Literatura académica sobre el tema "Bureau Greisch"

BackgroundSystemic sclerosis (SSc) is characterized by vasculopathy, inflammation and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognostic factor, SSc-PAH patients demonstrate disproportionately high mortality, presumably due to cardiac involvement [1].ObjectivesTo investigate the relation between cardiac involvement as revealed by Cardiovascular Magnetic Resonance (CMR) and systemic microvascular disease severity as measured with nailfold capillaromicroscopy (NCM) in SSc-PAH patients, compared to idiopathic PAH (IPAH) patients.MethodsSSc-PAH and IPAH patients underwent CMR, transthoracic echocardiography (TTE), and NCM with post-occlusive reactivity hyperemia (PORH) testing on the same day [2-4]. CMR imaging included T2 mapping, native and postcontrast T1 mapping, to assess edema and fibrosis, and adenosine-stress perfusion imaging to measure the relative myocardial upslope (to determine microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of edema, fibrosis and myocardial perfusion.ResultsSSc-PAH patients (n=20) had higher extracellular volume fraction (ECV) and T2 values than IPAH patients (n=5), and lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with native T1, ECV, and T2 values (r=-0.431, -0.443, and -0.464, respectively, p<0.05 for all), and with markers of diastolic dysfunction on echocardiography. Furthermore, PORH-testing, but not NCD, correlated with the relative myocardial upslope by stress CMR (r=0.421, p<0.05) (Table 1).Table 1.Nailfold capillaroscopy with post occlusive hyperemia reactivity testingSSc-PH (n=20)IPAH (n=5)p-valueAverage capillary density (n/mm)4 [3-6]10 [10-11]<0.001Pattern (n)Normal04 (80%)Non-specific01 (20%)Systemic sclerosis: early pattern1 (4%)0Systemic sclerosis: active pattern1 (4%)0Systemic sclerosis: late pattern18 (72%)0Post-occlusive reactivity hyperemia testingRest (n/mm2)55 [39-73]93 [80-97]0.006Average capillaries after PORH (n/mm2)53 [46-77]100 [81-120]0.006Total recruitment of capillaries (n/mm2)1 [-4-5)23 [-3-27)<0.05Average capillaries at venous congestion (n/mm2)55 [50-78]106 [81-126]0.006Total recruitment of capillaries (n/mm2)5 [1-11]11 [-9-30]0.613Values are in medians [interquartile range] or number (%).Abbreviations:NT-proBNP, N-terminal pro-Brain Natriuretic Peptide; POHR, post-occlusive reactivity hyperemia testConclusionSSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared to IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionately high mortality in SSc-PAH patients.References[1]Chung L, Domsic RT, Lingala B, Alkassab F, Bolster M, Csuka ME, et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken). 2014;66(3):489-95.[2]Smith V, Herrick AL, Ingegnoli F, Damjanov N, Angelis, Denton CP, et al. Standardisation of nailfold capillaroscopy for the assessment of patients with Raynaud’s phenomenon and systemic sclerosis. Autoimmun Rev. 2020:102458.[3]Liu A, Wijesurendra RS, Liu JM, Greiser A, Jerosch-Herold M, Forfar JC, et al. Gadolinium-Free Cardiac MR Stress T1-Mapping to Distinguish Epicardial From Microvascular Coronary Disease. J Am Coll Cardiol. 2018;71(9):957-68.[4]Serne EH, Gans RO, ter Maaten JC, Tangelder GJ, Donker AJ, Stehouwer CD. Impaired skin capillary recruitment in essential hypertension is caused by both functional and structural capillary rarefaction. Hypertension. 2001;38(2):238-42.Acknowledgements:NIL.Disclosure of InterestsJaqueline Vos: None declared, Jacqueline Lemmers: None declared, Saloua ElMessaoudi: None declared, Miranda Snoeren: None declared, Arie van Dijk: None declared, Toon Duijnhouwer: None declared, Laura Rodwell: None declared, Sander van Leuven: None declared, Marco Post Speakers bureau: Janssen, Consultant of: Janssen, MSD, Grant/research support from: Janssen, St. Antonius Research fund, ZonMw, Madelon Vonk Speakers bureau: Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Janssen, MSD, Novartis and Roche, Consultant of: Boehringer Ingelheim and Janssen, Grant/research support from: Boehringer Ingelheim, Janssen, Ferrer and Galapagos, Robin Nijveldt Speakers bureau: Sanofi, BMS, Bayer, Boerhinger Ingelheim, Consultant of: Sanofi, BMS, Grant/research support from: Philips Volcano, Biotronik.

BackgroundImmune-mediated inflammatory arthritis (IMIA) is a group of diseases characterized by chronic synovitis including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Some disease modifying antirheumatic drugs (DMARDs) have demonstrated efficacy in several of these diseases (e.g. TNFα inhibitors) while others have not (e.g. IL-17A inhibitors in RA). Furthermore, within each disease there are patient subgroups experiencing different responses to the same drug, which underlines the need for further elucidation of pathogenic processes to guide personalized in IMIAs.ObjectivesHere we investigated if clinical features and synovial transcriptional signature could predict in vitro efficacy of specific DMARDs across different IMIAs.MethodsSynovial fluid mononuclear cells (SFMCs) from patients with SpA (n=13), RA (n=16), PsA (n=13), juvenile idiopathic arthritis (JIA) (n=7) or undifferentiated arthritis (n=5) were included. SFMCs from each patient were cultured for 48 hours (drugs listed in Table 1). Culture medium and DMSO were used as negative controls. In vitro drug response was assessed by measuring monocyte chemoattractant protein 1 (MCP-1) by ELISA. SFMC baseline gene expression of 270 genes related to inflammation was measured using the NanoString nCounter Human Inflammation V2 Panel. Drug responses (ΔMCP-1) were compared with clinical diagnosis, serostatus in RA patients, HLA-B27 status in SpA patients, DAS28-CRP score, years since diagnosis, failed modes of action and transcriptional signatures.Table 1.DrugTargetAdalimumabTNFαEtanerceptTNFαTocilizumabIL-6AnakinraIL-1βUstekinumabIL-12/23SecukinumabIL-17ATofacitinibJAK1/3BaricitinibJAK2/3ResultsDMARDs with a similar molecular target had comparable effects on ΔMCP-1. The TNFα inhibitors adalimumab and etanercept (r=0.86) had similar drug responses, and so had the JAK inhibitors tofacitinib and baricitinib (r=0,71). In contrast, drugs with different modes of action had diverse responses (Figure 1). High HLA-DRA gene expression associated with high responses to TNFα inhibitors (both p<0.05). JAK inhibitors reduced MCP-1 secretion significantly more in SFMCs from seropositive than seronegative RA patients (p<0.05). Drug response was greater in SFMCs from patients with low DAS28-CRP scores (DAS28-CRP <2.5) compared with patients with a high DAS28-CRP score (DAS28-CRP >5.2) for TNFα inhibitors, tocilizumab and JAK inhibitors (all p<0.05). Patients clustered with either an overall high or an overall low response to almost all DMARDs, or with a significant response to only one or a few of the DMARDs. Transcriptional signature of patient SFMCs primarily responding to TNFα inhibitors was different compared with the signature of patient SFMCs primarily responding to JAK inhibitors. Diagnosis, HLA-B27 status, failed modes of action and years since diagnosis did not affect ΔMCP-1 in this in vitro setup.Figure 1.Association between DMARD molecular target and in vitro response as measured by change in MCP-1 secretion.ConclusionSimilarities and differences in mode of action for 8 different DMARDs were captured in drug response as measured by MCP-1 change in SFMC cultures from 54 patients with inflammatory arthritis. We were able to identify interesting differences in gene expression when comparing cells responding to TNF inhibitors to cells responding to JAK inhibitors. Drug responses were only to a minor extent associated with clinical features.AcknowledgementsSincere thanks to Stinne Greisen, Malene Hvid, Maithri Aspari and Amalie Broksø for continuous guidance during the laboratory work.Disclosure of InterestsMads Brüner Kristensen: None declared, Ulvi Ahmadov: None declared, Morten Aagaard Nielsen: None declared, Lasse Sommer Kristensen: None declared, Tue Wenzel Kragstrup Shareholder of: Co-founder and clinical developer in iBio tech ApS., Speakers bureau: Speaking fees from Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, UCB, and Abbvie., Consultant of: Consultancy fees from Bristol-Myers Squibb and Gilead., Grant/research support from:. Research grants from Gilead.

BackgroundSingle cell sequencings studies have identified a CXCL14+ synovial fibroblast cluster in synovial tissue. This CXCL14+ cluster express CD34 and correlate to lower DAS28 and swollen joint count, while being similar between genders, age or sero status [1]. The biological role of CXCL14 in rheumatoid arthritis (RA) is unknown, but CXCL14+ synovial fibroblasts have been shown to express abundant GAS6, which regulate remission functions in MerTK+CD206+ synovial tissue macrophages [2]. This may suggest an anti-inflammatory or pro-remission role of the CXCL14+ synovial fibroblast cluster in specific RA pathotypes [1].ObjectivesOur study aimed to investigate soluble CXCL14 in plasma and synovial fluid and its potential connection to long term joint deterioration and disease activity in RA.MethodsWe used optimized commercial CXCL14 ELISA kits to investigate CXCL14 levels in 3 cohorts. 1) Plasma samples from patients with early RA (eRA) from the methotrexate arm of the CIMESTRA trial (N=80) [3]. 2) Plasma and synovial fluid from patients with established RA included at time of therapeutic arthrocentesis (the INART cohort) (N=41). 3) Plasma from matched healthy controls (HC) (N=44).ResultsPlasma CXCL14 was significantly higher compared to synovial fluid, median 2.3 ng/ml. CXCL14 levels in the two compartments corelate.Plasma and synovial fluid CXCL14 were not influenced by gender, ACPA, smoking status, disease duration or time since sampling. Age and rheumatoid factor status may affect plasma CXCL14 levels, but this was not consistent in both RA cohorts.Analysis showed a significant higher amount of plasma CXCL14 in patients with RA from the INART cohort, median 6.9 ng/ml, compared to eRA, median 4.8 ng/ml and HC, median 4.3 ng/ml.Plasma CXCL14 did not change significantly in patients with eRA after 1 year of treatment. Baseline plasma CXCL14 in patients with eRA significantly correlated to baseline tender joint count, but not DSA28, swollen joint count or total sharp score.Baseline plasma CXCL14 correlated to DAS28 after 5 years of treatment. Evaluating DAS28 after 11 years of treatment we observed a difference between patients in remission (DAS<2.6) and patients with active disease (DAS28 ≥ 2.6). For patients in remission, baseline CXCL14 correlated inversely with DAS28, whereas this correlation was positive in patients with active disease (Figure1).No associations were present between CXCL14 and change in total sharp score over a 11-year period.ConclusionSoluble CXCL14 can be measured in both plasma and synovial fluid from patients with RA. Plasma CXCL14 levels are higher compared to synovial fluid but a significant correlation is present between to two compartments. This suggests plasma CXCL14 as a potential proxy for CXCL14 activity in the joint and joint fluid. CXCL14 was not affected by gender, disease duration, smoking or 1 year of cDMARD treatment.Baseline CXCL14 correlated to higher DAS28 in the CIMESTRA cohort after 5 years and in patients with active disease after 11 years. Interestingly, we noticed that baseline CXCL14 may associate to lower DAS28 in patients in remission after 11 years. Together, this may support previous studies associating CXCL14 to an active anti-inflammatory (positive CXCL14/DAS28 correlation in active disease group) and pro-remission (negative CXCL14/DAS28 in remission group) role in RA.References[1]Micheroli, R., et al., Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis. RMD Open, 2022. 8(1).[2]Alivernini, S., et al., Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med, 2020. 26(8): p. 1295-1306.[3]Hetland, M.L., et al., Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum, 2006. 54(5): p. 1401-9.Figure 1.Acknowledgements:NIL.Disclosure of InterestsSøren Lomholt: None declared, Louisa Hunskjær: None declared, Stinne Ravn Greisen: None declared, Tue Wenzel Kragstrup Shareholder of: Co-founder and clinical developer in Aptol Pharma., Speakers bureau: Speaking fees from Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, UCB, and Abbvie., Consultant of: Consultancy fees from Bristol-Myers Squibb, UCB, Gilead, and Eli-Lilly., Grant/research support from: Research grants from Gilead.

<p>The newest footbridge in Liège, known as "La Belle Liégeoise", was opened on 2nd May 2016. Located upstream of the landscape window created by Guillemins esplanade, this bridge provides a connection for soft transport modes from the railway station across the Meuse to La Boverie park, maintaining clearance for navigation.</p><p>The main span over the Meuse is 163 metres for a total length of 294 metres. The 5.5 metre wide decking is positioned laterally to the supporting structure.</p><p>Bureau Greisch, in association with the landscape architect Corajoud, was responsible for the complete design mission for the bridge.</p><p>The aim of this article is to detail the whole process of the conception of the bridge, from first sketches to erection control.</p>

<p>The newest footbridge in Liège, known as "La Belle Liégeoise", was opened on 2nd May 2016. Located upstream of the landscape window created by Guillemins esplanade, this bridge provides a connection for soft transport modes from the railway station across the Meuse to La Boverie park, maintaining clearance for navigation.</p><p>The main span over the Meuse is 163 metres for a total length of 294 metres. The 5.5 metre wide decking is positioned laterally to the supporting structure.</p><p>Bureau Greisch, in association with the landscape architect Corajoud, was responsible for the complete design mission for the bridge.</p><p>The aim of this article is to detail the whole process of the conception of the bridge, from first sketches to erection control.</p>