The Effects of Hyperbaric Oxygen on Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this investigation is to determine the effects and ease of using hyperbaric oxygen therapy HBO2 for the treatment of rheumatoid arthritis joint pain and prevention of disease progression. In this study it is our intention to not only evaluate effects and ease of treatment but time, cost, possible adverse events and effect size in an attempt to predict an appropriate sample size and improve on the study design prior to a more extensive study.

Detailed Description
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Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of unknown etiology that primarily involves synovial joints, typically symmetrically. If untreated and/or uncontrolled, joint destruction due to erosion of cartilage and bone can cause joint destruction, joint deformities, loss of physical function, severe disability, and difficulties maintaining employment. American College of Rheumatology (ACR)/EULAR 2010 classification criteria is a score-based algorithm which adds scores of 4 categories including, joint involvement, serology, acute-phase reactants and duration of symptoms. A score of >6/10 is needed for classification of a patient as having definite RA. Non-pharmacologic and supplementary therapies include patient education, rest, exercise, nutrition counseling, cardiovascular disease risk reduction, and immunizations to decrease risk of infectious complications of immunosuppression. These are important in the comprehensive management of RA in all stages of disease and are used in addition to drug therapy. Pharmacologic therapies typically start with a disease-modifying anti-rheumatic drug (DMARD), preferably as soon as possible after diagnosis. DMARDs are commonly used in combination with anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids which are often used as bridging therapies until the DMARDs become effective. The goal is disease remission. To assess response, disease activity scores are used along with inflammatory markers. Three patients with active RA treated in the multi-place hyperbaric facility at David Grant Medical Center (DGMC), Travis Air Force Base, California, for non RA-related indications, all noted significant improvement in arthralgias, sleep patterns and overall well-being during the course of therapy. Two were treated at 2 atmospheres absolute (ATA) oxygen for 90 minutes daily Monday through Friday. One patient received 2 ATA air on the same treatment protocol as a participant in a research study, and a subsequent course of hyperbaric oxygen (HBO2) at 2 ATA. This is a pilot study. Patients will be recruited through the Rheumatologists, IRB-approved HIPAA waiver to contact patients that have been seen in the military treatment facility (MTF) within the past year with a diagnosis of RA, flyers in the Rheumatology Clinic or thru Commander Calls. During the initial screening visit: The rheumatologist will discuss the trial and at this point the subject will be consented and the inclusion/exclusion criteria will be reviewed. If subject qualifies they will see the Hyperbaric physician who will do physical examination to determine if it is safe for the subject to receive HBO2. An human chorionic gonadotrophin (HCG) by point of care testing (POCT) will be completed by the coordinator in women capable of pregnancy. After this exam is done the subject will be scheduled for a trial Hyperbaric session. Baseline visit will be done after the subject has tolerated the trial hyperbaric session. This visit includes: A visit with the rheumatologist to do routine assessments to establish baseline measurement using the Disease Activity Scale (DAS28) Labs (CRP and Erythrocyte Sedimentation Rate (ESR), basic metabolic panel (BMP) and microparticles), will be completed. Magnetic resonance imaging (MRI) with and without contrast and ultrasound will be done on both hands from wrists to proximal phalanges the wrist. BMP is done pre-MRI to guarantee adequate kidney function. Subjective patient reporting will be captured using the Routine Assessment of Patient Index Data (RAPID 3) Sleep quality will be tracked using the Pain and Sleep Quality Questionnaire (PSQ-3). Visual Analog Scores (VAS) for pain will be tracked. Surveys will be done by a study team member The subject at this time will be scheduled to start HBO2 treatments. Screening, baseline, first HBO2 treatment all in one month. Participants will complete 30 sessions within 10 weeks. If the subject reports pain relief (> 40% or zero pain) during the HBO2 treatments the will be referred to the rheumatologist for assessment. Pain improvement will be based on a pain assessment (1-10 scale reported verbally) at hyperbaric treatment visits. Labs will be drawn at this time. RAPID 3, PSQ-3 and VAS will be done at least six times while undergoing HBO2 treatment to track subject progress. Labs (CRP, ESR, microparticles) will be repeated at the conclusion of the HBO2 treatments. At the month 3 and month 6 visit (+/- 2 week window) the subject will see the rheumatologist to track disease activity using the DAS-28. The date of the visit will be scheduled for three and six months from the baseline visit. The rheumatologist will order the MRI, ultrasound and lab studies prior to the visit. RAPID 3, PSQ-3 and VAS will be administered at this time. Lab samples will be collected prior to the Rheumatology appointment. The six month visit marks the end of the trial. Patients will continue to be followed in Rheumatology Clinic every three months. If the patient's RA symptoms worsen during the study, the physicians will institute measures to address the cause. The medical monitor will be notified and if any adverse events are involved, they will be recorded and reported to the Institutional Review Board (IRB). Data: Data will be entered by authorized study personnel only. Demographic information will be collected including sex, age and ethnic background in accordance with HIPPA compliance. Data collected during this study will be analyzed at various points in time to include physician exams, labs (CRP, ESR, BMP, analysis of microparticles, neutrophil and platelet activation), radiologic studies, joint inspection. Changes in joint pain will be determined by self-reporting and results of the standard outcome measures questionnaires (RAPID 3, PSQ-3 and VAS). A separate sleep survey will be administered.

Official Title
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The Effects of Hyperbaric Oxygen on Rheumatoid Arthritis: A Pilot Study

Conditions
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RheumatoId Arthritis

Intervention / Treatment
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* Device: Hyperbaric Oxygen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 Active duty or Department of Defense (DoD) beneficiary Diagnosed with rheumatoid arthritis meeting ACR/EULAR 2010 classification criteria and any one of the following: Patient does not want to be on rheumatologic medications Patient has contraindications to standard rheumatologic medications Patient has failed treatment or an incomplete response with standard rheumatologic medications Women of childbearing age must have a negative pregnancy test and currently be on a reliable form of birth control Exclusion Criteria: Severe depression Dementia, mental disability Claustrophobia Uncontrolled seizure disorder Uncontrolled asthma/severe chronic obstructive pulmonary disease (COPD) with partial pressure of carbon dioxide (pCO2) > 45 mmHg on arterial blood gas Grade 4 congestive heart failure Unstable angina Chronic/acute otitis media/sinusitis Major tympanic membrane trauma Severe kyphoscoliosis Prior chemotherapy with Bleomycin and evidence of deterioration in diffusion capacity of the lung for carbon monoxide (DLCO) after a single hyperbaric oxygen exposure History of renal insufficiency or glomerular filtration rate (GFR)< 30 Women that are currently pregnant or breast feeding or intend on becoming pregnant while enrolled in the study

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hyperbaric Oxygen<br>Hyperbaric Oxygen | Device: Hyperbaric Oxygen<br>* 30 treatments of Hyperbaric Oxygen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep Quality - Trouble Falling Asleep, 6 Weeks | The Pain Sleep Quality (PSQ)-3 questionnaire will be used to measure outcome. Participants will score the question How often have you had trouble falling asleep because of pain? by placing a slash (/) on a 10 cm line directly beneath the question. The line will have never and always at each end. A ruler will be used to determine were the slash falls. The value between, 0-10, that corresponds on the ruler with the slash will be documented. 0 is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to obtain a median and inter-quartile range at 6 weeks | 6 weeks | 
| Sleep Quality - Trouble Falling Asleep, 6 Months | The PSQ-3 questionnaire will be used to measure outcome. Participants will score the question How often have you had trouble falling asleep because of pain? by placing a slash (/) on a 10 cm line directly beneath the question. The line will have never and always at each end. A ruler will be used to determine were the slash falls. The value between, 0-10, that corresponds on the ruler with the slash will be documented. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 months. | 6 months | 
| Sleep Quality - Morning Pain, 6 Weeks | The PSQ-3 questionnaire will be used to measure outcome. Participants will score the question How often have you been awakened by pain during the morning? by placing a slash (/) on a 10 cm line directly beneath the question. The line will have never and always at each end. A ruler will be used to determine were the slash falls. The value between, 0-10, that corresponds on the ruler with the slash will be documented. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 weeks | 6 weeks | 
| Sleep Quality - Morning Pain, 6 Months | The PSQ-3 questionnaire will be used to measure outcome. Participants will score the question How often have you been awakened by pain during the morning? by placing a slash (/) on a 10 cm line directly beneath the question. The line will have never and always at each end. A ruler will be used to determine were the slash falls. The value between, 0-10, that corresponds on the ruler with the slash will be documented. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 months | 6 months | 
| Sleep Quality - Night Pain, 6 Weeks | The PSQ-3 questionnaire will be used to measure outcome. Participants will score the question How often have you been awakened by pain during the night? by placing a slash (/) on a 10 cm line directly beneath the question. The line will have never and always at each end. A ruler will be used to determine were the slash falls. The value between, 0-10, that corresponds on the ruler with the slash will be documented. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 weeks | 6 weeks | 
| Sleep Quality - Night Pain, 6 Months | The PSQ-3 questionnaire will be used to measure outcome. Participants will score the question How often have you been awakened by pain during the night? by placing a slash (/) on a 10 cm line directly beneath the question. The line will have never and always at each end. A ruler will be used to determine were the slash falls. The value between, 0-10, that corresponds on the ruler with the slash will be documented. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 months | 6 months | 
| DAS28 - Global Health (GH), 3 Months | DAS28 quantifies disease activity based on visual analogue scales (VAS) assessment of well-being rated on a scale of 0-100 mm.0is a better outcome, and 100 is a worse outcome. The value for each participant will be combined to obtain a median and inter-quartile range at 3 months | 3 months | 
| DAS28 - Global Health (GH), 6 Months | DAS28 quantifies disease activity based on visual analogue scales (VAS) assessment of well-being rated on a scale of 0-100 mm. 0is a better outcome, and 100 is a worse outcome. The value for each participant will be combined to obtain a median and inter-quartile range at 6 months | 6 months | 
| DAS28 - C-reactive Protein (CRP), 3 Months | DAS28 quantifies disease activity based on a mathematical formula that computes four variables: number of swollen and tender joints (total number of joints assessed is 28), CRP (mg/L) and visual analogue scales (VAS) for patient global assessment of well-being (0-100 mm). 0is a better outcome, and 100 is a worse outcome. The value for each participant will be combined to obtain a median and inter-quartile range at 3 months | 3 months | 
| DAS28 - C-reactive Protein (CRP), 6 Months | DAS28 quantifies disease activity based on a mathematical formula that computes four variables: number of swollen and tender joints (total number of joints assessed is 28), CRP (mg/L) and visual analogue scales (VAS) for patient global assessment of wellbeing (0-100 mm). 0is a better outcome, and 100 is a worse outcome. The value for each participant will be combined to obtain a median and inter-quartile range at 6 months | 6 months | 
| DAS28 - Erythrocyte Sedimentation Rate (ESR), 3 Months | DAS28 quantifies disease activity based on a mathematical formula that computes four variables: number of swollen and tender joints (total number of joints assessed is 28), ESR (mm/h) and visual analogue scales (VAS) for patient global assessment of well-being (0-100 mm). 0is a better outcome, and 100 is a worse outcome. The value for each participant will be combined to obtain a median and inter-quartile range at 3 months | 3 months | 
| DAS28 - Erythrocyte Sedimentation Rate (ESR), 6 Months | DAS28 quantifies disease activity based on a mathematical formula that computes four variables: number of swollen and tender joints (total number of joints assessed is 28), ESR (mm/h) and visual analogue scales (VAS) for patient global assessment of well-being (0-100 mm). 0is a better outcome, and 100 is a worse outcome. The value for each participant will be combined to obtain a median and inter-quartile range at 6 months | 6 months | 
| RAPID 3 - Abilities, 6 Weeks | A questionnaire that assesses abilities on a scale of 0-10. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 weeks. | 6 weeks | 
| RAPID 3 - Abilities, 6 Months | A questionnaire that assesses abilities on a scale of 0-10. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 months | 6 months | 
| RAPID 3 - Pain, 6 Weeks | A questionnaire that assesses pain on a scale of 0-10. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 weeks | 6 weeks | 
| RAPID 3 - Pain, 6 Months | A questionnaire that assesses pain on a scale of 0-10. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 months | 6 months | 
