduction La maitrise de la semiologie ne semble pas bien correlee aux resultats a l’examen national classant (ECN). Un etudiant bien classe peut ne pas savoir interroger et examiner un patient. Certains etudiants deviennent internes sans maitriser l’examen clinique. Il semble important de definir des methodes efficaces d’apprentissage de la semiologie lors des stages hospitaliers. Nous rapportons la mise en place, au sein de notre service de medecine interne, d’une nouvelle methode d’apprentissage de la semiologie clinique au cours des stages de 2e cycle, que nous avons baptisee « masterclass de semiologie ». Patients et methodes Les 5 medecins seniors du service ont liste les items de l’examen clinique a maitriser pour devenir performant en semiologie. Une methode Delphi a ete appliquee. Resultats Nous avons retenu 43 items. Nous nous sommes accordes sur les criteres de bonne realisation de chacun des items. Par exemple, pour evaluer la taille de la rate il fallait allonger le patient, palper l’abdomen en debutant par les cadrans inferieurs et en finissant pas l’hypochondre gauche, et faire inspirer profondement a plusieurs reprises. Des l’accueil des etudiants dans notre service nous leur remettons une liste des 43 items selectionnes, qu’ils doivent maitriser pour l’evaluation de fin de stage. Ils ont pour consigne de stimuler les seniors a leur enseigner les items qu’ils maitrisent mal. La demarche est donc active de leur part. De plus, une heure de cours de semiologie est assuree pendant leur stage ou les items habituellement les moins maitrises sont expliques. Les etudiants peuvent alors s’examiner les uns les autres sous la supervision d’un medecin senior. L’evaluation de fin de stage est realisee par 2 seniors qui jugent de facon subjective et concertee. L’etudiant tire au hasard 5 items et doit decrire sa technique d’examen et l’appliquer sur un des examinateurs si possible. La maitrise d’au moins 4 items/5 est necessaire a la validation du stage. Discussion Vingt-deux externes, durant 3 periodes de stages ont experimente cette technique d’enseignement. Tous les etudiants evalues ont ete valides. L’evaluation d’un etudiant durait entre 10 et 15 minutes. La validation est vecue comme un moment convivial par les etudiants. Conclusion Dans notre experience, responsabiliser les etudiants quant a la maitrise de l’examen clinique est une technique efficace d’apprentissage de la semiologie.

Introduction La maladie de Behcet (MB) est caracterisee par des ulcerations buccales et genitales, des lesions cutanees, une inflammation intraoculaire, et de nombreuses autres atteintes viscerales. Une association forte entre la MB et des polymorphismes du gene codant pour l’IL-23R/IL-12RB2 a ete montree, et l’implication des lymphocytes T helper (Th) 1 et Th17 a ete suggeree dans plusieurs etudes. L’ustekinumab, anticorps monoclonal anti-IL-12/IL-23, pourrait ainsi etre une option therapeutique interessante au cours de la MB. L’objectif de cette etude etait d’evaluer l’efficacite et la tolerance de l’ustekinumab au cours de la MB. Patients et methodes Nous avons realise une etude prospective de phase 2, ouverte, evaluant l’efficacite et la tolerance de l’ustekinumab chez les patients atteints de MB ( NCT02648581 ). Les criteres d’inclusion etaient : un diagnostic de MB selon les criteres de classification internationaux, et la presence d’ulceres buccaux ou genitaux recurrents definis comme ≥ 2 episodes dans les 3 derniers mois et resistant au moins a la colchicine a une dose ≥1 mg/j. Des injections sous-cutanees d’ustekinumab a la dose de 90 mg etaient realisees aux semaines (S) 0, 4 et 16, et des injections supplementaires etaient realisees a S28 et S40 chez les patients repondeurs a S24. Le critere de jugement principal etait la modification du nombre d’ulceres buccaux a S24 par rapport a la visite d’inclusion. Une reponse complete etait definie comme l’absence de toute ulceration buccale ou genitale, et une reponse partielle comme une diminution de ≥ 50 % du nombre d’ulceres buccaux. Le critere de jugement principal a ete evalue par un