Effects of a home-based exercise combined yoga and resistance training in enthesitis-related arthritis in China: study protocol for a randomised controlled trial

Abstract

Introduction

Enthesitis-related arthritis (ERA) is a category of juvenile idiopathic arthritis (JIA). The complications of JIA include pain, muscle weakness, limited movement and worsening quality of life. Yoga is an effective exercise therapy for rheumatoid arthritis and may have similar benefits for JIA. Considering the limitation of yoga for strengthening muscles, combined yoga and resistance training (CYRT) may compensate for the shortcomings and provide more benefits for JIA patients. Despite this, there is currently a lack of studies investigating the effectiveness of CYRT for JIA patients. Due to the inaccessibility of traditional exercise therapy, home-based exercise is needed. The study aims to assess the effectiveness of home-based CYRT on JIA.

Methods and analysis

This is a 12-week randomised single-blind controlled trial study. 60 patients with ERA will be randomised into two groups: the home-based exercise group (HBE) and the health education (HE) group. The HBE group (n=30) will perform the CYRT programme 3 times a week at home for 12 weeks and receive HE. The HE group (n=30) will only receive HE. The outcomes include primary outcome (pain levels) and secondary outcomes (lower limb muscle strength, motion range of joint, aerobic fitness, function ability, fatigue levels, mental health, quality of life and blood biomarkers). The assessments will be conducted at baseline, postintervention (12 weeks) and follow-up (24 weeks). Data will be analysed by intention to treat.

Ethics and dissemination

This study has been approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine in December 2023 (approval no. XHEC-C-2023-059-3). This study will require informed consent from all subjects and guardians of children under 18 years of age. The findings will be published in a peer-reviewed journal and international conferences.

Trial registration number

ChiCTR2300073446.

MZ, JL and YS are joint first authors.

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The inclusion of a single type enthesitis-related arthritis (ERA) in this study will help mitigate potential confounding variables resulting from subtype differences.

• Comprehensive and systematic outcomes including objective clinical outcomes, subjective clinical outcomes and blood biomarkers will be employed to systematically assess the effects of exercise on ERA.

• The application of monitoring online and behaviour change strategies will increase the accessibility and adherence to combined yoga and resistance training.

• This study will not be blinded to the subjects due to the nature of exercise therapy, potentially introducing some bias into the findings.

Introduction

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood,¹ which is categorised into seven mutually exclusive subtypes according to the International League of Associations for Rheumatology criteria.² In seven categories, enthesitis-related arthritis (ERA) is the most common subtype in Southeast Asia affecting approximately 30% of all JIA and is associated with a poorer prognosis than other subtypes.^{3 4} Distinguishing clinical characteristics related to ERA include probable enthesitis and spinal involvement, and peripheral arthritis often presents as asymmetric arthritis of the lower extremities.^{5 6} These arthritis symptoms can lead to muscle weakness around the involved joints, limited range of joint motion, impaired aerobic fitness, fatigue, and resultant decreased function ability, reduced physical activity (PA), and an increase in the risk of fracture.^{7 8} These consequences may further affect their social participation and mental health, ultimately resulting in a lower quality of life and a higher economic burden for individuals, families and society.^{7 9}

Although the pathogenesis of JIA is extremely complex and the exact understanding is still unclear, dysregulation of the immune system including innate and adaptive immunity triggered by environmental and genetic factors is generally accepted.^10–12 In the intricate realm of inflammatory responses, cytokines may play an important role. Such key cytokines include proinflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17)) and anti-inflammatory cytokines (mainly IL-10).^13–17 Previous studies have observed elevated levels of the proinflammation cytokines mentioned above in synovial fluid.^18–20 Furthermore, heterodimeric complexes S100A8/A9 (MRP8/14) and S100A12 protein are highly studied as proinflammatory proteins with potential associations with disease activity in rheumatoid arthritis (RA) and JIA.^20–23 Local infiltration of these inflammatory factors in synovium can act on pain receptors and thus cause joint pain and swelling, activity limitation and decreased quality of life.^24–26

The 2019 American College of Rheumatology recommended that pharmacological therapy should be combined with family, nurses, therapists, ophthalmologists and psychologists, creating a multidisciplinary, collaborative management paradigm for patients with JIA.²⁷ Among them, physical therapy and occupational therapy are the necessary components for managing JIA.²⁷ Exercise therapy, as a component of physical therapy, is recognised as the most potential approach to manage the negative consequences of JIA.^{7 27–31} Yoga, a body-mind exercise, is recently popular with patients with RA and osteoarthritis.^32–35 In the context of JIA, limited studies have indicated that yoga also seems to be a potential method for improving the function ability of lower extremities, pain levels and quality of life in patients with JIA.^{36 37} However, as a low-intensity mind-body exercise, the improvement of yoga on muscle strength is limited.³⁸ Considering the importance of muscle strength for patients with JIA, it is necessary to incorporate additional exercises to optimise the yoga programme. Resistance training (RT) is a basic component of physical therapy for improving muscle strength and endurance.³⁹ Previous studies have demonstrated that RT can enhance muscle strength and improve functional ability.^{24 40 41} Therefore, the additional involvement of RT may be able to compensate for the limitations of the low intensity of yoga, resulting in a more comprehensive benefit for children with JIA. Additionally, both yoga and resistance training have the potential to decrease the release of inflammatory mediators, which may lead to pain relief, improved functional ability and enhanced quality of life.^42–44 Despite the potential advantages of combined yoga and resistance training (CYRT), there is currently a lack of studies investigating its effectiveness for patients living with JIA.

Due to the high time-consuming and healthcare expenditure of traditional exercise therapy, there is a growing demand for home-based exercise (HBE) in the long-term management of JIA.^{24 41 45} Previous studies have demonstrated that HBE has an acceptable adherence rate of approximately 70%.^{24 41 45} Based on these encouraging findings, the exercise programme of this study will be conducted at home under online monitoring.

This is a 12-week, randomised, single-blind, controlled trial superiority study. The aims of this study are to (1) evaluate the effects of the home-based exercise programme combined yoga and resistance training (HBECYRT) on primary outcome (pain levels), and secondary outcomes (lower limb muscle strength, motion range of joint, aerobic fitness, function ability, fatigue levels, mental health, quality of life and blood biomarkers) in children with JIA and (2) investigate the underlying mechanism of exercise on JIA and its complications.

Methods and analysis

Study setting

This is a 12-week single-blind randomised controlled trial superiority study conducted at Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, China. Children and adolescents meeting the eligibility criteria will be recruited and assigned randomly to two groups: the home-based exercise group (HBE) and the health education group (HE). The HBE group will undergo a 12-week HBECYRT programme under online monitoring, while the HE group will only receive HE. Assessments will be conducted at three time points: baseline, postintervention (12 weeks) and follow-up (24 weeks). The schedule of the enrolment, interventions and assessments can be seen in table 1. The flow diagram of this study can be seen in figure 1.

Figure 1. The flow diagram of this study

Table 1

Schedule of recruitment, interventions and assessments

Study period	Recruitment	Allocation	Intervention		Close-out	Follow-up
Time point	Before 0 week	0 week	0 week	1–12 weeks	13 weeks	24 weeks
Inclusion and exclusion criteria	×
Informed consent	×
Demographic data		×
Randomised allocation		×
Home-based exercise				×
Health education				×
Pain levels			×		×	×
Lower limb muscle strength			×		×	×
Motion range of joint			×		×	×
Aerobic fitness			×		×	×
Function ability			×		×	×
Fatigue levels			×		×	×
Mental health			×		×	×
Quality of life			×		×	×
Blood biomarkers			×		×	×
Physical activity control			×	×	×	×
Adverse events				×	×	×
Adherence rate				×	×	×
Drop-out				×	×	×

Inclusion criteria

• Children and adolescents who meet the 2018 Pediatric Rheumatology International Trials Organization classification criteria for ERA.⁴⁶

• Children and adolescents aged 8–16.

• Patients experiencing joint pain.

• Participants with stable disease conditions.

• Individuals without a regular exercise habit or physical therapy routine.

• Children and adolescents who can exercise under parental supervision.

• Participants who have provided informed consent.

Exclusion criteria

• Subjects with serious primary diseases affecting exercise, such as cardiorespiratory comorbidities, contractures and other musculoskeletal disorders.

• Participants with a history of joint corticosteroid injections within the past 3 months.

• Participants who have undergone joint surgery in the past 3 months or are scheduled to undergo joint surgery in the next 6 months.

Randomisation and blind

Subjects who meet the eligibility criteria will be informed of the purpose, procedures and potential risks involved in this study. If they express interest in participating, they will be asked to sign an informed consent form. Following enrolment, a blinded biostatistician will use a computer software (SPSS V.27.0) to generate a simple randomisation sequence. Subsequently, the subjects will be randomised into two groups of equal size: the HBE group and the HE group. The randomisation and group allocation data will be stored as an opaque electronic document by a researcher not directly involved in the study. The intervention will be conducted by a therapist from the study staff following the specific programme for each group. The therapist will be the only one to be aware of group allocation.

Intervention

To ensure participants’ familiarity with the key information and procedure of the intervention, the participants in the HBE group will undergo three preintervention sessions about the HBECYRT in the hospital. On the other hand, participants in the HE group will only receive HE lessons.

The home-based exercise programme

This is a home-based combined exercise programme. The participants in the HBE group will be asked to access researcher-customised software, which will contain preuploaded exercise videos recorded by the researchers. These exercise videos will be recorded by a yoga instructor with 5 years of yoga teaching experience and an experienced physical therapist, who has participated in 2–3 clinical education sessions about the clinical manifestations and functional disorders of JIA before recordings. The HBE group will engage in the HBECYRT programme for 45–60 min three times a week for 12 weeks. Each programme session is divided into four sections: warm-up consisting of breath and joint mobility training for 5 min, yoga poses for 20–30 min, resistance training for 10–15 min and cool-down consisting of stretching exercises and meditation for 10 min. Every section will be guided by a prerecorded video recorded by a professional yoga instructor and physical therapist. The details are presented in table 2.

