Molecular Reclassification to Find Clinically Useful Biomarkers for Systemic Autoimmune Diseases: Inception Cohort (PRECISESADSI)

Connective tissue diseases (CTD) or systemic autoimmune diseases (SADs) as they are known today are a group of chronic inflammatory conditions with autoimmune aetiology with few treatment options and difficult diagnosis.Brest team contribute to performe a new classification of the following systemic autoimmune diseases in a European Union's Seventh Framework Programme. The aim of this research consiteis to reclassify the individuals affected by SADs into molecular clusters instead of clinical entities through the determination of molecular profiles using several "Omics" techniques.

Study Overview

• Status: Completed
• Conditions: Systemic Autoimmune Diseases

Detailed Description

The overall objective of the PRECISESADS IMI project is to reclassify the individuals affected by SADs into clusters of molecular, instead of clinical entities through the determination of molecular profiles using several "-omics" techniques.

The identification of the clusters relies on a cross sectional (CS) cohort/protocol where 2666 individuals (2000 patients and 666 controls) including a sub-study of 288 deeply characterized individuals (240 patients and 48 controls) are to be recruited.

In parallel a longitudinal inception cohort/protocol will be started in order to further explore the clinical relevance of the identified clusters and their evolution over time.

The objectives of the CS study and sub-study are:

1. To identify a systemic taxonomy for patients with SADs by producing the following data in individuals with SADs and controls: genetic, epigenomic, transcriptomic, flow cytometric (from peripheral blood mononuclear cells (PBMCs)), metabolomics and proteomic in plasma and urine, exosome analysis, classical serology (antibodies and autoantibodies), and clinical data.
2. To better characterize individual SADs at the omics level.
3. To perform clustering analyses to determine the groups of individuals who, differentially from other groups, share specific molecular features (precision medicine).
4. A deeper analysis will be done in a substudy of 288 individuals.

The clustering process will be data-driven with the aim to find the most homogenous and differentiated clusters of diseases that clearly separate differentiate individuals from controls and other patient clusters.

Aims of the Inception cohort:

Specifically, this inception cohort aims at:

1. assign individuals newly diagnosed with an systemic autoimmune disease (SAD) to any of the reclassification clusters discovered in the CS study,
2. to study the development and modifications of OMICS signatures/clusters occurring in each individual patient in the course of the disease, including the impact of treatment on their individual pattern, and
3. to perform deep (thorough) OMICs studies to compare their patterns of OMICS as a group, with the patterns obtained in the CS cohort.

The inception cohort will have patient follow up and sample collection at baseline, month 6(±1 month) and month 18 (±1 month).

As the newly diagnosed patients we plan to recruit will have minimum or no treatment, we will identify differences and similitudes to patients from the cross-sectional study that have undergone long-term treatment.

• Study Type: Observational
• Enrollment (Actual): 215

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Université catholique de Louvain - Cliniques Universitaires Saint-Luc (UCL)
  • Leuven, Belgium
    • UZ Leuven - KU Leuven, Department of Rheumatology (KU LEUVEN)
• France
  • Brest, France, 29609
    • CHRU de Brest
• Germany
  • Berlin, Germany
    • Deutsches Rheuma-Forschungszentrum Berlin (DRFZ)
• Italy
  • Milan, Italy
    • Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico (IRCCS)
• Spain
  • Barcelona, Spain
    • Hospital Clinic I Provicia- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
  • Cordoba, Spain
    • Hospital Universitario Reina Sofía Andaluz de Salud
  • Granada, Spain
    • Hospital Universitario San Cecilio Servicio Andaluz de Salud
  • Granada, Spain
    • Hospital Virgen de las Nieves Granada
• Switzerland
  • Geneve, Switzerland
    • Hospitaux Universitaires de Géneve (UNIGE)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patient with systemic autoimmune diseases

Description

Inclusion Criteria:

• · Aged 18 years or older at the time of consent

  • Diagnosed according to prevailing criteria for one of the following systemic autoimmune diseases (see Annex 2)

    • Rheumatoid arthritis (RA)
    • Scleroderma or systemic sclerosis (SSc)
    • Primary Sjögren's syndrome (SjS)
    • Systemic lupus erythematosus (SLE)
    • Primary antiphospholipid syndrome (PAPS)
    • Mixed Connective Tissue Disease (MCTD)
    • Patients with undifferentiated connective tissue disease (UCTD) for over 1 year and that do not fulfill the diagnosis of any of the above diseases.
  • Signed the informed consent form

Exclusion Criteria:

• · Patients unable to understand the procedures related to the protocol should not be included. The study is voluntary and patients must be able to give their informed consent.

  • Pregnant women
  • Neonatal lupus
  • Drug-induced lupus
  • Patients whose condition is so serious that they cannot take part in the study
  • Severe nephrotic syndrome with proteinuria >=3,5 g/day
  • Patients with stable doses of steroids >15mg/day for the last 3 months or with IV corticosteroids in the last 3 months

  • Patients under immunosuppressants for the last 3 months prior to recruitment with:

    • Methotrexate ≥25mg/week
    • Azathioprine ≥2.5mg/kg/day
    • Cyclosporine A > 3mg/kg/day
    • Mycophenolate Mofetil > 2gr/day
  • Treatment with cyclophosphamide (any dose or route of administration) or Belimumab in the past 6 months
  • Patients with combined therapy of two or more immunosuppressants
  • Patients on depletative therapy such as Rituximab in the last year
  • Patients receiving experimental
  • Overlap syndromes

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gene expression in total blood	Gene expression will be done using commercial gene expression microarrays in total blood from all samples using the RNA Paxgene tube.	2 years
Flow cytometry analysis to determine cell proportions in the total blood mixture in all individuals.	9 optimized panels of antibodies will be used to determine cell subpopulations in peripheral blood (including very minor cell populations).	24 hours
Genotyping	Genotyping will be done using a whole genome array.	2 years
Metabolite determination	Metabolite determination in plasma and urine using Nuclear Magnetic Resonance	2 years
Exosome isolation from plasma and urine	set up of the methodology for isolating exosomes in these bodily fluids for gene expression analysis	2 years
Cytokine profile determination	88 different cytokines will be assessed with Luminex	2 years
routine autoantibodies in serum	set of serum autoantibodies will be determined in a European validated laboratory. Also, they will perform detection of antibodies against small lipid moieties i.e.antiphosphorylcholine),lupus anticoagulant and complement proteins in plasma.	2 years
Gene methylation in total blood	Methylation analysis will be done using the methylome 450k array using the DNA obtained from total blood. MicroRNA gene expression arrays using total blood.	2 years

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza Progreso y Salud
• Collaborators: Karolinska Institutet; Eli Lilly and Company; Medical University of Vienna; Sanofi; Bayer; Charite University, Berlin, Germany; Hannover Medical School; KU Leuven; Institut d'Investigació Biomèdica de Bellvitge; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; University Hospital, Brest; Université Catholique de Louvain; Andaluz Health Service; UCB Biopharma S.P.R.L.; Universidad de Granada; Institut de Recherches Internationales Servier; Szeged University; National Research Council, Spain; University of Milan; University of Geneva, Switzerland; Innovative Medicines Initiative; Centro Hospitalar do Porto; Servicio Cántabro de Salud; Atrys Health; August Pi Sunyer Biomedical Research Institute; Klinikum der Universität Köln; Quartz Bio S.A.; The Cyprus Foundation for Muscular Dystrophy Research

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: August 22, 2016
• First Submitted That Met QC Criteria: August 31, 2016
• First Posted (Estimate): September 7, 2016

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: October 14, 2021
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: SADs; Molecular Reclassification
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases
• Other Study ID Numbers: PRECISESADS INCP (RB 15.007)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided