The Healthy Living in Inflammatory Arthritis (HELIA) trial is an open-label, randomized controlled trial and takes place at the Erasmus MC, an academic hospital in Rotterdam, The Netherlands.

Patients are randomized with a 1:1 allocation ratio into the intervention group (participating in the online, interactive lifestyle intervention program) or the control group (receiving general nutrition recommendations), using ALEA clinical software (ALEA Clinical B.V.). The allocation sequence was balanced for diagnosis (RA or PsA). Patients, treating physicians, RNs, and researchers will know to which group patients are randomized. The principal investigator will generate the allocation sequence and will assign participants to interventions using ALEA clinical software. RNs will enroll participants and do not have access to the randomization sequence. During statistical analysis, treatment allocation will remain concealed through the use of masked group labels.

Patients have a personal responsibility for the implementation of the online lifestyle intervention program theory or general nutrition recommendations into their own lives. All food products are available at the local grocery store or butcher, and participants should buy them at their own expense. To measure adherence to the lifestyle program, a questionnaire is included to assess diet compliance. In addition, a sensitivity analysis will be performed on patients who have ≥5% weight loss after the intensive part of the lifestyle intervention program because we assume that this weight loss is associated with program adherence.

The use of DMARDs, oral prednisone (or equivalent) at a dose ≤7.5 mg as cointerventions are permitted if participants have received a stable dose for ≥6 months prior to randomization. Tapering, continuation, or intensification of treatment during the study is left to the discretion of the treating rheumatologist in consultation with the patient, using current treatment recommendations as a guideline. There are no specifically excluded concomitant medications.

Escape medication is defined as any new therapeutic intervention or a significant change to ongoing therapy made because a participant is experiencing worsening or exacerbation of their disease. Only the following prespecified escape medications are allowed:

Criteria for discontinuing are as follows:

The health risk of the intervention is expected to be low. AEs are defined as any undesirable experience occurring to a participant during the study, whether or not considered related to the intervention. All AEs reported spontaneously by the participant or observed by the investigator or research staff will be recorded. AEs of special interest during the study will be collected at each study visit through patient questionnaires and/or physician reports. Such AEs include the following:

A serious adverse event (SAE) is any untoward medical occurrence or effect that:

An elective hospital admission will not be considered as an SAE. The investigator will report all SAEs that occur during the 2-year follow-up period to the sponsor without undue delay after obtaining knowledge of the events.

Patients will be assessed at baseline and after 3, 6, 12, and 24 months. At each visit, patients will fill out online questionnaires (~30 min) and are assessed by the RN, who calculates the DAS28 or DAPSA depending on the diagnosis. Study visits will take 30 minutes or less. The timeline and extensive data collection overview are shown in Figure 2 and Table 2. Data collection is the same for both the intervention group and the control group.

The primary objective is the proportional difference in DAS28 and DAPSA remission and/or successful tapering of DMARD treatment after 12 months of follow-up. Meeting either criterion is sufficient to qualify for the primary outcome.

Disease activity in patients with RA and PsA is measured with the DAS28 and DAPSA, respectively [23,24]. The DAS28 is a pooled index that involves the incorporation of a 28-joint count for tenderness (TJC28), a 28-joint count for swelling (SJC28), an erythrocyte sedimentation rate (ESR) and GH (measured with a Visual Analog Scale [VAS] 0‐100 mm) into a formula to obtain a numerical indicator of disease activity. The DAS28 formula is 0.56√(TJC28)+0.28√(SJC28)+0.70ln(ESR)+0.014(GH) [23]. The DAPSA is also a pooled index, which is made up of the following five domains: (1) a 68-joint count for tenderness, (2) a 66-joint count for swelling, (3) a CRP (expressed in mg/dL), (4) a patient’s assessment of the disease activity (VAS, 0‐10 cm), and (5) a patient’s assessment of pain severity (VAS, 0‐10 cm). The numerical values of the aforementioned 5 domains are summed to provide the DAPSA score [24]. The threshold values for DAS28 and DAPSA remission are <2.6 and ≤4, respectively [24,26]. The minimal clinically important differences (MCIDs) for the change in DAS28 and DAPSA are 1.2 and 7.2, respectively [27,28]. Tapering of treatment is left to the discretion of the treating rheumatologist in consultation with the patient, with current treatment recommendations as a guideline.