Table 2

Details of home-based exercise programme

Warm-up (5 min)
Yoga poses (20–30 min)
Poses description				Progress programme	Maintain (s)/
					Repetition (time)
Mountain pose Standing on a mat, feet together or slightly apart, with the weight of the body evenly distributed over the feet. Spine straight, place arms naturally at the sides of the body, tighten the abdomen, keep the body relaxed. Look forward, focus on the sensations of the body and the breath.				1–4 weeks Hip-width apart	30/1
				5–8 weeks Stand with feet together	60/1
				9–12 weeks Stand with feet together, close eyes	60/1
Swaying palm tree pose (tiryaka tadasana) Feet together or hip-width apart, fingers extended. Raise arms upward slowly with palms facing each other, gaze forward. Exhale, bend the upper body to the left side; inhale back to centre; exhale to the right side bend, inhale back to centre.				1–4 weeks Feet hip-width apart	5/3
				5–8 weeks Stand with your feet together	5/3
				9–12 weeks Stand with your feet together, close eyes	5/3
Warrior I (virabhadrasana I) From mountain pose, stand forward one leg, knee flexion at a 90° angle and keep the back leg extended straight and the toes turned outward. Raise arms and gaze forward or slightly upward. Breathe naturally. Alternate between both sides.				1–4 weeks Simplified warrior I: Knee at a proper degree depends on pain levels	10/3
				5–8 weeks Simplified warrior I: Knee at proper degree depends on pain levels	15/3
				9–12 weeks Standard warrior I	15/3
Warrior II (virabhadrasana II) Stand with your feet slightly wider than shoulder-width apart. Keep your arms parallel to the floor with palms facing down. Step your legs wide apart and bend one knee at a 90° angle while extending the knee of the other leg. Alternate between both sides.				1–4 weeks Simplified warrior II: Knee at proper degree depends on pain levels	10/3
				5–8 weeks Simplified warrior II: Knee at proper degree depends on pain levels	15/3
				9–12 weeks Standard warrior II	15/3
Extended triangle pose (trikonasana) Stand with feet slightly wider than shoulder-width apart, keeping the body straight. Turn one foot to the side with the toes pointing outward, and the toes of the other foot pointing forward. Extend both arms parallel to the floor, palms facing down. Bend the body sideways towards one side, reaching one hand towards the floor and the other hand straight up. Gaze at the hand pointing upward.				1–4 weeks Simplified triangle pose	10/3
				5–8 weeks Same as the programme at 1–4 weeks	15/3
				9–12 weeks Same as the programme at 1–4 weeks	15/3
Cat-cow pose (marjaryasana-bitilasana) Start with hands and knees on the floor. Exhale, arch the spine upward, draw the belly inwards and gaze towards the waist. Inhale, slowly lift the head and chest, allowing the spine to curve downward, while lifting the tailbone upward.				1–4 weeks Cat-cow pose	10/3
				5–8 weeks Cat-cow pose	10/5
				9–12 weeks Cat-cow pose	10/5
Tiger pose (vyaghrasana) Kneel on the yoga mat with knees aligned with hips, hands aligned with shoulders and arms perpendicular to the floor. Extend one leg backward and lift it parallel to the ground, maintaining balance. Extend the opposite arm straight ahead with the palm facing down, maintaining it parallel to the floor. Alternate between both sides.				1–4 weeks Simplified tiger pose: only extend one leg back, not extend forward the opposite arm	10/3
				5–8 weeks Standard tiger pose	15/3
				9–12 weeks Standard tiger pose	20/3
Bridge pose (setu bandhasana) On supine position with feet flat on the ground, knees bent and heels close to the hips. Allow both arms to rest naturally at the sides of the body. Slowly lift the hips, activating the core and hip muscle groups.				1–4 weeks Bridge pose	5/10
				5–8 weeks Bridge pose	10/10
				9–12 weeks Bridge pose	10/10
Resistance training programme (10–15 min)
Weeks	Intensity (% 1RM)	Sets	Repetitions	Exercises	Interval between sets (s)
1–4	60%–65%	2	12	Hip abduction, knee extension, ankle dorsiflexion, crunch core exercises, bicycle crunches	30
5–8	70%–75%	3	10	Hip abduction, knee extension, ankle dorsiflexion, crunch core exercises, bicycle crunches	30
9–12	75%–80%	3	8	Hip abduction, knee extension, ankle dorsiflexion, crunch core exercises, bicycle crunches	30
Cool down (10 min)

1RM, one-repetition maximum.

The warm-up consists of breathing exercises and joint mobility training, aiming to gently warm up the entire body. The yoga poses focus on various basic poses rooted in classic Hatha yoga. These poses are performed at a slow pace, emphasising correct posture and technique. The yoga protocol is modified from some asanas in the study by Yasar et al.³⁷ Mountain pose, swaying palm tree pose, warrior I, warrior II, extended triangle pose, cat-cow pose, tiger pose and bridge pose will be included. The main aims of these poses are to activate the body, enhance core stability, stretch the spine to reduce the tension of muscles, and thus relieve pain. The yoga programme will progress by increasing the maintenance time of movement and the difficulty of poses every 4 weeks.

Following the yoga session, participants will proceed to resistance training, mainly targeting the lower extremities and core muscle groups. Before this study, participants in the HBE group will employ a one-repetition maximum (1RM) test to assess participants’ muscle strength to determine the suitable intensity for the Thera-band resistance training. The resistance training consists of Thera-band resistance training (hip abduction, knee extension and ankle dorsiflexion) and body weight resistance training (crunch core exercises and bicycle crunches). The participants will perform 8–12 repetitions and 2–3 sets. Based on previous research, the exercise intensity of the resistance training section for this study will be set at 60%–80% of 1RM, with a 5%–10% range of progressive intensity.⁴⁷ Once subjects successfully completed two sets at a specific intensity, an increase in exercise intensity could be considered.⁴⁸ Exercise intensity will be progressed every 4 weeks. Subjects in the HBE group will be asked to receive an exercise assessment every 4 weeks to determine the increase in exercise intensity. The intensity will be progressed by increasing the number of sets or intensity of Thera-band.

At the end of each session, a 10 min cool-down session will be implemented, which includes stretching exercises and meditation.

Modifications to the exercise programme

This study will employ an individually tailored exercise programme. The yoga section will initially employ a standardised yoga exercise protocol, which can be adjusted according to pain levels during exercise. The Thera-band resistance training section will be based on a 1 RM value for each individual, which can also be adjusted according to pain levels during exercise. If pain levels are ≤3 (Numeric Rating Pain Scale, NRP), the established exercise protocol would be followed; if >3 (NRP), exercise difficulty would be reduced.

HE programme

All participants have access to HE lessons recorded by the researchers (an experienced rheumatologist and an experienced physical therapist). The content will include the diagnostic criteria, pathogenesis, categorisation, risk factors, long-term prognosis of JIA, management strategy, physical therapy and occupational therapy, PA, and daily considerations for JIA. Each HE session will last 45 min and will occur once a month, as detailed in table 3. Participants will be allowed to watch the courses as many times as they wish during the study.

Table 3

Details of the health education programme

Weeks	No of courses	Education session topic	Duration (min)
1–4	1	Diagnostic criteria, pathogenesis, categorisation, risk factors and long-term prognosis of JIA	45
5–8	1	Management strategy (pharmacological and non-pharmacological treatment)	45
9–12	1	Physical and occupational therapy, PA and daily considerations	45

JIA, juvenile idiopathic arthritis; PA, physical activity.

