Soluble markers of B cell activation suggest a role of B cells in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension

IntroductionSoluble markers of B cell activation are interesting diagnostic and prognostic tools in autoimmune diseases. Data in systemic sclerosis (SSc) are scarce and few studies focused on their association with disease characteristics.Methods1. Serum levels of 14 B cell biomarkers (β2-microglobulin, rheumatoid factor (RF), immunoglobulins (Ig) G, IgA, IgM, BAFF, APRIL, soluble (s)TACI, sBCMA sCD21, sCD23, sCD25, sCD27, CXCL13) were measured in SSc patients and healthy controls (HC). 2. Associations between these biomarkers and SSc characteristics were assessed. 3. The pathophysiological relevance of identified associations was explored by studying protein production in B cell culture supernatant.ResultsIn a discovery panel of 80 SSc patients encompassing the broad spectrum of disease manifestations, we observed a higher frequency of RF positivity, and increased levels of β2-microglobulin, IgG and CXCL13 compared with HC. We found significant associations between several biomarkers and SSc characteristics related to disease phenotype, activity and severity. Especially, serum IgG levels were associated with pulmonary hypertension (PH); β2-microglobulin with Nt-pro-BNP and DLCO; and BAFF with peak tricuspid regurgitation velocity (TRV). In a validation cohort of limited cutaneous SSc patients without extensive ILD, we observed lower serum IgG levels, and higher β2-microglobulin, sBCMA, sCD23 and sCD27 levels in patients with pulmonary arterial hypertension (PAH). BAFF levels strongly correlated with Nt-pro-BNP levels, FVC/DLCO ratio and peak TRV in SSc-PAH patients. Cultured SSc B cells showed increased production of various angiogenic factors (angiogenin, angiopoietin-1, VEGFR-1, PDGF-AA, MMP-8, TIMP-1, L-selectin) and decreased production of angiopoietin-2 compared to HC.ConclusionSoluble markers of B cell activation could be relevant tools to assess organ involvements, activity and severity in SSc. Their associations with PAH could plead for a role of B cell activation in the pathogenesis of pulmonary microangiopathy. B cells may contribute to SSc vasculopathy through production of angiogenic mediators

Prevalence and Clinical Associations of Antiphospholipid Antibodies in Systemic Sclerosis: New Data From a French Cross-Sectional Study, Systematic Review, and Meta-Analysis

Objectives: Antiphospholipid antibodies (aPL) can be present in the sera of systemic sclerosis (SSc) patients. This study aimed to determine the prevalence of aPL in a cross-sectional study of SSc patients, to assess their clinical associations, to perform a systematic review of published reports and a meta-analysis to estimate the worldwide prevalence of aPL in SSc.Methods: Two-hundred and forty-nine SSc patients were consecutively tested once for lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2glycoprotein I (anti-β2GpI) antibodies. Clinical associations with aPL positivity were studied using a logistic regression model. A systematic review of the literature was carried out in PubMed and Embase. Meta-analysis was performed using number of aPL positive (at least one of the three antibodies positive) and negative patients. Meta-regression was used to study potential factors explaining the heterogeneity between studies.Results: In our cross-sectional study, aPL positivity was found in 16 patients (prevalence 6.4%; 95%CI [3.8–10.4]). In multivariate analysis, there was a significant association between aPL positivity and venous thrombosis (VT) (OR 6.25 [1.18–33.00]; p = 0.028) and miscarriage (OR 5.43; 95%CI [1.31–22.13]; p = 0.017). Twenty-four studies were included in the meta-analysis, representing a total population of 3036 SSc patients. The overall pooled prevalence of aPL in SSc was 14% (9–20) with a high degree of heterogeneity among studies.Conclusion: This study found a prevalence of aPL positivity in our SSc population of 6.4% (3.8–10.4) and an overall worldwide pooled prevalence of 14% (9–20). In our SSc population, aPL positivity was associated with VT and miscarriage. These data provide additional insights into the role of aPL in the vasculopathy observed in SSc

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Les auto-anticorps, marqueurs immunologiques de l’hétérogénéité de la sclérodermie systémique

Systemic sclerosis (SSc) is a connective tissue disease (CTD) characterized by vasculopathy, auto-immunity and fibrosis. This condition is associated with a significant morbi-mortality, and the therapeutic armamentarium is limited. The pathological mechanisms of SSc are partially known, but the links between the immune system and fibrosis appear tight. ScS can be considered as a prototypical model for the study of the links between immunity and fibrosis. There is a high heterogeneity in SSc. The clinical phenotypes of patients are highly variable, making the classification of patients into homogeneous groups complex. A better understanding of this heterogeneity could lead to the identification of endotypes, which are needed to study the pathophysiological processes of each group.This PhD Thesis aimed to better decipher this clinical heterogeneity and to assess the immunological components, in particular auto-antibodies, as biomarkers of heterogeneity.The first work was a without any a priori cluster analysis in the EUSTAR (European Scleroderma Trials and Research Group) cohort using 24 selected variables (encompassing clinical involvement and auto-antibodies). Two then 6 homogeneous clusters were obtained, with significantly different survival curves. We suggested that there could be homogeneous groups of patients beyond the classical dichotomy diffuse cutaneous form vs. limited. Organ involvement as well as antibody status were suggested to play a major role in defining homogeneous groups of patients with different prognosis.Our second work assessed the value of serum free light chain (SFLC) in SSc. The SFLC level was higher in SSc patients than in controls and was associated with severity parameters, such as Rodnan skin score, disease activity score, pulmonary pressures and DLCO. This study suggested that B cells could play an active role in the mechanisms of SSc.Then we estimated the prevalence of anti-RNA polymerase III antibodies in SSc in our cohort of patients followed by a systematic review with meta-analysis. We showed that the prevalence was highly heterogeneous between centers. Potential factors explaining partly the observed heterogeneity were geographical factors, which underscore the probable implication that genetic background and environmental factors play a role.Finally we focused on CTD-associated pulmonary arterial hypertension (PAH) in a large cohort of patients from the United Kingdom national reference center for PAH. We assessed whether anti-U1 RNP antibodies could be a prognostic factor in CTD-associated PAH with a focus on SSc- associated PAH. Anti-U1RNP antibodies were significantly associated with a decreased mortality in CTD-PAH patients. There was a trend towards a decreased mortality in SSc-PAH patients with anti-U1RNP antibodies.Auto-antibodies are strong biomarkers of diagnosis and prognosis in SSc. They allow to partly capture the clinical heterogeneity of this condition, and should be integrated in the future classifications of patients. Their pathogenic role remains to be shown. We plan to identify new auto-antibodies in SSc and to study their direct effects on the fibroblast, which is the key effector cell of fibrosis.La sclérodermie systémique (ScS) est une connectivite associant atteinte vasculaire, auto-immunité et fibrose. Cette pathologie est associée à une morbi-mortalité importante, et les ressources thérapeutiques sont limitées. La physiopathologie de la ScS n’est que partiellement connue, mais il apparait que les liens entre le système immunitaire et la fibrose sont étroits. Ainsi, la ScS peut être considérée comme un modèle prototypique d’étude des liens immunité-fibrose. Il s’agit d’une maladie hétérogène, c’est-à-dire que les phénotypes cliniques présentés par les patients sont variables, rendant complexe l’établissement d’une classification des patients en groupes homogènes. Mieux comprendre cette hétérogénéité est un préalable indispensable à la constitution d’endotypes, permettant l’étude des mécanismes physiopathologiques propres à chacun d’entre eux.L’objectif de cette Thèse a été de mieux appréhender cette hétérogénéité clinique et d’étudier la place des marqueurs immunologiques, en particulier les auto-anticorps, en tant que biomarqueurs de cette hétérogénéité.Le premier travail a été une classification sans a priori des patients de la cohorte européenne EUSTAR (European Scleroderma Trials and Research Group) par une analyse en cluster sur 24 variables sélectionnées (atteintes cliniques, auto-anticorps). Deux puis 6 groupes de patients homogènes ont été obtenus, dont la survie était significativement différente. Ce travail a suggéré qu’il existait des groupes homogènes de patients au-delà de la dichotomie historique forme cutanée diffuse vs. limitée. La présence d’atteintes viscérales et le statut des auto-anticorps apparaissent comme des éléments importants dans la constitution des groupes.Le deuxième travail s’est intéressé au dosage des chaines légères libres sériques (serum free light chain : SFLC) dans la ScS. Le taux de SFLC est plus élevé chez les patients ScS que chez les contrôles et est associé à des paramètres de gravité de la maladie tels que le score de Rodnan, les scores d’activité, les pressions pulmonaires et la DLCO. Cette étude apporte des arguments supplémentaires pour évoquer la participation active des lymphocytes B à la physiopathologie de la ScS.Nous avons ensuite réalisé une estimation de la prévalence des anticorps anti-ARN polymérase de type III dans notre cohorte de patients avec ScS avant d’inclure ces données dans une revue systématique avec méta-analyse. Ce travail a montré que la prévalence de ces anticorps était hétérogène entre les centres. Les facteurs potentiels pouvant expliquer une partie de cette hétérogénéité sont des facteurs géographiques, suggérant l’implication de facteurs génétiques et/ou environnementaux.Le dernier travail a été dédié à l’hypertension artérielle pulmonaire (HTAP) des connectivites, en particulier de la ScS. A partir d’une cohorte de patients provenant du centre de référence de l’HTAP du Royaume-Uni, les anticorps anti-U1RNP ont été analysés en tant que marqueur pronostique. Ces anticorps sont associés de façon significative à une meilleure survie des patients avec connectivite et HTAP. Dans la ScS, on observe une tendance vers une meilleure survie également chez les patients porteurs de ces anticorps.Les auto-anticorps constituent donc des biomarqueurs diagnostiques et pronostiques puissants dans la ScS. Ils permettent de mieux cerner l’hétérogénéité de cette pathologie, et devraient probablement être intégrés dans les futures classifications. Leur rôle pathogénique reste encore à démontrer. Les perspectives de notre travail sont d’identifier de nouveaux auto-anticorps et d’étudier leurs effets sur le fibroblaste, cellule effectrice centrale de la fibrose

Auto-antibodies in systemic sclerosis, immunological markers of heterogeneity

La sclérodermie systémique (ScS) est une connectivite associant atteinte vasculaire, auto-immunité et fibrose. Cette pathologie est associée à une morbi-mortalité importante, et les ressources thérapeutiques sont limitées. La physiopathologie de la ScS n’est que partiellement connue, mais il apparait que les liens entre le système immunitaire et la fibrose sont étroits. Ainsi, la ScS peut être considérée comme un modèle prototypique d’étude des liens immunité-fibrose. Il s’agit d’une maladie hétérogène, c’est-à-dire que les phénotypes cliniques présentés par les patients sont variables, rendant complexe l’établissement d’une classification des patients en groupes homogènes. Mieux comprendre cette hétérogénéité est un préalable indispensable à la constitution d’endotypes, permettant l’étude des mécanismes physiopathologiques propres à chacun d’entre eux.L’objectif de cette Thèse a été de mieux appréhender cette hétérogénéité clinique et d’étudier la place des marqueurs immunologiques, en particulier les auto-anticorps, en tant que biomarqueurs de cette hétérogénéité.Le premier travail a été une classification sans a priori des patients de la cohorte européenne EUSTAR (European Scleroderma Trials and Research Group) par une analyse en cluster sur 24 variables sélectionnées (atteintes cliniques, auto-anticorps). Deux puis 6 groupes de patients homogènes ont été obtenus, dont la survie était significativement différente. Ce travail a suggéré qu’il existait des groupes homogènes de patients au-delà de la dichotomie historique forme cutanée diffuse vs. limitée. La présence d’atteintes viscérales et le statut des auto-anticorps apparaissent comme des éléments importants dans la constitution des groupes.Le deuxième travail s’est intéressé au dosage des chaines légères libres sériques (serum free light chain : SFLC) dans la ScS. Le taux de SFLC est plus élevé chez les patients ScS que chez les contrôles et est associé à des paramètres de gravité de la maladie tels que le score de Rodnan, les scores d’activité, les pressions pulmonaires et la DLCO. Cette étude apporte des arguments supplémentaires pour évoquer la participation active des lymphocytes B à la physiopathologie de la ScS.Nous avons ensuite réalisé une estimation de la prévalence des anticorps anti-ARN polymérase de type III dans notre cohorte de patients avec ScS avant d’inclure ces données dans une revue systématique avec méta-analyse. Ce travail a montré que la prévalence de ces anticorps était hétérogène entre les centres. Les facteurs potentiels pouvant expliquer une partie de cette hétérogénéité sont des facteurs géographiques, suggérant l’implication de facteurs génétiques et/ou environnementaux.Le dernier travail a été dédié à l’hypertension artérielle pulmonaire (HTAP) des connectivites, en particulier de la ScS. A partir d’une cohorte de patients provenant du centre de référence de l’HTAP du Royaume-Uni, les anticorps anti-U1RNP ont été analysés en tant que marqueur pronostique. Ces anticorps sont associés de façon significative à une meilleure survie des patients avec connectivite et HTAP. Dans la ScS, on observe une tendance vers une meilleure survie également chez les patients porteurs de ces anticorps.Les auto-anticorps constituent donc des biomarqueurs diagnostiques et pronostiques puissants dans la ScS. Ils permettent de mieux cerner l’hétérogénéité de cette pathologie, et devraient probablement être intégrés dans les futures classifications. Leur rôle pathogénique reste encore à démontrer. Les perspectives de notre travail sont d’identifier de nouveaux auto-anticorps et d’étudier leurs effets sur le fibroblaste, cellule effectrice centrale de la fibrose.Systemic sclerosis (SSc) is a connective tissue disease (CTD) characterized by vasculopathy, auto-immunity and fibrosis. This condition is associated with a significant morbi-mortality, and the therapeutic armamentarium is limited. The pathological mechanisms of SSc are partially known, but the links between the immune system and fibrosis appear tight. ScS can be considered as a prototypical model for the study of the links between immunity and fibrosis. There is a high heterogeneity in SSc. The clinical phenotypes of patients are highly variable, making the classification of patients into homogeneous groups complex. A better understanding of this heterogeneity could lead to the identification of endotypes, which are needed to study the pathophysiological processes of each group.This PhD Thesis aimed to better decipher this clinical heterogeneity and to assess the immunological components, in particular auto-antibodies, as biomarkers of heterogeneity.The first work was a without any a priori cluster analysis in the EUSTAR (European Scleroderma Trials and Research Group) cohort using 24 selected variables (encompassing clinical involvement and auto-antibodies). Two then 6 homogeneous clusters were obtained, with significantly different survival curves. We suggested that there could be homogeneous groups of patients beyond the classical dichotomy diffuse cutaneous form vs. limited. Organ involvement as well as antibody status were suggested to play a major role in defining homogeneous groups of patients with different prognosis.Our second work assessed the value of serum free light chain (SFLC) in SSc. The SFLC level was higher in SSc patients than in controls and was associated with severity parameters, such as Rodnan skin score, disease activity score, pulmonary pressures and DLCO. This study suggested that B cells could play an active role in the mechanisms of SSc.Then we estimated the prevalence of anti-RNA polymerase III antibodies in SSc in our cohort of patients followed by a systematic review with meta-analysis. We showed that the prevalence was highly heterogeneous between centers. Potential factors explaining partly the observed heterogeneity were geographical factors, which underscore the probable implication that genetic background and environmental factors play a role.Finally we focused on CTD-associated pulmonary arterial hypertension (PAH) in a large cohort of patients from the United Kingdom national reference center for PAH. We assessed whether anti-U1 RNP antibodies could be a prognostic factor in CTD-associated PAH with a focus on SSc- associated PAH. Anti-U1RNP antibodies were significantly associated with a decreased mortality in CTD-PAH patients. There was a trend towards a decreased mortality in SSc-PAH patients with anti-U1RNP antibodies.Auto-antibodies are strong biomarkers of diagnosis and prognosis in SSc. They allow to partly capture the clinical heterogeneity of this condition, and should be integrated in the future classifications of patients. Their pathogenic role remains to be shown. We plan to identify new auto-antibodies in SSc and to study their direct effects on the fibroblast, which is the key effector cell of fibrosis

Dysarthrie et troubles de la déglutition dans la myosite à inclusions. Revue de la littérature sur les méthodes d’évaluation et les prises en charge orthophoniques

La myosite à inclusions est une pathologie neuromusculaire rare touchant principalement les adultes âgés de plus de 50 ans. L’incidence de la dysphagie y est la plus élevée au sein des myopathies inflammatoires. La dysarthrie est un symptôme clinique pouvant également être présent. Actuellement, aucune revue ne s’est spécifiquement intéressée à la place occupée par l’orthophoniste dans l’évaluation et la prise en charge de cette pathologie. Cette revue de la littérature a pour but de faire un état des lieux de la recherche scientifique concernant l’évaluation de la dysarthrie et de la dysphagie dans la myosite à inclusions ainsi que des méthodes de rééducation orthophonique existantes

Pulmonary hypertension in systemic sclerosis: different phenotypes

Pulmonary hypertension (PH) is a frequent and severe complication of systemic sclerosis (SSc). PH in SSc is highly heterogeneous because of the various clinical phenotypes of SSc itself and because the mechanisms of PH can vary from one patient to another. PH in SSc may be due to vasculopathy of the small pulmonary arteries (group 1; pulmonary arterial hypertension), interstitial lung disease (group 3; PH due to lung disease or chronic hypoxia) or myocardial fibrosis leading to left ventricular systolic or diastolic dysfunction (group 2; PH due to chronic left-heart disease). Pulmonary veno-occlusive disease is not uncommon in SSc and may also cause PH in some patients (group 1′). There is a high prevalence of each of these conditions in SSc and, as such, it may be difficult to determine the dominant cause of PH in a particular patient. However, careful phenotyping of PH in SSc is important as the therapy required for each of these underlying conditions is very different. In this review, we will decipher the different phenotypes of SSc-PH

Severe toxoplasmosis in immunocompetent hosts: be aware of atypical strains.

International audienc

A Decentralized Framework for Biostatistics and Privacy Concerns

International audienceBiostatistics and machine learning have been the cornerstone of a variety of recent developments in medicine. In order to gather large enough datasets, it is often necessary to set up multi-centric studies; yet, centralization of measurements can be difficult, either for practical, legal or ethical reasons. As an alternative, federated learning enables leveraging multiple centers' data without actually collating them. While existing works generally require a center to act as a leader and coordinate computations, we propose a fully decentralized framework where each center plays the same role. In this paper, we apply this framework to logistic regression, including confidence intervals computation. We test our algorithm on two distinct clinical datasets split among different centers, and show that it matches results from the centralized framework. In addition, we discuss possible privacy leaks and potential protection mechanisms, paving the way towards further research