| RAPID 3 - Illness/Health, 6 Weeks | A questionnaire that assesses illness/health on a scale of 0-10. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 weeks | 6 weeks | 
| RAPID 3 - Illness/Health, 6 Months | A questionnaire that assesses illness/health on a scale of 0-10. 0is a better outcome, and 10 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 months | 6 months | 
| RAPID 3 - Cumulative Scores, 6 Weeks | The combined abilities, pain and illness/health scores. Recorded as a number between 0-30. 0is a better outcome, and 30 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 weeks | 6 weeks | 
| RAPID 3 - Cumulative Scores, 6 Months | The combined abilities, pain and illness/health scores. Recorded as a number between 0-30. 0is a better outcome, and 30 is a worse outcome. The value for each participant will be combined to report a median and inter-quartile range at 6 months | 6 months | 
| RAPID 3 - Weighed Scores, 6 Weeks | The cumulative score conversion (based on a table). Recorded as a number between 0-10. 0-1 is near remission, 1.3-2 is low severity, 2.3 -4 is moderate severity, and 4.3 - 10 is high severity. The value for each participant will be combined to report a median and inter-quartile range at 6 weeks | 6 weeks | 
| RAPID 3 - Weighed Scores, 6 Months | The cumulative score conversion (based on a table). Recorded as a number between 0-10. 0-1 is near remission, 1.3-2 is low severity, 2.3 -4 is moderate severity, and 4.3 - 10 is high severity. The value for each participant will be combined to report a median and inter-quartile range at 6 months | 6 months | 
| VAS Pain Scale - 6 Weeks | A pain assessment using a horizontal line with numbers, 0-10, along the axis with endpoints no pain to worse possible pain. 0is a better outcome, and 10 is a worse outcome. Participants will mark on the line the level of pain they are experiencing now. The value for each participant will be combined to report a median and inter-quartile range at 6 weeks | 6 weeks | 
| VAS Pain Scale - 6 Months | A pain assessment using a horizontal line with numbers, 0-10, along the axis with endpoints no pain to worse possible pain. 0is a better outcome, and 10 is a worse outcome. Participants will mark on the line the level of pain they are experiencing now. The value for each participant will be combined to report a median and inter-quartile range at 6 months | 6 months | 
| MRI - Synovitis, Combined Score (CS), Right, 3 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 3 months will then be calculated for each participant. Participants with a lower median score at 3 months relative to baseline will be considered improved for the 3 month time point. The number of participants with improved scores will be added to form the total number with improvement at 3 months | 3 months | 
| MRI - Synovitis, Combined Score (CS), Right, 6 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 6 months will then be calculated for each participant. Participants with a lower median score at 6 months relative to baseline will be considered improved for the 6 month time point. The number of participants with improved scores will be added to form the total number with improvement at 6 months | 6 months | 
| MRI - Synovitis, Combined Score (CS), Left, 3 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 3 months will then be calculated for each participant. Participants with a lower median score at 3 months relative to baseline will be considered improved for the 3 month time point. The number of participants with improved scores will be added to form the total number with improvement at 3 months | 3 months | 
| MRI - Synovitis, Combined Score (CS), Left, 6 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 6 months will then be calculated for each participant. Participants with a lower median score at 6 months relative to baseline will be considered improved for the 6 month time point. The number of participants with improved scores will be added to form the total number with improvement at 6 months | 6 months | 
| MRI - Bone Erosion, Combined Score (CS), Right, 3 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-10 based on the proportion of bone involved. 0 is best outcome, 10worse outcome. The median score of all 23 joints at baseline and 3 months will then be calculated for each participant. Participants with a higher median score at 3 months relative to baseline will be considered improved for the 3 month time point. The number of participants with improved scores will be added to form the total number with improvement at 3 months | 3 months | 
