This R21 project will consist of three phases: 1) treatment manual development; 2) initial administration and refinement of treatment; 3) a pilot study to evaluate treatment outcome compared to an attention wait-list control condition. These three phases are briefly summarized below.
Phase one (3 months)
During this phase, the initial version of the manual will be written. Based on our preliminary studies described above, this manual will describe yoga, breath and meditation exercises that are consistent with specific needs of young RA patients. Attention will also be given to how the poses can best be modified to ensure patients' joints and areas of weakness are protected. The manual will be developed by the study yoga teacher, who will review the intervention with senior Iyengar yoga teachers. During this phase, we will also develop a protocol to evaluate IY instructors' adherence to the manual.
Phase two (3 Months)
We will further develop the protocol by conducting an initial IY group. We will also train an additional experienced IY instructor and two assistant instructors. The two IY teachers, with their assistants, will teach a small class of 3 AYA RA patients each (total n = 6) to refine the protocol. The purpose of the assistant instructors is threefold: to promote class safety by assisting patients safely in and out of poses and to record adverse events to bring to the attention of the Safety Board (described below); to take class attendance for determination of patient adherence; and to record the poses and modifications used in each class to be evaluated by the Board (described below) for teacher adherence to the core set of poses. The assistants will note for each student: which poses were performed, which props were used, and any difficulties experienced. Weekly team meetings chaired by the PI will be conducted to solicit suggestions on additional refinements to the protocol.
Phase three (18 Months)
In this final phase, IY teachers will administer the IYP using the revised manual to 70 participants who will be assigned to either treatment (n = 35) or usual care control (n = 35). The controls will be immediately assigned to IYP at the end of the control phase (see Figure ).
A randomized control trial (RCT) design will be used to examine the impact of IYP for adolescents and young adults aged 16-35 years with RA on the primary outcomes of general and arthritis-specific functioning, and the secondary outcomes of DAS28, pain and mood.
The overall design of the study is depicted in Figure below. After participants have completed the telephone screening and meet the study's eligibility criteria, they will be randomized into the IYP or usual care control group. All participants will be asked to fill out consent forms before their initial medical assessment, which includes a phlebotomy, measurement of blood pressure/resting heart rate, and a joint count conducted by a physician who will be kept unaware of group assignment. Before the medical assessment, a research assistant will send a link to the questionnaires for participants who choose to complete them online. A hard copy of the questionnaires will be taken to the medical assessment if the participant chooses to complete the paper-based version in a private medical office.
Those assigned to the IYP will then engage in the 6-week program; they will repeat the baseline assessments immediately following treatment and again at a two-month follow-up. Patients initially assigned to the wait-list group will continue their usual care. Both the yoga and control groups will either receive weekly phone calls or e-mails to monitor symptoms, medication use and physical activity. After 6 weeks, control participants will be re-assessed to ensure that they still meet study eligibility criteria; those that continue to meet criteria will then take part in the IYP. Following the IYP, participants will then repeat the baseline assessments at post-treatment and two-month follow-up.
Young women and men will be eligible for the study if they meet the following criteria:
• Age 16-35 years.
• Diagnosis of RA, according to the revised 1987 ACR criteria for at least 6 months.
• Concomitant use of disease modifying antirheumatic medications (hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, etc.) and/or biologic agents (infliximab, etanercept, adalimumab, abatacept, rituximab, anakinra) is permitted provided that the dose(s) have been stable for 8 weeks prior to screening, and subjects may reasonably be expected to remain on stable doses throughout the study.
• Concomitant use of NSAIDs and low dose corticosterioids (e.g., prednisone at doses of 10 mg/day prednisone or equivalent) is permitted provided that the dose(s) have been stable for 4 weeks prior to screening, and subjects may be expected to remain on stable doses throughout study duration.
• Disease activity, as defined using a 28 joint count by ≥ 5 tender joints, ≥ 5 swollen joints, and one of the following: Erythrocyte Sedimentation Rate (ESR) ≥ 28 mm/hour, C-reactive protein (CRP) ≥ 1.5 mg/dL, duration of a.m. stiffness ≥ 45 minutes.
• Able and willing to give written informed consent and comply with the requirements of the study.
• Ability to speak and understand English.
Patients will be excluded from the study based on the following criteria:
• Intra-articular steroid injections within 4 weeks of screening.
• Treatment with any investigational agent within 8 weeks of screening or 5 half-lives of the investigational drug (whichever is longer).
• History of drug, alcohol, or chemical abuse within 6 months prior to screening.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion that might affect the interpretation of the results or render the patient at high risk from treatment complications.
• Inability to comply with study and follow-up procedures.
• Currently pregnant.
• Previous practice of Iyengar yoga within the past three months.
• Inability to speak and understand English.
According to the Power/Sample Size calculations outlined below, we will recruit 35 patients each for the IYP and control conditions. After accounting for our projected attrition rate of 20%, we estimate there will be roughly 28 treatment completers in each condition. To accommodate 56 participants during the 36-month study period, we plan to conduct 4 initial IYP groups and 4 initial control groups, with approximately 8 patients in each group.
Sample Size Determination and Power Analysis
A power analysis was conducted to determine the appropriate sample size. Using a pre-test post-test for randomized groups, calculating power of the interaction of treatment by time, the sample size estimate is a total sample of 54, or 27 subjects per group (at a 0.05 significance level, 80% power for a medium effect size). We calculated a medium effect size given that our recent single-arm pilot study found an effect size of .46 (Cohen's d) for the HAQ, our arthritis-specific primary outcome measure. Assuming a 20% attrition rate that is consistent with our previous yoga studies, we will recruit 35 participants for each group (total n = 70).
Before completing the baseline assessments, participants will be randomly allocated to the intervention or control group. The research team will assign the patient to the groups using randomization schedules generated by UCLA Biomathematics for group assignment in blocks of 4. As each patient is enrolled, he or she will be assigned to the next number on the list and the associated condition, yoga or usual care.
Participants will be recruited from the UCLA Division of Rheumatology, the UCLA pediatric rheumatology program, private medical offices of rheumatologists, UCLA Student Psychological Services, health newsletter ads, the young adult support network of the Southern California Chapter of the Arthritis Foundation, and community resources, such as library and other public notice boards, as well as websites, such as Craigslist. The UCLA Division of Rheumatology has a current patient population of 150 individuals with RA who are 16-21 years of age. The UCLA pediatric rheumatology program sees 100 patients with arthritis 16 years and older. Private practice rheumatologists in Los Angeles who have agreed to assist with our project can refer an additional 200 patients with RA in our targeted age range. The Southern California chapter of the Arthritis Foundation will help us recruit from their pool of several hundred RA patients who regularly receive their email announcements and mailed bulletins. In all, we anticipate being able to recruit from a pool of over 500 individuals with RA in the targeted age-range.
The project director will meet with health care providers, staff and support group leaders to inform them about the project and to ask them to distribute and post flyers about the study. The flyers will describe the project and ask interested volunteers to call the project manager to establish their eligibility. Additionally, a lay advisory board comprised of young adults with RA will be formed and consulted with in the development of recruitment materials as well as in the finalization of the protocol and research instruments.
Effort will be made to recruit the patient sample to be broadly representative of the general population of RA patients in the targeted age range. Epidemiological data suggest that the racial composition of RA in the U.S. is approximately 84.4% non-Hispanic whites, 8.3% non-Hispanic blacks, 2.3% Mexican American and 5% other [50
]. Women are between 60-75% more likely to experience RA than men [50
]. We will also attempt to recruit patients to reflect the demographic composition of the Greater Los Angeles area which is estimated to be approximately 75% White, 13% Asian, 10% African-American, 1% American Indian/Alaska Native, and 1% Native Hawaiian/Other Pacific Islander; ethnic makeup will be 45% Hispanic and 55% Non-Hispanic.
Iyengar Yoga Program (IYP)
IY is a traditional form of yoga taught in the lineage of BKS Iyengar, who is known for his prominent texts on yoga and innovative teaching techniques. Iyengar has developed specific methods of teaching therapeutic yoga practices to people with health problems [52
]. IY is an ideal form of activity for people with RA, as the emphasis on alignment in this practice protects joints, is unlikely to irritate inflamed joints and involves sufficient movement to tap the beneficial effects of exercise. Young RA patients with fatigue, restricted motion and painful joints can perform postures with the support of props (blocks, bolsters, chairs, straps and blankets) that allow postures to be held without stress. Yoga postures are designed to promote circulation, stimulate the hormonal system and circulate lymph through body position and muscle activity. The use of props allows inverted postures to be held for long periods of time without fatigue so that the lymph is well circulated without strain. Challenging back bending postures designed to stimulate the adrenal glands can also be held for longer periods of time with the support of props. The poses to be included in this intervention are based on the teachings of BKS Iyengar. The poses include supine poses, passive backbends, standing poses, seated poses, forward bends and supported inversions. All will be done with use of props as needed (see Figure ).
Yoga taught in the Iyengar tradition is known for an extensive teacher training program. Iyengar teachers study for at least seven years before being certified to work with students who have therapeutic needs. They must pass several certification tests before an impartial national board. These tests include teaching, performance of poses and breathing techniques, anatomy and therapeutic sequences. Because of this training, IY teachers across the country and around the world can accurately reproduce the IYP in this study.
The proposed IYP will be administered twice a week for 1.5 hours duration per session for 6 weeks. Due to the extensive time commitment required for the IYP, there will be no instructions for home practice, but neither will participants be discouraged from practicing at home. At the end of the 6-week IYP, those participants who ask for referrals to IY studios/teachers in the community will be given a list of referrals. All home practice as well as post-IYP yoga classes will be monitored during the weekly phone calls/e-mails and at the post-treatment and follow-up assessments; the extent of home practice will be evaluated in the analyses for its potential impact on outcome.
Should subjects experience a flare-up during the IYP, the research team will consult with the patient's rheumatologist and a modified version of the IYP will be offered to the subject consisting of restorative poses that do not place strain on the affected joints.
As illustrated in Figure , two streams of yoga classes will run concurrently to minimize the overall length of the study and to maximize the likelihood that yoga classes will be convenient for patients' schedules. For example, Stream 1 classes will be held on Mondays and Wednesdays, while Stream 2 classes will be held on Tuesdays and Thursdays. Stream 1 and Stream 2 will comprise the first Wave of patients (Wave 1). Upon the completion of Wave 1, a second wave of patients (Wave 2) will consist of two additional Streams of classes. A make-up class will be scheduled each week for any patient not able to attend their usual session. Thus, all patients should be able to receive the full course of IYP since classes will be run 5 days per week (e.g., make-up classes held on Fridays). We will make note of how many make-up classes each patient attends and test for possible differential effects due to missing regular classes. Patients in the control groups will be given the opportunity to take part in the IYP at the end of the 6-week control period. To increase patient safety and accurate practice of poses, IY classes will hold a maximum of 9 patients.
Usual care control
Patients initially assigned to this condition will be instructed to continue with their on-going medical care. During the control period, these patients will be telephoned or emailed by study personnel to complete the weekly monitoring form (described below) to monitor symptoms, functioning and mood.