Biomarkers in Rheumatoid Arthritis Treated With Anti-interleukin-6 Therapy

Study Overview
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Brief Summary
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The use of anti-interleukin (IL)-6 therapy, including tocilizumab, in rheumatoid arthritis or giant cell arteritis, led to the improvement or even control of disease in some patients for whom no further therapeutic options were available. Nevertheless, the evaluation of the efficacy of these treatments are negatively impacted by the lack of reliable biomarkers. Indeed, usual inflammatory biomarkers used during the follow-up of these patients to detect persistent disease activity or intercurrent infection, such as C-reactive protein, fibrinogen and procalcitonin, are dependant on IL-6. Thse usual biomarkers cannot therefore be reliably used during anti-IL-6 therapy. Some other experimental biomarkers are totally or partially independent of IL-6, or even of inflammasome, and thus are credible candidates for the follow-up of patients treated with anti-IL-6 therapy. Here investigators propose a controlled, prospective, monocentric, observational study evaluating several biomarkers, usual and experimental, in patients suffering from rheumatoid arthritis treated with anti-IL-6 therapy. This study will include 25 patients suffering from rheumatoid arthritis requiring an anti-IL-6 therapy and 25 healthy controls. In patients suffering from rheumatoid arthritis, usual and experimental biomarkers will be assessed at D0, D15, W24 and W52 from the introduction of anti-IL-6 therapy, or during an intercurrent infection. Investigators thus hypothesized that experimental biomarker levels will still be increased at D15, contrary to usual biomarkers dependant on IL-6 which will be normal whereas rheumatoid arthritis is still active based on usual radiological and clinical criteria, and that all biomarkers will be normal a W24.

Official Title
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Biomarkers in Patients Suffering From Rheumatoid Arthritis Treated With Anti-interleukin-6 Therapy: a Prospective Monocentric Controlled Study

Conditions
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Rheumatoid Arthritis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for patients: Adult patients suffering from rheumatoid arthritis diagnosed according to American College of Rheumatology/European League Against Rheumatism 2010 criteria and requiring an anti-IL-6 therapy by intravenous or subcutaneous injection Non-opposition of the patient Inclusion Criteria for healthy controls: Adult patients not suffering from acute or chronic inflammatory disease at inclusion (normal C-reactive protein and fibrinogen levels) Non-opposition of the subject Exclusion Criteria for patients: Patient is already treated with anti-IL-6 therapy Pregnancy or breastfeeding women Person under judicial protection, guardianship Patient suffering from another chronic inflammatory disease Patient suffering from another acute inflammatory disease at inclusion Person not beneficiaries of the social security system Exclusion Criteria for healthy controls: Pregnancy or breastfeeding women Person under judicial protection, guardianship Patient suffering from acute or chronic inflammatory disease at inclusion Previous history of chronic inflammatory disease Ongoing anti-inflammatory or immunosuppressive treatment, except aspirin and derivatives at anti-platelet aggregation dose, non-steroidal anti-inflammatory drugs stopped for 10 days or systemic steroids stopped for 1 month Person not beneficiaries of the social security system

Ages Eligible for Study
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Minimum Age: 18 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 patients<br>Adult patients suffering from rheumatoid arthritis, diagnosed according to American College of Rheumatology/European League Against Rheumatism 2010 criteria and requiring a anti-IL-6 treatment | |
| Healthy controls<br>Healthy controls not suffering from acute or chronic inflammatory disease at inclusion. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of usual biomarkers (C-reactive protein, fibrinogen, procalcitonin, serum protein electrophoresis) | C-reactive protein and fibrinogen measured by turbidimetry; procalcitonin by an enzyme immunoassay kit, serum protein electrophoresis by electrophoresis | Day 15 | 
| Levels of experimental biomarkers (IL-8, IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-10, IL-12/23, IL-17, IL-18, IL-21, IFN-gamma, TNF-alpha, TGF-beta, S100 proteins, ceruloplasmin, C3, C4, CH50, serum amyloid A, factor VIII, neutrophil/lymphocyte ratio) | IL-8, IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-10, IL-12/23, IL-17, IL-18, IL-21, IFN-gamma, TNF-alpha, TGF-beta and S100 proteins measured by Meso Scale Discovery assay, ceruloplasmin, C3, C4, serum amyloid A by nephelometry, CH50 by an enzyme immunoassay kit, factor VIII by turbidimetry, neutrophil/lymphocyte ratio by an automated method | Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of usual biomarkers (C-reactive protein, fibrinogen, procalcitonin, serum protein electrophoresis) | C-reactive protein and fibrinogen measured by turbidimetry; procalcitonin by an enzyme immunoassay kit, serum protein electrophoresis by electrophoresis | Day 15 compared to Day 0 | 
| Levels of experimental biomarkers (IL-8, IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-10, IL-12/23, IL-17, IL-18, IL-21, IFN-gamma, TNF-alpha, TGF-beta, S100 proteins, ceruloplasmin, C3, C4, CH50, serum amyloid A, factor VIII, neutrophil/lymphocyte ratio) | IL-8, IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-10, IL-12/23, IL-17, IL-18, IL-21, IFN-gamma, TNF-alpha, TGF-beta and S100 proteins measured by Meso Scale Discovery assay, ceruloplasmin, C3, C4, serum amyloid A by nephelometry, CH50 by an enzyme immunoassay kit, factor VIII by turbidimetry, neutrophil/lymphocyte ratio by an automated method | Day 15 compared to Day 0 | 
| Levels of usual biomarkers (C-reactive protein, fibrinogen, procalcitonin, serum protein electrophoresis, erythrocyte sedimentation rate) | C-reactive protein and fibrinogen measured by turbidimetry; procalcitonin by an enzyme immunoassay kit, serum protein electrophoresis by electrophoresis, erythrocyte sedimentation rate by an automated method | Week 24 compared to Day 15 | 
| Levels of experimental biomarkers (IL-8, IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-10, IL-12/23, IL-17, IL-18, IL-21, IFN-gamma, TNF-alpha, TGF-beta, S100 proteins, ceruloplasmin, C3, C4, CH50, serum amyloid A, factor VIII, neutrophil/lymphocyte ratio) | IL-8, IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-10, IL-12/23, IL-17, IL-18, IL-21, IFN-gamma, TNF-alpha, TGF-beta and S100 proteins measured by Meso Scale Discovery assay, ceruloplasmin, C3, C4, serum amyloid A by nephelometry, CH50 by an enzyme immunoassay kit, factor VIII by turbidimetry, neutrophil/lymphocyte ratio by an automated method | Week 24 compared to Day 15 | 
| Levels of usual biomarkers (C-reactive protein, fibrinogen, procalcitonin, serum protein electrophoresis, erythrocyte sedimentation rate) | C-reactive protein and fibrinogen measured by turbidimetry; procalcitonin by an enzyme immunoassay kit, serum protein electrophoresis by electrophoresis, erythrocyte sedimentation rate by an automated method | Within 72 hours following infection occuring after week 24 | 
| Levels of experimental biomarkers (IL-8, IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-10, IL-12/23, IL-17, IL-18, IL-21, IFN-gamma, TNF-alpha, TGF-beta, S100 proteins, ceruloplasmin, C3, C4, CH50, serum amyloid A, factor VIII, neutrophil/lymphocyte ratio) | IL-8, IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-10, IL-12/23, IL-17, IL-18, IL-21, IFN-gamma, TNF-alpha, TGF-beta and S100 proteins measured by Meso Scale Discovery assay, ceruloplasmin, C3, C4, serum amyloid A by nephelometry, CH50 by an enzyme immunoassay kit, factor VIII by turbidimetry, neutrophil/lymphocyte ratio by an automated method | Within 72 hours following infection occuring after week 24 |