Behavioural change techniques

This study will employ the behaviour change techniques reported by Bennell et al⁴⁹ to motivate participants to perform the exercise programme.

• Motivation increasing: Explanation that exercise would not worsen arthritis and description of the benefits of exercise for arthritis in the exercise videos and HE lessons.

• Goal setting: Establishing a clear exercise training schedule, including frequency of exercise and dosage for each yoga exercise and resistance exercise.

• Reduction of barrier factors: Regular group discussions about adherence barriers and problem-solving will be conducted in the monthly assessment sessions.

• Self-monitoring: Encouraging subjects and their guardians to engage in self-monitoring.

• Relapse prevention: Instructing patients on how to modify exercise details to prevent adverse events.

• Rewards: Encouraging patients to use self-incentives to improve their adherence to exercise.

Monitoring programme

The researchers will distribute the exercise programme videos and schedule of exercises through customised software. There should be a 1-day interval between the two training sessions. On training days, the researchers will send messages to remind subjects in HBE to perform the exercise. After completion of the exercise, participants will be required to upload their exercise videos to the customised software. Subsequently, researchers will provide feedback and corrections based on the exercise videos uploaded by participants, which will further improve the adherence to the exercise protocol. The backend of the software will allow access to participants’ exercise information, including duration, frequency and rating of perceived exertion according to the Borg scale. If a participant is unable to attend the scheduled training session, a makeup session will be arranged within the same week.

Outcome

To evaluate the short-term and long-term effects of the HBECYRT programme and HE, outcomes will be evaluated at three time points: baseline (0 week), postintervention (12 weeks) and follow-up (24 weeks).

Primary outcome

Pain levels

The NRP, ranging from 0 to 10, will be employed to assess pain intensity, where a score of 0 indicates no pain and a score of 10 indicates extreme pain.⁵⁰

Secondary outcome

Objective outcomes

Lower limb muscle strength

The strength of the muscles around the hip, knee and ankle will be assessed using a hand-held dynamometer (HHD, Lafayette Instrument, Lafayette, UK).^{51 52} The HHD has been validated as a portable, reliable, cost-effective method for assessing muscle strength.⁵¹ The HHD protocol used in this study will be based on the method reported by Hébert et al.⁵³ The dynamometer will be positioned between the leg and a strap fastened to the bed frame to reduce reliance on the strength of the assessor. Before the actual test, participants will be instructed to perform two warm-up contractions at 50% of their maximum effort to familiarise themselves with the task. In the actual testing, the participants will be required to exert their utmost to complete isometric contraction of target muscle groups for 10 s. Three repetitions of the test will be conducted, with a 1 min interval between each repetition. Finally, the average value will be calculated.

Range of motion

The passive range of motion and active range of motion of the hip, knee and ankle will be measured using a universal goniometer. The measurements will be conducted 3 times, and the average value will be calculated.

Aerobic fitness

The 6 min walking test (6-MWT) will be used to assess aerobic fitness. Lelieveld et al⁵⁴ have established the validity and reliability of the 6-MWT in the population with JIA. The measurement will be conducted in an 8 m hallway, and participants will be instructed to cover the maximum distance possibly within six min. During the test, subjects will be permitted to pause and rest based on their physical condition but the timing will continue. At the end of the six min, the assessor will calculate the total distance covered during the test.

Function ability

Children Health Assessment Questionnaire (CHAQ), a widely used tool with reliability and validity,⁵⁵ will be used for assessing functional ability over the past week. The CHAQ encompasses the following eight items: dressing and grooming, rising and sitting, eating, walking, self-hygiene, reaching, grip, and activity. Each item is scored on a scale ranging from 0 to 3 and the total scores are the average scores of the eight items. A score of 0 indicates no limitation in activity, while a score of 3 indicates extreme limitations in activity.⁵⁵

Subjective outcomes

Fatigue levels

The fatigue levels will be assessed through the PedsQL Multidimensional Fatigue Scale, which has demonstrated reliability and validity among children with chronic diseases, with self-reported and parent-reported versions.⁵⁶ The scale encompasses three modules: general fatigue, rest fatigue and cognitive fatigue. The scale is rated on a 5-point Likert scale, with 0 representing ‘never’ and 4 as ‘always’. The final scores should be transformed into a percentage system (0=100, 1=75, 2=50, 3=25, 4=0). Mean scores of both the overall scale and each dimension will be calculated. Lower scores indicate higher fatigue levels.⁵⁶

Mental health

The Children’s Depression Inventory (CDI) and the Screen for Child Anxiety Related Emotional Disorders (SCARED) will be used to assess mental health.^{57 58} The CDI has been demonstrated as a self-report tool that can be widely used to assess depressive symptoms in children aged 7–17.⁵⁹ It consists of 27 items related to sadness, self-blame, sleep difficulties, poor appetite, interpersonal relationships and school adaptation.⁵⁸ Participants will be asked to assess the frequency of each item over the last 2 weeks using a 3-point scale ranging from 0 to 2. The average scores of all items will be calculated. The SCARED, a self-reported tool, is usually used to assess anxiety levels in the past week in children aged 8–18.⁵⁷ It encompasses 5 factors (panic/somatic, generalised anxiety, separation anxiety, social phobia and school phobia) and 41 items.⁵⁷ It is rated using a 3-point scale, and higher scores mean higher levels of anxiety.

Health-related quality of life

The Paediatric Quality of Life Inventory 3.0 Rheumatology Module (PedsQL 3.0 RM) is a commonly used tool to assess the quality of life in JIA patients.⁶⁰ The Chinese version of the PedsQL 3.0 RM, with appropriate modifications, has been demonstrated to be a reliable and valid tool for assessing the health-related quality of life (HRQOL) of JIA patients.⁶¹ It comprises 22 items across 5 domains: pain, daily life, therapy, worries and communication, with children’s self-report and parent proxy assessment. It is rated on a 5-point scale, where 0 represents ‘never happen’ and 4 represents ‘always happen’. The final scores will be transformed into a percentage system (0=100, 1=75, 2=50, 3=25, 4=0). Higher scores indicate a better quality of life.

