Rheumatoid Arthritis Real-world Cohort Study in China (ReALSA): protocol for a multicentre prospective, longitudinal cohort study.

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STRENGTHS AND LIMITATIONS OF THIS STUDY

Comprehensive real-world database: this prospective cohort establishes a dynamic, multimodal database tracking rheumatoid arthritis (RA) progression and complications (eg, sarcopenia, cardiovascular diseases (CVD), malignancies, infections) to enable future mechanistic and interventional research.

Innovative biomarker discovery: it identifies clinical, biochemical, histopathological and imaging biomarkers to develop multimodal models predicting outcomes in high-risk RA subgroups like difficult-to-treat RA.

Comorbidity focus: the protocol systematically evaluates understudied RA complications—sarcopenia, CVD, malignancies and specific infections—addressing critical gaps in holistic management and risk stratification.

Real-world efficiency: as a prospective dynamic cohort, it enhances patient representativeness while offering operational efficiency (time/resource/cost savings) over randomised trials.

Regional limitation: generalisability may be constrained by recruitment solely from three centres in Guangdong Province, potentially under-representing geographic/ethnic variations in RA phenotypes or care practices.

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by inflammation of the synovium, leading to joint pain, swelling and eventually joint damage. 1 The global prevalence of RA is estimated to be approximately 0.5% to 1%, with variations observed among different countries and ethnic groups. The annual incidence of RA is generally reported to be between 5 and 50 cases per 100 000 people. 2 RA can reduce the quality of life due to disability, increase the risk of premature mortality and cause huge economic burden. 3 5

A sharp increase in the proportion of patients with RA achieving clinical remission has been identified between 2004 and 2015, from 6% to 32%, 6 after treat-to-target strategies and disease-modifying antirheumatic drugs (DMARDs) recommended to be used at the time of the initial diagnosis of RA. 7 8 According to recent UK National Audit data, over 50% of patients with RA achieved clinical remission within 6 months of their initial diagnosis of RA. 9 However, there are still many patients without sufficient control of disease activity. Furthermore, an ongoing therapeutic challenge exists for those patients with multidrug-resistant RA, which has been recently termed as difficult-to-treat RA by the European League Against Rheumatism (EULAR). 10 Therefore, emphasis still needs to be paid on the efficient treatment strategies and the prognosis of RA, not to mention those with difficult-to-treat RA.

It is increasingly recognised that RA can affect multiple organs and/or systems, beyond the joints. 11 RA-related complications/comorbidities include sarcopenia, cardiovascular diseases (CVD), infections, depression and cancers, which also aggravate the disease burden for patients, caregiver and society. 12 13 Unlike primary (age-related) sarcopenia in older individuals, RA-associated sarcopenia affects approximately 25% of patients in all ages. 14 Our previous cross-sectional study reported 45.1% of 457 Chinese RA patients with low muscle mass (myopenia) 15 and 54.5% in the elderly patients with RA (age ≥60 years). 16 Many cross-sectional studies reported that several demographic and clinical characteristics, such as age, body mass index, disease duration, a history of fracture and C-reactive protein (CRP), were associated with the risk of sarcopenia in patients with RA. 17 19 Notably, there were few longitudinal studies of patients with RA focusing on the diagnosis and prognosis of sarcopenia available in China, or even worldwide. Our prospective study of 1-year follow-up showed that baseline myopenia independently predicts 1-year aggravated joint destruction in Chinese patients with RA. 20 Currently, no pharmacological therapy has been approved for sarcopenia, 21 and resistance-based physical activity is recommended as the primary treatment. 22 Aerobic, resistance, aquatic and mind-body exercises were recommended for RA management in 2022 by the American College of Rheumatology (ACR) guideline. 23 However, excessive training in patients with RA may exacerbate joint destruction, and individuals experiencing active disease of RA might face difficulties of exercises due to painful joints. 24 Managing sarcopenia in patients with RA is becoming a challenging issue to improve the long-term prognosis of RA. 25

Besides, the risk of mortality from CVD, malignancies and infections in patients with RA was found to be higher than the general population. 26 28 The excess risk of CVD in RA is attributed to the combination of chronic inflammation and well-documented traditional risk factors for CVD such as hypertension and dyslipidaemia. 29 The 2021 European Society of Cardiology Guidelines recommended a multiplication of calculated total CVD risk by a factor of 1.5 in patients with RA. 30 An increase in the overall cancer risk of patients with RA (3.99, 95% CI 3.40 to 4.65) was reported, and most cancers develop 9 years after the diagnosis of RA, suggesting that long-term monitoring of cancer is warranted in patients with RA. 31 RA patients with immunosuppressive treatments, especially biological DMARDs, have an increased risk of infections. 8 Analyses of anti-tumour necrosis factor (TNF) datasets suggest the rates of serious infection resulting in hospitalisation or death of 4–5/100 person-years of treatment. 32 China has the third largest number of tuberculosis cases (7.1%) in the world, following India (27%) and Indonesia (10%). 33 A Chinese multicentre, cross-sectional study revealed that the prevalence of active tuberculosis was 371/100 000 in patients with RA. 34 An increase in the risk of herpes zoster infection has been well recognised in the users of TNF inhibitors 35 and Janus kinase (JAK) inhibitors. 36 A real-world RA data from Hong Kong reported that herpes zoster infection was significantly more common with the JAK inhibitors than TNF inhibitors (3.49 vs 0.94 per 100 patient-years). 37 Hepatitis B virus (HBV) infection is a major public health problem in China. 38 The risk of HBV reactivation in RA patients with chronic hepatitis B increases by biological DMARDs and is the highest among those receiving B cell-depleting therapies, and glucocorticoid treatment in combination with biological DMARDs. 39 The problem that needs to be pointed out is that data on the prognosis of these RA patients in large real-world studies are still limited.

Therefore, an ongoing long-term prospective cohort study is conducted by our team, which is dedicated to recruiting patients with RA, to identify the development of clinical, biomedical, histopathological and imaging biomarkers for the diagnosis and prognosis of difficult-to-treat RA, and RA-related complications/comorbidities including sarcopenia, CVD, malignancies, specific infections (especially tuberculosis, herpes zoster and HBV reactivation), and to evaluate their impact on the long-term prognosis of RA. In this protocol, the design of the study is described in detail.

Objectives

To improve the prognosis of RA, this study includes the following objectives:

Construct a useful database to explore the secular dynamic progress of RA, including RA progression and complications (eg, sarcopenia, CVD, malignancies, infections), as well as to improve our understanding of the life course factors affecting the process that will facilitate future research activities.

Identify the potential biomarkers (clinical, biochemical, histopathological and imaging markers) to develop multimodal models predicting outcomes in high-risk RA subgroups like difficult-to-treat RA.

Develop the related multimodal prediction models with clinical, biomedical and imaging variables to improve the diagnosis and prognosis of RA.

Methods and analysis

Study design and setting

The Rheumatoid Arthritis Real-world Cohort Study in China (ReALSA) is designed as a 5-year follow-up prospective real-world study to recruit patients with RA. Serial clinical assessment, muscle assessment, histopathological assessment, and comprehensive biomedical and imaging examinations are conducted regularly to record the changing pattern of RA disease and RA-related complications/comorbidities in the hospital-based Chinese patients with RA. This protocol is reported according to the Standard Protocol Items: Recommendations for Interventional Trials. 40

Study participants and sample size

The patients with RA will be consecutively recruited during 2024 and 2033 from the Department of Rheumatology, Sun Yat-sen Memorial Hospital (SYSMH) of Sun Yat-sen University; The Affiliated Panyu Central Hospital (PYCH) of Guangzhou Medical University in Guangzhou; and ShenShan Medical center, Memorial Hospital of Sun Yat-sen University (SS-SYSMH) in Shanwei, P.R. China. The inclusion criteria for this study are as follows: (1) diagnosis with RA according to 1987 ACR 41 or 2010 ACR/EULAR classification criteria; 42 (2) age ≥18 years old. The exclusion criteria are as follows: (1) patients do not plan to receive long-term healthcare at SYSMH, PYCH or SS-SYSMH; (2) unable to provide written informed consent.

