Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects synovial joints. Although the incidence of RA shows regional variation, its worldwide prevalence is approximately 0.5% [1]. RA typically affects symmetrical joints and causes pain, swelling, and redness. In severe cases, it can lead to permanent joint deformity or affect other organs such as the lungs, heart, skin, blood vessels, and eyes [2]. RA can also impose a considerable socioeconomic burden, leading to progressive disability and an increased risk of death [3]. Studies have shown that patients with RA have a 47% higher risk of mortality compared to the general population, with a life expectancy reduced by 3–10 years [4].

Although the underlying mechanisms of RA are controversial, it is known to induce pathogenic changes owing to the initiation of an autoimmune response. Immune cells such as macrophages, T cells, B cells, neutrophils, mast cells, and dendritic cells induce an inflammatory response by producing chemical mediators and interleukins (ILs) [5]. Chronic synovial inflammation results in synovial membrane hypertrophy and even causes bone destruction and joint deformity [6]. Most treatments for RA exert their effects by targeting and regulating the inflammatory pathways.

Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs) are the most well-known treatment options for RA [7]. These medications aim not only to reduce major complaints such as joint pain and swelling but also to prevent further pathogenic changes such as bone damage, other articular manifestations, and declines in patients' quality of life [8]. DMARDs, which block cytokines related to RA symptoms, are the mainstay of RA intervention; however, they show limited efficacy in some patients and may cause several side effects such as gastrointestinal disorders, pneumonitis, hepatotoxicity, nephrotoxicity, and increased cardiovascular risks [5,9]. According to a previous study on methotrexate (MTX), the first-line DMARD, approximately 30% of patients with RA fail to achieve an adequate treatment response, and 20% discontinue treatment owing to toxicity [10].

In traditional Chinese medicine (TCM), extensive efforts have been made to discover more effective treatments for RA, largely focusing on the inflammatory pathway. Herbal medicine, a common intervention in TCM, is used to reduce the symptoms of RA and prevent additional pathogenic changes [11,12]. Among these herbal remedies, the Yi Shen Juan Bi (YSJB) pill is a compound of herbal drugs including Davallia, Radix Rehmanniae Preparata, Cynanchi Paniculati Radix, Eupolyphaga seu Steleophaga, Nidus Vespae, Honeysuckle Flower, Pheretima, Epimedium brevicornu Maxim, Kadsura interior, Caulis spatholobi, and Scolopendra subspinipes. YSJB has been widely used for the treatment of RA and has shown good efficacy in reducing its symptoms and regulating the inflammatory pathway [13]. It has been found to reduce inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-1, nitric oxide (NO), and prostaglandin E in rat models of adjuvant arthritis [14]. Other studies have reported that YSJB downregulates caspase-3, an apoptosis-related protein [15]. The compound Caulis spatholobi, one of the components of YSJB, has also demonstrated anti-inflammatory activity by inhibiting cyclooxygenase-1 [16].

The bone-protecting effects of YSJB are particularly notable, with several studies reporting that YSJB can reduce bone destruction and bone loss induced by arthritis in mice models [17,18]. Moreover, Davallia mariesii, a component of YSJB, has been reported to have potent osteogenic activities [19]. Furthermore, extracts of Pheretima, another component of YSJB, have been shown to stimulate bone generation and inhibit bone destruction [20]. Considering that the goal of RA treatment is to prevent further pathogenic changes, YSJB may offer a more effective option. Furthermore, a previous study on patients with RA reported that compared to the MTX-only group, the combination of YSJB and MTX resulted in significantly increased efficacy and a lower adverse effect rate [21].

Despite these previous studies, no evidence-based review has investigated the clinical effectiveness of YSJB. Additionally, owing to some of the compounds included in the pill, an investigation into the safety of YSJB is necessary. Therefore, the purpose of this systematic review (SR) is to analyze the effectiveness and safety of YSJB.

1. Study design

This SR and meta-analysis will be conducted in compliance with the Preferred Reporting Items for Systemic Reviews and Meta-Analyses Protocols (PRISMA-P) 2020 statement. The protocol has been registered in PROSPERO (CRD42023421940) [22].

2. Eligibility criteria

1) Participants

This study will include individuals diagnosed with RA regardless of age, sex, and race, with no restrictions based on the severity of symptoms. However, patients with other types of arthritis, such as osteoarthritis, will be excluded. Only patients diagnosed according to official criteria, such as the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) RA criteria [23], will be included.

2) Types of intervention

Randomized controlled trials (RCTs) evaluating the use of YSJB for RA will be included. If YSJB contains the same herbs, regardless of the individual amounts of each herb, the RCTs will be included in this study. Additionally, any form of orally administered YSJB, such as pills, powder, or decoction, will be accepted. The control group will include conservative treatments such as medications (NSAIDs, DMARDs, and glucocorticoids), physiotherapy, and occupational therapy. The use of combination treatment with YSJB should be consistent between the experimental and control groups. Comparisons between traditional Chinese interventions, including other herbal decoctions and acupuncture, will be excluded, except for YSJB.

3) Language

The SR will have no language restrictions.

4) Types of studies

RCTs that examine the effects of YSJB will be included. This study will exclude non-RCTs such as in vivo and in vitro studies, case studies, observational studies, and SRs. Additionally, RCTs that employed incorrect randomization methods, such as alternate allocation or allocation according to birthdate, will be excluded. If a study omits the word “randomization,” it will be excluded. However, if a study includes the word “randomization” but does not provide a detailed randomization method, it will be included in the SR but assessed as having a high risk of selection bias. Both parallel and crossover studies will be included. In crossover studies, only the first-phase data will be used for the meta-analysis.

5) Outcome measures

The disease activity score will be our primary outcome measure and will include the following:

(1) Effective rate: Improvement in patients' symptoms can be evaluated in three or four stages: cured, improved, significantly improved, or non-responsive. The effective rate will be calculated by summing the number of cured, improved, and significantly improved patients.

(2) Swollen joint count: This count will be included in the Disease Activity Score, which will be used to evaluate the disease activity of RA.

(3) Tender joint count: This will also be included in the Disease Activity Score for evaluating RA activity [24].

(4) Morning stiffness: This is another important factor in RA because its duration is related to the development of erosive arthritis, and the presence of symptoms indicates clinically active disease [25]. These measures will help assess the overall effectiveness of the treatment in managing the symptoms of RA.

Our secondary outcome measures include blood test results and adverse events:

(1) TNF-α: A proinflammatory cytokine involved in the pathogenesis of RA. Increased expression in patients with RA stimulates synovial fibroblasts and macrophages, contributing to autoimmune arthritis [26].

(2) IL-1: Another proinflammatory cytokine with increased expression in RA, playing a significant role in disease progression.

(3) Erythrocyte sedimentation rate, (4) C-reactive protein, and (5) Rheumatoid factor: Commonly used biomarkers for the diagnosis, prognosis, and management of RA [27].

(6) Adverse events: Monitoring and reporting any adverse events associated with the treatment.

3. Information sources and search strategy

Researchers will independently conduct the search from the inception of each database until June 2024. The following databases will be searched: two English databases (MEDLINE, Cochrane Library), two Chinese databases (China National Knowledge Infrastructure; CNKI, Wanfang), two Japanese databases (CiNii, J-STAGE), and six Korean databases (KoreaMed, Korean Medical Database, Korean Studies Information Service System; KISS, National Digital Science Library, Korea Institute of Science and Technology Information, and Oriental Medicine Advanced Searching Integrated System). The search terms will include both disease and intervention keywords. We will use combinations of the terms “arthritis,” “rheumatoid” or “rheumatoid arthritis,” and “Yi Shen Juan Bi pill” or “YSJB” in the language of each database. We will also perform manual searches on Google Scholar and follow references from related articles. Additionally, “gray literature” such as degree theses and conference proceedings will be included (Table 1).

Table 1

Search strategy.

No.	Search terms
1	Rheumatoid arthritis
2	Rheumatoid
3	Arthritis
4	OR #1-3
5	Randomized controlled trial OR random*
6	Controlled clinical trial OR trial
7	Placebo
8	OR #5-7
9	Yi shen juan bi pill
10	Yi shen juan bi
11	OR #9-10
12	#4 AND #8 AND #11

1) Study selection

Two researchers (GEP and JHM) will independently select the studies according to titles, abstracts, and full texts. After removing duplicates, irrelevant reports will be screened by their titles and abstracts. Finally, the full texts of the remaining studies will be evaluated. In the event of any discrepancy between the researchers, a consensus will be reached through discussion; if a consensus cannot be achieved, a third researcher (WSS) will mediate to resolve the doubts. The study selection process will be reported according to the PRISMA statement (Fig. 1).

Figure 1. PRISMA flow diagram.

2) Data extraction and management

The following data will be extracted from the selected studies: identification information (title, authors, publication year), general information (sample size, number of participants who dropped out, study design), patient characteristics (age, sex, morbidity period, etc.), intervention (process, duration, follow-up, etc.), outcome measurement, and research quality. If any data are incomplete, we will contact the authors to obtain the missing information. If this is not possible, we will include the available data and describe the omitted data. EndNote X20, a reference management software, will be used for data management.

3) Data synthesis and analysis

The changes from baseline to completion of intervention will be combined for analysis. We will conduct a meta-analysis between studies using identical interventions and outcome measures. To evaluate the effect, we will calculate the mean difference and 95% confidence intervals (CIs) for the same outcome measures and the standardized mean difference and 95% CIs for different outcome measures. A random-effects model will be used if heterogeneity is significant; otherwise, a fixed-effects model will be applied [28].

The Review Manager software (The Cochrane Collaboration, Oxford, UK) for Windows will be used for the meta-analysis. Heterogeneity between the results will be evaluated using Chi-squared and I-squared tests and will be interpreted as follows: 0%–40% (unimportant heterogeneity), 30%–60% (moderate heterogeneity), 50%–90% (substantial heterogeneity), and 75%–100% (considerable heterogeneity) [29]. These interpretations will guide the selection of the appropriate model (random-effects or fixed-effects) for the meta-analysis.

If possible, subgroup analysis will be conducted based on the main intervention of the control group, and if necessary, meta-regression or sensitivity analysis will be performed for potential variables. Outlier data that are significantly different from the rest of the data will be excluded. A narrative synthesis will be used as an alternative if quantitative synthesis cannot be conducted. If there are more than 10 studies, publication bias will be assessed using a funnel plot. If an asymmetric funnel plot is observed, we will attempt to explain the reason. The Grades of Recommendation, Assessment, Development, and Evaluation system will be used to rate the quality of evidence [30].

4) Risk-of-bias assessment

Two researchers will use the “Risk of Bias” tool from the Cochrane Collaboration to assess the risk of bias and methodological quality of each article. This tool consists of seven areas, through which selection bias, performance bias, detection bias, attrition bias, and reporting bias will be evaluated. The seven areas are sequence generation, allocation concealment, blinding of participants and investigators, blinding of outcome assessment, completeness of outcome data, selective outcome reporting, and other biases. Each area will be assessed as low risk, high risk, or unclear risk of bias [31].

5) Ethics

As this study will not involve the collection of personal information of the patients, ethical approval will not be required.

RA is a chronic disease that not only reduces the quality of life of the affected individuals but also imposes a considerable socioeconomic burden. Although medications such as NSAIDs and DMARDs are recommended treatment options, they have limitations in terms of efficacy and can cause several adverse effects. Consequently, several alternative complementary treatments, including TCM, have been introduced for RA.

Among TCM treatments, several herbal medicines, including Gui zhi-shao yao-zhi mu decoction and Bi qi capsule, have shown efficacy in the treatment of RA [32,33]. YSJB has also been shown to exert anti-inflammatory and bone-protecting effects in several previous studies. Macrophages play an important role in the immune response, and their activation generates TNF-α and NO. Although NO is essential for the immune system, its chronic expression causes inflammatory disorders such as RA and other autoimmune diseases. Previous studies have reported that YSJB regulates the inflammatory and immunological systems of cells [14]. This study will focus on the clinical efficacy of YSJB in the treatment of RA, aiming to propose a new approach to managing the disease.

Additionally, YSJB includes some compounds that require investigation from a safety perspective. For instance, it has been reported that large doses of Eupolyphaga seu Steleophaga can increase aspartate aminotransferase and alanine aminotransferase levels [34]. Previous studies have also implied that Scolopendra can induce liver injury [35]. Although Scolopendra is processed by boiling and drying before administration to remove its toxicity, its overuse can lead to side effects such as acute hepatic failure [36]. Eupolyphaga seu Steleophaga has been recorded as a mildly toxic medicine in the traditional Chinese Pharmacopoeia. Although acute toxicity tests and 30-day feeding studies conducted by the Ministry of Health of the People's Republic of China have reported its safety [37], it is still necessary to monitor for any toxic side effects caused by its clinical application.

The results of this SR will address these safety concerns and supplement the existing studies, providing an evidence-based review for patients, clinicians, and researchers.

This study was supported by the Traditional Korean Medicine R&D program funded by the Ministry of Health and Welfare through the Korean Health Industry Development Institute (KHIDI) (grant No. HF21C0077).

JH Kim, and BK Seo oversee project administration and WS Sung is the guarantor of the review. WS Sung conceived the topic. SH Park and SD Lee provided the methodology, and GE Park and JH Moon conducted investigation. GE Park wrote the first draft of the protocol, and WS Sung reviewed and edited. All authors checked the final version and agreed on the journal to which the article will be submitted.

The authors declare no conflict of interest.