Very Early Diagnosis of Systemic Sclerosis: Deciphering the heterogeneity of systemic sclerosis in the very early stages of the disease

International audienceThe early diagnosis of systemic sclerosis has been a major challenge for the scleroderma community in the past 50 years. The recent publication of the predictive value of the VEDOSS (Very Early Diagnosis of Systemic Sclerosis) criteria in the Lancet Rheumatology in December 2021 has provided an unprecedented insight in the early stages of the disease. This editorial discusses the main findings from this 2021 VEDOSS publication and highlights key unanswered questions to be proposed on the research agenda in very early systemic sclerosis

Macrophage polarization and systemic sclerosis : links with autoimmunity induced by crystalline silica and therapeutic perspectives in vitro and in vivo

La sclérodermie systémique est une maladie auto-immune caractérisée par l’existence d’une vasculopathie chronique et la présence de phénomènes inflammatoires et fibrosants touchant notamment la peau et le poumon. De par leur capacité à adopter un profil de polarisation à la fois pro-inflammatoire et pro-fibrosant, les macrophages pourraient occuper une place importante dans la physiopathologie de la sclérodermie. Cette polarisation macrophagique est conditionnée par les signaux et cytokines présents dans le milieu et qui dépendent notamment des voies de signalisation JAK/STAT. Ce travail démontre que les inhibiteurs de JAK, une classe thérapeutique utilisée dans certaines pathologies inflammatoires chroniques, permettent de limiter à la fois la polarisation pro-inflammatoire et pro-fibrosante des macrophages humains in vitro. Le ruxolitinib, inhibiteur de JAK1/2 permet en particulier de prévenir les manifestations pulmonaires et cutanées. La survenue d’une sclérodermie systémique peut être favorisée par une exposition à certains contaminants environnementaux tels que l’inhalation de silice cristalline. L’élimination de cellules apoptotiques, un processus de résolution de l’inflammation appelé efferocytose, est altérée dans les macrophages dérivés de monocytes sanguins circulants au cours de la sclérodermie systémique. Ce travail démontre que la silice cristalline altère les capacités d’efferocytose de macrophages humains in vitro, dans des proportions similaires à celles observées dans les macrophages de patients sclérodermiques. Cet effet est également observé in vivo dans les macrophages alvéolaires de souris exposées par voie transorale à la silice cristalline. In vitro, des inhibiteurs de la voie RhoA/ROCK permettaient de limiter la diminution de l’efferocytose induite par la silice cristalline.Systemic sclerosis (also called scleroderma) is an autoimmune disorder characterized by a chronic vasculopathy with inflammatory and pro-fibrotic manifestations in lungs and skin. As they can adopt pro-inflammatory and pro-fibrotic activation states, macrophages could play a key role in the pathogenesis of scleroderma. Macrophage polarization depends on surrounding activating factors such as cytokines that involve pathways including JAK/STAT signaling. This work demonstrates that JAK inhibitors, a new therapeutic class currently in use for the treatment of some inflammatory chronic diseases, can limit pro-inflammatory and pro-fibrotic polarization profile of human macrophages in vitro. Ruxolitinib, a JAK1/2 inhibitor can prevent the cutaneous and pulmonary manifestations of the disease in a mouse model of scleroderma and limits pro-inflammatory and pro-fibrotic activation of macrophages in these tissues.Although it is considered as an idiopathic disorder, the onset of systemic sclerosis can be triggered by exposure to environmental contaminants such as crystalline silica inhalation. A defect of apoptotic cell clearance, a process also called efferocytosis, is noticed in monocyte-derived-macrophages from patients with systemic sclerosis. This work demonstrates that crystalline silica impairs efferocytosis capacities of human macrophages in vitro, similarly to the defect observed in scleroderma patients. The same effect is observed in vivo, in alveolar macrophages from mice exposed to crystalline silica through transoral instillation. In vitro, inhibitors of the RhoA/ROCK pathway can limit the impairment of efferocytosis capacities of macrophages induced by exposure to crystalline silica

Reframing non-communicable diseases

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From (re-)framing NCDs to shaping public health policies on NCDs and communicable diseases

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Dynamique laitière dans le Sud des Deux-Sèvres : Etats des lieux et perspectives

Le Sud des Deux-Sèvres est une zone de transition entre des aires céréalières au Sud et d’élevage au Nord. La production laitière y est présente en vache comme en chèvre (leader à l’échelle nationale pour les caprins). Depuis la mise en place des quotas, la dynamique de diminution du nombre d’élevages bovins laitiers concomitamment à une augmentation de leur taille a conduit à des structures en faible nombre mais de dimension économique importante (« zone de polyculture élevage à faible densité laitière », Chatellier et al, 2013). Ces évolutions sont particulièrement rapides depuis les travaux en 2007 sur les exploitations laitières du secteur (Havet et al, 2010). Notre objectif est de repérer les éléments induisant ces changements tant au sein des élevages que des territoires associés et de mettre en avant des leviers de pilotage possibles pour un maintien voire un développement des structures d’élevage

Emerging drugs for the treatment of scleroderma: a review of recent phase 2 and 3 trials

International audienceINTRODUCTION: Systemic sclerosis (SSc) has the highest case-specific mortality of all connective tissue diseases. Its underlying disease mechanism affects several organs and remains incompletely understood. Ongoing work clarifying its etiopathogenesis is helping to develop targeted therapy. AREAS COVERED: Several clinical trials have evaluated the safety and efficacy of agents targeting different mechanisms of this disease. This review article reviews those mechanisms and surveys four key recent phase II or III clinical trials that are contributing to the landscape of SSc therapy. The reported trials primarily focus on patients with systemic sclerosis in the early phase of disease. EXPERT OPINION: Traditional therapies for SSc center on immunosuppressive and cytotoxic agents. A new cadre of therapies is borne from improved understandings of SSc pathobiology and target the inflammatory-fibrotic pathways. Scleroderma trials have entered the initial phase of personalized medicine, recognizing molecular subsets that will improve upon cohort enrichment and maximize the measurable benefit of future therapies

Contribution of monocytes and macrophages to the pathogenesis of systemic sclerosis: recent insights and therapeutic implications

International audiencePURPOSE OF REVIEW: To discuss recent studies addressing the role of monocytes and macrophages in the pathogenesis of systemic sclerosis (SSc) based on human and mouse models. RECENT FINDINGS: Studies indicate that monocyte adhesion could be increased in SSc secondary to an interferon-dependent loss of CD52, and chemotaxis up-regulated through the CCR3/CCL24 pathway. Beyond the conventional M1/M2 paradigm of macrophage subpopulations, new subpopulations of macrophages have been recently described in skin and lung biopsies from SSc patients. Notably, single-cell ribonucleic acid sequencing has provided evidence for SPP1+ lung macrophages or FCGR3A+ skin macrophages in SSc. Impaired pro-resolving capacities of macrophages such as efferocytosis, i.e. the ability to phagocyte apoptotic cells, could also participate in the inflammatory and autoimmune features in SSc. SUMMARY: Through their potential pro-fibrotic and pro-inflammatory properties, macrophages are at the cross-road of key SSc pathogenic processes and associated manifestations. Investigative drugs targeting macrophage polarization, such as pan-janus kinase inhibitors (tofacitinib or ruxolitinib) impacting both M1 and M2 activations, or Romilkimab inhibiting IL-4 and IL-13, have shown promising results in preclinical models or phase I/II clinical trials in SSc and other fibro-inflammatory disorders. Macrophage-based cellular therapy may also represent an innovative approach for the treatment of SSc, as initial training of macrophages may modulate the severity of fibrotic and autoimmune manifestations of the disease

Emerging cellular and immunotherapies for systemic sclerosis: from mesenchymal stromal cells to CAR-T cells and vaccine-based approaches

International audiencePURPOSE OF REVIEW: Although two targeted therapies have received recent approval for systemic sclerosis (SSc)-associated interstitial lung disease, they do not show major disease-modifying activity, highlighting the need for novel therapies and innovative paradigms. To that end, cellular therapies may represent a new opportunity for the treatment of SSc. The purpose of this review is to provide an up-to-date overview of emerging cell-based disease-modifying therapies in SSc. RECENT FINDINGS: Initial small studies in patients with severe refractory systemic lupus erythematosus (SLE) using engineered regulatory cells show promising results. CD19-directed CAR-T have shown promising results in one case report of refractory diffuse cutaneous SSc patients. T cells engineered to express a chimeric autoantibody receptor (CAAR-T cells) may be even more relevant via the specific elimination of auto-reactive B cells. Targeting pro-fibrotic or senescence-related pathways may also constitute promising approaches in SSc. SUMMARY: Building on the classification of the clinical phenotype and prediction of clinical trajectory based on individual patients’ autoantigen and/or autoantibody profile, cellular therapies targeting the same autoantigen or related autoreactive cells may represent an unprecedented opportunity to implement personalized medicine in SSc

Occupational exposure to respirable crystalline silica and autoimmunity: sex differences in mouse models

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Results from omic approaches in rat or mouse models exposed to inhaled crystalline silica: a systematic review

Abstract Background Crystalline silica (cSiO2) is a mineral found in rocks; workers from the construction or denim industries are particularly exposed to cSiO2 through inhalation. cSiO2 inhalation increases the risk of silicosis and systemic autoimmune diseases. Inhaled cSiO2 microparticles can reach the alveoli where they induce inflammation, cell death, auto-immunity and fibrosis but the specific molecular pathways involved in these cSiO2 effects remain unclear. This systematic review aims to provide a comprehensive state of the art on omic approaches and exposure models used to study the effects of inhaled cSiO2 in mice and rats and to highlight key results from omic data in rodents also validated in human. Methods The protocol of systematic review follows PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Eligible articles were identified in PubMed, Embase and Web of Science. The search strategy included original articles published after 1990 and written in English which included mouse or rat models exposed to cSiO2 and utilized omic approaches to identify pathways modulated by cSiO2. Data were extracted and quality assessment was based on the SYRCLE’s Risk of Bias tool for animal studies. Results Rats and male rodents were the more used models while female rodents and autoimmune prone models were less studied. Exposure of animals were both acute and chronic and the timing of outcome measurement through omics approaches were homogeneously distributed. Transcriptomic techniques were more commonly performed while proteomic, metabolomic and single-cell omic methods were less utilized. Immunity and inflammation were the main domains modified by cSiO2 exposure in lungs of mice and rats. Less than 20% of the results obtained in rodents were finally verified in humans. Conclusion Omic technics offer new insights on the effects of cSiO2 exposure in mice and rats although the majority of data still need to be validated in humans. Autoimmune prone model should be better characterised and systemic effects of cSiO2 need to be further studied to better understand cSiO2-induced autoimmunity. Single-cell omics should be performed to inform on pathological processes induced by cSiO2 exposure