Blood biomarkers

Blood samples will be collected at three different time points: 48 hours before the intervention, 1 week after the completion of the 12-week intervention and 12 weeks after the intervention, under fasting conditions in the early morning. The laboratory parameters include general inflammatory markers (erythrocyte sedimentation rate (ESR) and C reactive protein (CRP)), proinflammatory cytokines (IL-1β, IL-6, IL-17, TNF-α), anti-inflammatory cytokine (IL-10) and calprotectin (S100A8/A9 and S100A12). ELISA will be employed to detect the concentrations of cytokines (IL-1β, IL-6, IL-17, TNF-α and IL-10) as well as calprotectin (S100A8/A9 and S100A12) in the serum. The ESR will be determined using an automated ESR analyser. The levels of CRP in the serum will be measured using a fluorescence immunoassay analyser. All blood samples will be analysed at the Laboratory of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine.

Physical activity control

The Chinese Physical Activity Level Questionnaire for Children aged 7–18 years will be used to assess the level of PA to monitor whether the participants perform additional activity apart from the assigned programme.⁶² The questionnaire consists of 27 items including exercise types, frequency, duration and intensity, as well as 3 self-report items. Researchers will calculate the number of performing PA for weekdays and weekends separately based on the participant’s responses regarding exercise types and frequency. The intensity of PA will be determined using a reference table based on the exercise types and self-perceived exertion levels.

Safe monitoring

Adverse events and severe adverse events that occur during the study will be recorded and evaluated by an experienced rheumatologist to ascertain any possible correlation with the intervention, which will be crucial in evaluating the safety of the HBE programme. If required, individuals who suffer from this will be provided with proper medical attention and will be assessed whether they can continue to exercise. If applicable, they will be offered proper medical compensation.

Adherence/fidelity

In this study, the adherence or fidelity to the exercise programme will be assessed based on the number and percentage of completed exercise sessions and viewed HE lessons, exercise duration recorded in the exercise software and viewing duration of HE lessons, the frequency of access to the exercise software and the number of exercise programme deviation by monitoring the videos uploaded by participants.

Sample size calculation

In this study, PASS (V.15.0) was used to calculate the sample size. Previous studies have demonstrated that pain is one of the most common symptoms. Therefore, pain, as the primary outcome, was used to compute the required sample size. According to recent studies conducted at the Centre for Health, Exercise and Sports Medicine, the minimal clinically important difference for pain (NRP) was 1.8 units with an SD of 2.3.⁴⁹ Assuming a mean difference in pain scores before and after the intervention of 1.8, an SD of 2.3, 80% power and an alpha of 0.05, the software calculated a sample size of 54 (27 per group). Taking into account a 10% attrition rate, the sample size was increased to 60 (30 per group).

Statistical analysis

All data will be analysed using the statistical software SPSS (V.27.0). Data of all subjects will be analysed based on the intention to treat. If the presence of missing data, multiple interpolations will be considered for calculating the values. Continuous data will be presented as mean±SD or medians and quartiles. Categorical variables will be presented as counts and proportions. The Shapiro-Wilk test will be used to assess the normality of the data distribution. For categorical variables, the χ² test will be used. For continuous primary outcome measure, secondary outcome measures and other outcome measures, between-group comparisons of pre–post intervention differences will be conducted using mixed-effects linear regression models. Time effects and the interaction effects between time and groups will be analysed as fixed effects, and random effects for participants will also be analysed. In order to compare the improvement based on global change between groups, risk differences and risk ratios calculated from generalised estimating equations will be used. The significance level will be set at 0.05.

Data management

All of the data in this study will be collected in the case report forms and will be stored in data management software (Microsoft Excel 365). To ensure the secrecy of the data, identification numbers will be provided for every subject. The computer and database will be protected by a specific password with only access to the researchers in this study. The data will be stored for 5 years and will be destroyed after that time. To ensure the authenticity of the trial data, the monitoring test will regularly be conducted by the data monitoring committee, which consists of clinical experts, trial specialists, investigators and statisticians and is independent from both the sponsors and competing interests.

Patient and public involvement

The patients and the public were not involved in the design of this study.

Study status

This study was registered with the Chinese Clinical Trial Registry (ChiCTR2300073446) on 11 July 2023. The study will be performed from 10 January 2024 to 30 August 2025.

Ethics and dissemination

This study has been approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine in December 2023 (approval no. XHEC-C-2023-059-3). This study will require informed consent from all subjects and guardians of children under 18 years of age. The findings of the study will be published in a peer-reviewed journal and will be presented at national or international academic conferences.

Strengths and limitations

First, this is the first randomised controlled trial study focusing on a specific subtype ERA to investigate the effects of exercise. It is reported that ERA is the most prevalent subtype in Asia and Southeast Asia,³ with worse pain and quality of life, especially in patients with sacroiliac joint involvement.^{63 64} Thus, it is imperative to explore a feasible and effective complementary treatment to improve the prognosis of ERA. However, current studies have rarely centred on ERA, with only a pilot study.³⁷ Therefore, this study will provide more evidence for the clinical practice of ERA.

Second, this is the first study to employ CYRT to manage JIA, aiming to provide a diverse exercise programme that may systematically improve primary symptoms associated with JIA. We hypothesise that the combined exercise may synergistically overcome their respective limitations and provide greater benefits for JIA patients.

Third, this is the first study to employ comprehensive and systematic clinical outcomes including objective clinical outcomes (low limb muscle strength, motion range of joint, aerobic fitness and function ability), subjective outcomes (pain levels, fatigue levels, mental health, HRQOL) and blood biomarkers to systematically evaluate the effects of exercise on JIA. It is well known that pain and fatigue are strongly correlated with emotion and stress.⁶⁵ This highlights the importance of considering the mental health of JIA patients. Additionally, blood biomarkers will be detected in this study to investigate the potential mechanism of changes induced by the HBE programme.

Fourth, this study will include the assessment of the outcomes at follow-up (24 weeks) to investigate the long-term effects of exercise on JIA. A systematic review and meta-analysis conducted by Kuntze et al highlighted the scarcity of studies investigating the long-term effects of exercise on JIA.⁷ Therefore, this study aims to provide more evidence about the long-term effects of exercise on JIA.

Fifth, this study will provide a home-based exercise to manage the participants with JIA, which will assist patients and their caregivers to overcome limitations related to time, geography and economics. Meanwhile, remote monitoring, including the backend monitoring of participants’ exercise duration and frequency via exercise software, as well as researchers providing feedback and corrections based on the exercise videos uploaded by participants, will further improve adherence to the exercise protocol. Additionally, behaviour change strategies will also be incorporated to motivate children and adolescents to adhere to exercise.

Nevertheless, we must concede the limitations of this study. First, this study will be unblinded to the subjects due to the nature of the exercise therapy, potentially introducing some bias into the findings. Second, the exercise programme, consisting of two types of exercises, yoga (20–30 min) and resistance training (10–15 min), will lengthen the total exercise duration to 45–60 min. Although the duration of exercise in current studies ranges from 40 to 60 min, a longer duration of exercise may potentially impact participants’ adherence to the intervention and hinder a true assessment of the effectiveness of the exercise programme. Third, the findings of this study may be specific to ERA, and the extension of this exercise programme to other JIA subtypes should be supported by further clinical evidence.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).

Footnote

MZ, JL and YS contributed equally.

GG and NC contributed equally.

Contributors MZ, JL and YS contributed equally to this study. MZ, JL, YS, NC and GG conceptualised the study and designed methodology. MZ and JL drafted the original draft. MZ and YS reviewed the original draft. JL and YS contributed to data analysis and manuscript revision. GG and NC provided the leadership and supervision into the protocol, verified the validation of the trial design and provided a review of this manuscript. All authors approved the publication of this protocol.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

References

¹ Martini A, Lovell DJ, Albani S, et al. Juvenile idiopathic arthritis. Nat Rev Dis Primers 2022; 8: 5. doi:10.1038/s41572-021-00332-8

² Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision. J Rheumatol 2001: 390–2.

³ Çakan M, Aktay-Ayaz N, Keskindemirci G, et al. Subtype frequencies, demographic features, and remission rates in juvenile idiopathic arthritis - 265 cases from a Turkish center. Turk J Pediatr 2017; 59: 548–54. doi:10.24953/turkjped.2017.05.007

⁴ Kunjir V, Venugopalan A, Chopra A. Profile of Indian patients with juvenile onset chronic inflammatory joint disease using the ILAR classification criteria for JIA: a community-based cohort study. J Rheumatol 2010; 37: 1756–62. doi:10.3899/jrheum.090937

⁵ Shen C-C, Yeh K-W, Ou L-S, et al. Clinical features of children with juvenile idiopathic arthritis using the ILAR classification criteria: a community-based cohort study in Taiwan. J Microbiol Immunol Infect 2013; 46: 288–94. doi:10.1016/j.jmii.2012.03.006

⁶ Li J, Zhu Y, Guo G. Enthesitis-related arthritis: the clinical characteristics and factors related to MRI remission of sacroiliitis. BMC Musculoskelet Disord 2022; 23. doi:10.1186/s12891-022-06028-8

⁷ Kuntze G, Nesbitt C, Whittaker JL, et al. Exercise Therapy in Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analysis. Arch Phys Med Rehabil 2018; 99: 178–93. doi:10.1016/j.apmr.2017.05.030

⁸ Räsänen K, Markula-Patjas K, Kantanen S, et al. Impaired cardiorespiratory and neuromuscular fitness in children and adolescents with juvenile idiopathic arthritis: a cross-sectional case-control study in the era of biologic drug therapies. Pediatr Rheumatol Online J 2023; 21: 26. doi:10.1186/s12969-023-00808-9

⁹ Minden K, Niewerth M, Listing J, et al. Burden and cost of illness in patients with juvenile idiopathic arthritis. Ann Rheum Dis 2004; 63: 836–42. doi:10.1136/ard.2003.008516

¹⁰ La Bella S, Rinaldi M, Di Ludovico A, et al. Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis. Int J Mol Sci 2023; 24: 1846. doi:10.3390/ijms24031846

¹¹ Lin Y-T, Wang C-T, Gershwin ME, et al. The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis. Autoimmun Rev 2011; 10: 482–9. doi:10.1016/j.autrev.2011.02.001

¹² Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet 2011; 377: 2138–49. doi:10.1016/S0140-6736(11)60244-4

¹³ Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369–76. doi:10.1172/JCI2629

¹⁴ Grom AA. Natural killer cell dysfunction: A common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum 2004; 50: 689–98. doi:10.1002/art.20198

¹⁵ Möller JC, Paul D, Ganser G, et al. IL10 promoter polymorphisms are associated with systemic onset juvenile idiopathic arthritis (SoJIA). Clin Exp Rheumatol 2010; 28: 912–8.

¹⁶ Pickens SR, Volin MV, Mandelin AM, et al. IL-17 Contributes to Angiogenesis in Rheumatoid Arthritis. J Immunol 2010; 184: 3233–41. doi:10.4049/jimmunol.0903271

¹⁷ Rooney M, David J, Symons J, et al. Inflammatory cytokine responses in juvenile chronic arthritis. Br J Rheumatol 1995; 34: 454–60. doi:10.1093/rheumatology/34.5.454

¹⁸ Kutukculer N, Caglayan S, Aydogdu F. Study of pro-inflammatory (TNF-alpha, IL-1alpha, IL-6) and T-cell-derived (IL-2, IL-4) cytokines in plasma and synovial fluid of patients with juvenile chronic arthritis: correlations with clinical and laboratory parameters. Clin Rheumatol 1998; 17: 288–92. doi:10.1007/BF01451007

¹⁹ Saxena N, Aggarwal A, Misra R. Elevated concentrations of monocyte derived cytokines in synovial fluid of children with enthesitis related arthritis and polyarticular types of juvenile idiopathic arthritis. J Rheumatol 2005; 32: 1349–53.

²⁰ Rosina S, Natoli V, Santaniello S, et al. Novel biomarkers for prediction of outcome and therapeutic response in juvenile idiopathic arthritis. Expert Rev Clin Immunol 2021; 17: 853–70. doi:10.1080/1744666X.2021.1945441

²¹ Aljaberi N, Tronconi E, Schulert G, et al. The use of S100 proteins testing in juvenile idiopathic arthritis and autoinflammatory diseases in a pediatric clinical setting: a retrospective analysis. Pediatr Rheumatol Online J 2020; 18: 7. doi:10.1186/s12969-020-0398-2

²² La C, Lê PQ, Ferster A, et al. Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis. RMD Open 2021; 7: e001646. doi:10.1136/rmdopen-2021-001646

²³ Naveen R, Guleria S, Aggarwal A. Recent updates in enthesitis-related arthritis. Rheumatol Int 2023; 43: 409–20. doi:10.1007/s00296-023-05274-w

²⁴ Sandstedt E, Fasth A, Eek MN, et al. Muscle strength, physical fitness and well-being in children and adolescents with juvenile idiopathic arthritis and the effect of an exercise programme: a randomized controlled trial [ Pediatric rheumatology online journal 2013;11(1 ]. Pediatr Rheumatol Online J 2013; 11: 7. doi:10.1186/1546-0096-11-7

²⁵ Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth 2001; 87: 3–11. doi:10.1093/bja/87.1.3

²⁶ Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353: 1959–64. doi:10.1016/S0140-6736(99)01307-0

²⁷ Ringold S, Angeles-Han ST, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis. Arthritis Care Res (Hoboken) 2019; 71: 717–34. doi:10.1002/acr.23870

²⁸ Cavallo S, Brosseau L, Toupin-April K, et al. Ottawa Panel Evidence-Based Clinical Practice Guidelines for Structured Physical Activity in the Management of Juvenile Idiopathic Arthritis. Arch Phys Med Rehabil 2017; 98: 1018–41. doi:10.1016/j.apmr.2016.09.135

²⁹ Gualano B, Sá Pinto AL, Perondi B, et al. Evidence for prescribing exercise as treatment in pediatric rheumatic diseases. Autoimmun Rev 2010; 9: 569–73. doi:10.1016/j.autrev.2010.04.001

³⁰ Iversen MD, Andre M, von Heideken J. Physical Activity Interventions in Children with Juvenile Idiopathic Arthritis: A Systematic Review of Randomized Controlled Trials. Pediatric Health Med Ther 2022; 13: 115–43. doi:10.2147/PHMT.S282611

³¹ Takken T, Van Brussel M, Engelbert RHH, et al. Exercise therapy in juvenile idiopathic arthritis: a Cochrane Review. Eur J Phys Rehabil Med 2008; 44: 287–97.

³² Wang CC, Li K, Choudhury A, et al. Trends in Yoga, Tai Chi, and Qigong Use Among US Adults, 2002-2017. Am J Public Health 2019; 109: 755–61. doi:10.2105/AJPH.2019.304998

³³ Sofia MS, Pedro DOC, Danilo RC, et al. Effect of yoga on the quality of life of patients with rheumatic diseases: Systematic review with meta-analysis. Complement Ther Med 2019; 46: 9–18.: S0965-2299(19)30488-1. doi:10.1016/j.ctim.2019.07.006

³⁴ Saud A, Abbasi M, Merris H, et al. Harnessing the benefits of yoga for myositis, muscle dystrophies, and other musculoskeletal disorders. Clin Rheumatol 2022; 41: 3285–97. doi:10.1007/s10067-022-06280-2

³⁵ Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis and Cartilage 2019; 27: 1578–89. doi:10.1016/j.joca.2019.06.011

³⁶ Feinstein AB, Cohen LL, Masuda A, et al. Yoga Intervention for an Adolescent With Juvenile Idiopathic Arthritis: A Case Study. Adv Mind Body Med 2018; 32: 13–20.

³⁷ Yasar E, Kavlak E, Turkucar S, et al. Yoga versus home exercise program in children with enthesitis related arthritis: A pilot study. Complement Ther Med 2021; 58. doi:10.1016/j.ctim.2021.102696

³⁸ Zhu R, Wang W, Zhao L, et al. Comparisons of tai chi and Iyengar yoga intervention effects on muscle strength, balance, and confidence in balance. J Sports Med Phys Fitness 2021; 61: 1333–8. doi:10.23736/S0022-4707.20.11752-3

³⁹ Legerlotz K. The Effects of Resistance Training on Health of Children and Adolescents With Disabilities. Am J Lifestyle Med 2020; 14: 382–96. doi:10.1177/1559827618759640

⁴⁰ Tarakci E, Yeldan I, Baydogan SN, et al. Efficacy of a land-based home exercise programme for patients with juvenile idiopathic arthritis: a randomized, controlled, single-blind study. J Rehabil Med 2012; 44: 962–7. doi:10.2340/16501977-1051

⁴¹ Sieczkowska SM, Astley C, Marques IG, et al. A home-based exercise program during COVID-19 pandemic: Perceptions and acceptability of juvenile systemic lupus erythematosus and juvenile idiopathic arthritis adolescents. Lupus 2022; 31: 443–56. doi:10.1177/09612033221083273

⁴² Akyuz G, Kenis-Coskun O. The Efficacy of Tai Chi and Yoga in Rheumatoid Arthritis and Spondyloarthropathies: A narrative biomedical review. Rheumatol Int 2018; 38: 321–30. doi:10.1007/s00296-017-3867-2

