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Oral Metagenomic Biomarkers in Rheumatoid Arthritis

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ClinicalTrials.gov Identifier: NCT02544334
Recruitment Status : Recruiting
First Posted : September 9, 2015
Last Update Posted : September 14, 2018
Sponsor:
Collaborators:
United States Department of Defense
VA Medical Center-Gainesville
Information provided by (Responsible Party):
University of Florida

Brief Summary:

Rheumatoid Arthritis (RA) is a chronic and potentially severe autoimmune disease affecting 2 million in the United States. The role of environmental factors in modulating autoimmunity pathogenesis has been clearly described and yet the specific mechanisms of action remain poorly understood. A growing body of evidence implicates microbiota of mucosal surfaces in the development of autoimmune disorders. Various studies have clearly linked RA to periodontal disease. The latter is linked to the red-complex that includes the oral bacterium Porphyromonas gingivalis. And yet there has not been a systematic analysis of the oral microbiota in RA to determine whether there are specific markers for P. gingivalis (and other oral bacteria) that are linked to RA.

In this study, the investigators will characterize oral microbial composition (microbiome) and gene content (metagenome) of DNA isolated from oral samples obtained from patients with (i) early stage RA prior to biologics treatments and (ii) subsets of RA patients who are responsive or unresponsive to anti-TNF-alpha therapy. The innovative aspect of this study is going beyond the identification of oral bacterial species, to the level of strains and genes that are associated with these groups. The overall hypothesis is that oral microbial variation exists between individuals that influences development of autoimmunity and autoimmune disease.


Condition or disease Intervention/treatment
Rheumatoid Arthritis Procedure: Dental Plaque Other: Multi-dimensional health assessment questionnaire (MDHAQ) Other: Saliva Collection

Detailed Description:

This is a multi-disciplinary research study with five investigators from different, yet complementary, disciplines to establish this new collaboration. There is a high translational potential for information gained from this project based on the collaboration of a rheumatologist, a dentist, oral biologists, and infectious disease experts with expertise in immunology, microbiology, and genomics. In brief, RA participants will be recruited by the rheumatologist. A total of 100 participants will be recruited for two groups to be studied; one group of subjects with RA and the other group will be healthy controls. These two groups will be divided into the following groups for participation in the study: Group 1: will consist of 25 RA adult subjects who have not been treated with biologics which will be compared to 25 healthy controls from age-matched members of the same household. Group 2 will consist of 25 RA adult subjects responsive to first line anti-TNF therapy which will be compared to 25 subjects of the same age and sex with RA who are resistant to two or more TNF antagonists. The participants will be scheduled for a research study visit at the University of Florida Dental Clinic Research Unit. During the exam the following will take place: the multidimensional health assessment questionnaire (MDHAQ), dental exam, saliva collection, and dental plaque will be removed from different tooth surfaces for supragingival.

The supragingival will be subjected to deep sequencing in the genomics lab. To test two specific aims: 1) testing the hypothesis that oral microbiome profiles based on 16S RNA data are associated with the development of RA or with the response to a specific therapy, and 2) testing the hypothesis that the specific genes, variants, and functional capabilities (metagenome) are associated with RA or with therapeutic response. Upon completion of this pilot study, the investigators will have systematically identified bacterial biomarkers (e.g. species, subspecies, genes) that correlate with RA and may serve as potential targets for disease treatment. These markers may be developed into new drug targets for RA therapy in future studies.


Study Type : Observational
Estimated Enrollment : 170 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Oral Metagenomic Biomarkers in Rheumatoid Arthritis
Study Start Date : May 2016
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
RA - naïve to biologics
This group will consist of 25 Rheumatoid Arthritis (RA) adult subjects who have not been treated with biologics (naïve to biologics). During the exam the following will take place: the multidimensional health assessment questionnaire (MDHAQ), dental exam, saliva collection, and dental plaque will be removed from different tooth surfaces for supragingival.
Procedure: Dental Plaque
All participants will have dental plaque removed from different tooth surfaces for supragingival.

Other: Multi-dimensional health assessment questionnaire (MDHAQ)
The RA groups will receive the multi-dimensional health assessment questionnaire (MDHAQ) for physical function, pain, and global status.
Other Name: MDHAQ

Other: Saliva Collection
All participants will have a saliva collection.

Healthy Controls
This group will consist of 25 adult subjects which will be healthy controls from members of the same household as the 25 naive to biologics, and be of the same age. During the exam the following will take place: dental exam, saliva collection, and dental plaque will be removed from different tooth surfaces for supragingival.
Procedure: Dental Plaque
All participants will have dental plaque removed from different tooth surfaces for supragingival.

