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Trial record 1 of 1 for:    METYLAS
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Analysis of DNA Methylation in Spondyloarthritis (METYLAS)

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ClinicalTrials.gov Identifier: NCT03092583
Recruitment Status : Recruiting
First Posted : March 28, 2017
Last Update Posted : November 20, 2019
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Besancon

Brief Summary:
The aim of this project is to quantify global DNA methylation in patients with Ankylosing Spondylitis or Axial Spondyloarthritis as compared with control subjects.

Condition or disease Intervention/treatment Phase
Spondylitis, Ankylosing Axial Spondyloarthritis DNA Methylation Other: Blood sample Not Applicable

Detailed Description:

Spondyloarthritis covers a group of diseases with common clinical, genetic and radiographic characteristics. Ankylosing spondylitis (AS) is the most common of these, and is usually diagnosed in the presence of bilateral sacroiliitis by conventional x-ray, according to the modified New York criteria. Axial spondyloarthritis (Ax-SpA) mainly affects the axial skeleton and progresses towards the formation of bone or bony structures around the sacro-iliac joint and spine, leading to the gradual formation of a bony bridge from the sacro-iliac joint and ligamentous ossifications to the spine. Early forms of the disease do not present such modifications to the sacro-iliac joint and therefore, show no visible sacroiliitis on conventional x-ray. Thus, it is possible to classify a patient aged <45 years with inflammatory lower back pain as having Ax-SpA, irrespective of the presence of sacroiliitis by x-ray. Indeed, inflammation of the sacro-iliac joint and spine occurs before the process of ossification and inflammation, and can be detected by MRI. This led the Assessment of SpondyloArthritis international Society (ASAS) group to propose candidate classification criteria for Ax-SpA, notably adapted to early forms of the disease. Accordingly, patients with Ax-SpA without radiographic sacroiliitis are considered to have non-radiographic Ax-SpA. Classification criteria for peripheral SpA are also available.

The determinants of AS and SpA are complex, and involve both genetic and environmental factors. In addition to these factors, several studies in recent years have also highlighted the emerging role of epigenetics in the pathophysiology of inflammatory diseases.

The term epigenetics refers to heritable and reversible modifications in gene expression without any change in the coding DNA sequence. This process may be involved in the pathophysiology of different diseases and their clinical expression. Several different epigenetic mechanisms may concur to modify gene functioning. Changes to the chromatin and to DNA (without modification of the encoding sequence itself) have been shown to be important for the control of gene expression through suppressive or permissive factors. Thus, DNA methylation could play a role in auto-immune or inflammatory diseases by regulating gene expression, particularly those coding for pro-inflammatory mediators such as certain cytokines, thereby contributing to dysregulation of the immune system.

DNA methylation is regulated by the activity of DNA methyltransferase enzymes (DNMT). In multicellular eukaryotic organisms, DNA methylation is associated with chromatin repression, and thereby, inhibition of gene expression. DNA methylation can be evaluated across the whole genome, but also at the level of a specific candidate gene, such as the gene encoding a pro-inflammatory cytokine.

The level of DNA methylation has been evaluated in rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE), and a "methylated-DNA" signature has been observed in these auto-immune diseases. Currently, there is no available data regarding DNA methylation in AS or SpA in general. In this study, the investigators aim to analyse the global DNA methylation in patients with AS or Ax-SpA.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Analysis of DNA Methylation in Spondyloarthritis
Actual Study Start Date : February 15, 2017
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Patient group
Subjects must meet the modified New York criteria for AS, or the ASAS criteria for Ax-SpA, and must be naïve of biologic therapy (anti-TNF-α agents) at the time of inclusion, or have received but subsequently discontinued anti-TNF-α therapy at least 3 months before inclusion. A blood sample will be drawn (35 mL) to these patients.
Other: Blood sample
35 mL, 7 tubes

Control group
Subjects must be free from any inflammatory or auto-immune disease. A blood sample will be drawn (35 mL) to these controls subjects.
Other: Blood sample
35 mL, 7 tubes




Primary Outcome Measures :
  1. Overall level of DNA methylation [ Time Frame: D0 (day of inclusion) ]
    The level of methylation will be evaluated using the global quantification technique for DNA


Secondary Outcome Measures :
  1. Expression of DNMT1 and MBD2 [ Time Frame: D0 (day of inclusion) ]
    Expression of DNMT1 and MBD2 will be quantified on RNA extracted from monocytes and CD4 T cells, by quantitative real-time polymerase chain reaction

  2. Methylation of the promoter region of TNF [ Time Frame: D0 (day of inclusion) ]
    Methylation of the promoter region of TNF will be evaluated on DNA from monocytes and CD4 T cells (bisulfite genomic sequencing)

  3. Serum TNF-α [ Time Frame: D0 (day of inclusion) ]
    Serum TNF-α will be quantified by ELISA.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Subjects included in the Patient group must meet the modified New York criteria for AS, or the ASAS criteria for Ax-SpA, and must be naïve of biologic therapy (anti-TNF-α agents) at the time of inclusion, or have received but subsequently discontinued anti-TNF-α therapy at least 3 months before inclusion.

Subjects included in the Control group must be free from any inflammatory or auto-immune disease. Subjects being followed for spinal disc disease (herniated disc) or abarticular mechanical disease (tendonitis) will be eligible, as well as healthy subjects.

The following inclusion criteria are common to both control and patient groups:

  • Adult patients (≥18 years).
  • Provide written informed consent indicating that the subject has understood the aims of the study, as well as the procedures involved, and that he/she accepts to participate and adhere to the demands and restrictions imposed by the study participation.
  • All subjects must have social security coverage.
  • Maximum age is 80 years.

Exclusion Criteria:

  • Subjects being treated by systemic corticosteroids with a prednisone equivalent dose >10 mg/day.
  • Subjects with limited legal capacity.
  • Subjects judged by the investigator to be unlikely to comply with study procedures
  • Subjects with no social security coverage.
  • Pregnant women.
  • Subjects still in the exclusion period of another study, or according to the national registry of clinical trial participants.
  • Inability to understand the study objectives; psychiatric disorders deemed by the investigator to be incompatible with inclusion in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03092583


Contacts
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Contact: Eric Toussirot, Professor 0381218396 etoussirot@chu-besancon.fr

Locations
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France
University Hospital Recruiting
Besançon, France, 25000
Sponsors and Collaborators
Centre Hospitalier Universitaire de Besancon
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Responsible Party: Centre Hospitalier Universitaire de Besancon
ClinicalTrials.gov Identifier: NCT03092583    
Other Study ID Numbers: P/2015/252
First Posted: March 28, 2017    Key Record Dates
Last Update Posted: November 20, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Spondylitis
Spondylarthritis
Spondylitis, Ankylosing
Bone Diseases, Infectious
Infection
Bone Diseases
Musculoskeletal Diseases
Spinal Diseases
Arthritis
Joint Diseases
Spondylarthropathies
Ankylosis