Secondary end points include cost-effectiveness, health risk, and (self-reported) disease burden (refer to Table S1 in Multimedia Appendix 1). Cost-effectiveness will be evaluated through the ICER, which is the ratio of the difference in costs to incremental benefits between the online interactive lifestyle intervention program and general nutrition recommendations. For the cost-effectiveness analysis, we will calculate the quality-adjusted life years (QALYs) and total costs. QALYs express the impact of the disease on patients’ health over time. Living in perfect health corresponds to a QALY of 1 and a QALY of 0 reflects death [29]. QALYs are determined by calculating the area under the curve of the EQ-5D-5L [30]. Costs are divided into direct and indirect costs. We will analyze direct and indirect costs from a societal perspective. Direct costs are the costs of treatment and medical consumption, whereas indirect costs are costs due to loss of productivity [31]. Medication costs are calculated from doses reported in the patients’ case records, valued according to the Dutch National Health Care Institute [32]. Medical consumption, including duration of hospitalizations and admission diagnosis, are recorded every 3 months with the Institute for Medical Technology Assessment medical consumption questionnaire. We will use the Dutch average length of stay by diagnosis if the duration of hospitalization is unknown. Indirect costs include not fully functioning (presenteeism), sick leave (absenteeism), and reduction in work time [33]. Work Productivity and Activity Impairment (WPAI) outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.

The health risk is assessed by measuring weight, BMI, and waist circumference. BMI is calculated by dividing the patient’s weight (kg) by the square of their height (m). A BMI ranging from 18.5 to <25 is classified as a healthy weight. A BMI between 25 and <30 is categorized as overweight, while a BMI ≥30 is considered obese. Conversely, a BMI <18.5 is classified as underweight [34]. Sex-specific thresholds for waist circumference are associated with an elevated risk of metabolic complications. In males, a waist circumference ≥94 cm is linked to an increased risk, whereas a measurement of ≥102 cm corresponds to a substantially increased risk. For females, these thresholds are ≥80 cm and ≥88 cm, respectively [34].

Disease burden is measured through the following PRO measurements: GH, pain, morning stiffness, fatigue, functional ability, and quality of life. GH, fatigue, and pain are measured with a VAS (0‐100 mm), whereby higher scores reflect greater severity. The MCIDs for the aforementioned outcomes are ≥10 [35-37]. Fatigue is also measured with the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire (FACIT-F) [38]. The FACIT-F consists of 13-items with a 7-day recall period. Items are scored on a 0‐4 response scale with anchors ranging from “Not at all” to “Very much so.” All items are summed to create a single fatigue score with a range from 0 to 52 and higher scores represent less fatigue [38]. The MCID is 15.9 [39]. Morning stiffness (severity and duration in min) is measured with a Numeric Rating Scale and is interpreted similarly to GH. The MCID for morning stiffness is ≥1 [40]. Functional ability is measured with the Health Assessment Questionnaire [41]. Higher Health Assessment Questionnaire scores indicate poorer function, and the MCID is 0.22 [41,42].

Quality of life is measured with the EQ-5D-5L (MCID ≥0.04) [43,44]. Higher scores represent a higher quality of life. We will also use the 36-item Short-Form Health Survey (SF-36) that assesses 8 domains on a scale of 0‐100, with higher scores indicating a better health status [45]. The SF-36 addresses the following domains: physical functioning, bodily pain, role limitations due to physical health problems and social or emotional problems, mental health, vitality, and GH perceptions. These domains are also combined into a physical and mental component score. The MCIDs for the physical component score and mental component score are 2.5 and 5, respectively [30,45,46].

Although the primary outcome will be assessed after 12 months of follow-up, we will follow all participants for 2 years to determine the long-term effect of the lifestyle intervention and whether the intervention has led to a permanent behavioral change.

Exploratory end points include self-reported disease activity (states), sleep, perceived stress, physical activity, and diet compliance (refer to Table S1 in Multimedia Appendix 1). Self-reported disease activity is measured with the Routine Assessment of Patient Index Data 3 (RAPID-3) [47]. Thresholds for remission and moderate-to-high disease activity are respectively <3.1 and ≥6.1 on a 0‐30 scale. The MCID for the RAPID-3 is 3.8 [48].

The quality of sleep is measured with the Medical Outcomes Study sleep scale (MOS-SS) [49]. The MOS-SS includes 12 items assessing sleep disturbance, sleep adequacy, somnolence, quantity of sleep, snoring, and awakening. A sleep problems index, grouping items from each of the former domains, is also available. The MCID for the sleep problem index is ≥6 [50].

Perceived stress is measured with the Perceived Stress Scale (PSS-10) [51]. The PSS-10 consists of 10 items, and items are scored on a 0‐4 response scale. Higher scores represent higher levels of stress. The MCID of perceived stress is ≥11 [52].

Physical activity is measured with the Dutch Physical Activity Guideline (Nederlandse Norm Gezond Bewegen [NNGB]) [53]. The NNGB measures whether an individual complies with the Dutch Guidelines for Physical Activity, and a higher score corresponds with better compliance.

Diet compliance is measured with a self-developed questionnaire consisting of 17 items based on the 17-item Mediterranean diet questionnaire [54]. Each dietary compliance item is scored as 1 if it aligns with the principles of the Mediterranean diet, and 0 otherwise. Total scores range from 0 to 17, with a score of 0 to 7 equating to a low dietary compliance, a score of 8 to 10 for an average degree of dietary compliance, and a score of 11 to 17 for a high degree of dietary compliance.

At baseline, we will also gather data on demographics and comorbidities. We will also perform a general physical examination. The demographic dataset will include age, sex, ethnicity, marital status, work status, education, smoking status, and alcohol consumption, as well as disease duration, autoantibody status, and presence of erosions. Furthermore, we will ask for the presence of the following comorbidities: diabetes, inflammatory bowel disease, cardiovascular diseases, urinary tract disorders, and malignancies. During the general physical examination, we will measure the height, weight, and waist circumference. Height and weight will be used to calculate the BMI.

The HELIA is a superiority trial, powered to detect a 20% difference in DAS28 and DAPSA remission and/or successful tapering of DMARD treatment after 12 months of follow-up. Meeting either criterion is sufficient to qualify for the primary outcome. Murray et al [55] showed that after the first year of diagnosis, remission rates are up to 30%. Although tapering of treatment is still not standard of care, previous research has shown that tapering of treatment in patients with LDA is possible [56]. Based on these data, we assumed that 30% of the patients in the control group, general nutrition recommendations, will reach remission or be able to successfully taper their medication and that this will be 20% higher in patients who will follow the online, interactive lifestyle intervention program. Thus, to detect this 20% difference using a significance level of α=.05 (2-sided) and a power of 80%, 100 patients per group (~75 RA and ~25 PsA) are needed, also taking a 10% dropout ratio into account, which is based on previous trials conducted in the Erasmus MC [57,58].

The principal investigator ensures that monitoring procedures are performed before, during, and after the study. Prior to enrollment, a member of the study team will train staff on the procedures for obtaining informed consent, record keeping, and reporting of SAEs to the principal investigator. Monitoring includes inspection and reviewing eCRFs, participants’ source documents, and all other study documentation by a member of the study team in accordance with the study monitoring plan. All aspects of the study will be carefully monitored for compliance with applicable governmental laws and regulations concerning good clinical practice and the General Data Protection Regulation.

