Alloimmune Response to Citrullinated Shared Epitope Sequence in Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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Rheumatoid arthritis (RA) is an autoimmune and sistemic disease,characterized by joint sinovitis and the production of autoantibodies (Ab). The Ab against citrullinated peptides (ACPA) are the most specific (92-98%), and high sensitivity (75-81%) and they are of prognostic value. ACPA are already in the beginning of the disease in most cases, having been found years before its onset. Recent studies have suggested that ACPA may have a role in perpetuating inflammation, in the generation of bone erosions and in pain in RA. Citrullination is a post-translational modification mediated by the PAD, which transforms an arginine into a citrulline. In vivo, this enzyme acts in proinflammatory environments. Despite being widely studied, none of the natural citrullinated substrates have been shown to be the triggering and/or perpetuating factor in the response of B cells in RA, understanding this response as the production of ACPA. In fact, the most specific and sensitive commercial test for the detection of ACPA uses synthetic peptides protected by a patent. In the other hand, the genetic factor that most increases susceptibility to develop RA is a shared sequence of aminoacids (QKRAA, QRRAA i RRRAA), in the HLA-DRB1 gene, known as the shared epitope (SE). Also, SE, confers prognostic value, and is associated with the presence of ACPA. These SE sequences contain arginines (R), which are susceptible to be citrullinated by the PAD enzyme. We propose the hypothesis that citrullinated SE act as an antigen capable of activating the inflammatory response mediated by B and T cells in RA. The recognition of an HLA as a foreign one, would originate an answer of alloimmune type, not valued to date. The objective of the study is to test the immune response mediated by B cells and T cells, in cases and control samples, through an in vitro model that confronts them with peptides containing the citrullinated-SE sequence. In addition, we will evaluate the association between these results with the clinical features of cases (RA included in the study). Their role as a biomarker, as well as their potential to improve the tests currently available to detect ACPA will be explored.

Official Title
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Alloimmune Model in Rheumatoid Arthritis. Alloimmune Response to Citrullinated Shared Epitope Sequence in Patients With Rheumatoid Arthritis.Alloimmune Response to Citrullinated Shared Epitope Sequence in Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Diagnostic Test: Research new biomarker for RA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with RA who meet 1987 ACR criteria Patients with arthritis no RA Exclusion Criteria: Having an intellectual disability that allows understanding the informed consent to participate in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Rheumatoid arthritis<br>Patients who meet the criteria of the 1987 ACR | Diagnostic Test: Research new biomarker for RA<br>* Analyze T and B cell response against new citrullinated peptides<br>|
| Arthritis not Rheumatoid arthritis<br>Patients with psoriatic arthritis, peripheric spondyloarthropathies and connective tissue diseases. | Diagnostic Test: Research new biomarker for RA<br>* Analyze T and B cell response against new citrullinated peptides<br>|
| Healthy controls<br>From health blood donors | Diagnostic Test: Research new biomarker for RA<br>* Analyze T and B cell response against new citrullinated peptides<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T cell response | Proliferation against new citrullinated peptides | 2 years | 
| B cell response | Detection antibodies against new citrullinated peptides | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HLA-DRB1 | Typing HLA-DRB1 | 2 years | 
| Rheumatic factor | Turbidimetric assay | 2 years | 
| Anti-Citrullinated Peptides Antibodies | ELISA assay | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Shared epitope, HLA-DRB1, Citrullinated peptides, Autoantibodies