Understanding the dual mobility concept for total hip arthroplasty. Investigations on a multiscale analysis-highlighting the role of arthrofibrosis

International audienceIn hip implants, UHMWPE (ultra high molecular weight polyethylene) liner wear is believed to be a key issue affecting the lifetime of the artificial joint. Dual mobility, a THA (total hip arthroplasty) concept where the liner moves inside the metallic shell, has become popular due to its low dislocation rate. To understand the tribological behavior of this particular implant, especially the role of the second mobility, 12 representative explants were selected from a bank of 250 explants. The implants used were Profil® femoral stem and Novae® metallic shell. The external surface, involved in the second mobility, was examined by 3D profilometry, SEM (scanning electron microscopy) and CMM (coordinate measuring machine). This study highlights a correlation between roughness and CMM evolutions and surgical parameters. A particular wear zone and a wear scenario were identified and validated according to the type of metal-back. A metal transfer between the metal back and the liner was isolated. CMM allowed to measure second mobility wear volume at a macroscopic scale. Thus a realistic wear mechanism has been suggested for this specific implant

Concept de double mobilité pour les prothèses totales de hanche : analyses multi-échelles de son fonctionnement

National audience120000 prothèses de hanche sont implantées chaque année, en France, 800000 en Europe. Cet acte chirurgical représente un enjeu de santé publique majeur, dans les années à venir. Dans l'optique d'augmenter la durée de vie des implants, un concept original de l'articulation d'une prothèse de hanche, le concept de double mobilité, représente maintenant 30 % des implants de hanche en France. 250 explants ont été conservés avec leurs caractéristiques complètes, ainsi que celles des patients. Une population homogène d'explants de LIP sans descellement acétabulaire, à même embase fémorale Profil ® a été ciblée. Puis, une première analyse visuelle et les données opératoires ont dégagé 12 explants caractéristiques. Une analyse de rugosimétrie de surface de la convexité a été menée (profilométries 2D et 3D) sur 5 zones de 1 mm² pour 2 latitudes choisies ainsi que le sommet (11 surfaces) [1,2]. La cartographie intégrale, relevés tridimensionnels macroscopiques, a été réalisée. La microscopie électronique à balayage munie d'une sonde EDS a permis de caractériser les transferts métalliques, insert sur metal back, dus à la 2 e mobilité. L'évolution de paramètres particuliers de rugosité 3D a permis de mettre en évidence les différents mécanismes d'usure de la 2 ème mobilité. Les metal backs en alliage de titane, ainsi que les échecs par fibrose capsulaire ont montré un fluage du UHMWPE (Ultra High Molecular Weight PolyEthylen) sans usure significative, ce qui explique une LIP précoce par un contact plus fréquent sur la collerette de rétentivité. Les surfaces de metal-back en acier présentent une phase de fluage puis une phase de frottement sur une bande caractéristique. L'usure du metal back en miroir corrèle cette observation. Le dessin prothétique et la balance de Pauwels permettent d'expliquer finement cette bande d'usure. De plus, il a été mis en évidence que l'usure n'est pas liée à l'âge ou au diamètre de l'insert. Il a été possible d'établir un scénario du mouvement de la deuxième mobilité, à partir des explants étudiés, en tenant compte des matériaux, de la taille des éléments prothétiques et de toutes les données disponibles

Etude de l'influence des facteurs de risque traditionnels et de l'inflammation sur le risque cardiovasculaire de la polyarthrite rhumatoïde selon une approche épidémiologique et physiopathologique

Introduction : Au cours de la polyarthrite rhumatoïde (PR), il existe une augmentation de la morbidité et de la mortalité d'origine cardiovasculaire CV. Ce sur-risque CV implique les facteurs de risques CV traditionnels et l'inflammation systémique qui pourrait constituer un facteur de risque indépendant. Certains traitements de la PR pourraient diminuer ce risque, notamment les anti-TNF. Objectifs : Nous avons choisi d'étudier le risque CV dans la PR selon une approche épidémiologique en évaluant la prévalence des facteurs de risque CV traditionnels. Nous avons par ailleurs suivi une approche physiopathologique en étudiant l'impact du TNF et des anti-TNF sur l'expression des récepteurs impliqués dans la captation (CD36) et l'efflux (ABCA1) du cholestérol par les monocytes. Méthodes : Pour notre approche épidémiologique nous avons d'abord effectué une méta-analyse des résultats des études cas-témoins ayant évalué la prévalence des facteurs de risque CV au cours de la PR, puis nous avons élaboré une étude cas-témoins évaluant la prévalence des facteurs de risque CV dans une cohorte française de rhumatismes inflammatoires débutants (ESPOIR) par comparaison à une cohorte issue de la population générale (MONICA). Pour notre approche épidémiologique nous avons étudié in vitro l'effet du TNF et d'un anti-TNF, l'adalimumab, sur l'expression de CD36 et d'ABCA1 par les monocytes humains. Nous avons par ailleurs étudié les mécanismes impliqués dans la régulation de CD36 et les conséquences de cette régulation sur la captation des LDL acétylés par les monocytes. Résultats : La méta-analyse à porté sur 2956 patients et 3713 contrôles. Dans cette étude il existait dans la population des patients atteints de PR, en comparaison aux témoins, une augmentation significative du tabagisme et du diabète, ainsi qu'une diminution du taux de HDL cholestérol, sans modification de la prévalence de l'hypertension ou de l'hypercholestérolémie. L'étude cas témoins a porté sur 609 patients et 1827 contrôles appariés sur l'âge et le sexe. Nous avons mis en évidence, après ajustement sur l'indice de masse corporelle, une faible diminution de la pression artérielle diastolique et de la glycémie, non associée à l'état inflammatoire. Une diminution significative du cholestérol total et de ses fractions HDL et LDL, associée au niveau inflammatoire, évaluée par le taux de CRP ou d'IL6, indépendamment du type de rhumatisme inflammatoire a été mise en évidence. Dans notre approche physiopathologique nous avons mis en évidence que le TNF inhibait de façon dose dépendante l'expression de CD36 en inhibant l'activation de PPAR gamma et que l'anti-TNF augmentait significativement l'expression de CD36 par un effet propre et en activant une NADPH oxydase. Nous avons par ailleurs mis en évidence que le TNF diminuait la captation des LDL par les monocytes et que l'anti-TNF l'augmentait. Nous n'avons pas mis en évidence de modification significative de l'expression d'ABCA1 par le TNF ou l'anti-TNF. Conclusions : Au cours de la PR il semble exister une modification de la prévalence de certains facteurs de risque CV traditionnels, en particulier au début de la maladie. Certains facteurs de risque , comme le tabagisme ou la baisse du HDL, pourraient contribuer à une augmentation du risque CV alors que d'autres, comme la baisse du LDL, pourraient contribuer à le diminuer. Ces modifications des facteurs de risque CV ne permettent pas à elles seules d'expliquer le sur-risque CV observé au cours de la PR, qui pourrait faire intervenir l'inflammation en tant que facteur de facteur de risque CV indépendant. Notre travail montre que le TNF et l'anti-TNF peuvent moduler l'expression des récepteurs impliqués dans le métabolisme du cholestérol par les monocytes, comme le CD36. Un contrôle optimal de l'inflammation pourrait contribuer à une diminution du sur-risque cardiovasculaire observé au cours de la PR.Introduction: there is an increase in CV morbidity and mortality in RA. This excess of risk implicates traditional CV risk factors and systemic inflammation which could be an independent CV risk factor. RA treatments may modify CV risk, and in particular anti-tumor necrosis factors (anti-TNF) may decrease this risk. Objectives: we use an epidemiologic approach to evaluate the prevalence of CV traditional risk factors in RA. By using a physiopathologic approach we evaluated the impact of TNF and anti-TNF on the expression of receptors implicated in cholesterol capture (CD36), and in cholesterol efflux (ABCA1) by human monocytes. Methods: In our epidemiologic approach we first realized a meta-analysis to evaluate the prevalence of traditional CV risk factors in case-control studies. Then we elaborated a case-control study assessing the prevalence of traditional CV risk factors in a French early arthritis cohort (ESPOIR) by comparison with a general population cohort (MONICA). In our physiopathologic approach we analyzed the effect of TNF and anti-TNF, adalimumab, on CD36 and ABCA1 expression by human monocytes. We also analyzed the mechanisms implicated in the regulation of CD36 by these agents and its consequences on the capture of acetylated LDL by human monocytes. Results: the meta-analysis included 2956 patients and 3713 controls. In this study there was a significant increase in the prevalence of smoking, diabetes mellitus, and a decrease in HDL level, without modification of hypertension or hypercholesterolemia in RA by comparison with controls. The case-control study included 609 patients and 1827 age and sex-matched controls. After adjusting with body mass index, this study demonstrated a slightly lower diastolic blood pressure and glycaemia which were not linked with inflammatory status in early arthritis patients. The level of total cholesterol and its fractions was significantly lower in patients and linked with inflammatory status as assessed by IL6 and CRP level. This was independent from the subclass of early arthritis disease. In the physiopathologic approach, our results show that TNF decreases CD36 expression in a dose dependent manner through an inhibition of PPAR gamma activation. The Anti-TNF independently induced CD36 expression. This induction was independent of the Fc portion of adalimumab and involved redox signalling via NADPH oxidase activation. We also found that TNF decreased and anti-TNF increased acetylated LDL capture by monocytes. We did not find any difference in ABCA1 expression in monocytes in the presence of TNF or anti-TNF. Conclusions: During RA there is a modification of the prevalence of traditional CV risk factors, in particular at the beginning of the disease. Smoking and low HDL level could contribute to increase CV risk, but low LDL level could contribute to decrease this risk. These modifications of the prevalence of traditional CV risk factors only cannot explain the increase of CV risk observed in RA. This risk could implicate the inflammatory process as an independent CV risk factor. Moreover our results show that TNF and anti-TNF modulate the expression of receptors implicated in cholesterol metabolism such as CD36 in human monocytes. An optimal control of inflammation could permit to decrease the excess of CV risk observed in RA

Wear analysis of hip explants, dual mobility concept: Comparison of quantitative and qualitative analyses

International audienceTotal hip replacement (THR) fails mainly because of wear. It is of interest to analyze wear to be able to increase the longevity of the hip implants. One way to achieve it is to use instruments on explants but the most suitable depends on the application. This paper aims at comparing several methods of surface analysis in the particular application of wear determination in a series of dual mobility explants. Wear measurement could help understand the wear mechanism only partially known. A CMM, Coordinate Measuring Machine, is used to get 3D points representing the explants, then Pro/Engineer ® and Matlab ® are used to calculate wear. A mechanical (SOMICRONIC®) and an optical profilometer (Bruker nanoscope Wyko® NT 9100, ex. Veeco) are used to access roughness parameters. The comparisons of the two software showed similar results for wear calculation except in a few cases where differences are due to the theoretical volumes calculation. The comparison of the two profiling techniques resulted in similar results particularly for Sa and Sdr. The comparison of the results showed that wear is present for four explants; it is relevant with the observed characteristics. The mechanical profilometer showed better accuracy than the optical one which enable to conclude that it must not be neglected for that particular application, even if measurements need more time

Maintenance of cytomegalovirus-specific CD4pos T-cell response in rheumatoid arthritis patients receiving anti-tumor necrosis factor treatments