comite d’adjudication independant. Les criteres de jugements secondaires etaient l’evolution du nombre et de la douleur des aphtes, des scores d’activite de la MB (BSAS allant de 0 a 100, BDCAF allant de 0 a12) et des scores de qualite de vie (BDQol allant de 0 a 30, SF36, et RAPID3 allant de 0 a 30), et la tolerance du traitement. Un nombre de 15 patients etait necessaire afin de pouvoir demontrer une efficacite du traitement par ustekinumab chez > 50 % des patients. Resultats Quinze patients ont ete inclus et ont recu au moins une injection d’ustekinumab. L’âge moyen a l’inclusion etait de 35,5 ± 9,5 ans. A l’inclusion, le nombre moyen d’aphtes buccaux etait de 2,1 ± 1,3 et seuls 2 patients presentaient des aphtes genitaux. A S24, une reponse clinique etait observee chez 11 patients (73,3 % [60,0–95,7]), dont 9 (60 % [35,2–84,8]) reponses completes et 2 (13,3 % [0–30,5]) reponses partielles. Parmi les quatre patients en echec a S24, trois avaient interrompu l’ustekinumab pour une rechute ou une absence d’efficacite, avec un relais par infliximab dans 2 cas et cyclophosphamide dans un. Les causes d’echec etaient : la survenue d’abces aseptiques avec atteinte vasculaire arterielle grave necessitant une prise en charge chirurgicale urgente, une atteinte cutanee avec aphtose bipolaire et erytheme noueux, et enfin une orchite avec arthralgies et aphtose buccale. Sous traitement par ustekinumab, le nombre moyen d’ulceres buccaux diminuait de 2,1 ± 1,3 a 0,3 ± 0,5 a S24 (p = 0,0002). Il y avait egalement une diminution des scores d’activite et une amelioration des scores de qualite de vie a S24 : baisse du BSAS de 38 ± 13 a 14 ± 12 (p = 0,0006), du BDCAF de 3,7 ± 1,5 a 1,6 ± 1,5 (p = 0,001), du BD-QoL de 13,2 ± 7,4 a 8,2 ± 8,6 (p = 0,05) et du RAPID3 de 13,4 ± 5,6 a 4,7 ± 3,2 (p = 0,002). A S52, la reponse etait maintenue chez 10/11 patients (90,9 % [73,9-100]), dont 9 avec une reponse complete, avec un nombre moyen d’aphtes buccaux de 0,3 ± 0,8 (p = 0,0002 comparativement a la visite d’inclusion). Un seul patient a presente un effet indesirable grave, sous la forme d’un syndrome grippal justifiant une hospitalisation, avec une recuperation sans sequelle. Il n’y a eu aucun arret du traitement du fait d’un effet indesirable. Conclusion Cette etude montre une efficacite de l’ustekinumab pour le traitement de l’aphtose buccale resistante au cours de la MB, avec un excellent profil de tolerance.

Resume La maladie de Rendu-Osler(-Weber), ou telangiectasie hemorragique hereditaire, est une maladie genetique entrainant une deregulation de l’angiogenese et conduisant a la formation de telangiectasies cutaneo-muqueuses et de shunts intravisceraux. La telangiectasie hemorragique hereditaire peut engager le pronostic vital par l’intermediaire d’une insuffisance cardiaque a debit eleve en presence de multiples shunts intrahepatiques. La telangiectasie hemorragique hereditaire expose egalement au risque d’infections, notamment intracerebrales en presence de malformations arterio-veineuses pulmonaires. La survenue d’infections osteoarticulaires a ete plus rarement decrite au cours de la telangiectasie hemorragique hereditaire. Nous rapportons le cas d’une patiente de 77 ans ayant presente des infections osteoarticulaires recidivantes a Staphylococcus aureus sensible a la methicilline dans un contexte de telangiectasie hemorragique hereditaire avec atteinte multiviscerale severe ayant necessite un traitement par bevacizumab. L’association entre telangiectasie hemorragique hereditaire et infections osteoarticulaires, et les hypotheses physiopathogeniques emises sont discutees. Des mesures preventives (decolonisation des gites staphylococciques, antibioprophylaxie) peuvent etre proposees chez les patients a risque d’infections recurrentes. Le traitement par bevacizumab a revolutionne la prise en charge des formes severes, mais son role preventif dans la survenue des infections reste a determiner. La reconnaissance de la telangiectasie hemorragique hereditaire, aux criteres diagnostiques simples et etablis, est donc importante pour le rhumatologue.