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OBJECTIVE: To evaluate extent of interstitial lung disease (ILD) and oesophageal involvement using high-resolution computed tomography (HRCT) in early diffuse SSc patients after autologous haematopoietic stem cell transplantation (aHSCT). METHODS: Overall chest HRCT, lung function and skin score changes were evaluated in 33 consecutive diffuse SSc patients before and after aHSCT during yearly routine follow-up visits between January 2000 and September 2016. Two independent radiologists blindly assessed the ILD extent using semi-quantitative Goh and Wells method, the widest oesophageal diameter (WOD) and the oesophageal volume (OV) on HRCT. Patients were retrospectively classified as radiological responders or non-responders, based on achieved stability or a decrease of 5% or more of HRCT-ILD at 24 months post-aHSCT. RESULTS: Using a linear mixed model, the regressions of the extent of ILD and of ground glass opacities were significant at 12 months (ILD P = 0.001; ground glass opacities P = 0.0001) and at 24 months (ILD P = 0.007; ground glass opacities P = 0.0008) after aHSCT, with 18 patients classified as radiological responders (probability of response 0.78 [95% CI 0.58, 0.90]). Meanwhile the WOD and the OV increased significantly at 12 months (WOD P = 0.03; OV P = 0.34) and at 24 months (WOD P = 0.002; OV P = 0.007). Kaplan-Meier analyses showed a trend towards better 5-year survival rates (100% vs 60%; hazard ratio 0.23 [95% CI 0.03, 1.62], P = 0.11) among radiological responders vs non-responders at 24 month follow-up after aHSCT. CONCLUSION: Real-world data analysis confirmed significant improvement in extent of HRCT SSc-ILD 24 months after aHSCT, although oesophageal dilatation worsened requiring specific attention.
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Transplante de Células-Tronco Hematopoéticas , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Humanos , Estudos Retrospectivos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagem , Escleroderma Sistêmico/terapia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Tomografia Computadorizada por Raios X , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , PulmãoRESUMO
Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the clinical response after AHSCT have yet to be well characterized. In particular, the pivotal role of the Human Leukocyte Antigen (HLA) system is not well understood, including the role of non-classical immuno-modulatory HLA-E and HLA-G molecules in developing tolerance and the role of Natural Killer cells (NK) in the immunomodulation processes. We retrospectively tested whether the genetic and/or circulating expression of the non-classical HLA-E and HLA-G loci, as well as the imputed classical HLA determinants of HLA-E expression, influence the observed clinical response to AHSCT at 12- and 24-month follow-up. In a phenotypically well-defined sample of 46 SSc patients classified as clinical responders or non-responders, we performed HLA genotyping using next-generation sequencing and circulating levels of HLA-G and quantified HLA-E soluble isoforms by ELISA. The -21HLA-B leader peptide dimorphism and the differential expression level of HLA-A and HLA-C alleles were imputed. We observed a strong trend towards better clinical response in HLA-E*01:03 or HLA-G 14bp Del allele carriers, which are known to be associated with high expression of the corresponding molecules. At 12-month post-AHSCT follow-up, higher circulating levels of soluble HLA-E were associated with higher values of modified Rodnan Skin Score (mRSS) (p = 0.0275), a proxy of disease severity. In the non-responder group, the majority of patients carried a double dose of the HLA-B Threonine leader peptide, suggesting a non-efficient inhibitory effect of the HLA-E molecules. We did not find any correlation between the soluble HLA-G levels and the observed clinical response after AHSCT. High imputed expression levels of HLA-C alleles, reflecting more efficient NK cell inhibition, correlated with low values of the mRSS 3 months after AHSCT (p = 0.0087). This first pilot analysis of HLA-E and HLA-G immuno-modulatory molecules suggests that efficient inhibition of NK cells contributes to clinical response after AHSCT for SSc. Further studies are warranted in larger patient cohorts to confirm our results.
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Transplante de Células-Tronco Hematopoéticas , Escleroderma Sistêmico , Antígenos HLA-C , Antígenos HLA-G , Transplante de Células-Tronco Hematopoéticas/métodos , Antígenos de Histocompatibilidade Classe II , Humanos , Sinais Direcionadores de Proteínas , Estudos Retrospectivos , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/terapia , Transplante AutólogoRESUMO
OBJECTIVES: In severe rapidly progressive SSc, autologous haematopoietic stem cell transplantation (AHSCT) allows significant improvements in overall and event-free survival. We undertook this study to identify, appraise and synthesize the evidence on health-related quality of life (HRQoL) before and after AHSCT for SSc. METHODS: We performed a systematic review of the literature, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, in PubMed and ScienceDirect from database inception to 1 February 2019. All articles with original HRQoL data were selected. RESULTS: The search identified 1080 articles, of which 8 were selected: 3 unblinded randomized controlled trials [American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST), Autologous Stem Cell Transplantation International Scleroderma, Scleroderma: Cyclophosphamide or Transplantation), 3 uncontrolled phase I or II trials and 2 cohort studies. HRQoL data from 289 SSc patients treated with AHSCT and 125 treated with intravenous CYC as a comparator with median 1.25-4.5 years follow-up were included. HRQoL was evaluated with the HAQ Disability Index (HAQ-DI; 275 patients), the 36-item Short Form Health Survey (SF-36; 249 patients) and the European Quality of Life 5-Dimensions questionnaire (EQ-5D; 138 patients). The quality of the studies was moderate to low. AHSCT was associated with significant improvement in the HAQ-DI (P = 0.02-<0.001), SF-36 Physical Component Summary score (P = 0.02-<0.0001) and EQ-5D index-based utility score (P < 0.001). The SF-36 Mental Component Summary score improved in the ASSIST (n = 19) and one small retrospective cohort (n = 30 patients, P = 0.005) but did not improve significantly in 2 randomized controlled trials (n = 200 patients, P = 0.1-0.91). CONCLUSION: AHSCT in severe SSc patients is associated with significant and durable improvement in physical HRQoL.
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Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Escleroderma Sistêmico/terapia , Antirreumáticos/uso terapêutico , Ciclofosfamida/uso terapêutico , Humanos , Escleroderma Sistêmico/fisiopatologia , Escleroderma Sistêmico/psicologia , Índice de Gravidade de Doença , Transplante Autólogo , Resultado do TratamentoRESUMO
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 13th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures in September 2022 in Lille, France. The aim of this workshop is to update the mobilization and conditioning protocols for autologous hematopoietic stem cell transplantation for autoimmune diseases, and to specify contraindications for transplant, conditioning regimen selection, immunosuppressive treatment discontinuation before mobilization and disease-specific surveillance.
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Doenças Autoimunes , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante Autólogo , Transplante de Medula Óssea , Doenças Autoimunes/terapia , Imunossupressores/uso terapêutico , França , Sociedades Médicas , Condicionamento Pré-TransplanteRESUMO
Systemic sclerosis (SSc) is a rare and chronic autoimmune disease characterized by a pathogenic triad of immune dysregulation, vasculopathy, and progressive fibrosis. Clinical tools commonly used to assess patients, including the modified Rodnan skin score, difference between limited or diffuse forms of skin involvement, presence of lung, heart or kidney involvement, or of various autoantibodies, are important prognostic factors, but still fail to reflect the large heterogeneity of the disease. SSc treatment options are diverse, ranging from conventional drugs to autologous hematopoietic stem cell transplantation, and predicting response is challenging. Genome-wide technologies, such as high throughput microarray analyses and RNA sequencing, allow accurate, unbiased, and broad assessment of alterations in expression levels of multiple genes. In recent years, many studies have shown robust changes in the gene expression profiles of SSc patients compared to healthy controls, mainly in skin tissues and peripheral blood cells. The objective analysis of molecular patterns in SSc is a powerful tool that can further classify SSc patients with similar clinical phenotypes and help predict response to therapy. In this review, we describe the journey from the first discovery of differentially expressed genes to the identification of enriched pathways and intrinsic subsets identified in SSc, using machine learning algorithms. Finally, we discuss the use of these new tools to predict the efficacy of various treatments, including stem cell transplantation. We suggest that the use of RNA gene expression-based classifications according to molecular subsets may bring us one step closer to precision medicine in Systemic Sclerosis.
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Doenças Autoimunes , Escleroderma Sistêmico , Humanos , Medicina de Precisão , Escleroderma Sistêmico/terapia , Escleroderma Sistêmico/tratamento farmacológico , Fibrose , Autoanticorpos/uso terapêuticoRESUMO
Mesenchymal stromal cells (MSCs) have recently emerged as an interesting therapeutic approach for patients with progressive systemic sclerosis (SSc), a rare and life-threatening orphan autoimmune disease. Whereas MSC immunomodulatory potential is considered as a central mechanism for their clinical benefit, very few data are available on the impact of MSCs on immune cell subsets in vivo. In the current extended study of a phase I/II clinical trial exploring the injection of a single dose of allogeneic bone marrow-MSCs (alloBM-MSCs) in patients with severe SSc (NCT02213705), we performed a longitudinal in-depth characterization of circulating immune cells in 19 MSC-treated patients, including 14 responders and 5 non-responders. By a combination of flow cytometry and transcriptomic analyses, we highlighted an increase in circulating CD24hiCD27posCD38lo/neg memory B cells, the main IL-10-producing regulatory B cell (Breg) subset, and an upregulation of IL10 expression in ex-vivo purified B cells, specifically in responder patients, early after the alloBM-MSC infusion. In addition, a deeper alteration of the B-cell compartment before alloBM-MSC treatment, including a higher expression of profibrotic cytokines IL6 and TGFß by sorted B cells was associated with a non-responder clinical status. Finally, BM-MSCs were able to directly upregulate IL-10 production in activated B cells in vitro. These data suggest that cytokine-producing B cells, in particular Breg, are pivotal effectors of BM-MSC therapeutic activity in SSc. Their quantification as activity biomarkers in MSC potency assays and patient selection criteria may be considered to reach optimal clinical benefit when designing MSC-based clinical trials.
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Linfócitos B Reguladores , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Escleroderma Sistêmico , Humanos , Interleucina-10/metabolismo , Medula Óssea , Citocinas/metabolismo , Escleroderma Sistêmico/terapia , Escleroderma Sistêmico/metabolismoRESUMO
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 12th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures on September 2021 in Lille, France. In the absence of specific national or international recommendation, the French working group for autologous stem Cell transplantation in Auto-immune Diseases (MATHEC) proposed guidances for vaccinations of patients undergoing autologous hematopoietic stem cell transplantation for autoimmune disease, including in the context of SARS-Cov-2 pandemic.
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Doenças Autoimunes , COVID-19 , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Medula Óssea , Transplante Autólogo , COVID-19/prevenção & controle , SARS-CoV-2 , Doenças Autoimunes/terapia , Sociedades Médicas , Vacinação , FrançaRESUMO
Contribution of mesenchymal stromal cell transplantation in systemic scleroderma Systemic scleroderma is a rare chronic autoimmune disease with the highest mortality rate among rheumatologic diseases. Its pathophysiology is based on three mechanisms: endothelial damage with initial vasculopathy, activation of the immune response, progressive fibrosis of the skin and various organs. Cellular therapy allows to envision new perspectives: autologous hematopoietic stem cell transplantation has been widely validated to treat severe forms of the disease, but its use is restricted to the most severely affected patients and contraindicated in advanced forms of the disease. The use of mesenchymal stromal cells, and their immunomodulatory, pro-angiogenic and anti-fibrotic properties, as well characterized in vitro and in vivo, broadens the field of possibilities. The use of mesenchymal stromal cells in targeted indications (treatment of graft versus host disease, crohn's disease fistulas, etc.) Has received market authorization and is currently being studied in systemic scleroderma with very promising results.
Apport de la greffe de cellules stromales mésenchymateuses dans la sclérodermie systémique La sclérodermie systémique (SSc) est une maladie auto-immune chronique rare dont la mortalité est la plus élevée des maladies rhumatologiques. Sa physiopathologie repose sur trois mécanismes : atteinte endothéliale avec vasculopathie initiale, activation de la réponse immunitaire, fibrose progressive de la peau et de différents organes. La thérapie cellulaire ouvre des perspectives : si la greffe de cellules souches hématopoïétiques autologues est désormais validée pour traiter les formes sévères de ssc, elle reste cependant réservée aux patients les plus atteints et est contre-indiquée à un stade trop tardif de la maladie. L'injection de cellules stromales mésenchymateuses (CSM), dont les propriétés immuno-modulatrices, proangiogéniques et antifibrotiques sont bien caractérisées in vitro et in vivo, élargit alors le champ des possibles. Déjà utilisées en thérapie cellulaire dans des indications ciblées (prévention du rejet de greffe de moelle, fistules de la maladie de crohn ), les CSM sont actuellement à l'étude dans la sclérodermie systémique, avec des résultats très prometteurs et un effet probablement accru par des perfusions répétées.
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Doenças Autoimunes , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Escleroderma Sistêmico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Escleroderma Sistêmico/terapia , Transplante AutólogoRESUMO
Autism spectrum disorder (ASD) represents a set of heterogeneous neurodevelopmental conditions defined by impaired social interactions and repetitive behaviors. The number of reported cases has increased over the past decades, and ASD is now a major public health burden. So far, only treatments to alleviate symptoms are available, with still unmet need for an effective disease treatment to reduce ASD core symptoms. Genetic predisposition alone can only explain a small fraction of the ASD cases. It has been reported that environmental factors interacting with specific inter-individual genetic background may induce immune dysfunctions and contribute to the incidence of ASD. Such dysfunctions can be observed at the central level, with increased microglial cells and activation in ASD brains or in the peripheral blood, as reflected by high circulating levels of pro-inflammatory cytokines, abnormal activation of T-cell subsets, presence of auto-antibodies and of dysregulated microbiota profiles. Altogether, the dysfunction of immune processes may result from immunogenetically-determined inefficient immune responses against a given challenge followed by chronic inflammation and autoimmunity. In this context, immunomodulatory therapies might offer a valid therapeutic option. Mesenchymal stromal cells (MSC) immunoregulatory and immunosuppressive properties constitute a strong rationale for their use to improve ASD clinical symptoms. In vitro studies and pre-clinical models have shown that MSC can induce synapse formation and enhance synaptic function with consequent improvement of ASD-like symptoms in mice. In addition, two preliminary human trials based on the infusion of cord blood-derived MSC showed the safety and tolerability of the procedure in children with ASD and reported promising clinical improvement of core symptoms. We review herein the immune dysfunctions associated with ASD provided, the rationale for using MSC to treat patients with ASD and summarize the current available studies addressing this subject.
