Periodontal Disease, Psoriatic Arthritis, Rheumatoid Arthritis
Conditions
Keywords
rheumatoid arthritis, psoriatic arthritis, periodontitis, microbiota, microbiome, vancomycin, doxycycline, T cell, Th17
Brief summary
Rheumatoid arthritis (RA) is an inflammatory form of arthritis that causes joint pain and damage. RA attacks the lining of the joints (synovium), causing swelling that can result in aching and throbbing, and eventually deformity. Even though there have been many advances in the treatment of RA, psoriatic arthritis (PsA), and other inflammatory arthritis, doctors still do not know what causes this inflammation in joints. It is likely that RA occurs as a result of a complex combination of factors, including a person's genes; lifestyle choices, such as smoking and diet; and things in a person's environment, including bacteria or viruses. This study investigates the hypothesis that bacteria living in a person's mouth and/or intestinal tract are responsible, at least in part, for the development of Rheumatoid Arthritis. The investigators believe that by killing those bacteria with antibiotics, they might be able to understand how the immune system works and, maybe, what causes RA.
Detailed description
If you would like to participate in this study, we will first ask you several questions regarding the status of your arthritis, the medications you use or have used in the recent past, your social and dietary habits, and your medical and surgical history. If your answers tell us that you are the right patient for our study, we will go over a consent form which describes in more detail how we will study your intestinal and mouth bacteria, the immune cells in your blood and other genes, enzymes and proteins that tell us about your disease status. If you have Psoriatic Arthritis (PsA) or are healthy with no history of arthritis, and would like to participate in this study, your participation would involve only one or two visits, and no treatment. If you have Rheumatoid Arthritis (RA), your participation would involve six visits, and you would be randomly assigned to receive treatment with the antibiotic doxycycline, or the antibiotic vancomycin, or no antibiotic treatment.
Interventions
DRUGdoxycycline
doxycycline - 100 mg twice per day, for 2 months
DRUGvancomycin
vancomycin, 250 mg four times a day, for 2 weeks
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Memorial Sloan Kettering Cancer Center
NYU Langone Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Rheumatoid Arthritis (RA) patients must meet American College of Rheumatology (ACR) criteria for RA * RA patients: duration of disease will be greater than 6 weeks and less than 2 years. * RA patients should have a Disease Activity Score 28 (DAS28) greater than or equal to 5. * PsA patients will be required to have disease duration and DAS28 similar to the RA patients, and to meet Moll and Wright criteria for PsA. * Allowable medications for both groups at study entry will include: prednisone (or equivalent) 5 mg or less per day (stable dose for at least 2 months); methotrexate 15 mg or less per week (stable dose for at least 2 months); and nonsteroidal anti-inflammatory drugs (NSAIDs) at FDA-approved doses. * Healthy controls will be age- and sex-matched individuals with no personal or family history of inflammatory arthritis.
Exclusion criteria
* Patients who are unable to provide informed consent. * Pregnant or lactating women. * Recent (\<3 months prior) use of any antibiotic therapy * Current consumption of probiotics * Current extreme diet (parenteral nutrition, macrobiotic diet, etc.) * Prednisone \>5 mg/day or equivalent * Use of other disease-modifying antirheumatic drugs (DMARDs) with known antibiotic properties (Gold salts, hydroxychloroquine, sulfasalazine or minocycline). * Use of biologic DMARDs * Known inflammatory bowel disease * Known gastrointestinal (GI) tract neoplasm. * Recent GI tract infection (gastroenteritis, colitis, diverticulitis, appendicitis) * Chronic unexplained diarrhea. * Any GI tract surgery leaving permanent residua (e.g., gastrectomy; bariatric surgery; colectomy) * Significant liver, renal or peptic ulcer disease, defined as: * Liver: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \> 2 x upper limit of normal (ULN) * Renal: Creatinine \>1.5 or endstage renal disease * Peptic ulcer disease: recent ulcer or GI bleed (within past 12 months) * Inability or unwillingness to abstain from alcohol consumption.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alteration of Microbiota, Alteration of T Cell Function/Activation | 6 months | Oral and intestinal microbiota, and T cell function and activation, will be assessed at baseline, and at 1, 2, 3, 4 and 5 months after baseline, to determine whether changes are associated with vancomycin treatment versus doxycycline treatment versus no treatment. Results are reported as number of participants who experienced changes in oral/intestinal microbiota, T cell function/activation. Methods/criteria to assess change in microbiota: change in relative abundance of microorganisms at genus and species level (as assessed high-throughput 16S rDNA sequencing). Methods/criteria to assess change in T cell function/activation: change in percentage of inhibition of regulatory T cells as measured by interferon gamma levels in in-vitro assays. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Units Change in DAS28 From Baseline to 6 Months | 6 months | DAS28 (disease activity score with 28 joint count). Possible score range: 0 to 10. This is a composite index calculated from 4 measures: two from a physician (28 tender joint count, 28 swollen joint count), one from the patient (patient global estimate of disease activity), and one laboratory biomarker (erythrocyte sedimentation rate or ESR). A score of 0 represents best possible health status (no apparent disease activity) and 10 represents worst possible. The outcome is reported as mean change in DAS28 score from baseline to 6 months. The mean changes reported are negative values for downward change in score (i.e., improvement in health status). |
Countries
United States
Participant flow
Recruitment details
Dates of recruitment period: January 2010 - August 2012 Locations: Medical clinics and faculty practice offices
Participants by arm
| Arm | Count |
|---|---|
| Rheumatoid Arthritis (RA) - Doxycycline Patients with rheumatoid arthritis (RA) meeting inclusion criteria, randomized to receive doxycycline, 100 mg twice a day, for 2 months.
doxycycline: doxycycline - 100 mg twice per day, for 2 months | 5 |
| Rheumatoid Arthritis (RA) - Vancomycin Patients with rheumatoid arthritis (RA) meeting inclusion criteria, randomized to receive vancomycin, 250 mg four times a day, for 2 weeks
vancomycin: vancomycin, 250 mg four times a day, for 2 weeks | 10 |
| Rheumatoid Arthritis (RA) Randomized to no Treatment Patients with rheumatoid arthritis (RA) meeting inclusion criteria, randomized to receive no antibiotic treatment and followed prospectively for 6 months, for comparison with Doxycycline- and Vancomycin-treated patients. | 19 |
| Early RA Cross-sectional Cohort Patients with rheumatoid arthritis (RA) meeting inclusion criteria who opted to participate ONLY in cross-sectional analysis (one-time sample collection equivalent to the involvement of PsA and health control subjects). | 66 |
| Psoriatic Arthritis (PsA) Patients with psoriatic arthritis (PsA), to provide baseline samples of oral and intestinal microbiota for comparison with RA patients. | 20 |
| Healthy Volunteers Healthy individuals with no history of arthritis, to provide baseline samples of oral and intestinal microbiota for comparison with RA patients. | 58 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Rheumatoid Arthritis (RA) - Doxycycline | Rheumatoid Arthritis (RA) - Vancomycin | Rheumatoid Arthritis (RA) Randomized to no Treatment | Early RA Cross-sectional Cohort | Psoriatic Arthritis (PsA) | Healthy Volunteers |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 1 Participants | 0 Participants | 1 Participants | 8 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 167 Participants | 4 Participants | 10 Participants | 18 Participants | 58 Participants | 19 Participants | 58 Participants |
| Age, Continuous | 44.2 years | 44.0 years | 41.5 years | 39.2 years | 49.1 years | 45.5 years | 40.7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 117 Participants | 3 Participants | 7 Participants | 15 Participants | 41 Participants | 8 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 2 Participants | 3 Participants | 4 Participants | 25 Participants | 12 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 0 Participants | 1 Participants | 3 Participants | 4 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants | 2 Participants | 1 Participants | 1 Participants | 17 Participants | 1 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 94 Participants | 2 Participants | 6 Participants | 14 Participants | 29 Participants | 8 Participants | 35 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 38 Participants | 1 Participants | 2 Participants | 1 Participants | 16 Participants | 6 Participants | 12 Participants |
| Region of Enrollment United States | 178 participants | 5 participants | 10 participants | 19 participants | 66 participants | 20 participants | 58 participants |
| Sex: Female, Male Female | 139 Participants | 4 Participants | 7 Participants | 14 Participants | 53 Participants | 11 Participants | 50 Participants |
| Sex: Female, Male Male | 39 Participants | 1 Participants | 3 Participants | 5 Participants | 13 Participants | 9 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 4 | 1 / 10 | 0 / 163 |
| serious Total, serious adverse events | 0 / 4 | 0 / 10 | 0 / 163 |
Outcome results
Primary
Alteration of Microbiota, Alteration of T Cell Function/Activation
Oral and intestinal microbiota, and T cell function and activation, will be assessed at baseline, and at 1, 2, 3, 4 and 5 months after baseline, to determine whether changes are associated with vancomycin treatment versus doxycycline treatment versus no treatment. Results are reported as number of participants who experienced changes in oral/intestinal microbiota, T cell function/activation. Methods/criteria to assess change in microbiota: change in relative abundance of microorganisms at genus and species level (as assessed high-throughput 16S rDNA sequencing). Methods/criteria to assess change in T cell function/activation: change in percentage of inhibition of regulatory T cells as measured by interferon gamma levels in in-vitro assays.