The enrolment is planned to start on 1 January 2024 and will be ended on 31 December 2033. Participant recruitment will be initiated following the publication of this protocol. The annual number of patients with RA in the Department of Rheumatology of SYSMH, PYCH and SS-SYSMH is about 200, 100 and 100, respectively. Therefore, we expect to initially enrol 2000 individuals from SYSMH (around 1000), PYCH (around 500) and SS-SYSMH (around 500) over a period of 10 years. According to the incidence of RA (approximately 0.42 %) in the Chinese population, 43 this number will be sufficient to conduct longitudinal research on the progression of RA. This study is primarily an epidemiological investigation without any prespecified statistical hypothesis to test, making a prior sample size calculation unnecessary. 44 With reference to similar protocols of other cohort studies, 44 47 a sample size of 2000 participants in this project is determined to ensure adequate statistical power for robust analyses.

Study procedure

The procedure of the ReALSA study is shown in figure 1 . After signing the informed consent form, all eligible subjects are invited to complete the baseline survey, such as sociodemographic characteristics, clinical assessment, muscle assessment, histopathological assessment, imaging examination and biological samples collection. After baseline assessment, the follow-up visits will be conducted at the 1st, 3rd, 6th and 12th months during the first year and subsequently every 6 months until 5 years to repeat the assessments and collect the information of interested outcomes. The schedule of all data collection is shown in table 1 .

Data collection

The sociodemographic and clinical information is collected in face-to-face interview by well-trained and experienced assessors. It includes the demographic characteristics (eg, age, sex, income, education, etc.), lifestyle factors (eg, smoking status and alcohol consumption), disease activity, radiographic indicators, physical function, medical history (eg, hypertension, diabetes, dyslipidaemia, stroke, CVD, infectious disease, pulmonary disease, kidney disease, digestive diseases, endocrine disease, hematonosis and malignancies), previous and current medication used (eg, glucocorticoids, non-steroidal anti-inflammatory drugs, conventional synthetic DMARDs, biological DMARDs, targeted synthetic DMARDs, antidiabetic, lipid-lowering, antihypertensive, antiplatelet or anticoagulant drugs), routine blood and urine tests (eg, biochemical tests, thyroid function tests, vitamin D levels and urine protein), and physical examination (eg, weight, height and blood pressure). 48

Disease activity is assessed with a disease activity score in 28 joints with four variables including erythrocyte sedimentation rate (DAS28-ESR), disease activity score in 28 joints with four variables including CRP (DAS28-CRP), Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). These indicators are calculated by tender joints count (TJC), swollen joints count (SJC), pain Visual Analogue Scale (VAS), patient global assessment of disease activity (PtGA), provider global assessment of disease activity (PrGA), ESR or CRP. 49 The serum levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) are also tested. Chinese language version of the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is used to assess physical activity function in eight categories (dressing, rising, eating, walking, hygiene, reaching, gripping and activities). 41 Quality of life is measured by the Five-Level EuroQol Five-Dimensional Questionnaire (EQ-5D-5L). 50 RA-associated fatigue is measured by the Chinese language version of the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire and the revised Bristol Rheumatoid Arthritis Numerical Rating Scales. 51 Chinese Patient-Reported Activity Index with Rheumatoid Arthritis (CPRI-RA) is used for patient-reported outcomes measurement information system in RA patients. 52

Muscle assessment includes measurements of muscle mass and function. Muscle mass is measured by bioelectric impedance analysis (BIA) using an InBody 230 device (Biospace Co., Shanghai, China), which measures body composition indicators including body fat percentage, the mass and distribution of muscle and fat in trunk and appendicular extremities. 53 The appendicular skeletal muscle mass index (ASMI) is defined as appendicular skeletal muscle mass/height 2 (kg/m 2 ). Muscle function includes muscle strength and physical performance. Handgrip strength is used to indicate skeletal muscle strength, which is measured by a dynamometer. Physical performance is measured by a 6 m walk. 54

The imaging examinations which include X-ray for bilateral hands and feet; MRI for joints of the extremities; high-resolution computed tomography (HRCT) for chest; ultrasounds for joints, carotid, thyroid and salivary glands; and dual-energy X-ray absorptiometry (DXA) for bone mineral density in spine, hip and whole body are performed. X-ray radiographs of bilateral hands and feet are assessed by the Sharp/van der Heijde modified score, including modified total Sharp score (mTSS, range 0–448, with higher scores indicating more damage), joint space narrowing (JSN, range 0–280) subscore and joint erosion (JE, range 0–168) subscore. 55

Synovium tissues (1~3 mm 3 ) for histopathological assessment will be collected from participants only when clinically justified (eg, in patients with joint swelling/pain or synovial hyperplasia confirmed by clinical examination requiring diagnostic or therapeutic intervention) at baseline and at the 60-month visit, after obtaining additional procedure-specific informed consent. Similarly, available joint synovial fluid (1~5 mL) will be collected from consenting participants when clinically justified (eg, in patients presenting with joint effusion requiring diagnostic or therapeutic intervention) at baseline or during follow-up. Synovial tissue specimens will be preserved by paraffin embedding and stored in liquid nitrogen, while synovial fluid will be stored at −80°C. One millilitre of peripheral blood serum, 2 mL of whole blood and 1 mL of peripheral blood mononuclear cells (PBMCs) are collected and will be stored in a polypropylene tube at −80°C for future proteomics and biomarkers testing. T cell receptor and B cell receptor repertoire, as well as other characteristics of immunity, will also be examined for immune state assessment.

Outcomes

The long-term prospective purpose of this project is to find possible evidence to delay the deterioration of patients with RA, as outlined in the Objectives section. To achieve these objectives, the outcomes of interest in this cohort include RA disease outcomes and RA-related complication or comorbidity outcomes.

RA disease outcomes

Three predefined co-primary end-points of RA disease are assessed at 60 months. The primary clinical end-point is the proportion of patients achieving CDAI remission (CDAI ≤2.8). 56 The primary functional end-point is the proportion of patients with functional limitation (HAQ-DI >1). 15 The primary radiographic end-point is the proportion of patients without radiographic progression defined as no increase in mTSS from baseline to 60 months (ΔmTSS ≤0). 57 Radiographs are scored by two experienced and well-trained readers (a radiologist and a rheumatologist) who are aware of the chronological order of the sets of images but not unaware of all other data. 58

Predefined other RA disease end-points are the proportions of patients achieving ACR/EULAR remission (defined by DAS28-CRP <2.6, DAS28-ESR <2.6, SDAI ≤3.3 or Boolean 2.0 criteria (TJC ≤1, SJC ≤1, CRP ≤1 mg/dL and PtGA ≤2)), achieving ACR/EULAR low disease activity (defined by DAS28-CRP <3.2, DAS28-ESR <3.2, SDAI ≤11.0 or CDAI ≤11.0) and achieving ACR20, ACR50 and ACR70 responses (defined as the improvements from baseline of 20%, 50% and 70% or more, respectively, in TJC, SJC and at least three of five important domains: PtGA, PrGA, Pain VAS, HAQ-DI and an acute-phase reactant) at 60 months. 56 59 60 RA disease end-points also include the proportions of patients with radiographic progression (defined as a ΔmTSS ≥0.5 change) and rapid radiographic progress (defined as a ΔmTSS ≥5 change over 12 months). 61 Additional RA disease end-points are changes between baseline and 60-month follow-up in the following outcomes: disease activity (DAS28-CRP, DAS28-ESR, SDAI and CDAI), physical function (HAQ-DI), quality of life (EQ-5D-5L), radiographic indicators (mTSS, JSN and JE).

RA-related complication or comorbidity outcomes

Predefined RA-related complication or comorbidity end-points are muscular, cardiovascular, malignant and specific infectious outcomes and additional adverse events.

The muscular outcomes include sarcopenia (defined as myopenia and low muscle function according to the Asian Working Group for Sarcopenia), myopenia (ASMI <7.0 kg/m 2 in men and <5.7 kg/m 2 in women), and low muscle function including low muscle strength (handgrip strength <28 kg for men and <18 kg for women) or low physical performance (6 m walk <1.0 m/s). 62

The cardiovascular outcomes include adjudicated major adverse cardiovascular events (MACE) and the composite of incident CVD. Adjudicated MACE is defined as death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. 63 The composite of incident CVD consists of coronary heart disease (International Classification of Diseases (ICD)-10: I20–I25), heart failure (ICD-10: I50), stroke (ICD-10: I60–I69), peripheral artery disease (ICD-10: I70.2, I73.9) and CVD-death (ICD-10:I00–I99). 64

The malignant outcomes are cancers in oesophagus, stomach, colon, rectum, liver, gallbladder, extrahepatic ducts, pancreas, brain, nervous system, thyroid gland, nasopharynx, larynx, lung, skin, breast, cervix uteri, vulva, other female genital system, prostate, kidney, bladder, ureter, renal pelvis, Hodgkin disease, non-Hodgkin’s lymphoma, multiple myeloma, leukaemia and others. 31 The cancer diagnosis is confirmed by histopathology of biopsy or sampling of surgical specimens according to the ICD-10 criteria. The occurrence of cancer and malignancy risk factors (including family history of breast or colon cancer and personal history of inflammatory bowel disease) are documented. 65

The specific infectious outcomes are serious infections (defined as infections requiring hospitalisation), active tuberculosis, latent tuberculosis, herpes zoster, and adjudicated hepatitis A, B and C, especially hepatitis B surface antigen (HBsAg) reverse seroconversion (RS). 39 66 HBsAg RS is defined as reappearance of HBsAg in the serum in patients with resolved hepatitis B (RHB). Hepatitis flare was defined as a serum alanine aminotransferase level at least twice the baseline level and more than threefold the upper limit normal. 39

Additional adverse events include adjudicated deaths from any cause, venous thromboembolism (including deep vein thrombosis and pulmonary embolism), interstitial lung disease, gastrointestinal perforations, clinically significant laboratory abnormalities and blood pressure levels. 63

Data on cardiovascular, malignant and specific infectious outcomes and additional adverse events are collected with questionnaires during subsequent visits or telephone follow-ups and then ascertained from medical records. 65 66 All adverse events are collected from the time the subject signs the informed consent form until the end of the follow-up period. Adverse event reporting is conducted in compliance with the Good Clinical Practice Guidelines jointly issued by the National Medical Products Administration and the National Health Commission of China.

Quality control and queue maintenance

All data are collected by experienced and well-trained questionnaire investigators who receive regular training at least twice a year. The data will be deposited at an online platform called Research Electronic Data Capture. For quality assurance, a logic check function is programmed into the data entry system beforehand to prevent entry errors. Data administrators will check the data regularly according to the documented questionnaires from the archives to check for quality.

The patients with RA in this cohort will be assigned 12 follow-up visits from recruitment to 5 years. One week in advance before each visit, assessors will remind patients to complete each visit on time by phone or WeChat accounts of patients or their relatives collected at baseline. Additionally, our cohort has its own official WeChat account, which will be mainly used to post care tips, important notices or reminders for patients. We will also use this account to provide support and counsel for patients with RA, which could increase the compliance and decrease the loss of follow-up rate of the cohort. If a patient is unavailable or misses a visit, follow-up survey at this visit is also performed by video telephone or online meeting apps.

Statistical analysis

To interpret and report the results reasonably, relevant guidelines (eg, STROBE, Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis [TRIPOD]) will be used. Baseline characteristics of all patients will be described. For continuous variables, means and SDs will be used to present normally distributed data; for other data, we will use median and IQRs. For categorical variables, frequencies with percentages will be reported. Potential group differences will be calculated by t-test or analysis of variance (ANOVA) (continuous data) or χ 2 (categorical data) or non-parametric tests.

For missing data, depending on the identified pattern and proportion of missingness, appropriate methods will be employed including complete case analysis for those less than 5%, last observation carried forward for longitudinal measures when applicable, or multiple imputation method. The robustness of results will be assessed through sensitivity analyses using complete cases or after imputing missing data. The proportion and patterns of missing data will be documented in accordance with STROBE guidelines through flow diagrams and baseline characteristics tables.

To better clarify the relationship between possible risk factors and end-point events, appropriate statistical methods will be used to analyse the data according to the type of data, such as logistic regression model for categorical outcomes, Cox regression for survival outcomes, linear mixed-effect model for repeated measurement data, and the least absolute shrinkage and selection operator model for developing the predictive model with a large number of predictors. The performance of the developed predictive model will be evaluated with discrimination, calibration and clinical usefulness in the internal validation or even external validation (if possible). Additional analyses, such as subgroup or stratified analyses, according to any potential confounder (age, sex, history of disease at baseline, etc.) will also be conducted. To analyse different trajectories of predictor variables across multiple waves of data, path analyses and structural equation modelling will be used. Novel statistical methods (eg, machine learning, generalised estimating equation and Markov modelling) will also be tested for multimodal prediction. Statistical significance will be defined as p<0.05 (two-sided).

Patient and public involvement

Neither participants nor the public has been or will be involved in the process of designing, conducting or reporting this study.

Ethics and dissemination

This project (protocol ID: version 1.0, 21/11/2023) has been approved by the Medical Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (ID: SYSKY-2023-1235-01); the Affiliated Panyu Central Hospital of Guangzhou Medical University (ID: PYRC-2024-214-01); and ShenShan Medical center, Memorial Hospital of Sun Yat-sen University (ID: 2024-SSKY-118-01). The study protocol has been registered in Clinical Trial ( NCT06233929 ) on 31 January 2024.

Any modifications to the study protocol that may affect participant safety, study conduct or ethical considerations must be formally submitted as protocol amendments to the Institutional Review Board (IRB)/Ethics Committee (EC) for approval. Substantial amendments (eg, changes to study objectives, design, population, interventions, or risk-benefit assessment) will be communicated in writing to all relevant parties, including investigators, study sites, regulatory authorities and trial registries within 15 business days of IRB/EC approval.

Written informed consent including agreement for the collection, storage and future use of clinically residual biological specimens (including but not limited to peripheral blood serum, whole blood and PBMCs, synovial tissue specimens and joint synovial fluid collections) when available will be obtained from all the participants after objectives and procedures of the research have been fully explained to them by a member of the research team. For invasive procedures (eg, arthrocentesis for synovial biopsy or joint synovial fluid extraction), additional procedure-specific consent will be obtained at the time of clinical indication. Participants will also be informed that they can withdraw from the research at any time without giving any reasons.

All personal information collected from all the participants will be handled with strict confidentiality measures in compliance with applicable data protection regulations. Identifiable data including names, contact information and medical records will be pseudonymised using unique study identification codes, with the encryption key maintained separately in password-protected files accessible only to authorised study personnel. Following study completion, all electronic records will be archived for 5 years per regulatory requirements before secure deletion, while paper documents will be shredded. Published results will contain only aggregated data that cannot be linked to individuals. Participants will be informed that their privacy is protected throughout the research process.

All participants will continue to receive standard clinical care for their condition throughout the trial period. For any injury or harm directly attributable to study participation, the study institution will provide necessary medical treatment and appropriate compensation, as determined by an independent adjudication committee following local regulations.

Results from the cohort study will be disseminated by publications in the peer-reviewed scientific journals, presentations at both national and international conferences. The general results will be shared with participants through mass media releases or public education activities.

Data sharing

The individual de-identified participant data (including data dictionary), statistical code, and any other materials are available from the corresponding author Professor Dai on reasonable request.

Funding: This work has been supported by Guangzhou Municipal Science and Technology Project (grant number 2024A03J0912 and 202201010861), and Sun Yat-Sen Memorial Hospital Clinical Research 5010 Program (grant number SYS-5010-202407). The funders had no role in study design, data collection, analysis, interpretation, or manuscript preparation, despite authors’ affiliations with the funders.

Prepublication history for this paper is available online. To view these files, please visit the journal online ( https://doi.org/10.1136/bmjopen-2024-092583 ).

Patient consent for publication: Not applicable.

Provenance and peer review: Not commissioned; externally peer reviewed.

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

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