The Role of Microbiome on Biological Therapy Efficacy in axSpA and RA (MicroSpA & RA)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Arthritis, Rheumatoid; Axial Spondyloarthritis
• Intervention / Treatment: Biological: biological disease-modifying antirheumatic drugs (bDMARDs)

Detailed Description

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.

• Study Type: Observational
• Enrollment (Anticipated): 90

Contacts and Locations

• Study Contact: Name: Fernando Pimentel-Santos, PhD Agg; Phone Number: 00351917305093; Email: pimentel.santos@nms.unl.pt

Study Locations

• Portugal
  • Aveiro, Portugal
    • Not yet recruiting
    • Centro Hospitalar Baixo Vouga - Hospital Infante D. Pedro
    • Contact: Anabela Barcelos, MD; Email: barcelos.anabela@gmail.com
  • Braga, Portugal
    • Not yet recruiting
    • Hospital de Braga, E.P.E.
    • Contact: Ana Ribeiro, MD; Email: anaroxoribeiro@gmail.com
  • Guarda, Portugal
    • Not yet recruiting
    • Hospital Sousa Martins - Unidade de Saúde Local da Guarda
    • Contact: Cláudia Vaz, MD; Email: claudiacvaz@gmail.com
  • Lisboa, Portugal
    • Recruiting
    • Centro Hospitalar Lisboa Ocidental - Hospital Egas Moniz
    • Contact: Fernando Pimentel-Santos, PhD Agg; Phone Number: 00351917305093; Email: pimentel.santos@nms.unl.pt
  • Lisboa, Portugal
    • Not yet recruiting
    • Centro Hospitalar Universitário de Lisboa Norte - Hospital Santa Maria
    • Contact: Elsa Vieira-Sousa, MD, PhD; Email: elsacvsousa@gmail.com
  • Lisboa, Portugal
    • Not yet recruiting
    • Instituto Portugues De Reumatologia
    • Contact: Helena Santos, MD; Email: helena.santos@ipr.pt
  • Oporto, Portugal
    • Not yet recruiting
    • Centro Hospitalar Universitario Sao Joao
    • Contact: José Miguel Bernardes, PhD; Email: mbernardes09@gmail.com
  • Ponte de Lima, Portugal
    • Not yet recruiting
    • Unidade Local de Saúde do Alto Minho, Hospital Conde de Bertiandos
    • Contact: José Costa, MD; Email: josecosta99@gmail.com
  • Torres Novas, Portugal
    • Not yet recruiting
    • Centro Hospitalar de Médio Tejo - Hospital Rainha Santa Isabel - Torres Novas
    • Contact: João Madruga-Dias, MD; Email: joao_alexandre@hotmail.com
  • Vila Nova De Gaia, Portugal
    • Not yet recruiting
    • Centro Hospitalar de Vila Nova da Gaia/Espinho
    • Contact: Patrícia Pinto, MD; Email: patriciaampinto@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with axSpA or RA according to ASAS and 2010 ACR/EULAR classification criteria, respectively, with indication to start bDMARD according to Portuguese Rheumatology Society.

Description

Inclusion Criteria:

1. Diagnosis of axSpA (according to ASAS classification criteria) or RA (according to 2010 ACR/EULAR classification criteria);
2. Indication for bDMARD therapy, according to the Portuguese recommendations for the use of biological therapies in patients with axSpA and RA;
3. Oral corticosteroids (equivalent to prednisolone ≤ 10mg/day) and/or nonsteroidal anti-inflammatory drugs allowed at stable dose ≥4 weeks before baseline;
4. Conventional DMARDs allowed at stable dose ≥12 weeks before baseline;
5. Ability to provide informed consent.

Exclusion Criteria:

1. History of rheumatic disorder other than axSpA or RA;
2. History of Inflammatory Bowel Disease;
3. Previous treatment with bDMARD;
4. Current pregnancy or breastfeeding;
5. Malignancy (except for completely treated squamous or basal cell carcinoma);
6. Any uncontrolled medical condition (e.g., uncontrolled diabetes mellitus, unstable ischemic heart disease);
7. History of any documented gastrointestinal disease or tract surgery leaving permanent residua (e.g., gastrectomy, bariatric surgery, or colectomy);
8. Intraarticular injections of extra-axial joints and tendons within 28 days before or at baseline;
9. 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.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
axSpA; 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); bDMARD therapy (TNF inhibitors), according to the Portuguese recommendations for the use of biological therapies in patients with axSpA and RA
RA; 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); bDMARD therapy (TNF inhibitors), according to the Portuguese recommendations for the use of biological therapies in patients with axSpA and RA
Control; Healthy participants, e.g. with no clinical diagnosis of rheumatic inflammatory disease, crossed by age, gender and diet profile

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Universidade Nova de Lisboa
• Collaborators: Centro Hospitalar de Vila Nova de Gaia/Espinho; Centro Hospitalar Lisboa Ocidental Hospital Egas Moniz; Centro Hospitalar Universitário de São João; Centro Hospitalar Universitário de Lisboa Norte - Hospital de Santa Maria; Instituto Português de Reumatologia; Centro Hospitalar Médio Tejo - Hospital Rainha Santa Isabel - Torres Novas; Centro Hospitalar Baixo Vouga - Hospital Infante D. Pedro; CHRC-Comprehensive Health Research Centre, FCM|NMS, UNL; iNOVA4Health - Rheumatic Diseases Lab; Unidade Local de Saúde do Alto Minho, Hospital Conde de Bertiandos; Hospital de Braga E.P.E.; Hospital Sousa Martins - Unidade de Saúde Local da Guarda
• Investigators: Principal Investigator: Fernando Pimentel-Santos, PhD Agg, NOVA Medical School, Universidade NOVA de Lisboa; CHLO Hospital Egas Moniz

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2020
• Primary Completion (Anticipated): January 31, 2022
• Study Completion (Anticipated): January 31, 2022

Study Registration Dates

• First Submitted: June 22, 2021
• First Submitted That Met QC Criteria: July 12, 2021
• First Posted (Actual): July 22, 2021

Study Record Updates

• Last Update Posted (Actual): July 22, 2021
• Last Update Submitted That Met QC Criteria: July 12, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Biomarker; Microbiota; Tumor Necrosis Factor alpha inhibitor
• Additional Relevant MeSH Terms: Infections; Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Spinal Diseases; Bone Diseases; Bone Diseases, Infectious; Arthritis; Arthritis, Rheumatoid; Spondylitis; Spondylarthritis; Antirheumatic Agents
• Other Study ID Numbers: MicroSpA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No