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Evaluation of a novel screening strategy for rheumatoid arthritis (RA) and a primary prevention trial in RA

Applicant Finckh Axel
Number 120639
Funding scheme Project funding
Research institution Service de Rhumatologie Département de Médecine Interne Hôpital Cantonal Universitaire de Genève
Institution of higher education University of Geneva - GE
Main discipline Diseases of Bones and Joints
Start/End 01.11.2008 - 31.12.2013
Approved amount 243'000.00
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All Disciplines (2)

Discipline
Diseases of Bones and Joints
Clinical Immunology and Immunopathology

Keywords (3)

Epidemiology of Rheumatoid Arthritis; Primary Prevention; Autoimmunity

Lay Summary (French)

Lead
Lay summary
IntroductionLa polyarthrite rhumatoïde (PR) est une maladie d'origine immunologique qui affecte environ 1-2% de la population, avec d’importantes conséquences personnelles, sociales et économiques pour les individus atteints. Alors que cette pathologie était jusqu’à peu perçue comme une maladie inexorablement progressive, la PR est devenu récemment une maladie potentiellement curable avec l'utilisation très précoce de traitement antirhumatismaux de fonds. En effet, des études sur des phases très précoces de la maladie ont montré qu’il existait une opportunité de modifier de façon permanente l’évolution de la maladie à ce stade, voir même d’obtenir une guérison. Par conséquent, poser précocement le diagnostic de PR et identifier la PR pré-symptomatique est devenu un enjeu important.La physiopathologie de la PR débute avec une activation pathologique du système immunitaire adaptatif (ou début immunologique de la maladie); processus qui aboutit progressivement au début clinique de la maladie. Le début immunologique de la maladie est donc généralement asymptomatique (phase préclinique) et dure des mois ou des années avant que la maladie devienne cliniquement apparente. Pendant cette phase préclinique, des auto-anticorps spécifiques sont souvent déjà présents et une synovite (=inflammation du tissu peri-articulaire) peut déjà être démontrée sur des analyses histologiques d’articulations pourtant asymptomatiques. Des études sur de grandes cohortes de donneurs de sang ont ainsi démontré qu’on peut des patients à haut risque de développer une PR, plusieurs années avant que la maladie ne se déclare cliniquement. En résumé, des marqueurs biologiques de PR pré-symptomatique existent et suggèrent qu’une stratégie de dépistage pour des populations à risque est du domaine du possible.Hypothèses-La phase préclinique de la PR peut-être adéquatement identifiée par des facteurs de risque cliniques marqueurs et des biologiques.-Les parents de patients souffrant de PR, concernés par l'héritabilité potentielle de cette maladie, seront intéressés par un dépistage visant à détecter des individus à haut risque de développer eux-mêmes la maladie.Objectifs-Tester la capacité discriminante (sensibilité, spécificité) de différents marqueurs biologiques et cliniques pour dépister la PR dans la phase asymptomatique, préclinique.-Développer et évaluer une stratégie de dépistage de la PR chez des parents de patients avec PR.MéthodesNous assemblerons une cohorte des individus à risques accrus de développer une PR, à savoir des parents de premier-degré de patients avec une PR. Tous les participants seront évalués pour d’éventuels facteurs de risques et la présence de marqueurs de susceptibilité pour la PR. Les participants seront suivis annuellement pendant 3 à 5 ans ou jusqu'à ce qu'ils développent une PR.SignificationCette étude adresse une question clé pour une possible stratégie de prévention de la PR dans une population à risque, à savoir la fiabilité diagnostique des facteurs de risque cliniques et des marqueurs biologiques de susceptibilité de la PR.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Primary prevention of rheumatoid arthritis: A qualitative study in a high-risk population
Novotny Fiona, Haeny Sylvie, Hudelson Patricia M., Escher Monica, Finckh Axel S. (2013), Primary prevention of rheumatoid arthritis: A qualitative study in a high-risk population, in Joint Bone Spine, 80(6), 673-674.
Ultrasound Doppler Activity correlates with systemic autoimmunity and swollen joints in a healthy population at risk for RA
Brulhart Laure (2013), Ultrasound Doppler Activity correlates with systemic autoimmunity and swollen joints in a healthy population at risk for RA, in Ann Rheum Dis, 72(Suppl3), 392-392.
Barriers to Recruit Unaffected Family Members of Patients with Rheumatoid Arthritis.
Finckh A Debost-Legrand A et al. & F Cornélis for the European pre-RA consortium (EPRAC). (2012), Barriers to Recruit Unaffected Family Members of Patients with Rheumatoid Arthritis., in Arthritis & Rheum, 2012, Vol 64 (Suppl. 10), (N° 1573), Washington DC.
EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis (RA): Report from the Study Group for Risk Factors for RA.
Gerlag DM Raza K van Baarsen EG Brouwer E Buckley CD Burmester GR Gabay C Catrina A Cope A (2012), EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis (RA): Report from the Study Group for Risk Factors for RA., in Ann Rheum Dis, 71(5), 638-641.
Tooth Loss is associated with swollen joints in a cohort of healthy individuals at increased risk of developing RA.
A Finckh RB Müller B Möller J Dudler D Kyburz UA Walker I Von Muehlenen S Bas C Gabay P Zuf (2012), Tooth Loss is associated with swollen joints in a cohort of healthy individuals at increased risk of developing RA., in European Congress of Rheumatology EULAR 2012 , Berlin.
A novel screening strategy for preclinical rheumatoid arthritis (RA) in first degree relatives of patients with RA
Finckh A Müller RB Möller B Dudler J Kyburz D Walker UA Bas S Liang MH Gabay C (2011), A novel screening strategy for preclinical rheumatoid arthritis (RA) in first degree relatives of patients with RA, in Ann Rheum Dis 2011;70(Suppl3):282, London.
Factors Involved in the Decision to Take Medications to Prevent Rheumatoid Arthritis in First Degree Relatives of Patients with Rheumatoid Arthritis. A Discrete Choice Experiment.
Axel Finckh1 Monica Escher2 Matthew H. Liang3 and Nick Bansback (2011), Factors Involved in the Decision to Take Medications to Prevent Rheumatoid Arthritis in First Degree Relatives of Patients with Rheumatoid Arthritis. A Discrete Choice Experiment., in Arthritis & Rheum, 2011, Vol 63 (Suppl. 10), S807-8 (N° 2072), Chicago.
The long-term impact of early treatment of rheumatoid arthritis on radiographic progression: a population-based cohort study
Kyburz D, Gabay C, Michel BA, Finckh A (2011), The long-term impact of early treatment of rheumatoid arthritis on radiographic progression: a population-based cohort study, in RHEUMATOLOGY, 50(6), 1106-1110.
Early inflammatory arthritis versus rheumatoid arthritis.
Finckh Axel (2009), Early inflammatory arthritis versus rheumatoid arthritis., in Current opinion in rheumatology, 21(2), 118-23.
Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis.
Finckh Axel, Bansback Nick, Marra Carlo A, Anis Aslam H, Michaud Kaleb, Lubin Stanley, White Marc, Sizto Sonia, Liang Matthew H (2009), Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis., in Annals of internal medicine, 151(9), 612-21.

Collaboration

Group / person Country
Types of collaboration
Hôpital de St. Gall Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Hôpital Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Hôpital Universitaire de Zurich (USZ) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Hôpital Universitare de Bâle Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Université d’Evry, Val d’Essonne France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Université d'Auvergne France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
CHUV Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Harvard University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Colorado, Denver United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Inselspital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Journées romandes de Rhumatologie Talk given at a conference 07.11.2013 Changins, VD, Switzerland Finckh Axel;
EULAR workshop on the earliest forms of rheumatoid arthritis 2012 Talk given at a conference 08.06.2012 Berlin, Germany Finckh Axel;
1st Investigator meeting of EPRAC (European Pre-Rheumatoid Arthritis Consortium) Talk given at a conference 09.03.2012 Clermond Ferrand, France Finckh Axel;
2nd Investigator meeting for EPRAC Investigators (European Pre-Rheumatoid Arthritis Consortium) Talk given at a conference 28.02.2012 Université d'Evry, Paris, France, France Finckh Axel;
ACR annual scientific Congress Poster 29.10.2011 Chicago, United States of America Finckh Axel;
EULAR Annual Scientific Congress Talk given at a conference 25.05.2011 London, Great Britain and Northern Ireland Finckh Axel;
First International Workshop on Pre-clinical RA Talk given at a conference 25.01.2011 Amsterdam , Netherlands, Netherlands Finckh Axel;


Self-organised

Title Date Place
4th Joint Meeting for Clinical Research and Translational Research 04.11.2013 Fribourg, Switzerland
3rd Joint Meeting for Clinical Research and Translational Research 13.05.2013 Fribourg, Switzerland
2nd Joint Meeting for Clinical Research and Translational Research 10.09.2012 Fribourg, Switzerland
1st Joint Meeting for Clinical Research and Translational Research 03.04.2012 Fribourg, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Colloque de Formation continue des Rhumatologues Genevois 19.05.2011 Genève, Hôpital Cantonal, Switzerland Finckh Axel;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media La polyarthrite rhumatoïde: une maladie évitable? Sun Store Préférence 126, hiver 2014 German-speaking Switzerland Western Switzerland 2014
Talks/events/exhibitions Journée de la Polyarthrite Western Switzerland 2012
Media relations: print media, online media Polyarthrite Rhumatoïde: Le diagnostic précoce est essentiel Tribune Médicale public, 2/2012 German-speaking Switzerland Western Switzerland 2012
Media relations: print media, online media Studie zur Früherkennung der Rheumatoiden Arthritis (RA) Rheumaliga Schweiz News Western Switzerland Italian-speaking Switzerland German-speaking Switzerland 2012
Media relations: print media, online media Umweltbedingte Risikofaktoren für die Erkrankung an Rheumatoider Arthritis Polyarthritiker Zeitschrift German-speaking Switzerland Western Switzerland 2012
Talks/events/exhibitions Dépistage de la polyarthrite chez les membres de famille Western Switzerland 2010

Associated projects

Number Title Start Funding scheme
192471 Digestive Microbiome in the development of rheumatoid arthritis 01.05.2020 Project funding

Abstract

INTRODUCTION:Rheumatoid arthritis (RA) is a disease of immunological origin, which occurs in ~1% of the population and has a high personal and societal toll and major economic impact. Once viewed as an inexorably progressive disease, RA has become a potentially curable disease with very early use of disease-modifying antirheumatic therapy. Therefore, diagnosing RA early and identifying pre-clinical RA as accurately as possible has become a high-stakes undertaking.The contemporary view of its pathophysiology is a process that starts with a pathologic activation of the adaptive immune system (or ‘immune onset of the disease’), followed by an asymptomatic period (or preclinical phase), which eventually leads to the ‘clinical onset of the disease’. During the preclinical phase of RA, auto-antibodies are often already present and synovitis can be demonstrated on histology in clinically uninflamed joints. Biomarkers and clinical risk factors of pre-symptomatic disease exist and suggest that screening at risk populations for early detection of RA and treatment are not out of the realm of the possible.HYPOTHESES:- Pre-clinical RA can be accurately identified by biologic markers and clinical risk factors.- First-degree relatives of patients with RA, concerned by the potential heritability of this disease, will participate in a screening procedure aimed at detecting individuals with pre-clinical disease and at high risk of developing active RA.- RA can be prevented at the pre-clinical stage by an early therapeutic intervention in a certain number of subjects.SPECIFIC AIMS:- Aim 1: Develop and evaluate a screening strategy for the development of RA in first degree relatives of patients with RA.- Aim 2: Establish the proof of concept of primary prevention of RA in first degree relatives.- Aim 3: Test the efficacy of a limited antirheumatic therapy to prevent the development of RA.METHODS:Screening study (Aim 1): We will assemble a cohort of individuals at increased risk of RA, namely first-degree relatives of patients with RA. Participants will have risk factors for RA determined and be tested for biomarkers of RA susceptibility and followed prospectively until they develop RA.Primary prevention trial (Aim 2 & 3): We will establish proof-of-concept for a primary prevention trial in individuals at very high risk of developing RA and determine the efficacy of a therapeutic intervention on the development of RA.SIGNIFICANCE:This study addresses two major questions in the prevention of RA in high risk populations: The screening study will establish the diagnostic accuracy of clinical risk factors and biomarkers of RA susceptibility in family members of RA patients. The nested trial will establish feasibility and the efficacy of a preventive intervention in high risk individuals. Ultimately this proposal will test whether early detection and treatment of pre-clinical RA can prevent RA, in an analogousfashion to our controlling hypertension and high cholesterol to reduce the risk of cardiovascular disease.
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