⁴³ Bower JE, Greendale G, Crosswell AD, et al. Yoga reduces inflammatory signaling in fatigued breast cancer survivors: a randomized controlled trial. Psychoneuroendocrinology 2014; 43: 20–9. doi:10.1016/j.psyneuen.2014.01.019

⁴⁴ Jiang Y, Angeletti PC, Hoffman AJ. Investigating the Physiological Mechanisms between Resistance Training and Pain Relief in the Cancer Population: A Literature Review. J Cancer Ther 2023; 14: 80–101. doi:10.4236/jct.2023.142008

⁴⁵ Van Oort C, Tupper SM, Rosenberg AM, et al. Safety and feasibility of a home-based six week resistance training program in juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2013; 11: 46. doi:10.1186/1546-0096-11-46

⁴⁶ Martini A, Ravelli A, Avcin T, et al. Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First StepsPediatric Rheumatology International Trials Organization International Consensus. The Journal of Rheumatology 2019; 46: 190–7. doi:10.3899/jrheum.180168

⁴⁷ Stricker PR, Faigenbaum AD, McCambridge TM, et al. Resistance Training for Children and Adolescents. Pediatrics 2020; 145: e20201011. doi:10.1542/peds.2020-1011

⁴⁸ Lewelt A, Krosschell KJ, Stoddard GJ, et al. Resistance strength training exercise in children with spinal muscular atrophy. Muscle Nerve 2015; 52: 559–67. doi:10.1002/mus.24568

⁴⁹ Bennell KL, Schwartz S, Teo PL, et al. Effectiveness of an Unsupervised Online Yoga Program on Pain and Function in People With Knee Osteoarthritis: a Randomized Clinical Trial. Ann Intern Med 2022; 175: 1345–55. doi:10.7326/M22-1761

⁵⁰ Miró J, Castarlenas E, de la Vega R, et al. Validity of three rating scales for measuring pain intensity in youths with physical disabilities. Eur J Pain 2016; 20: 130–7. doi:10.1002/ejp.704

⁵¹ Eek MN, Kroksmark AK, Beckung E. Isometric muscle torque in children 5 to 15 years of age: normative data. Arch Phys Med Rehabil 2006; 87: 1091–9. doi:10.1016/j.apmr.2006.05.012

⁵² Trudelle-Jackson E, Jackson AW, Frankowski CM, et al. Interdevice reliability and validity assessment of the Nicholas Hand-Held Dynamometer. J Orthop Sports Phys Ther 1994; 20: 302–6. doi:10.2519/jospt.1994.20.6.302

⁵³ Hébert LJ, Maltais DB, Lepage C, et al. Isometric muscle strength in youth assessed by hand-held dynamometry: a feasibility, reliability, and validity study. Pediatr Phys Ther 2011; 23: 289–99. doi:10.1097/PEP.0b013e318227ccff

⁵⁴ Lelieveld OTHM, Takken T, van der Net J, et al. Validity of the 6-minute walking test in juvenile idiopathic arthritis. Arthritis Rheum 2005; 53: 304–7. doi:10.1002/art.21086

⁵⁵ Lam C, Young N, Marwaha J, et al. Revised versions of the Childhood Health Assessment Questionnaire (CHAQ) are more sensitive and suffer less from a ceiling effect. Arthritis Rheum 2004; 51: 881–9. doi:10.1002/art.20820

⁵⁶ Varni JW, Burwinkle TM, Szer IS. The PedsQL Multidimensional Fatigue Scale in pediatric rheumatology: reliability and validity. J Rheumatol 2004; 31: 2494–500.

⁵⁷ Birmaher B, Khetarpal S, Brent D, et al. The Screen for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psychometric characteristics. J Am Acad Child Adolesc Psychiatry 1997; 36: 545–53. doi:10.1097/00004583-199704000-00018

⁵⁸ Kovacs M. Pediatric Rheumatology International Trials Organization International Consensus. The Encyclopedia of Clinical Psychology 2015. doi:10.1002/9781118625392

⁵⁹ Davanzo P, Kerwin L, Nikore V, et al. Spanish translation and reliability testing of the Child Depression Inventory. Child Psychiatry Hum Dev 2004; 35: 75–92. doi:10.1023/b:chud.0000039321.56041.cd

⁶⁰ Tarakci E, Baydogan SN, Kasapcopur O, et al. Cross-cultural adaptation, reliability, and validity of the Turkish version of PedsQL 3.0 Arthritis Module: a quality-of-life measure for patients with juvenile idiopathic arthritis in Turkey. Qual Life Res 2013; 22: 531–6. doi:10.1007/s11136-012-0180-0

⁶¹ Zhang H, Wang N, Sun J, et al. The Reliability and Validity of the Chinese Version of Pediatric Quality of Life lnventory^TM3.0 Rheumatology Module, ages 13-18. Chinese Journal of Nursing 2015.

⁶² Zhao C. Association between Meeting 24-Hour Movement Guideline andProblem Behaviour of Middle School Students in Shanghai. Shanghai University of Sport, 2022.

⁶³ Rumsey DG, Guzman J, Rosenberg AM, et al. Worse Quality of Life, Function, and Pain in Children With Enthesitis, Irrespective of Their Juvenile Arthritis Category. Arthritis Care Res (Hoboken) 2020; 72: 441–6. doi:10.1002/acr.23844

⁶⁴ Weiss PF, Beukelman T, Schanberg LE, et al. Enthesitis-related arthritis is associated with higher pain intensity and poorer health status in comparison with other categories of juvenile idiopathic arthritis: the Childhood Arthritis and Rheumatology Research Alliance Registry. J Rheumatol 2012; 39: 2341–51. doi:10.3899/jrheum.120642

⁶⁵ Armbrust W, Lelieveld OHTM, Tuinstra J, et al. Fatigue in patients with Juvenile Idiopathic Arthritis: relationship to perceived health, physical health, self-efficacy, and participation. Pediatr Rheumatol Online J 2016; 14: 65. doi:10.1186/s12969-016-0125-1