Evaluation globale standardisée systématique des rhumatismes inflammatoires chroniques: intérêts et limites

Introduction: National and international recommendations call for an annual standardized systematic holistic review in the management of chronic inflammatory rheumatism (CIR). This includes an assessment of disease activity and severity, as well as patient education on the disease, knowledge of pharmacological and non-pharmacological treatments, adherence to treatment and screening for comorbidities. Our study aims to recall the definition of a holistic review (HR), to present the evidence of their effectiveness and to give an overview of HR practices in France. Methods: A literature review was conducted in the Pubmed database to identify randomized controlled trials (RCTs) or meta-analyses reporting the efficacy of a multidisciplinary intervention in ICR or other chronic diseases. Two online surveys were sent to all rheumatology departments in France and to a sample of independent rheumatologists, with 34 and 19 questions respectively. These questionnaires were used to determine the profile of the responding center/rheumatologist, the existence of an HR and the obstacles or facilitators to its implementation. Results: Literature search yielded 872 articles, 24 of which were finally included: 16 RCTs and 8 meta-analyses. Only 3 articles concerned ICRs, including one meta-analysis of 10 RCTs in rheumatoid arthritis (RA). Of these 3 studies, 2 RCTs in systemic lupus and systemic sclerosis showed a favorable impact of a multidisciplinary approach on SLEDAI and grip strength and mouth opening respectively, while the meta-analysis in RA showed no benefit on disability or disease activity.The questionnaire was answered by 72 centers and 186 rheumatologists. A third of the centers had already implemented a HR during an day hospitalization. 70 % of centers estimated that they managed more than 10 patients per month, devoting an average of 35 minutes of rheumatologist time and 90 minutes of cumulative time for all other healthcare professionals (HCPs) involved in the program. Most of the HCPs involved were nurses (92 %), dieticians (56 %) and physiotherapists (56 %). The main obstacles to setting up a HR were the lack of paramedical resources, lack of economic value and lack of support from treating rheumatologists, while patient motivation was seen as a facilitating factor. Conclusion: Although HR is recommended, there is little evidence of its effectiveness in ICR. Only 36 % of responding centers have implemented such a program. This survey helps to identify the obstacles and facilitators, and to find solutions for extending this practice

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number: NCT00767325

Régulation de l'activité de la NADPH oxydase des neutrophiles par des enzymes du métabolisme du glucose et l'hétérocomplexe S100A8/S100A9 : application à la polyarthrite rhumatoïde

Rheumatoid Arthritis (RA) is caused by an inflammation of the synovial membrane leading to progressive joint destruction and deformation, related to the production NADPH oxidase related-reactive oxygen species (ROS) production. The phagocyte NADPH oxidase is a multi-protein complex formed by a catalytic core, i.e. the transmembrane cytochrome b558 and cytosolic regulators (p67phox, p47phox, p40phox and Rac1/2). We aimed at better analyzing the NADPH oxidase activation through the evaluation of the specificity of the interaction with 6PGDH or PFK2 and through the further analysis of the association with the S100A8/A9 heterocomplex. The RA-specific protein profiling was conducted in order to determine whether a PMN activation fingerprint could be revealed among RA specific proteins.Upon PMA stimulation, both 6PGDH and PFK2 co-imunoprecipitated with cytosolic factors p67phox, p47phox and p40phox. At the plasma membrane level, confocal microscopy experiments suggested a co-localization of either 6PGDH or PFK2 with the phagocyte NADPH oxidase in lipid rafts. 6PGDH enhanced the phagocyte NADPH oxidase activity by both improving the availability of cytosolic NADPH content and by increasing the affinity of the NADPH oxidase for its substrate. PFK2 also augmented the NADPH oxidase activity. PFK2 modulated the ATP concentration available for the phosphorylation of the phagocyte NADPH oxidase components and for the NDP Kinase related-Rac activation. The generation of truncated S100A8/S100A9 heterodimer chimera could reveal that the C-terminal region of S100A8 is involved in both the interaction and the activation of the phagocyte NADPH oxidase.In vivo, synovial fluid of RA patients was remarkably labelled with the PMN activation fingerprint. S100A8 and S100A9 proteins clearly distinguished RA synovial fluid from osteoarthritis and non RA-synovial fluids. An ectopic production of S100A8/S100A9 was shown in RA fibroblast like synoviocyte.In conclusion, 6PGDH, PFK2 and S100A8/A9 proteins are surrogate activating partners of the phagocyte NADPH oxidase. In RA, the activation of PMNs leads to the release of S100A8/A9 proteins which may constitute interesting biomarkers and promising therapeutic targets.La Polyarthrite Rhumatoïde est caractérisée par une synovite à l’origine de lésions progressives ostéo-articulaires induites par les formes réactives de l’oxygène (ROS) produites par la NADPH oxydase des polynucléaires neutrophiles (PMN). La NADPH oxydase des phagocytes, est formée d’un centre catalytique membranaire, le cytochrome b558, sur lequel vient s’associer des protéines cytosoliques régulatrices (p67phox, p47phox, p40phox et Rac1/2). Nous avons étudié la spécificité de l’interaction entre la (6-phosphofructokinase 2) et de la 6PGDH (6-phosphogluconate déshydrogénase) et la NADPH oxydase des PMN. D’autre part, nous avons caractérisé les domaines de l’hétérocomplexe S100A8/A9 impliqués dans l’activation de la NADPH oxydase phagocytaire. Par ailleurs, une étude de la signature protéique dans le liquide synovial a été menée afin de rechercher l’empreinte de l’activation du PMN dans la PR.Après stimulation par le PMA, la 6PGDH et la PFK2 co-imunoprécipitent avec les facteurs cytosoliques p67phox, p47phox and p40phox. Les expériences de microscopie confocale suggèrent une co-localisation de ces deux enzymes du métabolisme du glucose avec la NADPH oxydase, dans des micro-domaines membranaires : les radeaux lipidiques. La 6PGDH est impliquée dans l’activation de la NADPH oxydase phagocytaire en élevant la concentration du NADPH cytosolique mais également en augmentant l’affinité de cette enzyme pour son substrat, le NADPH. PFK2 est l’enzyme majeure de la régulation de la glycolyse, voie est essentielle pour la production d’ATP du PMN. L’utilisation du complexe S100A8/A9 et de protéines chimères de fusion nous a permis de révéler que la partie C-terminale de S100A8 est impliquée dans la liaison avec le cytochrome b558 et l’activation de la NADPH oxydase phagocytaire. In vivo, le profil protéique du liquide articulaire de PR a révélé l’empreinte de l’activation du PMN dans cette pathologie avec une surexpression des protéines S100A8 et S100A9. Une production ectopique de S100A8/A9 par les synoviocytes de type fibroblastique a été mise en évidence.En conclusion, la 6PGDH, la PFK2 et l’hétérodimère S100A8/A9 sont de nouveaux partenaires d’activation de la NADPH oxydase des phagocytes. Dans la PR, l’activation des PMNs conduit à la sécrétion de S100A8/A9 qui semblent constituer à la fois des biomarqueurs pertinents, mais également des cibles thérapeutiques potentielles

Régulation de l'activité de la NADPH oxydase des neutrophiles par des enzymes du métabolisme du glucose et l'hétérocomplexe S100A8/A9 Application à l'étude de la Polyarthrite Rhumatoïde

