Clinical relevance of endpoints in clinical trials for acid sphingomyelinase deficiency enzyme replacement therapy

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

Pseudomonas aeruginosa prosthetic joint-infection outcomes: Prospective, observational study on 43 patients

ObjectivesAnalysis the outcomes of Pseudomonas aeruginosa prosthetic joint infection (PJI), and of their clinical and microbiological characteristics, surgical strategies and antibiotic treatments.MethodsMonocenter cohort study in a Bone-and-Joint-Infection Referral Center (08/2004 to 10/2018) including all consecutive P. aeruginosa PJIs. Data were extracted from the prospective database, including the following events: relapses, new PJIs, related deaths.ResultsMedian [IQR]: among the 43 patients included (28 females; 72 [63–80] years old; 27 hip, 15 knee, and 1 shoulder PJIs), 29 (67%) had underlying comorbidities, 12 (28%) had previously been treated for another PJI and 9 (21%) had undergone previous surgeries for their P. aeruginosa PJI. Eleven (26%) PJIs were polymicrobial, 16 (37%) strains were wild type, 8 (19%) ciprofloxacin-resistant. PJIs were classified as late chronic (n = 33), early postoperative (n = 9) or acute hematogenous infection (n = 1). Forty patients underwent surgery: 27 one-stage and 5 two-stage exchanges, 3 debridement and implant retention, and 5 other surgical strategies. Antibiotic treatments were: 29 received 41 [37–43] days of combination therapy (IV anti-pseudomonal β-lactam and 3–5 days of amikacin, then β-lactam and oral ciprofloxacin), followed by oral ciprofloxacin for a total of 12 weeks; 10 received only IV antibiotics for 83 [77–86] days, including 37 [32–46] days of combination therapy; 49 days of ceftazidime alone for 1. During follow-up lasting 33 [24–64.5] months, 2 relapses, 3 new PJIs, and 2 related deaths occurred. Thirty-three (82%) patients and 93% of those managed with one-stage exchange experienced no event.ConclusionOutcomes of our cohort’s P. aeruginosa PJIs—predominantly monomicrobial, chronic, ciprofloxacin-susceptible, treated with one-stage exchange and prolonged IV antibiotics—were 82% favorable

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative.

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

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative

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 Fisiopatológico

Myélopathies et maladies systémiques (à propos de deux observations et revue de la littérature)

PARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

RECHUTES DES VASCULARITES ASSOCIEES AUX ANCA EN HEMODIALYSE (DES MEDECINE INTERNE)

PARIS5-BU Méd.Cochin (751142101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Of the importance of the clinical phenotypes in the interpretation of the studies dealing with Fabry disease

Abstract 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 with agalsidase alfa and beta have been available. In this letter we underline the different clinical and technical considerations the readers have to be aware of to interpret the results of studies dealing with Fabry disease and anti-agalsidase antibodies. We reaffirm that antibodies preferentially develop in the severe classic Fabry phenotype, which can mislead into interpreting that antibodies are associated with much severe clinical events

Co-infection VIH et Histoplasma capsulatum variant capsulatum en France métropolitaine à l'ère des multithérapies anti-rétrovirales

L histoplasmose à Histoplasma capsulatum var. capsulatum est une mycose d importation en France métropolitaine. C est une infection opportuniste au cours de l infection à VIH définissant le SIDA dans sa forme extra-pulmonaire. Peu de données sont disponibles sur l histoplasmose au cours du SIDA dans les zones non endémiques ainsi que sur son pronostic et son évolution. Ce travail est une étude rétrospective recensant tous les cas de co-infection histoplasmose-VIH diagnostiqués en France métropolitaine entre 1997 et 2006. Soixante-quatre patients ont été identifiés. Les principales informations issues de l analyse de ces observations sont que l histoplasmose est une pathologie d importation pouvant survenir jusqu à 15 ans après le retour de zone d endémie, qu elle est fréquemment (42% des cas) révélatrice de l infection par le VIH et qu elle survient dans un contexte d immunodépression profonde (taux moyen de CD4 28/ L). Certains tableaux sont particulièrement évocateurs : atteinte cutanéo-muqueuse (45%), syndrome d activation macrophagique (14%). La mortalité élevée (23%) et précoce rend nécessaire un diagnostic rapide. Les moyens diagnostiques à privilégier sont les examens directs et les cultures (dont hémoculture). La sérologie a un faible intérêt et la place de la détection du galactomannane reste à établir. L incidence du syndrome inflammatoire de reconstitution immunitaire est remarquablement élevée (13%).Histoplasma capsulatum var. capsulatum histoplasmosis is not endemic in metropolitan France. Extra-pulmonary histoplasmosis is an AIDS-defining opportunistic infection. Few data are available about AIDS-related histoplasmosis in non-endemic areas. All (i.e. 64) AIDS-related histoplasmosis cases diagnosed in metropolitan France between 1997 and 2006 have been included in the retrospective study. Analysis of these cases indicated that histoplasmosis can occur more than 15 years after the last travel in an endemic area, that histoplasmosis is frequently (42%) the first HIV-infection manifestation and that patients with histoplasmosis are deeply immucompromised (mean CD4 count 28/ L). Muco-cutaneous lesions (45%) and hemophagocytic syndrome (14%) are suggestive of histoplasmosis. High early mortlaty rate (23%) is a plea for an ealier diagnosis. Direct examination and fungal cultures are the most useful diagnosis tools. Anti-histoplasma antibodies detection sensitvity is very low. The usefulness of galactomannan remains to be evaluated. Interestingly, immune restoration inflammatory syndrome is frequent (13%).ST QUENTIN EN YVELINES-BU (782972101) / SudocSudocFranceF