Lysophosphatidic Acid / Autotaxin Axis in Rheumatoid Lung Disease

Study Overview
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Brief Summary
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Rheumatoid arthritis (RA) is a common chronic systemic autoimmune relapsing disease characterized by joint inflammation. Beside arthritis leading to progressive joint damage and loss of function, RA is also associated to extraarticular inflammatory conditions such as interstitial lung disease (ILD). This one develops in 30% of all RA patients with a median survival expectancy of 3 to 10 years once symptomatic. Unfortunately, there is no medical care recommendation so far as the pathophysiology is unknown. However, ILD share many similarities with idiopathic pulmonary fibrosis (IPF). Autotaxin (ATX), due to its lysophospholipase activity, produces a bioactive lipid, lysophosphatidic acid (LPA) under inflammation. LPA has pleiotropic actions inducing cell proliferation, survival, motility and differentiation. Increased ATX and LPA levels have been detected in synovial fluid of RA patients and in IPF patients. ATX is also currently the target for a phase 3 clinical trial in IPF. Given the previous described role of ATX/LPA axis in arthritis and inflammation-induced bone loss in RA and the similarities between RA-ILD and IPF, the investigators hypothesized that ATX/LPA axis may be also an attractive drug target for this pulmonary condition in RA and therefore that ATX and LPA may be increased in sputum from RA patients with ILD in comparison with sputum from RA patients without ILD.

Official Title
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Role of Lysophosphatidic Acid and Autotaxin in Rheumatoid Arthritis-associated Interstitial Lung Disease

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Other: Quantitative ATX and LPA determination in plasma and sputum


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General inclusion criteria Subject aged ≥ 18 and ≤ 70 years Patient with RA with ACPA in the state phase, meeting ACR / EULAR 2010 criteria For female subjects: Likely to procreate: negative pregnancy test at the inclusion visit and use of an effective method of contraception (hormonal contraceptives, intrauterine devices, vasectomized partner, abstinence) started at least 1 month before inclusion and continued during the entire study. Inability to procreate: menopause (absence of a rule for at least 1 year) or hysterectomy or bilateral oophorectomy or tubal ligation. Subject having given written consent to participate in the study Subject affiliated to the Social Security scheme or benefiting from an equivalent scheme Additional inclusion criteria for cases (RA patients with PID): - PID is defined as damage compatible with the thoracic scanner in thin sections according to international criteria with or without associated clinical signs. Additional inclusion criteria for control patients (RA patients without symptomatology without PID) - No functional lung complaints Exclusion Criteria: General exclusion criteria Vulnerable patient within the meaning of current French legislation (deprived of liberty by judicial or administrative decision, under guardianship or curatorship or under the protection of justice) Patient not fluent in French Woman breastfeeding or planning a pregnancy for the duration of the study Patient in exclusion period after participating in another clinical trial or in the process of participating in another clinical trial involving an experimental product Patient with occupational exposure to particles known to be responsible for PID (silica, etc.) Patient with an autoimmune disease other than RA or an auto-inflammatory disease Non-inclusion criteria for cases (RA patients with PID): - Patient with a history of asthma, COPD or any other pulmonary pathology or pulmonary symptom unrelated to PID Non-inclusion criteria for control patients (RA patients without PID) - Patient with a history of asthma, COPD, any other pulmonary pathology, any pulmonary symptom or any pulmonary CT abnormality.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Controls<br>Patients with RA and without ILD | Other: Quantitative ATX and LPA determination in plasma and sputum<br>* Determination of ATX and LPA levels in plasma and sputum from RA-ILD patients (cases) and in plasma and sputum from RA patients without ILD (controls) after sputum induction using hypertonic saline inhalation<br>|
| Other: Cases<br>Patients with RA and ILD | Other: Quantitative ATX and LPA determination in plasma and sputum<br>* Determination of ATX and LPA levels in plasma and sputum from RA-ILD patients (cases) and in plasma and sputum from RA patients without ILD (controls) after sputum induction using hypertonic saline inhalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ATX and LPA levels in sputum from RA patients with ILD in comparison with sputum from RA patients without ILD | All the samples will be frozen and ATX and LPA levels will be assessed in the plasma and sputum at the same time, at the end of the recruitment. | Month 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between ATX and LPA levels and severity of RA-ILD estimated by tomodensitometry | Determine the correlation between ATX and LPA levels and the severity of CT scan pulmonary involvement*. *Diffuse interstitial lung disease is defined as an attack compatible with the thoracic scanner in thin sections according to international criteria with or without associated clinical signs. | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, Interstitial lung disease, Autotaxin, Lysophosphatidic acid