This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the local medical research ethics committee of the Erasmus MC in Rotterdam (MEC-2022‐0448). The protocol follows SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (refer to SPIRIT checklist in Checklist 1). All study participants received full information about the study, and written informed consent was obtained from all individual study participants before inclusion. Through the consent form, study participants could also grant permission for secondary analyses in the future without additional consent. All study participants have the option to withdraw from the study at any time without providing a reason. The privacy and confidentiality of all study participants are guaranteed.

The HELIA trial is a randomized controlled trial comparing the effectiveness of an online, interactive lifestyle intervention program and general nutrition recommendations in patients with IA with LDA. This study aims to investigate the effectiveness from a clinical, societal, and patients’ point of view. Considering the current developments in health care, such as the increasing number of chronically ill people, rising health care costs, and turnover of professionals, lifestyle is becoming increasingly important to prevent disease or reduce the burden of disease and indirectly reduce the pressure on health care.

The World Health Organization (WHO) promotes a healthy lifestyle for its benefits in preventing and slowing chronic diseases [60,61]. In rheumatic and musculoskeletal diseases (RMDs), an unhealthy lifestyle worsens the disease burden [62]. Accordingly, the EULAR recommends applying the WHO lifestyle guidance to RMD care as an essential complement to medical treatment. These recommendations include regular physical activity to improve pain, function, and quality of life, as well as maintaining a healthy weight and a balanced diet [63].

Although EULAR’s lifestyle recommendations are largely based on expert opinion, growing evidence supports the beneficial effects of lifestyle intervention programs. A recent pilot study on the effect of an online, interactive lifestyle intervention program (organized by Voeding leeft) in patients with RMDs showed positive results [20]. Reported health risks and disease burden decreased in 88 patients with IA, 105 patients with osteoarthritis, and 71 patients with fibromyalgia. Among patients with IA, significant improvements were observed during the intensive phase in weight (mean −4.2, SD 0.7  kg), BMI (mean −1.4, SD 0.3), and waist circumference (mean −3.9, SD 0.7  cm). After the aftercare period, these improvements were largely maintained (weight: mean −3.5, SD 1.0  kg; BMI: mean −1.1 , SD 0.3; waist circumference: mean −4.0, SD 1.0  cm). Disease burden, assessed through PRO measurements, also improved, with reductions in morning stiffness severity (mean −1 , SD 0) and sleep disturbance (mean −6.1, SD 1.4) during the intensive phase. Over 24 months, significant improvements persisted for pain (mean −8, SD 3), morning stiffness (mean −1, SD 0), and sleep disturbance (mean −5.9, SD 1.8). However, this study had notable limitations, namely, no data on disease activity in patients with IA, no control group, and no assessment of social impact.

Another lifestyle intervention study, called “Plant for Joints,” also showed promising results, including reduced disease activity in RA, improved stiffness, pain, and function in osteoarthritis, and better metabolic status in both groups [16,17]. Yet, similar to the pilot study, data on disease burden and societal impact were limited. Given the small number of lifestyle intervention studies in rheumatology and generally low level of evidence, we set up the HELIA trial and chose our outcomes based on the aforementioned knowledge gaps.

With the HELIA trial, we hope to prove that lifestyle interventions can be integrated into standard care for patients with IA alongside DMARD treatment. The program’s strength lies in its focus on multiple lifestyle domains—nutrition, exercise, relaxation, and sleep—with the aim of achieving lasting behavioral change (based on the I-Change model) [18]. The study design also includes several strong features, such as a randomization procedure and an extensive follow-up period after the lifestyle intervention. The online, interactive lifestyle intervention, organized by Voeding Leeft, has also shown success in other patient groups, including the Reverse Diabetes 2 program [19]. We hope that the results of this study will encourage policymakers and insurers to recognize lifestyle interventions as reimbursable components of IA care.

The strengths and limitations of this study are as follows: