National Cohort of Subjects At Risk of Developing Rheumatoid Arthritis

PROMESS 1 is a multicenter cohort interventional study aiming at analyzing the factors associated with the risk of developing clinical arthritis among exposures or combinations of exposures in patients at risk of rheumatoid arthritis (RA), as they have high levels of anti-citrullinated peptides autoantibodies (ACPA ≥2 N).

The primary endpoint is the occurrence of clinical arthritis confirmed by ultrasound at two years of following for the subject's groups at risk of RA.

This may be explained by the following exposures or combinations of exposures: smoking, occupational exposure, physical activity, diet, hormonal exposure, drug exposure, trauma and psychological stress.

Other factors may also explain the occurrence of clinical arthritis:

* Other symptoms
* Comorbidities, medical history, drug exposures
* Current biology: ACPA levels, rheumatoid factor levels and isotypes, CRP levels at baseline, etc.
* Ultrasound and MRI abnormalities.

This is a multicenter interventional cohort study. The goal of this cohort is to analyze the factors associated with the risk of developing clinical arthritis, considering individual or combined exposures, in patients at high risk of rheumatoid arthritis (RA).

Four groups of adults will be included:

* Group 1: 50 subjects at very high risk of RA: ACPA≥2 N or (ACPA\>N and rheumatoid factor≥2 N) + presence of clinically suspicious arthralgia (CSA criteria ≥4)
* Group 2: 50 subjects at high risk of RA: ACPA≥2 N or (ACPA\>N and rheumatoid factor≥2 N) without clinically suspicious arthralgia (CSA criteria \<4)
* Group 3: 25 asymptomatic subjects, 1st degree relatives of subjects with RA (negative controls)
* Group 4: 25 patients with early RA prior to any disease-modifying therapy (positive controls) Patients in the control groups will be included based on the same age and sex as patients in the risk groups (1 \& 2) in the recruiting center.

The primary endpoint is the occurrence of clinical arthritis, confirmed by ultrasound, after two years of follow-up in the at-risk RA groups (Groups 1 \& 2).

This may be explained by the following exposures or their combinations: smoking, occupational exposure, physical activity, diet, hormonal exposure, drug exposure, trauma and psychological stress...

Other factors that may contribute to the occurrence of clinical arthritis include:

* Clinical elements and questionnaires assessing the other symptoms of the individuals (PRO) (subjective clinical suspicion of arthralgia CSA, painful joints at inclusion, BMI, stool consistency, functional respiratory signs, etc.)
* Comorbidities and antecedents via CNAM pathology mapping and drug exposure via data on dispensing in towns from the SNDS
* Current biology: ACPA levels, rheumatoid factor levels and isotypes, CRP levels at baseline, etc.
* Ultrasound and MRI abnormalities.

The controls groups (groups 3\&4) will allow for a cross-sectional analysis, comparing at-risk RA subjects with healthy individuals who share the same genetic background. They will have a single visit at baseline without follow-up.

However, the at-risk RA groups (groups 1 \& 2) will have four visits (M0, M6, M12 et M24). In addition to routine care examinations performed in RA risk situations, subjects will undergo blood and stool sample collection at baseline and at one year.

All subjects regardless of group, will undergo the following baseline assessments: MRI of the dominant hand or painful hand, a lactulose absorption test (to assess intestinal permeability), hair and saliva collection, a Schirmer test, and, in some centers, an induced sputum test (to assess pulmonary mucosa). Ultrasound of the hands and feet, as well as specific questionnaires assessing the exposome, will be conducted at all visits.

Eligibility Criteria:
Inclusion Criteria:

* Age between 18 and 80 years old
* Group 1: Individuals with high risk of RA (ACPA ≥ 2N or ACPA ≥ N and rheumatoid factor ≥ 2N) and clinical signs of arthralgia (CSA criteria ≥ 4).
* Group 2: High-risk individuals (ACPA ≥ 2N or ACPA ≥ N and rheumatoid factor ≥ 2N) without clinical arthralgia (CSA criteria \< 4).
* Group 3: First-degree relatives of RA patients (no symptoms, negative controls).
* Group 4: Newly diagnosed untreated RA patients (ACPA ≥ 2N or ACPA ≥ N and rheumatoid factor ≥ 2N) (positive controls).

Exclusion Criteria:

* Groupe1-2-3:

  • Presence of clinical joint swelling (synovitis) at the time of inclusion and previously noted by a doctor
* All groups:

  * Taking current or past background treatment for RA, even for another indication
  * Corticosteroid therapy ≥10 mg at baseline and in the previous week
  * Presence of another connective tissue disease (Sjögren's, dermatomyositis, scleroderma, Sharp syndrome, etc.)
  * Subject unable to read and/or write
  * Inability to follow the patient during the study period
  * Failure to obtain consent
  * Non-affiliation to a social security scheme,
  * Persons placed under legal protection, under curatorship or under guardianship
  * Pregnant or breastfeeding women
  * Person participating in another intervention research including an
  * exclusion period still in progress