| MRI - Bone Erosion, Combined Score (CS), Right, 6 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-10 based on the proportion of bone involved. 0 is best outcome, 10worse outcome. The median score of all 23 joints at baseline and 6 months will then be calculated for each participant. Participants with a higher median score at 6 months relative to baseline will be considered improved for the 6 month time point. The number of participants with improved scores will be added to form the total number with improvement at 6 months | 6 months | 
| MRI - Bone Erosion, Combined Score (CS), Left, 3 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-10 based on the proportion of bone involved. 0 is best outcome, 10worse outcome. The median score of all 23 joints at baseline and 3 months will then be calculated for each participant. Participants with a higher median score at 3 months relative to baseline will be considered improved for the 3 month time point. The number of participants with improved scores will be added to form the total number with improvement at 3 months | 3 months | 
| MRI - Bone Erosion, Combined Score (CS), Left, 6 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-10 based on the proportion of bone involved. 0 is best outcome, 10worse outcome. The median score of all 23 joints at baseline and 6 months will then be calculated for each participant. Participants with a higher median score at 6 months relative to baseline will be considered improved for the 6 month time point. The number of participants with improved scores will be added to form the total number with improvement at 6 months | 6 months | 
| MRI - Oedema, Combined Score (CS), Left, 3 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 3 months will then be calculated for each participant. Participants with a lower median score at 3 months relative to baseline will be considered improved for the 3 month time point. The number of participants with improved scores will be added to form the total number with improvement at 3 months | 3 months | 
| MRI - Oedema, Combined Score (CS), Left, 6 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 6 months will then be calculated for each participant. Participants with a lower median score at 6 months relative to baseline will be considered improved for the 6 month time point. The number of participants with improved scores will be added to form the total number with improvement at 6 months | 6 months | 
| MRI - Oedema, Combined Score (CS), Right, 3 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 3 months will then be calculated for each participant. Participants with a lower median score at 3 months relative to baseline will be considered improved for the 3 month time point. The number of participants with improved scores will be added to form the total number with improvement at 3 months | 3 months | 
| MRI - Oedema, Combined Score (CS), Right, 6 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 6 months will then be calculated for each participant. Participants with a lower median score at 6 months relative to baseline will be considered improved for the 6 month time point. The number of participants with improved scores will be added to form the total number with improvement at 6 months | 6 months | 
| Ultrasound - Synovitis, Combined Score (CS), Right, 3 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 3 months will then be calculated for each participant. Participants with a lower median score at 3 months relative to baseline will be considered improved for the 3 month time point. The number of participants with improved scores will be added to form the total number with improvement at 3 months | 3 months | 
| Ultrasound - Synovitis, Combined Scale (CS), Right - 6 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 6 months will then be calculated for each participant. Participants with a lower median score at 6 months relative to baseline will be considered improved for the 6 month time point. The number of participants with improved scores will be added to form the total number with improvement at 6 months | 6 months | 
| Ultrasound - Synovitis, Combined Score (CS), Left, 3 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 3 months will then be calculated for each participant. Participants with a lower median score at 3 months relative to baseline will be considered improved for the 3 month time point. The number of participants with improved scores will be added to form the total number with improvement at 3 months | 3 months | 
| Ultrasound - Synovitis, Combined Score (CS), Left, 6 Months | Each of the 23 joints in the hand/wrist will be assigned a score from 0-3 based on the proportion of bone involved. 0 is best outcome, 3worse outcome. The median score of all 23 joints at baseline and 6 months will then be calculated for each participant. Participants with a lower median score at 6 months relative to baseline will be considered improved for the t month time point. The number of participants with improved scores will be added to form the total number with improvement at t months | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, Hyperbaric Oxygen