International audienceINTRODUCTION: Anti-tumor necrosis factor (TNF)-α biotherapies have considerably changed the treatment of rheumatoid arthritis (RA). However, serious infections are a major concern in patients with rheumatic diseases treated with anti-TNF-α. Little is known about viral, especially latent, infections in anti-TNF-α treatments. Infections by cytomegalovirus (CMV), a β-herpes virus, are frequent and induce a strong CD4pos T-cell immunity, which participates in the control of infection. We thus have chosen to analyze the CD4pos T-cell response to CMV antigens as a model of antiviral response in RA patients treated with anti-TNF-α. CD28 expression was evaluated. METHODS: We have measured the CD4pos response to CMV antigens in RA patients, before and after initiation of treatment with an anti-TNF-α agent. The intracellular production of interferon (IFN)-γ in total and CD28neg CD4pos T cells in response to CMV antigens (Ags) was evaluated with flow cytometry. The proliferation of total CD4pos T cells in the presence of CMV antigens was measured with 3H-thymidine incorporation. RESULTS: Anti-TNF-α treatments impaired neither the anti-CD4pos anti-CMV IFN-γ response nor the proliferative response in patients. The percentage of CD28neg CD4pos cells remained constant. CONCLUSIONS: Our data suggest that the CD4pos T-cell response against CMV is not altered by anti-TNF-α treatments and that infection remains controlled in treated RA patients latently infected with CMV. Our observation brings new insight into the current knowledge of the risks of infection in patients treated with anti-TNF-α biotherapies

Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes

In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFα), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFα and adalimumab, a human anti-TNFα monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFα or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)γ in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFα inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARγ activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFα and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis

Polarization of Rheumatoid Macrophages by TNF Targeting Through an IL-10/STAT3 Mechanism

Macrophages contribute to the pathogenesis of rheumatoid arthritis (RA). They can display different states of activation or “polarization,” notably the so-called inflammatory “M1” and the various alternative “M2” polarizations, characterized by distinct functions. Data regarding the effects of RA anti-cytokine biological disease-modifying anti-rheumatic drugs (bDMARDs) on macrophage polarization are scarce. We aimed to assess in vitro modulation of macrophage polarization by bDMARDs targeting pro-inflammatory cytokines in RA. We generated monocyte derived macrophages using blood samples from 20 RA patients with active RA and 30 healthy controls. We evaluated in vitro the impact on M1 inflammatory macrophages of: etanercept (ETA), adalimumab (ADA), certolizumab (CZP), tocilizumab (TCZ), and rituximab (RTX). We assessed the impact on macrophage polarization using flow cytometry and RTqPCR to study the expression of surface markers and perform functional studies of cytokine production, phagocytosis, and negative feedback control of inflammation. Among evaluated bDMARDs, anti-TNF agents modulated the polarization of inflammatory macrophages by decreasing inflammatory surface markers (CD40, CD80) and favoring alternative markers (CD16, CD163, MerTK). Anti-TNF agents also induced alternative functions in macrophages activated in inflammatory condition with (i) the inhibition of inflammatory cytokines (TNF, IL-6, IL-12), (ii) an increase in phagocytosis. These findings were mechanistically related to an increase in early IL-10 production, responsible for higher negative feedback control of inflammation involving SOCS3 and Gas6. This IL-10 effect was STAT3-dependent. Anti-TNF agents not only inhibit in vitro inflammatory functions of macrophages, but also favor resolution of inflammation through polarization toward alternative features specifically involving the IL-10/STAT3 axis

A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for autoantibody production in rheumatoid arthritis

The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity

Tempo and drivers of plant diversification in the European mountain system

There is still limited consensus on the evolutionary history of species-rich temperate alpine floras due to a lack of comparable and high-quality phylogenetic data covering multiple plant lineages. Here we reconstructed when and how European alpine plant lineages diversified, i.e., the tempo and drivers of speciation events. We performed full-plastome phylogenomics and used multi-clade comparative models applied to six representative angiosperm lineages that have diversified in European mountains (212 sampled species, 251 ingroup species total). Diversification rates remained surprisingly steady for most clades, even during the Pleistocene, with speciation events being mostly driven by geographic divergence and bedrock shifts. Interestingly, we inferred asymmetrical historical migration rates from siliceous to calcareous bedrocks, and from higher to lower elevations, likely due to repeated shrinkage and expansion of high elevation habitats during the Pleistocene. This may have buffered climate-related extinctions, but prevented speciation along elevation gradients as often documented for tropical alpine floras