Four clinical and biological phenotypes in antiphospholipid syndrome: a cluster analysis of 174 patients with antinuclear antibody tests

IntroductionAntiphospholipid syndrome (APS) is an autoimmune thrombotic disease with various systemic presentations. This study aimed to identify homogeneous groups of patients based on a non-supervised hierarchical cluster analysis and assess the rate of relapse associated with antinuclear antibodies (ANA).MethodsThis retrospective observational study enrolled patients, over a 90-month period, who had APS as defined by the 2006 Sydney classification criteria, and for whom ANA workup was performed. Agglomerative unsupervised hierarchical clustering was conducted to classify patients into subgroups using 24 variables reflecting a range of clinical and biological baseline features associated with APS.ResultsHundred and seventy-four patients were included and were categorized into four phenotypes. Cluster 1 (n=73) associated mostly middle-aged men with risk factors for cardiovascular disease. Obstetrical APS with low-risk thrombosis made up cluster 2 (n=25). Patients with venous thromboembolism (VTE), microvascular findings and double/triple positive APL antibodies (50%) were represented in cluster 3 (n=33). Whereas cluster 4 (n=43) characterized a predominantly female subpopulation with positive ANA and systemic lupus (n=23) that exhibited a high thrombotic risk and more frequent relapses (n=38) (p<0.001).ConclusionsThis study identified four homogenous groups of patients with APS listed as: i) cardiovascular and arterial risk, ii) obstetrical, iii) VTE and microvascular, and iv) ANA-positive APS. We found that ANA-positivity was associated with higher rates of relapse. Applying ANA status to classification criteria could constitute a novel approach to tailoring management for APS, based on phenotypic patterns and risk assessment

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity

L' infection à Orientia tsutsugamushi n'est pas associée à une activation de l'endothélium et de la coagulation

Le typhus des broussailles, maladie fébrile du sud et de l'est de l'Asie, est causé par la bactérie intracellulaire Orientia tsutsugamushi, de la famille des Rickettsiaceae. La découvetre récente d'un possible effet inhibiteur de cette bactérie sur le VIH a relancé l'intérêt pour cette rickettsie encore mal connue. Nous avons dosé des paramètres endothéliaux, hémostatiques et fibrinolytiques chez 14 patients thaïlandais atteints de typhus des broussailles. Les résultats obtenus au cours des deux mois de suivi ont été comparés aux résultats de 30 témoins thaïlandais. Chez les patients, la stabilité et la normalité des marqueurs endothéliaux sont en faveur d'une absence d'activation ou de lésions de l'endothélium. Ces résultats contrastent avec les résultats obtenus dans les infections par les autres rickettsies qui ont un tropisme pour l'endothélium vasculaire et provoquent des lésions endothéliales. La cellule cible d'Orientia tsutsugamushi n'est pas connue avec certitude. En outre, nous ne mettons pas en évidence d'activation de la coagulation, pourtant fréquente dans les rickettioses. Enfin, notre étude révèle une activation tardive de la fibrinolyse, maximale environ deux semaines après le diagnostic, et se manisfestant par un raccourcissement du temps de lyse des euglobulines et par une décroissance du taux de PAI-1. Á notre connaissance, ce travail est la première étude de l'hémostase dans le typhus des broussailles et incite à penser que le mécanisme pathogène d'Orientia tsutsugamushi est différent de celui de Rickettia rickettsii et Rickettsia conorii, les rickettsies les plus étudiées.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

DataSheet_1_Four clinical and biological phenotypes in antiphospholipid syndrome: a cluster analysis of 174 patients with antinuclear antibody tests.docx

IntroductionAntiphospholipid syndrome (APS) is an autoimmune thrombotic disease with various systemic presentations. This study aimed to identify homogeneous groups of patients based on a non-supervised hierarchical cluster analysis and assess the rate of relapse associated with antinuclear antibodies (ANA).MethodsThis retrospective observational study enrolled patients, over a 90-month period, who had APS as defined by the 2006 Sydney classification criteria, and for whom ANA workup was performed. Agglomerative unsupervised hierarchical clustering was conducted to classify patients into subgroups using 24 variables reflecting a range of clinical and biological baseline features associated with APS.ResultsHundred and seventy-four patients were included and were categorized into four phenotypes. Cluster 1 (n=73) associated mostly middle-aged men with risk factors for cardiovascular disease. Obstetrical APS with low-risk thrombosis made up cluster 2 (n=25). Patients with venous thromboembolism (VTE), microvascular findings and double/triple positive APL antibodies (50%) were represented in cluster 3 (n=33). Whereas cluster 4 (n=43) characterized a predominantly female subpopulation with positive ANA and systemic lupus (n=23) that exhibited a high thrombotic risk and more frequent relapses (n=38) (pConclusionsThis study identified four homogenous groups of patients with APS listed as: i) cardiovascular and arterial risk, ii) obstetrical, iii) VTE and microvascular, and iv) ANA-positive APS. We found that ANA-positivity was associated with higher rates of relapse. Applying ANA status to classification criteria could constitute a novel approach to tailoring management for APS, based on phenotypic patterns and risk assessment.</p

Age dependency for coagulation parameters in paediatric populations: Results of a multicentre study aimed at defining the age-specific reference ranges

Understanding of developmental haemostasis is critical to ensure optimal prevention, diagnosis, and treatment of haemorrhagic and thrombotic diseases in children. As coagulation test results are known to be dependent on the reagents/analysers used, it is recommended for each laboratory to define the age-dependent reference ranges by using its own technical condition. That study was carried out in seven centers to establish age-specific reference ranges using the same reagents and analyser. Plasma samples were obtained from 1437 paediatric patients from the following age groups: 15 days-4 weeks (n=36), 1-5 months (n=320), 6-12 months (n=176), 1-5 years (n=507), 6-10 years (n=132) and 11-17 years (n=262). Indication of coagulation testing was pre-operative screening for non-acute diseases in most cases. PT values were similar in the different age groups to those in adults, whereas longer aPTTs were demonstrated in the younger children. Plasma levels of all clotting factors, except for FV, were significantly decreased (p<0.0001) in the youngest children, adult values being usually reached before the end of the first year. The same applied to antithrombin, protein C/S, and plasminogen. In contrast, FVIII and VWF levels were elevated in the youngest children and returned to adult values within six months. The same applied to D-dimer levels, which were found elevated, particularly until six months of life, until puberty. These data suggest that most coagulation test results are highly dependent on age, mainly during the first year of life, and that age-specific reference ranges must be used to ensure proper evaluation of coagulation in children

L’enseignent supérieur agricole bordelais en appui à la transition agroécologique

L’enjeu de l’agroécologie est aujourd’hui perçu et compris par une grande majorité du monde agricole et répond à une aspiration sociétale. En viticulture, il se cristallise autour de l’utilisation des produits phytosanitaires, mais aussi de la qualité et la fertilité des sols et la biodiversité des parcelles