Other: Saliva Collection
All participants will have a saliva collection.

RA responsive to anti-TNF
This group will consist of 25 adult subjects with Rheumatoid Arthritis (RA) who have been responsive to first line anti-TNF-alpha therapy. During the exam the following will take place: the multidimensional health assessment questionnaire (MDHAQ), dental exam, saliva collection, and dental plaque will be removed from different tooth surfaces for supragingival.
Procedure: Dental Plaque
All participants will have dental plaque removed from different tooth surfaces for supragingival.

Other: Multi-dimensional health assessment questionnaire (MDHAQ)
The RA groups will receive the multi-dimensional health assessment questionnaire (MDHAQ) for physical function, pain, and global status.
Other Name: MDHAQ

Other: Saliva Collection
All participants will have a saliva collection.

RA non responsive to anti-TNF
This group will consist of 25 adult subjects with Rheumatoid Arthritis (RA) who are resistant to two or more anti-TNF-alpha therapies, and be of the same age as the RA responsive to anti-TNF group. During the exam the following will take place: the multidimensional health assessment questionnaire (MDHAQ), dental exam, saliva collection, and dental plaque will be removed from different tooth surfaces for supragingival.
Procedure: Dental Plaque
All participants will have dental plaque removed from different tooth surfaces for supragingival.

Other: Multi-dimensional health assessment questionnaire (MDHAQ)
The RA groups will receive the multi-dimensional health assessment questionnaire (MDHAQ) for physical function, pain, and global status.
Other Name: MDHAQ

Other: Saliva Collection
All participants will have a saliva collection.




Primary Outcome Measures :
  1. Oral microbiome will be catalogued in each group for their association with RA. [ Time Frame: Day 1 ]
    A Wilcoxon rank-sum test will be computed on each profile to identify differential metagenomic gene content between each pair of groups (RA patients and controls). The potential microbial functional roles of the KEGG orthologues and eggnog orthologue groups markers in the oral microbiota of RA patients will also be assessed. All results will be corrected for multiple testing using a false discovery rate approach.

  2. Metagenomic analyses will be performed to find oral bacteria markers between the groups. [ Time Frame: 18 months ]
    A Wilcoxon rank-sum test will be computed on each profile to identify differential metagenomic gene content between each groups.


Biospecimen Retention:   Samples With DNA
Supragingival dental plaque will be pooled from different tooth surfaces using sterile periodontal curettes. DNA samples will be subjected to deep sequencing.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Rheumatoid Arthritis (RA) adult patients who have not been treated with biologics (naïve to biologics), RA patients responsive to first line anti-TNF therapy, RA patients who are resistant to two or more TNF antagonists, and healthy controls from age-matched members of the same household.
Criteria

Inclusion Criteria:

  • with at least 10 natural uncrowned teeth (excluding third molars) must be present.

Exclusion Criteria:

  • have less than 10 teeth;
  • have been treated with antibiotics within the past 3 months, including patients that require antibiotic prophylaxis prior to dental treatment;
  • are immune compromised individuals (HIV, AIDS, immuno-suppressive drug therapy);
  • participate in another clinical study involving the use of dental products one week prior to the start of the washout period or during the study period; and
  • are unwilling or unable to provide informed consent and follow the collection instructions.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02544334


Contacts
Contact: Edward K Chan, Ph.D. 352-273-8849 echan@ufl.edu
Contact: Michael R Bubb, MD 352-273-5340 Michael.Bubb@medicine.ufl.edu

Locations
United States, Florida
University of Florida College of Dentistry-Periodontics Recruiting
Gainesville, Florida, United States, 32610
Contact: Edward K Chan, Ph.D.    352-273-8849    echan@ufl.edu   
Contact: Marcelle M Nascimento, DDS    352-273-5858    mnascimento@dental.ufl.edu   
Randall Malcom VA Medical Center Recruiting
Gainesville, Florida, United States, 32611
Contact: Edward K Chan, Ph.D         
Sponsors and Collaborators
University of Florida
United States Department of Defense
VA Medical Center-Gainesville
Investigators
Principal Investigator: Michael R Bubb, MD University of Florida
Principal Investigator: Edward K Chan, Ph.D. University of Florida

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02544334     History of Changes
Other Study ID Numbers: IRB201500286
11712325 ( Other Grant/Funding Number: Department of Defense )
12.420 ( Other Grant/Funding Number: Department of Defense )
First Posted: September 9, 2015    Key Record Dates
Last Update Posted: September 14, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Florida:
Rheumatoid arthritis
Metagenome
microbiome

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases