Clinical Cohort Construction and Therapeutic Effect Evaluation of Integrated Traditional Chinese and Western Medicine in the Treatment of Rheumatoid Arthritis

Clinical Cohort Construction and Therapeutic Effect Evaluation of Integrated Traditional Chinese and Western Medicine in the Treatment of Rheumatoid Arthritis

This is a large-scale, multicenter observational study on the treatment of rheumatoid arthritis (RA) with integrated Traditional Chinese and Western medicine.

The study plans to enroll at least 10,000 patients, including a minimum of 1,000 cases with difficult-to-treat RA (D2T RA) and 1,000 cases with RA-associated interstitial lung disease (RA-ILD). Through long-term follow-up, data will be collected on Traditional Chinese Medicine (TCM) syndrome characteristics, treatment plans, adverse drug reactions, and complications. Biological samples, including blood and urine, will also be collected.

The research will utilize multi-omics technologies such as genomics and proteomics, combined with clinical data, to deeply explore the modern scientific connotation of the "disease-syndrome-symptom" framework in RA. The goal is to clarify the patterns and advantages of TCM syndrome differentiation and treatment. Based on these findings, a scientific and standardized efficacy evaluation system for integrated treatment will be established, and optimized treatment strategies for D2T RA and RA-ILD will be developed.

The project is led by multiple national TCM clinical research centers and regional diagnostic and treatment centers, including the First Teaching Hospital of Tianjin University of TCM and Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine. These institutions have mature clinical research platforms, biobanks, and databases, providing a solid foundation for the successful implementation of this study.

The results of this research will provide a scientific basis for the integrated treatment of RA, promote the standardization of diagnostic and treatment protocols, and ultimately improve the overall level of RA prevention and treatment in China.

1. Study Overview Rheumatoid arthritis (RA) is an autoimmune disease primarily characterized by erosive arthritis. Under the guidance of Traditional Chinese Medicine (TCM) syndrome differentiation theory, integrated treatment with TCM and Western medicine has demonstrated significant clinical benefits in managing difficult-to-treat RA (D2T RA) and RA-associated interstitial lung disease (RA-ILD). However, the biological association between RA phenotypes and TCM syndromes remains unclear, and the modern medical material basis of the "disease-syndrome-symptom" framework requires further elucidation. Therefore, employing a "disease-syndrome combination" approach to identify key biomarkers and core syndromes in RA pathogenesis, and to clarify the advantages of integrated treatment strategies, will provide a theoretical foundation for systematic research on RA diagnosis and treatment laws in integrated medicine.

   Building upon previous research, this study will enroll at least 10,000 patients in a multicenter cohort receiving integrated TCM and Western medicine treatment for RA, including no less than 1,000 patients with D2T RA and no less than 1,000 patients with RA-ILD. Data to be collected include TCM syndrome characteristics, clinical profiles, treatment regimens, adverse drug reactions, biological samples, complications, and follow-up information. Through systematic data collection and analysis, the study aims to establish a multicenter research cohort biobank and clinical database for integrated RA treatment. By summarizing clinical diagnosis and treatment patterns and integrating multi-omics research data, the study will further explore the modern scientific material basis of D2T RA and RA-ILD within the "disease-syndrome-symptom" framework. The research will focus on elucidating the advantages and patterns of TCM syndrome-based treatment in RA and establishing a scientific, standardized efficacy evaluation system. This study is expected to provide scientific evidence for integrated TCM and Western medicine treatment of RA, validate the unique efficacy of TCM in RA management, offer practical references for clinical practice, provide important theoretical support and practical basis for improving the overall level of RA prevention and treatment in China, and promote the standardization and normalization of integrated RA treatment.

2. Study Objectives and Content 2.1 Study Objectives Currently, the biological association between RA phenotypes and TCM syndromes remains unclear, and the modern medical material basis of the "disease-syndrome-symptom" framework requires further elucidation. Therefore, this study aims to observe the effectiveness and safety of integrated TCM and Western medicine in the clinical treatment of RA, establish an RA clinical information database and biobank, employ a "disease-syndrome combination" approach to explore key biomarkers and core syndromes in RA pathogenesis, identify optimal integrated treatment strategies, and subsequently develop a scientific and standardized efficacy evaluation system.

   2.2 Study Content

   This study will collect data from a multicenter cohort of 10,000 patients receiving integrated TCM and Western medicine treatment for RA, including at least 1,000 patients with D2T RA and at least 1,000 patients with RA-ILD. The main research components include the following:

   Collection of patient clinical data: Including TCM syndrome characteristics, treatment regimens, adverse drug reactions, complications, and follow-up status.

   Biological sample collection and analysis: Collecting blood, urine, and other biological samples from patients, and integrating genomics, proteomics, metabolomics and other multi-omics approaches to analyze the molecular biological characteristics of different patients.

   Efficacy evaluation of integrated treatment: Through controlled studies, analyzing the advantages of integrated TCM and Western medicine in RA treatment, exploring its therapeutic mechanisms, and clarifying the advantages of TCM syndrome-based treatment.

   Establishment of database and biobank: Through collected clinical data and biological samples, establishing a biobank and clinical database for the RA multicenter research cohort. This platform will serve as a foundation for subsequent research, supporting long-term scientific data accumulation and sharing.

   Elucidation of the modern scientific material basis of RA "disease-syndrome-symptom": Through integration of multi-omics data and clinical data, further exploring the scientific material basis of Wind-Damp Obstruction syndrome D2T RA and Liver-Kidney Yin Deficiency syndrome RA-ILD within the "disease-syndrome-symptom" framework, promoting the deepening of TCM modernization research.

   Construction of an efficacy evaluation system: Integrating clinical practice with multi-omics data to establish an efficacy evaluation system applicable to integrated TCM and Western medicine treatment of RA, ensuring scientific, standardized, and quantifiable assessment of therapeutic effects.

   Optimization and validation of integrated treatment protocols: By analyzing the effects of different treatment components, identifying and validating the advantageous components in D2T RA and RA-ILD integrated treatment protocols, forming treatment protocols with therapeutic advantages, and providing theoretical support for future clinical treatment.

3. Existing Facilities and Sample Resources The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, as the primary leading institution of this project, is a National Medical Center (TCM), a National Clinical Research Center for TCM, a Regional TCM Diagnosis and Treatment Center of the National Administration of Traditional Chinese Medicine, and a Key Laboratory of the National Administration of Traditional Chinese Medicine. It has undertaken and successfully completed the National Key Research and Development Program project "Optimization of TCM Protocols and Construction of Decision Platform for Rheumatoid Arthritis," which passed acceptance and provides platform support for optimizing TCM protocols for RA. The institution has undertaken more than twenty projects including National Key Research and Development Programs and National Natural Science Foundation projects, and has received more than ten national and provincial/ministerial-level awards, including a National Science and Technology Progress Second Prize.

Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, as the primary enrolling institution, is a Regional Diagnosis and Treatment Center of the National Administration of Traditional Chinese Medicine and a National Superior Specialty of TCM. It was nominated in the Rheumatology category of the 2023 Fudan Version Specialty Reputation Ranking. Previously, the hospital established a cohort of over 8,000 RA patients receiving integrated treatment and a cohort of over 5,000 RA-ILD patients receiving integrated treatment. Professor Chen Zhicai, a Shanghai renowned TCM practitioner, created the Quyu Qingfei Formula for treating RA-ILD, and basic and clinical research have confirmed its effectiveness and safety. This achievement received the Shanghai Integrated Traditional Chinese and Western Medicine Science and Technology Third Prize. In the past five years, the hospital has published over 80 SCI papers with a total impact factor of 241.61, including 4 papers with impact factors above 10, and 4 papers selected in the TOP100 of high-value papers in the field of Rheumatology and Immunology in China for 2022. The hospital is affiliated with the Institute of Joint Diseases of Shanghai Academy of Traditional Chinese Medicine, implementing an integrated hospital-institute management model, providing a complete clinical-research-translation integrated development platform for the advancement of rheumatology and immunology disciplines. The institute possesses an intelligently information-managed biobank and clinical database, with 20,000 RA biological samples in storage, including whole blood, plasma, serum, blood cells, synovium, and cartilage, providing abundant clinical resources for the research team.

Furthermore, in collaboration with multiple clinical institutions including Huashan Hospital Fudan University, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine affiliated with Shanghai University of Traditional Chinese Medicine, Henan Provincial Hospital of Traditional Chinese Medicine, and Guangxi Medical University, the research team possesses adequate research foundation conditions.

Inclusion Criteria:

1. Meet the RA classification criteria established by ACR in 1987 or the revised RA diagnostic criteria by ACR/EULAR in 2010;
2. D2T-RA must comply with the D2T-RA diagnostic criteria by ACR/EULAR in 2020 or the China D2T-RA diagnostic criteria in 2021;
3. RA-ILD patients require joint evaluation by rheumatologists and pulmonologists, with a clear diagnosis of ILD and exclusion of other possibilities such as pneumoconiosis, allergic alveolitis, idiopathic pulmonary fibrosis, and other connective tissue disease-related interstitial lung diseases (CTD-ILD);
4. Traditional Chinese medicine syndrome differentiation standards refer to the "Guidelines for Diagnosis and Treatment of Rheumatoid Arthritis" by the China Association of Chinese Medicine, the "Clinical Research Guidelines for New Traditional Chinese Medicine Drugs" by the National Medical Products Administration, and the "Diagnostic and Therapeutic Criteria for Traditional Chinese Medicine Diseases" by the Institute of Clinical Research of the China Academy of Chinese Medical Sciences;
5. Receive traditional Chinese medicine treatment;
6. Age ≥18 years;
7. Sign an informed consent form.

Exclusion Criteria:

1. Severe, progressive, or uncontrolled diseases of the kidneys, liver, blood, gastrointestinal tract, endocrine system, lungs, heart, nervous system, mental health, or brain, or current known malignant tumors;
2. Known clinically significant environmental exposures that may cause pulmonary fibrosis (PF), including but not limited to dust, asbestos, beryllium, radiation, amiodarone, bleomycin, etc.;
3. Poorly controlled severe asthma or chronic obstructive pulmonary disease (COPD) with medication adjustments within 3 months prior to screening;
4. Active infections that the investigator deems may interfere with study assessment;
5. Any clinically or laboratory abnormalities deemed significant by the investigator or other reasons that disqualify participants from this clinical study.