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BACKGROUND: Systemic sclerosis remains an orphan life-threatening autoimmune disease. The unique immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells provide a strong rationale for mesenchymal stromal cell-based therapy for systemic sclerosis, and treatment with mesenchymal stromal cells has shown benefits in preclinical models of this disease. The safety of allogeneic bone marrow-derived mesenchymal stromal cell administration in patients with severe systemic sclerosis has not yet been established. We aimed to test the safety and feasibility of a single intravenous injection of intrafamilial allogeneic bone marrow-derived mesenchymal stromal cells to treat severe diffuse systemic sclerosis. METHODS: We did an open-label, dose-escalation, proof-of-concept, phase 1/2 study at Saint-Louis-Hospital, Paris, France. Eligible patients were aged 18-70 years with severe diffuse systemic sclerosis, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism systemic sclerosis criteria, had a minimum modified Rodnan skin score of 15 (range 0-51), had severe lung, heart, or kidney involvement, and had inadequate response or contraindications to conventional immunosuppressive therapy or autologous haematopoietic stem cell transplantation. Patients with severe comorbidities were excluded. The first ten recipients were to receive a single intravenous infusion of 1 × 106 bone marrow-derived mesenchymal stromal cells per kg bodyweight, and the subsequent ten recipients were to be infused with a single dose of 3 × 106 bone marrow-derived mesenchymal stromal cells per kg bodyweight. The primary endpoint was immediate tolerance during infusion and within the first 10 days after infusion, measured as the occurrence of serious adverse events (grade 3 or higher) in all infused patients. Safety was assessed in all participants during the 24-month follow-up period. This study is registered with ClinicalTrials.gov, NCT02213705. FINDINGS: Between March 24, 2014, and Jan 6, 2020, 20 cisgender individuals (13 women and seven men) with severe diffuse systemic sclerosis were enrolled. All 20 patients were included in the primary outcome analysis. No infusion-related severe adverse events and three infusion-related adverse events occurred in the first 10 days after treatment; one patient had grade 1 flushing and another patient had grade 1 nausea and grade 2 asthenia. After ten days and up to a median follow-up of 24·1 months (IQR 20·8-24·5), 36 non-treatment-related severe adverse events in 14 (70%) patients and no treatment-related adverse event were reported. INTERPRETATION: A single infusion of allogeneic bone marrow-derived mesenchymal stromal cells was safe in patients with severe diffuse systemic sclerosis. Future placebo-controlled trials will help to definitively ascertain the efficacy of mesenchymal stromal cell-based cell therapy from various tissue sources in larger number of patients with systemic sclerosis. FUNDING: French Ministry of Health, Capucine Association, Fonds de Dotation de l'AFER pour la Recherche Médicale, and Agence Nationale de la Recherche (Infrastructure Program Ecell), France.
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BACKGROUND: All the cellular partners of the vascular system and especially endothelial cells are involved in the pathophysiology of the vasoocclusive crises associated with sickle cell disease. In sickle cell disease, circulating cells adhere abnormally to endothelial cells in a chronic pro-inflammatory context. Hydroxycarbamide is the only drug with demonstrated efficacy to reduce the frequency of vasoocclusive crises. Here, we investigated the effects of hydroxycarbamide and/or cytokines on the expression of genes related to adhesion events in endothelial cells from three different vascular sites. DESIGN AND METHODS: Endothelial cells representative of the macro- (HUVEC) or microcirculation (TrHBMEC and HPMEC) were grown in the presence or absence of hydroxycarbamide and/or cytokines (TNFα and IFNγ). Expression of genes encoding adhesion proteins was analyzed by RQ-PCR, ELISA, flow cytometry, in situ ELISA for extracellular matrix proteins, and Western blot. RESULTS: In cells from the microcirculation, expression of TSP-1, vWF, and PECAM-1 genes was decreased by hydroxycarbamide and/or cytokine treatment at the mRNA level. In the macro-circulation their expression was unaffected or increased. Hydroxycarbamide significantly decreased vWF incorporated in the TrHBMEC extracellular matrix. CD36 mRNA was strongly down-regulated by cytokines in HPMEC, the only cell type in which it is expressed. Hydroxycarbamide decreased soluble PECAM-1 in HUVEC supernatants. CONCLUSIONS: Our results highlight the heterogeneity of vascular endothelial cell responses to hydroxycarbamide and/or cytokines depending upon their origin. They also suggest that hydroxycarbamide has an anti-adhesogenic effect on endothelial cells, but by mechanisms which could vary according to their macro- or microcirculation and organ origin.