Time frame: 6 months
Population: Primary outcome only evaluated in first three groups of RA patients: 4 randomized to treatment with doxycycline; 10 randomized to treatment with vancomycin; 19 randomized to no treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rheumatoid Arthritis (RA) - Doxycycline | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in oral/intestinal microbiota | 4 participants |
| Rheumatoid Arthritis (RA) - Doxycycline | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in T cell function/activation | 2 participants |
| Rheumatoid Arthritis (RA) - Vancomycin | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in oral/intestinal microbiota | 10 participants |
| Rheumatoid Arthritis (RA) - Vancomycin | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in T cell function/activation | 6 participants |
| Rheumatoid Arthritis (RA) Randomized to no Treatment | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in oral/intestinal microbiota | 2 participants |
| Rheumatoid Arthritis (RA) Randomized to no Treatment | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in T cell function/activation | 19 participants |
| Early RA Cross-sectional Cohort | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in oral/intestinal microbiota | 0 participants |
| Early RA Cross-sectional Cohort | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in T cell function/activation | 0 participants |
| Psoriatic Arthritis (PsA) | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in oral/intestinal microbiota | 0 participants |
| Psoriatic Arthritis (PsA) | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in T cell function/activation | 0 participants |
| Healthy Volunteers | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in oral/intestinal microbiota | 0 participants |
| Healthy Volunteers | Alteration of Microbiota, Alteration of T Cell Function/Activation | Change in T cell function/activation | 0 participants |
Secondary
Mean Units Change in DAS28 From Baseline to 6 Months
DAS28 (disease activity score with 28 joint count). Possible score range: 0 to 10. This is a composite index calculated from 4 measures: two from a physician (28 tender joint count, 28 swollen joint count), one from the patient (patient global estimate of disease activity), and one laboratory biomarker (erythrocyte sedimentation rate or ESR). A score of 0 represents best possible health status (no apparent disease activity) and 10 represents worst possible. The outcome is reported as mean change in DAS28 score from baseline to 6 months. The mean changes reported are negative values for downward change in score (i.e., improvement in health status).
Time frame: 6 months
Population: Please note that only the first 3 groups (RA doxycycline, RA vancomycin, and RA randomized to no treatment) were analyzed for change from baseline to six months (outcomes). Groups 4, 5 and 6 (RA cross-sectional, Psoriatic Arthritis, and Healthy Volunteers) were analyzed for baseline measures only in a cross-sectional comparison.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rheumatoid Arthritis (RA) - Doxycycline | Mean Units Change in DAS28 From Baseline to 6 Months | -1.3 units on a scale |
| Rheumatoid Arthritis (RA) - Vancomycin | Mean Units Change in DAS28 From Baseline to 6 Months | -1.5 units on a scale |
| Rheumatoid Arthritis (RA) Randomized to no Treatment | Mean Units Change in DAS28 From Baseline to 6 Months | -2.5 units on a scale |