Rheumatoid Arthritis (RA) is the more frequent inflammatory arthritis. This disease is caused by an inflammation of the synovial membrane leading to progressive joint destruction and deformation. During joint inflammation flares, polymorphonuclear neutrophils (PMN) have a huge potential to directly inflict damage to tissue, bone and cartilage via the production NADPH oxidase related-reactive oxygen species (ROS). The phagocyte NADPH oxidase is a key enzyme of the innate immunity involved in superoxide anions O2* − production. It is a multi-protein complex formed by a catalytic core, i.e. the transmembrane cytochrome b558 and cytosolic regulators (p67phox, p47phox, p40phox and Rac1/2). Upon cell stimulation and association with cytosolic regulatory factors, the phagocyte NADPH oxidase becomes activated and produces a huge amount of superoxide anions O2* −. In a previous work, the characterization of the whole NADPH oxidase complex isolated, in a constitutively active form, from PMN [Paclet et al. 2007] revealed the presence of the 6-phosphofructo-2-kinase (PFK2) heart isoenzyme and the 6-phosphogluconate dehydrogenase (6PGDH). Since both enzymes were absent in the oxidase complex prepared with B-lymphocyte cytosol it was hypothesized that the interaction between PFK2 or 6PGDH and the phagocyte NADPH oxidase was specific. In another study, the S100A8/S100A9 heterodimer, constituting about 40% of the protein content of PMN cytosol, was shown to enhance phagocyte NADPH oxidase activity in vitro. Given the importance of PMN activation in RA pathogenesis, we aimed at better analyzing the molecular mechanisms of phagocyte NADPH oxidase activation through the evaluation of the specificity of the interaction with 6PGDH or PFK2 and through the further analysis of the association with the S100A8/A9 heterocomplex. The RA-specific protein profiling was conducted, using a proteomic approach, in order to, firstly, determine whether a PMN activation fingerprint could be revealed among RA specific proteins and, secondly, characterize RA biomarkers. Upon PMA stimulation, both 6PGDH and PFK2 co-imunoprecipitated with cytosolic factors p67phox, p47phox and p40phox. At the plasma membrane level, confocal microscopy experiments suggested a co-localization of either 6PGDH or PFK2 with the phagocyte NADPH oxidase in lipid rafts. 6PGDH enhanced the phagocyte NADPH oxidase activity by both improving the availability of cytosolic NADPH content and by increasing the affinity of the NADPH oxidase for its substrate. PFK2 also augmented the NADPH oxidase activity. PFK2 modulated the ATP concentration available for the phosphorylation of the phagocyte NADPH oxidase components and for the NDP Kinase related-Rac activation. The generation of truncated S100A8/S100A9 heterodimer chimera could reveal that the C-terminal region of S100A8 is involved in both the interaction and the activation of the phagocyte NADPH oxidase. In vivo, synovial fluid of RA patients was remarkably labelled with the PMN activation fingerprint. S100A8, S100A9 and S100A12 proteins clearly distinguished RA synovial fluid from osteoarthritis and non RA-synovial fluids. Of note, an ectopic production of S100A8/S100A9 was depicted in fibroblast like synoviocyte suggesting a potential involvement of these danger signals in RA etiopathogenesis. In conclusion, 6PGDH, PFK2 and S100A8/A9 proteins are surrogate activating partners of the phagocyte NADPH oxidase. In RA, the activation of PMNs leads to the release of S100A8/A9 proteins which may constituteLa Polyarthrite Rhumatoïde, caractérisée par une synovite à l'origine de lésions progressives ostéo-articulaires, est le plus fréquent des rhumatismes inflammatoires. Les formes réactives de l'oxygène (ROS) produites par la NADPH oxydase des polynucléaires neutrophiles (PMN) infiltrant le pannus rhumatoïde, sont responsables de lésions tissulaires. La NADPH oxydase des phagocytes, est formée d'un centre catalytique membranaire, le cytochrome b558, sur lequel vient s'associer des protéines cytosoliques régulatrices (p67phox, p47phox, p40phox et Rac1/2). L'étude du complexe NADPH oxydase isolé et constitutivement actif, à partir de PMN activés, a révélé la présence de deux enzymes impliquées dans la régulation du métabolisme du glucose. Il s'agit de la PFK2 (6-phosphofructokinase 2) et de la 6PGDH (6-phosphogluconate déshydrogénase) [Paclet et al. 2007]. De plus, l'étude des protéines cytosoliques retenues sur une matrice d'affinité ciblant p47phox, a établi que les protéines S100A8 et S100A9, constituant 40% des protéines cytosoliques du PMN, participent à l'activation de l'oxydase [Berthier et al. 2003]. L'hétérocomplexe S100A8/A9, augmente l'activité de la NADPH oxydase phagocytaire et induit un changement conformationnel du cytochrome b558. Au regard de l'importance de la stimulation du PMN dans la physiopathologie de la PR, notre objectif, à terme, est d'analyser les mécanismes de l'activation de la NADPH oxydase dans cette pathologie. D'une part, nous avons étudié la spécificité de l'interaction entre la 6PGDH ou la PFK2 et la NADPH oxydase des PMN. D'autre part, nous avons caractérisé les domaines de l'hétérocomplexe S100A8/A9 impliqués dans l'activation de la NADPH oxydase phagocytaire. Par ailleurs, une étude de la signature protéique dans le liquide synovial a été menée afin de rechercher l'empreinte de l'activation du PMN dans la PR et de caractériser des biomarqueurs spécifiques de cette pathologie. Après stimulation par le PMA, la 6PGDH et la PFK2 co-imunoprécipitent avec les facteurs cytosoliques p67phox, p47phox and p40phox. Les expériences de microscopie confocale suggèrent une co-localisation de ces deux enzymes du métabolisme du glucose avec la NADPH oxydase, dans des micro-domaines membranaires : les radeaux lipidiques. La 6PGDH est impliquée dans l'activation de la NADPH oxydase phagocytaire en élevant la concentration du NADPH cytosolique mais également en augmentant l'affinité de cette enzyme pour son substrat, le NADPH. PFK2 est l'enzyme majeure de la régulation de la glycolyse. Dans les neutrophiles, cette voie est essentielle pour la production d'ATP disponible, d'une part, pour la phosphorylation des facteurs cytosoliques de la NADPH oxydase et d'autre part, pour la NDP Kinase. Cette dernière enzyme pourrait, secondairement, activer Rac en formant du GTP à partir d'ATP. Les protéines S100A8/A9 sont directement impliquées dans les mécanismes de régulation de la NADPH oxydase. L'utilisation du complexe S100A8/A9 et de protéines chimères de fusion nous a permis de révéler que la partie C-terminale de S100A8 est impliquée dans la liaison avec le cytochrome b558 et l'activation de la NADPH oxydase phagocytaire. In vivo, le profil protéique du liquide articulaire de PR a mis en évidence l'empreinte de l'activation du PMN dans cette pathologie. Les protéines S100A8, S100A9 permettraient de différencier le liquide synovial rhumatoïde de celui de patients arthrosiques ou souffrant d'arthrites non rhumatoïdes. De manière intéressante, une production ectopique de S100A8/A9 par les synoviocytes de type fibroblastique a été mise en évidence, suggérant une implication potentielle de ces protéines dans la physiopathologie de la PR. En conclusion, la 6PGDH, la PFK2 et l'hétérodimère S100A8/A9 sont de nouveaux partenaires d'activation de la NADPH oxydase des phagocytes. Dans la Polyathrite Rhumatoïde, l'activation des PMNs conduit à la sécrétion de S100A8/A9 qui semblent constituer à la fois des biomarqueurs pertinents, mais également des cibles thérapeutiques potentielles

Regulation of phagocyte NADPH oxydase activity by enzymes regulating glucose metabolism and S100A8/S100A9 heterocomplex : application to rheumatoid arthritis

La Polyarthrite Rhumatoïde est caractérisée par une synovite à l’origine de lésions progressives ostéo-articulaires induites par les formes réactives de l’oxygène (ROS) produites par la NADPH oxydase des polynucléaires neutrophiles (PMN). La NADPH oxydase des phagocytes, est formée d’un centre catalytique membranaire, le cytochrome b558, sur lequel vient s’associer des protéines cytosoliques régulatrices (p67phox, p47phox, p40phox et Rac1/2). Nous avons étudié la spécificité de l’interaction entre la (6-phosphofructokinase 2) et de la 6PGDH (6-phosphogluconate déshydrogénase) et la NADPH oxydase des PMN. D’autre part, nous avons caractérisé les domaines de l’hétérocomplexe S100A8/A9 impliqués dans l’activation de la NADPH oxydase phagocytaire. Par ailleurs, une étude de la signature protéique dans le liquide synovial a été menée afin de rechercher l’empreinte de l’activation du PMN dans la PR.Après stimulation par le PMA, la 6PGDH et la PFK2 co-imunoprécipitent avec les facteurs cytosoliques p67phox, p47phox and p40phox. Les expériences de microscopie confocale suggèrent une co-localisation de ces deux enzymes du métabolisme du glucose avec la NADPH oxydase, dans des micro-domaines membranaires : les radeaux lipidiques. La 6PGDH est impliquée dans l’activation de la NADPH oxydase phagocytaire en élevant la concentration du NADPH cytosolique mais également en augmentant l’affinité de cette enzyme pour son substrat, le NADPH. PFK2 est l’enzyme majeure de la régulation de la glycolyse, voie est essentielle pour la production d’ATP du PMN. L’utilisation du complexe S100A8/A9 et de protéines chimères de fusion nous a permis de révéler que la partie C-terminale de S100A8 est impliquée dans la liaison avec le cytochrome b558 et l’activation de la NADPH oxydase phagocytaire. In vivo, le profil protéique du liquide articulaire de PR a révélé l’empreinte de l’activation du PMN dans cette pathologie avec une surexpression des protéines S100A8 et S100A9. Une production ectopique de S100A8/A9 par les synoviocytes de type fibroblastique a été mise en évidence.En conclusion, la 6PGDH, la PFK2 et l’hétérodimère S100A8/A9 sont de nouveaux partenaires d’activation de la NADPH oxydase des phagocytes. Dans la PR, l’activation des PMNs conduit à la sécrétion de S100A8/A9 qui semblent constituer à la fois des biomarqueurs pertinents, mais également des cibles thérapeutiques potentielles.Rheumatoid Arthritis (RA) is caused by an inflammation of the synovial membrane leading to progressive joint destruction and deformation, related to the production NADPH oxidase related-reactive oxygen species (ROS) production. The phagocyte NADPH oxidase is a multi-protein complex formed by a catalytic core, i.e. the transmembrane cytochrome b558 and cytosolic regulators (p67phox, p47phox, p40phox and Rac1/2). We aimed at better analyzing the NADPH oxidase activation through the evaluation of the specificity of the interaction with 6PGDH or PFK2 and through the further analysis of the association with the S100A8/A9 heterocomplex. The RA-specific protein profiling was conducted in order to determine whether a PMN activation fingerprint could be revealed among RA specific proteins.Upon PMA stimulation, both 6PGDH and PFK2 co-imunoprecipitated with cytosolic factors p67phox, p47phox and p40phox. At the plasma membrane level, confocal microscopy experiments suggested a co-localization of either 6PGDH or PFK2 with the phagocyte NADPH oxidase in lipid rafts. 6PGDH enhanced the phagocyte NADPH oxidase activity by both improving the availability of cytosolic NADPH content and by increasing the affinity of the NADPH oxidase for its substrate. PFK2 also augmented the NADPH oxidase activity. PFK2 modulated the ATP concentration available for the phosphorylation of the phagocyte NADPH oxidase components and for the NDP Kinase related-Rac activation. The generation of truncated S100A8/S100A9 heterodimer chimera could reveal that the C-terminal region of S100A8 is involved in both the interaction and the activation of the phagocyte NADPH oxidase.In vivo, synovial fluid of RA patients was remarkably labelled with the PMN activation fingerprint. S100A8 and S100A9 proteins clearly distinguished RA synovial fluid from osteoarthritis and non RA-synovial fluids. An ectopic production of S100A8/S100A9 was shown in RA fibroblast like synoviocyte.In conclusion, 6PGDH, PFK2 and S100A8/A9 proteins are surrogate activating partners of the phagocyte NADPH oxidase. In RA, the activation of PMNs leads to the release of S100A8/A9 proteins which may constitute interesting biomarkers and promising therapeutic targets

Régulation de l'activité de la NADPH oxydase des neutrophiles par des enzymes du métabolisme du glucose et l'hétérocomplexe S100A8/S100A9 : application à la polyarthrite rhumatoïde

Rheumatoid Arthritis (RA) is caused by an inflammation of the synovial membrane leading to progressive joint destruction and deformation, related to the production NADPH oxidase related-reactive oxygen species (ROS) production. The phagocyte NADPH oxidase is a multi-protein complex formed by a catalytic core, i.e. the transmembrane cytochrome b558 and cytosolic regulators (p67phox, p47phox, p40phox and Rac1/2). We aimed at better analyzing the NADPH oxidase activation through the evaluation of the specificity of the interaction with 6PGDH or PFK2 and through the further analysis of the association with the S100A8/A9 heterocomplex. The RA-specific protein profiling was conducted in order to determine whether a PMN activation fingerprint could be revealed among RA specific proteins.Upon PMA stimulation, both 6PGDH and PFK2 co-imunoprecipitated with cytosolic factors p67phox, p47phox and p40phox. At the plasma membrane level, confocal microscopy experiments suggested a co-localization of either 6PGDH or PFK2 with the phagocyte NADPH oxidase in lipid rafts. 6PGDH enhanced the phagocyte NADPH oxidase activity by both improving the availability of cytosolic NADPH content and by increasing the affinity of the NADPH oxidase for its substrate. PFK2 also augmented the NADPH oxidase activity. PFK2 modulated the ATP concentration available for the phosphorylation of the phagocyte NADPH oxidase components and for the NDP Kinase related-Rac activation. The generation of truncated S100A8/S100A9 heterodimer chimera could reveal that the C-terminal region of S100A8 is involved in both the interaction and the activation of the phagocyte NADPH oxidase.In vivo, synovial fluid of RA patients was remarkably labelled with the PMN activation fingerprint. S100A8 and S100A9 proteins clearly distinguished RA synovial fluid from osteoarthritis and non RA-synovial fluids. An ectopic production of S100A8/S100A9 was shown in RA fibroblast like synoviocyte.In conclusion, 6PGDH, PFK2 and S100A8/A9 proteins are surrogate activating partners of the phagocyte NADPH oxidase. In RA, the activation of PMNs leads to the release of S100A8/A9 proteins which may constitute interesting biomarkers and promising therapeutic targets.La Polyarthrite Rhumatoïde est caractérisée par une synovite à l’origine de lésions progressives ostéo-articulaires induites par les formes réactives de l’oxygène (ROS) produites par la NADPH oxydase des polynucléaires neutrophiles (PMN). La NADPH oxydase des phagocytes, est formée d’un centre catalytique membranaire, le cytochrome b558, sur lequel vient s’associer des protéines cytosoliques régulatrices (p67phox, p47phox, p40phox et Rac1/2). Nous avons étudié la spécificité de l’interaction entre la (6-phosphofructokinase 2) et de la 6PGDH (6-phosphogluconate déshydrogénase) et la NADPH oxydase des PMN. D’autre part, nous avons caractérisé les domaines de l’hétérocomplexe S100A8/A9 impliqués dans l’activation de la NADPH oxydase phagocytaire. Par ailleurs, une étude de la signature protéique dans le liquide synovial a été menée afin de rechercher l’empreinte de l’activation du PMN dans la PR.Après stimulation par le PMA, la 6PGDH et la PFK2 co-imunoprécipitent avec les facteurs cytosoliques p67phox, p47phox and p40phox. Les expériences de microscopie confocale suggèrent une co-localisation de ces deux enzymes du métabolisme du glucose avec la NADPH oxydase, dans des micro-domaines membranaires : les radeaux lipidiques. La 6PGDH est impliquée dans l’activation de la NADPH oxydase phagocytaire en élevant la concentration du NADPH cytosolique mais également en augmentant l’affinité de cette enzyme pour son substrat, le NADPH. PFK2 est l’enzyme majeure de la régulation de la glycolyse, voie est essentielle pour la production d’ATP du PMN. L’utilisation du complexe S100A8/A9 et de protéines chimères de fusion nous a permis de révéler que la partie C-terminale de S100A8 est impliquée dans la liaison avec le cytochrome b558 et l’activation de la NADPH oxydase phagocytaire. In vivo, le profil protéique du liquide articulaire de PR a révélé l’empreinte de l’activation du PMN dans cette pathologie avec une surexpression des protéines S100A8 et S100A9. Une production ectopique de S100A8/A9 par les synoviocytes de type fibroblastique a été mise en évidence.En conclusion, la 6PGDH, la PFK2 et l’hétérodimère S100A8/A9 sont de nouveaux partenaires d’activation de la NADPH oxydase des phagocytes. Dans la PR, l’activation des PMNs conduit à la sécrétion de S100A8/A9 qui semblent constituer à la fois des biomarqueurs pertinents, mais également des cibles thérapeutiques potentielles

Reactive Arthritis in SKG mice results from a dysfunctional T cell response and an exaggerated inflammatory response to Chlamydia muridarum infection

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Microbiotes et rhumatismes inflammatoires

