High levels of memory B cells are associated with response to a first tumor necrosis factor inhibitor in patients with rheumatoid arthritis in a longitudinal prospective study

Tumor necrosis factor inhibitor (TNFi) therapy is effective for rheumatoid arthritis (RA). Some reports suggested that the therapy affects B-cell homeostasis. We studied the effect of TNFi therapy on the distribution of peripheral B-cell subsets and elucidated B-cell-related biomarkers to predict the TNFi response. Peripheral B cells were analyzed for expression of CD19, CD27, CD38, and IgD in 31 healthy donors and 96 RA patients, including 21 who were followed 3 months after TNFi introduction. Treatment with steroids significantly altered the distribution of B-cell subsets. After adjustment for age, gender and steroid dose, patients with RA had similar B-cell subset proportions as controls. B-cell subset distribution did not differ by use of TNFi at baseline or before and after TNFi introduction. TNFi responders (according to European League Against Rheumatism criteria) at 3 months had significantly higher proportion of CD27+ memory B cells at baseline, and >= 26% CD27+ cells at inclusion was associated with a relative risk of 4.9 (1.3 to 18.6) of responding to TNFi treatment. CD27+ cells produced 3 times more TNFalpha than did naive B cells, and were correlated with interferon-gamma produced from CD4+ cells in patients without TNFi treatment. In patients with RA, high levels of baseline memory B cells were associated with response to TNFi, which may be related to TNFalpha-dependent activation of the T helper cell type 1 pathwa

2016 update of the EULAR recommendations for the management of early arthritis

Objectives: Since the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of the 2007 EULAR recommendations for management of early arthritis. Methods: In accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 health professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of “management” and selected the research questions. A systematic literature research (SLR) was performed by 2 fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process. Results: The updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research. Conclusion: These recommendations provide rheumatologists, general practitioners, health professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis

The reference site collaborative network of the european innovation partnership on active and healthy ageing

Seventy four Reference Sites of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) have been recognised by the European Commission in 2016 for their commitment to excellence in investing and scaling up innovative solutions for active and healthy ageing. The Reference Site Collaborative Network (RSCN) brings together the EIP on AHA Reference Sites awarded by the European Commission, and Candidate Reference Sites into a single forum. The overarching goals are to promote cooperation, share and transfer good practice and solutions in the development and scaling up of health and care strategies, policies and service delivery models, while at the same time supporting the action groups in their work. The RSCN aspires to be recognized by the EU Commission as the principal forum and authority representing all EIP on AHA Reference Sites. The RSCN will contribute to achieve the goals of the EIP on AHA by improving health and care outcomes for citizens across Europe, and the development of sustainable economic growth and the creation of jobs

Study of B cells in rheumatoid arthritis : phenotyping, regulatory B cell analysis and B cells as predictive biomarker of response to biodrugs

Le lymphocyte B (LB) joue un rôle important dans la polyarthrite rhumatoïde (PR), en produisant des auto-anticorps qui ont un rôle pathogène, en activant les lymphocytes T, en sécrétant des cytokines pro-inflammatoires et en permettant la formation de centres germinatifs. Plus récemment, il a été montré que le LB pouvait également produire de l'interleukine (IL) 10, une cytokine anti-inflammatoire qui lui procure des fonctions régulatrices. Ces B régulateurs ont notamment la capacité de différencier les lymphocytes T en T régulateurs. De nombreux traitements sont actuellement disponibles dans la PR, notamment les anti-TNF alpha et les inhibiteurs du récepteur de l'IL-6 (tocilizumab). Dans la première partie de cette thèse, nous avons comparé les LB circulants de patients atteints de PR et de contrôles. Nous avons étudié l'influence de l'activité de la maladie et des traitements sur les LB. Nous avons montré qu'il existait une lymphopénie B globale chez les patients atteints de PR avec une répartition des différents sous-types de LB superposable à celle des contrôles. Les patients ayant une maladie active avaient significativement plus de LB mémoires totaux, pré- et post-switch, CD24hiCD27+ et double négatifs que les patients ayant une maladie peu active. Les traitements anti-TNF et le tocilizumab ne modifiaient pas la répartition des sous-types de LB. Nous avons également montré qu'un taux de plus de 26% de LB mémoires CD27+ avant l'instauration d'un traitement par anti-TNF était associé à la réponse clinique à 3 mois. Les LB mémoires semblent produire plus de TNF que les LB naïfs et par ce biais pourraient induire une réponse Th1. Dans la seconde partie de cette thèse, nous avons tout d'abord cherché à mieux définir les LB régulateurs. Nous avons ensuite étudié leur présence et leur rôle dans la PR. Chez les sujets sains, les LB CD24hiCD27+ et CD24hiCD38hi semblent produire plus d'IL-10 que les autres LB, qui peuvent néanmoins en sécréter. Il semble donc plus adapter de définir les B régulateurs comme B producteurs d'IL-10 ou B10. Les patients atteints de PR avaient significativement moins de B10 que les contrôles en pourcentage et en valeur absolue. Chez les patients ayant un facteur rhumatoïde (FR) positif, il y avait une corrélation inverse entre le pourcentage de B10 et le taux de FR. Il y avait une corrélation inverse entre l'activité de la maladie (DAS28) et le pourcentage de B10, qui était particulièrement marquée pour les PR évoluant depuis moins de 5 ans. Chez ces patients, il y avait également une corrélation inverse entre les B10 et l'inflammation biologique (protéine C réactive). L'instauration d'anti-TNF ou de tocilizumab ne modifiait pas le taux de B10. Les CD24hiCD27+ et CD24hiCD38hi induisaient plus de lymphocytes T régulateurs chez les contrôles que les autres LB (CD24lo/-) alors que ça n'était plus le cas chez les patients atteints de PR, montrant que ces sous-types ont perdu cette fonction régulatrice dans la PR. En conclusion, bien qu'il existe une lymphopénie B, la répartition des sous-types de LB ne semble pas différente entre les patients atteints de PR et les contrôles. Néanmoins, il existe des anomalies fonctionnelles avec notamment une perte de la capacité à produire de l'IL-10 et à induire des T régulateurs chez les patients atteints de PR.B cells play an important role in rheumatoid arthritis (RA), producing autoantibodies which have a pathogenic role, activating T cells, secreting pro-inflammatory cytokines and allowing the formation of germinal centers. More recently, it was shown that the B cells could also produce interleukin (IL)-10, an anti-inflammatory cytokine which provides their regulatory functions. Those regulatory B cells have the ability to differentiate T cell into regulatory T cells. Many treatments are currently available in RA, including TNF-alpha inhibitors and IL-6 receptor inhibitor (tocilizumab). In the first part, we compared circulating B cells in RA patients and in controls, and we studied the influence of disease activity and treatment on B cells. We have shown that there is a global B cell lymphopenia in RA patients with a similar B cell subtype distribution as controls. Patients with active disease had significantly more pre- and post-switch, CD24hiCD27+ and double negative memory B cells than patients with low disease activity. Anti -TNF treatment and tocilizumab did not change the distribution of B cell subsets. We also showed than patient with more than 26% of CD27+ memory B cells prior TNF inhibitor initiation was associated with clinical response at 3 months. Memory B cells produced more TNF alpha than naive B cells and can potentially induce a Th1 response. B cell subtypes were not associated with response to tocilizumab. In the second part, we first sought to better define regulatory B cells. We then studied their presence and role in RA. In healthy subjects, CD24hiCD27+ and CD24hiCD38hi B cells seem to produce more IL-10 than the other B cells that can nevertheless rarely produce some. It seemed more acurate to define regulatory B cells as IL-10 producing B cells also called B10 cells. Patients with RA had significantly less B10 cells than controls in percentage and absolute values. In rheumatoid factor (RF) positive patients, there was an inverse correlation between the percentage of B10 and the rate of RF. There was an inverse correlation between disease activity (DAS28) and the percentage of B10, which was particularly significant for patients with a disease duration of less than 5 years. In these patients, there was also an inverse correlation between B10 and biological inflammation (C-Reactive Protein). TNF inhibitors or tocilizumab did not change B10 cell rate. The CD24hiCD27 + and CD24hiCD38hi induce more regulatory T cells in controls than other LB (CD24lo/-) while it was not the case in patients with RA, indicating that these subtypes have lost this regulatory function in RA. In conclusion, although there are B cell lymphopenia, the distribution of B cell subsets does not seem to differ between RA patients and controls. Nevertheless, there are functional abnormalities including a loss of the ability to produce IL -10 and induce regulatory T in patients with RA

Obesity and inflammatory arthritis: impact on occurrence, disease characteristics and therapeutic response

International audienceOverweight and obesity are increasing worldwide and now reach about one-third of the world's population. Obesity also involves patients with inflammatory arthritis. Knowing the impact of obesity on rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis) is thus an important issue. This article first reviews the epidemiological and clinical data available on obesity in inflammatory rheumatic diseases, that is, its impact on incident disease, disease characteristics and the therapeutic response. The second part of this review gives an overview of the factors potentially involved in the specifics of inflammatory arthritis in patients with obesity, such as limitations in the clinical assessment, diet, microbiota and adipokines

L' étanercept normalise la masse ventriculaire gauche des patients atteints de la polyarthrite rhumatoïde

Contexte : La mortalité cardiovasculaire est accrue chez les patients atteints de polyarthrite rhumatoïde (PR). La PR est associée à une augmentation de la rigidité artérielle et de la masse ventriculaire gauche (MVG). L'augmentation de la MVG est un marqueur prédictif fort de la mortalité cardiovas cul aire. Des études expérimentales suggèrent que le tumor necrosis factor a (TNF a) peut induire une hypertrophie VG. objectif : Evaluation de l'effet des anti-TNF a et des traitements de fond synthétiques (sDMARD) sur la morphologie du VG et sur la rigidité artérielle chez des patients atteints de PRo .Méthodes : Des patientes souffrant de PR active nécessitant l'introduction d'un traitement par etanercept (ETN) ou sDMARD et n'ayant pas d'antécédent ou de comorbidité cardiovasculaire, ont été incluses de façon consécutive. Le suivi clinique et biologique, l'échocardiographie cardiaque et la vitesse de propagation de l'onde de pouls (VOP) ont été effectuées à l'inclusion puis à 3 et 6 mois suivant l'initiation du traitement. Des t-Tests appariés ont été utilisés pour comparer l'évolution des différents paramètres sous traitement. Une analyse multivariée par régression linéaire a été utilisée pour rechercher les facteurs explicatifs des variations de MVG. Résultats : Quarante-huit patientes ont été incluses (28 dans le groupe ETN et 20 dans le groupe sDMARD). La MVG et la VOP étaient/plus élevés dans le groupe ETN à l'inclusion, mais de façon non significative. La MVG diminuait significativement à 3 et 6 mois chez les patients traités par ETN (-6,3 +- 7,6 et -14,2 +- 9,3 g / m2 , p <0,001) alors qu'elle n'était pas modifiée chez les sujets traités par sDMARD (moyenne +- SD: -2,2 +- 10,9 et -2,7 +- 10,2 g / m2 , respectivement). La pression artérielle et la VOP n'étaient modifiées dans aucun des deux groupes. Conclusion : L'ETN induit une diminution significative de MVG sans modifier la pression artérielle ni les paramètres de rigidité artérielle. Ces résultats suggèrent que le TNF a est un facteur important de l'hypertrophie VG. Ils pourraient expliquer en pa11ie le bénéfice précédemment décrit des anti-TNF sur la morbi-mortalité cardio-vasculaire dans la PRoMONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF

Analyse des lymphocytes B dans la polyarthrite rhumatoïde (phénotypage, étude des B régulateurs et des lymphocytes B comme biomarqueurs de réponse aux biomédicaments.)

Le lymphocyte B (LB) joue un rôle important dans la polyarthrite rhumatoïde (PR), en produisant des auto-anticorps qui ont un rôle pathogène, en activant les lymphocytes T, en sécrétant des cytokines pro-inflammatoires et en permettant la formation de centres germinatifs. Plus récemment, il a été montré que le LB pouvait également produire de l'interleukine (IL) 10, une cytokine anti-inflammatoire qui lui procure des fonctions régulatrices. Ces B régulateurs ont notamment la capacité de différencier les lymphocytes T en T régulateurs. De nombreux traitements sont actuellement disponibles dans la PR, notamment les anti-TNF alpha et les inhibiteurs du récepteur de l'IL-6 (tocilizumab). Dans la première partie de cette thèse, nous avons comparé les LB circulants de patients atteints de PR et de contrôles. Nous avons étudié l'influence de l'activité de la maladie et des traitements sur les LB. Nous avons montré qu'il existait une lymphopénie B globale chez les patients atteints de PR avec une répartition des différents sous-types de LB superposable à celle des contrôles. Les patients ayant une maladie active avaient significativement plus de LB mémoires totaux, pré- et post-switch, CD24hiCD27+ et double négatifs que les patients ayant une maladie peu active. Les traitements anti-TNF et le tocilizumab ne modifiaient pas la répartition des sous-types de LB. Nous avons également montré qu'un taux de plus de 26% de LB mémoires CD27+ avant l'instauration d'un traitement par anti-TNF était associé à la réponse clinique à 3 mois. Les LB mémoires semblent produire plus de TNF que les LB naïfs et par ce biais pourraient induire une réponse Th1. Dans la seconde partie de cette thèse, nous avons tout d'abord cherché à mieux définir les LB régulateurs. Nous avons ensuite étudié leur présence et leur rôle dans la PR. Chez les sujets sains, les LB CD24hiCD27+ et CD24hiCD38hi semblent produire plus d'IL-10 que les autres LB, qui peuvent néanmoins en sécréter. Il semble donc plus adapter de définir les B régulateurs comme B producteurs d'IL-10 ou B10. Les patients atteints de PR avaient significativement moins de B10 que les contrôles en pourcentage et en valeur absolue. Chez les patients ayant un facteur rhumatoïde (FR) positif, il y avait une corrélation inverse entre le pourcentage de B10 et le taux de FR. Il y avait une corrélation inverse entre l'activité de la maladie (DAS28) et le pourcentage de B10, qui était particulièrement marquée pour les PR évoluant depuis moins de 5 ans. Chez ces patients, il y avait également une corrélation inverse entre les B10 et l'inflammation biologique (protéine C réactive). L'instauration d'anti-TNF ou de tocilizumab ne modifiait pas le taux de B10. Les CD24hiCD27+ et CD24hiCD38hi induisaient plus de lymphocytes T régulateurs chez les contrôles que les autres LB (CD24lo/-) alors que ça n'était plus le cas chez les patients atteints de PR, montrant que ces sous-types ont perdu cette fonction régulatrice dans la PR. En conclusion, bien qu'il existe une lymphopénie B, la répartition des sous-types de LB ne semble pas différente entre les patients atteints de PR et les contrôles. Néanmoins, il existe des anomalies fonctionnelles avec notamment une perte de la capacité à produire de l'IL-10 et à induire des T régulateurs chez les patients atteints de PR.B cells play an important role in rheumatoid arthritis (RA), producing autoantibodies which have a pathogenic role, activating T cells, secreting pro-inflammatory cytokines and allowing the formation of germinal centers. More recently, it was shown that the B cells could also produce interleukin (IL)-10, an anti-inflammatory cytokine which provides their regulatory functions. Those regulatory B cells have the ability to differentiate T cell into regulatory T cells. Many treatments are currently available in RA, including TNF-alpha inhibitors and IL-6 receptor inhibitor (tocilizumab). In the first part, we compared circulating B cells in RA patients and in controls, and we studied the influence of disease activity and treatment on B cells. We have shown that there is a global B cell lymphopenia in RA patients with a similar B cell subtype distribution as controls. Patients with active disease had significantly more pre- and post-switch, CD24hiCD27+ and double negative memory B cells than patients with low disease activity. Anti -TNF treatment and tocilizumab did not change the distribution of B cell subsets. We also showed than patient with more than 26% of CD27+ memory B cells prior TNF inhibitor initiation was associated with clinical response at 3 months. Memory B cells produced more TNF alpha than naive B cells and can potentially induce a Th1 response. B cell subtypes were not associated with response to tocilizumab. In the second part, we first sought to better define regulatory B cells. We then studied their presence and role in RA. In healthy subjects, CD24hiCD27+ and CD24hiCD38hi B cells seem to produce more IL-10 than the other B cells that can nevertheless rarely produce some. It seemed more acurate to define regulatory B cells as IL-10 producing B cells also called B10 cells. Patients with RA had significantly less B10 cells than controls in percentage and absolute values. In rheumatoid factor (RF) positive patients, there was an inverse correlation between the percentage of B10 and the rate of RF. There was an inverse correlation between disease activity (DAS28) and the percentage of B10, which was particularly significant for patients with a disease duration of less than 5 years. In these patients, there was also an inverse correlation between B10 and biological inflammation (C-Reactive Protein). TNF inhibitors or tocilizumab did not change B10 cell rate. The CD24hiCD27 + and CD24hiCD38hi induce more regulatory T cells in controls than other LB (CD24lo/-) while it was not the case in patients with RA, indicating that these subtypes have lost this regulatory function in RA. In conclusion, although there are B cell lymphopenia, the distribution of B cell subsets does not seem to differ between RA patients and controls. Nevertheless, there are functional abnormalities including a loss of the ability to produce IL -10 and induce regulatory T in patients with RA.MONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF

Diagnosis, prognosis and classification of early arthritis: results of a systematic review informing the 2016 update of the EULAR recommendations for the management of early arthritis

To update the evidence pertaining to the diagnosis, prognosis and classification of patients with early arthritis (EA), and to inform the 2016 European League Against Rheumatism (EULAR) recommendations for the management of patients with EA. MEDLINE, EMBASE and Cochrane databases were searched up to October 2015. The first part of the systematic literature review (SLR) involved a search for studies investigating the recognition and referral of EA. The second part involved a search for studies to identify the place of laboratory and imaging tests in establishing a diagnosis and a prognosis in patients with EA. Regarding the issue of referral of patients with EA (1643 hits), 4 studies were included. These studies were in support of early referral for patients with EA. Regarding the issue of diagnosis and prognosis of patients with EA (11 435 hits), 88 studies were included, evaluating mainly the value of rheumatoid factor (RF) and anticitrullinated-peptide antibodies (ACPAs). Sensitivity of these antibodies for a RA diagnosis in patients with EA was moderate (40-80%). Specificity was higher, notably for ACPAs (frequently >80%). ACPAs also showed better prognostic performance than RF (negative predictive values around 80%). We confirmed that structural damage on baseline X-rays is predictive of further radiographic progression in patients with EA. Regarding other imaging modalities, data are sparse. This SLR highlights the importance of early referral for patients with EA and confirms that RF and mainly ACPAs as well as a search for structural X-rays changes may help in the diagnosis and prognosis of patients with E

IL-10 Producing B Cells Ability to Induce Regulatory T Cells Is Maintained in Rheumatoid Arthritis

Despite growing evidence highlighting the relevance of increasing IL-10-producing B cells (B10+cells) in autoimmune diseases, their functions in patients are still unknown. The aim of this study was to evaluate the functions of CpG-induced B10+ cells isolated from healthy controls (HC) and rheumatoid arthritis (RA) patients, on naïve T cell differentiation. We demonstrated that CpG-induced B10+ cells from HC drove naïve T cell differentiation toward regulatory T cells (Treg cells) and IL-10-producing T cells (Tr1) through IL-10 secretion and cellular contacts. B10+ cells from HC did not decrease T helper 1 (Th1) nor and tumor necrosis factor α producing T cell (TNFα+ T cell) differentiation. We showed that in RA, B10+ cells could also induce Treg cells and Tr1 from naïve T cells. Contrary to HC, B10+ cells from RA patients increased naïve T cell conversion into Th1. Interestingly, PD-L2, a programmed death-1 (PD-1) ligand that inhibits PD-L1 and promotes Th1 differentiation, was overexpressed on RA B10+ cells compared to HC B10+ cells. Together, our findings showed that CpG-induced B10+ cells may be used to increase Treg cells in patients with RA. However, CpG may not be the most adequate stimuli as CpG-induced B10+ cells also increased inflammatory T cells in those patients

Non-pharmacological and pharmacological interventions in patients with early arthritis: a systematic literature review informing the 2016 update of EULAR recommendations for the management of early arthritis

To perform a systematic literature review (SLR) on pharmacological and non-pharmacological treatments, in order to inform the European League Against Rheumatism (EULAR) recommendations for the management of early arthritis (EA). The expert committee defined research questions concerning non-pharmacological interventions, patient information and education, non-steroidal anti-inflammatory drug, glucocorticoid (GC) and disease-modifying antirheumatic drugs (DMARDs) use, as well as on disease monitoring. The SLR included articles published after the last EULAR SLR until November 2015 found in the MEDLINE, EMBASE and Cochrane databases and abstracts from the 2014 and 2015 American College of Rheumatology and EULAR conferences. Exercise programmes may improve pain and physical function in patients with EA. Patients with EA treated within the first 3 months of symptoms have better clinical and radiological outcomes than those treated beyond 3 months. The clinical and radiological efficacy of GCs is confirmed, with similar efficacy of oral and parenteral administrations. Long-term data raise concerns regarding cardiovascular safety when using GCs. Step-up DMARD therapy is as effective as intensive DMARD therapy 'ab initio' for the long-term outcome of EA. Short-term superiority of intensive therapy with bDMARDs is not maintained on withdrawal of bDMARD. Patients with early psoriatic arthritis have better skin and joint outcomes when tight control is used compared to standard care. The findings confirm the beneficial effect of exercise programmes and the importance of early drug therapy and tight control. They support the use of methotrexate and GCs as first-line drugs, although the long-term use of GCs raises safety concern