The Role of Microbiome on Biological Therapy Efficacy in axSpA and RA

Study Overview
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Brief Summary
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Spondyloarthritis (SpA) and Rheumatoid arthritis (RA) are among the most common chronic inflammatory rheumatic diseases. Introduction of Tumor Necrosis Factor alpha inhibitors (TNFi) to the therapeutic strategy improved acute inflammation and pain, but a significant percentage of patients develop severe adverse events or are still non responders or incomplete responders to these expensive treatments. There is an urgent need to identify new predictors of biological therapy response. It has been described the role of microbiota in some rheumatic diseases, however, clinical trials are scarce. We hypothesized that microbiota or their metabolites may play a role in therapeutic response to TNFi.

Detailed Description
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Thus, this project aimed to evaluate the influence of oral and gut microbiota in the therapeutic response to biologic therapies, in 60 patients. It is expected to enrolled 30 SpA and 30 RA patients and 30 controls, crossed by gender, age and diet profile. Oral and fecal microbiota will be characterized before TNFi therapeutic. Patients will have an additional microbiota and metabolic profile characterization 14 weeks late after. This will allow to identify specific profiles of oral and gut microbiome and/or specific biochemical patterns in these patients. At week 14 it will be possible to identify changes induced by TNFi. In addition, it will be possible to identify microbiota pattern associated clinical therapeutic TNFi response vs non-response. This will allow to predict isolate microbe or microbes patterns at baseline associated to clinical response obtained at week 14. These results may additionally contribute to clinical decision and a better evidenced-based treatment.

Official Title
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MicroSpA & MicroRA: The Role of Microbiome on Biological Therapy Efficacy in Axial Spondyloarthritis and Rheumatoid Arthritis - a New Paradigm

Conditions
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Axial Spondyloarthritis, Arthritis, Rheumatoid

Intervention / Treatment
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* Biological: biological disease-modifying antirheumatic drugs (bDMARDs)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of axSpA (according to ASAS classification criteria) or RA (according to 2010 ACR/EULAR classification criteria); Indication for bDMARD therapy, according to the Portuguese recommendations for the use of biological therapies in patients with axSpA and RA; Oral corticosteroids (equivalent to prednisolone ≤ 10mg/day) and/or nonsteroidal anti-inflammatory drugs allowed at stable dose ≥4 weeks before baseline; Conventional DMARDs allowed at stable dose ≥12 weeks before baseline; Ability to provide informed consent. Exclusion Criteria: History of rheumatic disorder other than axSpA or RA; History of Inflammatory Bowel Disease; Previous treatment with bDMARD; Current pregnancy or breastfeeding; Malignancy (except for completely treated squamous or basal cell carcinoma); Any uncontrolled medical condition (e.g., uncontrolled diabetes mellitus, unstable ischemic heart disease); History of any documented gastrointestinal disease or tract surgery leaving permanent residua (e.g., gastrectomy, bariatric surgery, or colectomy); Intraarticular injections of extra-axial joints and tendons within 28 days before or at baseline; Recent (<3 months prior) use of any antibiotic therapy, current extreme diet (e.g., parenteral nutrition or macrobiotic diet), current consumption of probiotics. Control group will be healthy participants, and the same inclusion and exclusion criteria will be applied except for rheumatic disease diagnosis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| axSpA<br>Patients with clinical diagnosis of axialSpondyloarthritis according to ASAS criteria, with indication for bDMARD (Portuguese Rheumatology Society Guidelines) | Biological: biological disease-modifying antirheumatic drugs (bDMARDs)<br>* bDMARD therapy (TNF inhibitors), according to the Portuguese recommendations for the use of biological therapies in patients with axSpA and RA<br>|
| RA<br>Patients with clinical diagnosis of Rheumatoid arthritis according to 2010 ACR/EULAR classification criteria, with indication for bDMARD (Portuguese Rheumatology Society Guidelines) | Biological: biological disease-modifying antirheumatic drugs (bDMARDs)<br>* bDMARD therapy (TNF inhibitors), according to the Portuguese recommendations for the use of biological therapies in patients with axSpA and RA<br>|
| Control<br>Healthy participants, e.g. with no clinical diagnosis of rheumatic inflammatory disease, crossed by age, gender and diet profile | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral and gut microbiota characterization in axSpA and RA patients at baseline |  | Before bDMARD | 
| Oral and gut microbiota characterization in axSpA and RA patients at week 14 |  | 14 weeks after start bDMARD | 
| Disease activity measured by ASAS20 in axSpA and ACR20 in RA |  | 14 weeks after start bDMARD | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Erythrocyte Sedimentation Rate (ESR, measured in mm/h) |  | Before bDMARD and 14-week after start bDMARD | 
| Changes in High-sensitivity C-reactive protein (hsCRP, measured in mg/dL) |  | Before bDMARD and 14-week after start bDMARD | 
| Disease activity characterization using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in axSpA | Scale from 0 (worse outcome) to 10 (better outcome) | Before bDMARD and 14-week after start bDMARD | 
| Disease activity characterization using Ankylosing Spondylitis Disease Activity Score - C-Reactive Protein (ASDAS-CRP) in axSpA | < 1.3 Inactive disease; > 3.5 Very high disease activity | Before bDMARD and 14-week after start bDMARD | 
| Disease activity characterization using Disease Activity Score-28 for Rheumatoid Arthritis with C-Reactive Protein (DAS28-CRP) for RA | Score greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission | Before bDMARD and 14-week after start bDMARD | 
| Quality of life evaluation with Short form 36 (SF36) at baseline and week 14 | Score from 0 (worse outcome) to 100 (better outcome) | Before bDMARD and 14-week after start bDMARD | 
| Quality of life evaluation with Ankylosing Spondylitis Quality of Life (ASQOL) at baseline and week 14 | Range from 0 -18 - High scores indicate worse quality of life | Before bDMARD and 14-week after start bDMARD | 
| Quality of life evaluation with Health Assessment Questionnaire (HAQ) at baseline and week 14 | Scores of 0 to 1 are generally considered to represent mild to moderate difficulty, 1 to 2 moderate to severe disability, and 2 to 3 severe to very severe disability | Before bDMARD and 14-week after start bDMARD | 
| Quality of life evaluation regarding depression and anxiety using Hospital Anxiety and Depression Scale (HADS) at baseline and week 14 | Scores of less than 7 indicate non-cases; 8-10 Mild; 11-14 Moderate;15-21 Severe | Before bDMARD and 14-week after start bDMARD | 
| Fatigue evaluation at baseline and week 14 | Visual analogic scale (0-10) | Before bDMARD and 14-week after start bDMARD | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tumor Necrosis Factor alpha inhibitor, Microbiota, Biomarker