The microbiota and dysbiosis are involved in various diseases. Many studies in mice and humans demonstrate its influence on inflammatory rheumatisms. In rheumatoid arthritis (RA), Prevotella copri, a Gram-negative bacteria of the intestinal flora, is found to be more prevalent in the early stages of the disease. Specific antibodies against this germ have been identified in RA patients, suggesting a role of this bacteria in the initiation of the disease. Oral microorganisms involved in periodontitis have also been associated with the development and the activity of RA. These discoveries imply new targets in the management of inflammatory rheumatisms

Gait and Axial Spondyloarthritis: Comparative Gait Analysis Study Using Foot-Worn Inertial Sensors

BackgroundAxial spondyloarthritis (axSpA) can lead to spinal mobility restrictions associated with restricted lower limb ranges of motion, thoracic kyphosis, spinopelvic ankylosis, or decrease in muscle strength. It is well known that these factors can have consequences on spatiotemporal gait parameters during walking. However, no study has assessed spatiotemporal gait parameters in patients with axSpA. Divergent results have been obtained in the studies assessing spatiotemporal gait parameters in ankylosing spondylitis, a subgroup of axSpA, which could be partly explained by self-reported pain intensity scores at time of assessment. Inertial measurement units (IMUs) are increasingly popular and may facilitate gait assessment in clinical practice. ObjectiveThis study compared spatiotemporal gait parameters assessed with foot-worn IMUs in patients with axSpA and matched healthy individuals without and with pain intensity score as a covariate. MethodsA total of 30 patients with axSpA and 30 age- and sex-matched healthy controls performed a 10-m walk test at comfortable speed. Various spatiotemporal gait parameters were computed from foot-worn inertial sensors including gait speed in ms–1 (mean walking velocity), cadence in steps/minute (number of steps in a minute), stride length in m (distance between 2 consecutive footprints of the same foot on the ground), swing time in percentage (portion of the cycle during which the foot is in the air), stance time in percentage (portion of the cycle during which part of the foot touches the ground), and double support time in percentage (portion of the cycle where both feet touch the ground). ResultsAge, height, and weight were not significantly different between groups. Self-reported pain intensity was significantly higher in patients with axSpA than healthy controls (P<.001). Independent sample t tests indicated that patients with axSpA presented lower gait speed (P<.001) and cadence (P=.004), shorter stride length (P<.001) and swing time (P<.001), and longer double support time (P<.001) and stance time (P<.001) than healthy controls. When using pain intensity as a covariate, spatiotemporal gait parameters were still significant with patients with axSpA exhibiting lower gait speed (P<.001), shorter stride length (P=.001) and swing time (P<.001), and longer double support time (P<.001) and stance time (P<.001) than matched healthy controls. Interestingly, there were no longer statistically significant between-group differences observed for the cadence (P=.17). ConclusionsGait was significantly altered in patients with axSpA with reduced speed, cadence, stride length, and swing time and increased double support and stance time. Taken together, these changes in spatiotemporal gait parameters could be interpreted as the adoption of a so-called cautious gait pattern in patients with axSpA. Among factors that may influence gait in patients with axSpA, patient self-reported pain intensity could play a role. Finally, IMUs allowed computation of spatiotemporal gait parameters and are usable to assess gait in patients with axSpA in clinical routine. Trial RegistrationClinicalTrials.gov NCT03761212; https://clinicaltrials.gov/ct2/show/NCT03761212 International Registered Report Identifier (IRRID)RR2-10.1007/s00296-019-04396-

Radiculopathy as a manifestation of Langerhans' cell histiocytosis.

International audienceLangerhans' cell histiocytosis (LCH) is a rare condition of children and young adults in which Langerhans' cells proliferate. The clinical spectrum ranges from solitary or few focal lesions to multisystem involvement mimicking vasculitis or hematological malignancy. Focal bone lesions, known as eosinophilic granulomas, are the most common manifestations. Eosinophilic granuloma usually presents with a variable combination of pain, swelling, fracture, and fever. Facial bone involvement may manifest as an ear discharge, hearing loss, or exophthalmos. Nerve root pain is rarely reported, even in patients with lesions in the axial skeleton. We report four cases of nerve root pain caused by LCH. Two male patients aged 25 and 34 years, respectively, presented with truncated femoral neuralgia related to acetabular granulomas. A 25-year-old woman with involvement of the L5 vertebral body and a 41-year-old man with a sacral lesion presented with sciatica