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Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Moléculas de Adesão Celular/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxiureia/farmacologia , Anemia Falciforme/fisiopatologia , Antidrepanocíticos/farmacologia , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , Análise em Microsséries , Trombospondina 1/genética , Fator de von Willebrand/genéticaRESUMO
Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by vasculopathy, dysregulation of innate and adaptive immune responses, and progressive fibrosis. SSc remains an orphan disease, with high morbity and mortality in SSc patients. The mesenchymal stromal cells (MSC) demonstrate in vitro and in vivo pro-angiogenic, immuno-suppressive, and anti-fibrotic properties and appear as a promising stem cell therapy type, that may target the key pathological features of SSc disease. This review aims to summarize acquired knowledge in the field of :1) MSC definition and in vitro and in vivo functional properties, which vary according to the donor type (allogeneic or autologous), the tissue sources (bone marrow, adipose tissue or umbilical cord) or inflammatory micro-environment in the recipient; 2) preclinical studies in various SSc animal models , which showed reduction in skin and lung fibrosis after MSC infusion; 3) first clinical trials in human, with safety and early efficacy results reported in SSc patients or currently tested in several ongoing clinical trials.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Escleroderma Sistêmico , Animais , Fibrose , Humanos , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/terapia , Pele/patologiaRESUMO
Two randomised trials (ASTIS, SCOT) of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) versus monthly Cyclophosphamide for severe Systemic Sclerosis (SSc) patients used similar inclusion criteria, but different primary endpoints: event-free-survival (EFS) at 24 months in ASTIS versus the global rank composite score (GRCS) at 54 months in SCOT. Here we analysed the French ASTIS cohort (n = 49) outcome using the same GRCS endpoint as reported in SCOT. All patients, randomised to AHSCT (n = 26) or Cyclophosphamide (n = 23), were evaluated for the non-parametric GRCS endpoint based on: death, EFS, forced vital capacity (FVC), Health Assessment Questionnaire Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 60 months. Secondary endpoints were: EFS, overall survival (OS), HAQ DI and organ status. In intention-to-treat analysis, the GRCS demonstrated superiority for AHSCT (median: 9 versus -19, p = 0.018), mRSS (Δ mRSS: -16 versus -9, p = 0.02), and HAQ-DI (ΔHAQ-DI: -0.89 versus -0.2, p = 0.05) with no significant difference in OS, EFS, lung, heart and kidney function between the groups. In conclusion, this study demonstrates long term benefits of non-myeloablative AHSCT when assessed by the five longitudinal measures within GRCS affording direct primary endpoint comparison between ASTIS and SCOT.
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Transplante de Células-Tronco Hematopoéticas , Escleroderma Sistêmico , Ciclofosfamida/uso terapêutico , Humanos , Intervalo Livre de Progressão , Escleroderma Sistêmico/terapia , Transplante AutólogoRESUMO
OBJECTIVE: To quantify the magnitude, domains, and duration of change in health-related quality of life (HRQoL) in patients with systemic sclerosis (SSc) who underwent autologous hematopoietic stem cell transplantation (HSCT) as compared to SSc patients with similar characteristics who did not undergo autologous HSCT. METHODS: The study was designed as a retrospective study comparing SSc patients who underwent autologous HSCT and SSc patients who met the criteria for transplantation but were treated with conventional care. Outcomes included scores on the 36-item Short Form (SF-36) health survey and the Health Assessment Questionnaire (HAQ) and its disease-specific symptom scales. Differences in scores between the groups were compared using linear models, adjusting for baseline scores and inverse probability of treatment and censoring weights. RESULTS: In total, 41 SSc patients who underwent autologous HSCT and 65 SSc patients treated with conventional care were compared. In marginal linear weighted models, the SF-36 physical component summary score was a mean ± SEM 7.02 ± 1.94 points higher at the first annual visit (P = 0.001) and 14.40 ± 6.16 points higher at the seventh annual visit (P = 0.03) in patients treated with autologous HSCT compared to the conventional care group. HAQ scores were significantly better in the autologous HSCT group compared to the conventional care group during follow-up (mean ± SEM difference from baseline -0.57 ± 0.13 [P < 0.001] at the first annual visit and -0.94 ± 0.49 [P = 0.07] at the seventh annual visit). There were no differences in the SF-36 mental component summary scores between the 2 groups either at baseline or during follow-up. CONCLUSION: This study provides robust complementary HRQoL data, including overall and event-free survival data, to expand on the standard repertoire of biomedical variables, thus potentially supporting the physical benefits of autologous HSCT in patients with SSc.
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Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Qualidade de Vida , Escleroderma Sistêmico/terapia , Transplante Autólogo , Atividades Cotidianas , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Escleroderma Sistêmico/fisiopatologia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Autologous hematopoietic cell transplantation (AHCT) is a new treatment option for patients with severe autoimmune diseases (AD), based on the use of intensive or myeloablative chemotherapy to eradicate the pathogenic autoreactive immune cells and to allow the installation of a new and tolerant immune system during immune reconstitution process. Immune reconstitution analysis after AHCT is required for patients clinical follow-up and to further identify biological and immunological markers of the clinical response to develop individualized AHCT protocols. These MATHEC-SFGM-TC good clinical practice guidelines were developed by a multidisciplinary group of experts including members of the french reference center for stem Cell Therapy in Auto-immune Diseases (MATHEC), hematologists from the French speaking Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and experts in immune monitoring and biobanking. The objectives are to provide practical recommandations for immune monitoring and biobanking of samples in patients with AD undergoing AHCT, for routine care purposes and investigational studies.
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Doenças Autoimunes/terapia , Transplante de Células-Tronco Hematopoéticas/normas , Reconstituição Imune , Monitorização Imunológica/normas , Autoenxertos , Doenças Autoimunes/imunologia , Bancos de Espécimes Biológicos , Humanos , Sociedades Médicas , Manejo de Espécimes/métodos , Manejo de Espécimes/normas , Resultado do TratamentoRESUMO
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a chronic autoimmune disease involving the peripheral nervous system, characterized by focal and segmental demyelination accounting for neurological deficit. CIDP diagnosis is based on several criteria and requires the presence of specific clinical symptoms and of demyelinating criteria on the electroneuromyogram (ENMG) or of additional supportive criteria (spinal fluid examination with dissociation between albumin level and cellular abnormalities, nervous abnormalities on MRI or other minor abnormalities on ENMG, demyelinating features on nerve biopsy or patient improvement under so-called first-line therapy with immunodulator treatment). After failure of two successive first line immunomodulating drug therapies (corticosteroids, immunomodulating immunoglobulins, or plasma exchange), several options can be considered as second line therapies. The efficacy of autologous hematopoietic cell transplantation (AHCT) has been shown in CIDP patients. The aim of these recommendations established by a working group of experts from the "Société française de greffe de moelle osseuse et thérapie cellulaire (SFGM-TC)", the group "maladies auto-immunes et thérapie cellulaire (MATHEC)" and the "filière de santé maladies rares neuromusculaire (FILNEMUS)" is to specify the eligibility criteria for AHCT in CIPD patients, to describe the mobilization and the conditioning regimen for the AHCT procedure, as well as the patient standardized post-transplant follow-up and the management of neurological treatment throughout the all procedure.
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Mobilização de Células-Tronco Hematopoéticas/normas , Transplante de Células-Tronco Hematopoéticas/normas , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia , Condicionamento Pré-Transplante , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Transplante AutólogoRESUMO
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 8th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2017 in Lille, France. In this article we give the indications of autologous stem cell transplantation in multiple sclerosis as well as recommendations regarding post-transplant follow-up of patients under the hospice of the SFGM-TC and the Francophone Society of Multiple Sclerosis.
Assuntos
Transplante de Células-Tronco Hematopoéticas/normas , Esclerose Múltipla/terapia , Fatores Etários , Autoenxertos , Transplante de Medula Óssea , Terapia Baseada em Transplante de Células e Tecidos , Contraindicações de Procedimentos , França , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Esclerose Múltipla/fisiopatologia , Sociedades Médicas , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/normas , Transplante HomólogoRESUMO
OBJECTIVE: To assess the reproducibility and the utility of the 6-minute walk test (6MWT) in systemic sclerosis (SSc). METHODS: All patients with SSc who underwent at least two 6MWT within a minimum 3-month interval plus simultaneous routine clinical, biological, and functional evaluations were consecutively enrolled in this observational study over 6 years. Following American Thoracic Society guidelines, each 6MWT was repeated twice to assess the 6-minute walk distance (6MWD) reproducibility, with the highest value being reported for subsequent analysis. RESULTS: Among 56 (38 female) included patients aged 46 ± SD 12.7 years, with 17 ± 10 modified Rodnan skin score (mRSS) and 1 ± 0.8 Scleroderma Health Assessment Questionnaire (SHAQ) at first referral, 277 6MWT evaluations (5 ± 3.9 6MWT per patient) were performed over 23 ± 22.5 months followup. Meanwhile, 8 deaths (87.5% SSc-related) occurred. The mean 6MWD absolute value was 457 ± 117 m with a 4 ± 2.2 mean Borg dyspnea score. The 6MWD intraclass correlation coefficient was 0.996 (95% CI 0.995-0.999, p < 0.0001). In multivariate linear regression analysis, these factors were independently associated with a lower 6MWD: sex (R2 = 0.47, p < 0.0001), mRSS (R2 = 0.47, p = 0.008), tendon friction rub (R2 = 0.47, p = 0.003), SHAQ (R2 = 0.47, p = 0.02), muscle disability score (R2 = 0.47, p = 0.03), DLCO% (R2 = 0.47, p = 0.0008), and left ventricular ejection fraction (R2 = 0.47, p = 0.006). The 6MWD at first referral was an independent predictor for the overall mortality (HR 0.99, 95% CI 0.988-0.999) and the SSc-related mortality (HR 0.99, 95% CI 0.988-0.999). CONCLUSION: We show strong reproducibility for the 6MWD and confirm the 6MWT utility to assess the overall prognosis of patients with SSc.
Assuntos
Tolerância ao Exercício/fisiologia , Escleroderma Sistêmico/fisiopatologia , Teste de Caminhada , Caminhada/fisiologia , Adulto , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Escleroderma Sistêmico/mortalidade , Taxa de SobrevidaRESUMO
To evaluate the immunological mechanisms associated with clinical outcomes after autologous hematopoietic stem cell transplantation (AHSCT), focusing on regulatory T- (Treg) and B- (Breg) cell immune reconstitution, 31 systemic sclerosis (SSc) patients underwent simultaneous clinical and immunological evaluations over 36-month posttransplantation follow-up. Patients were retrospectively grouped into responders (n = 25) and nonresponders (n = 6), according to clinical response after AHSCT. Thymic function and B-cell neogenesis were respectively assessed by quantification of DNA excision circles generated during T- and B-cell receptor rearrangements. At the 1-year post-AHSCT evaluation of the total set of transplanted SSc patients, thymic rebound led to renewal of the immune system, with higher T-cell receptor (TCR) diversity, positive correlation between recent thymic emigrant and Treg counts, and higher expression of CTLA-4 and GITR on Tregs, when compared with pretransplant levels. In parallel, increased bone marrow output of newly generated naive B-cells, starting at 6 months after AHSCT, renovated the B-cell populations in peripheral blood. At 6 and 12 months after AHSCT, Bregs increased and produced higher interleukin-10 levels than before transplant. When the nonresponder patients were evaluated separately, Treg and Breg counts did not increase after AHSCT, and high TCR repertoire overlap between pre- and posttransplant periods indicated maintenance of underlying disease mechanisms. These data suggest that clinical improvement of SSc patients is related to increased counts of newly generated Tregs and Bregs after AHSCT as a result of coordinated thymic and bone marrow rebound.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Sistema Imunitário/fisiologia , Escleroderma Sistêmico/terapia , Adulto , Linfócitos B/citologia , Medula Óssea/fisiologia , Feminino , Humanos , Sistema Imunitário/citologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/mortalidade , Linfócitos T Reguladores/citologia , Timo/citologia , Timo/fisiologia , Transplante Autólogo/métodos , Resultado do Tratamento , Adulto JovemRESUMO
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2017 in Lille, France and updated recommendations for indications and follow-up in autologous hematopoietic stem cell transplantation in autoimmune and autoinflammatory diseases, previously published under the auspices of SFGM-TC.