RA is a persistent autoimmune condition that is characterized by widespread inflammation throughout the body. It primarily affects the joints, causing pain, stiffness, and swelling. The prevalence of RA varies globally, with a higher incidence rate in women compared to men. The worldwide prevalence ranges from 0.5 to 1.0%. RA is characterized by the presence of neovascularization and abnormal synovial hyperplasia, which are pathological manifestations directly influenced by the infiltration of diverse immune and inflammatory cells within the affected area (1, 2). The infiltration of the affected area at a local level ultimately results in the gradual deterioration of both cartilage and bone, thus causing dysfunction of the joints and posing a higher risk of disability and even mortality. Oxidative stress is a condition characterized by an imbalance between the oxidative and antioxidant processes within the human body. The disruption in redox balance gives rise to an excess of free radicals, which surpasses the body’s ability to eliminate them through antioxidants. As a result, an excess of ROS, reactive nitrogen species (RON), and various other compounds build up, leading to oxidative damage. RA is significantly influenced by the presence of oxidative stress, which acts as a pivotal factor in its pathogenesis (3, 4). The research has uncovered a noteworthy and affirmative association between clinical indicators and oxidative stress indicators within the bloodstream of individuals suffering from RA. The measurement of serum oxidative stress markers has proven to be a reliable biomarker for effectively monitoring the progression of RA disease (4, 5). Elevated levels of mitochondrial ROS and inflammation have been found to be closely associated in the plasma of patients with RA. The treatment involving tumor necrosis factor (TNF) blockade has the capacity to inhibit oxidative stress and the occurrence of mitochondrial mutations induced by hypoxia, which in turn facilitates the process of disease rehabilitation (6).

At present, the clinical treatment strategies for this disease are mainly chemical drugs, such as NSAIDs, DMARDs, GCs and biological agents, but it is difficult for patients to accept long-term drug treatment and its side effects. Nowadays, the clinical acceptance of TCM has been increasing all over the world. In the theory of TCM, RA is thought to be caused by the attack of “wind, cold, damp humor,” and herbs with the effect of removing wind and dampness are used to relieve pain (7, 8). Wind in TCM is characterized by the sudden onset of illness, mobility of the affected area, variability in symptom presentation, and sensitivity to environmental changes. Wind-dominant arthralgia is commonly seen in the initial phase of RA and primarily affects the upper body. Damp is primarily associated with the weather. Being in water or resting on damp ground can trigger and exacerbate symptoms due to the moist surroundings. Cold-induced symptoms refer to the exacerbation of symptoms when exposed to cold temperatures, which can be alleviated by the application of heat. Cold-related arthritis primarily affects the hands and feet. Chinese herbal medicine can alleviate RA through multi-target, multi-link and multi-way, and concentrate on the regulation of oxidative stress and inflammation, both of which play pivotal roles in the progression of RA (8, 9). The objective of this research is to explore the RA-relevant anti-inflammatory/anti-oxidative effects of TCM herbs/herbal compounds. Through emphasizing the distinctive advantages of Chinese herbal medicine in dealing with these fundamental pathological processes, our objective is to shed light on potential innovative approaches to improve RA patient outcomes. Ultimately, the primary goal of this paper is to make a valuable contribution to the expanding pool of evidence that advocates for the incorporation of Chinese herbal medicine in conventional treatment plans for RA.

RA is initially characterized by persistent activation of cells, leading to autoimmunity in the joints or other affected organs (10). The primary presentation of the illness primarily arises as a result of inflammation in the synovial tissue and damage to the joints. Despite the absence of a cure for RA, early intervention with medication can effectively decrease the likelihood and severity of joint damage, while also slowing the progression of this debilitating disease. In the field of clinical treatment for RA, commonly used medications include NSAIDs, GCs, and DMARDs.

RA is characterized by a sophisticated interplay between genetic factors and environmental triggers (11). Over the course of recent decades, a substantial body of evidence has unequivocally demonstrated the pivotal role of genetic factors in triggering RA. At present, the genes HLA-DRB1, TNFRSF14, and PTPN22 have been identified as genetic factors that contribute to the development of RA, indicating a strong association between these genes and the onset of RA. Antigen-presenting cells have the capability to mistakenly present their antigens to T cells, a process that triggers T cell-mediated autoimmune reactions and directly contributes to the development of RA (12, 13). Moreover, RA is significantly influenced by various environmental factors (14). Smoking, individual dietary choices, and personal hygiene practices are among the major contributors (14, 15). These factors have a direct impact on the post-transcriptional modifications of specific genes and can also indirectly affect susceptible genes through epigenetic mechanisms.

Rheumatoid factor (RF) isotypes in combination with anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies yielded higher risk ratios for disease development than each factor separately, suggestive of an interaction between RFs and anti-cyclic citrullinated peptide antibody (ACPA) (16). IgM-RF enhanced the capacity of ACPA immune complexes to further stimulate cytokine production by macrophages, and consequently that RF would affect the immune process and/or the pathogenicity of ACPA immune complexes in RA (17, 18). Researches indicate that there exist two distinct genetic types of RA, known as ACPA positive and ACPA negative, which exhibit varying degrees of association and shared epitopes among patients (11, 19). When specific alterations occur within the surrounding conditions, the arginine undergoes a conversion into citrulline, initiated by the enzymes known as peptidylarginine deiminases (PADs). The presentation of citrullinated proteins to antigen-presenting cells (APCs) of T cells via specific major histocompatibility complexs (MHCs) can result in the production of ACPAs, subsequently initiating an autoimmune response in individuals with RA against citrullinated autoantigens (20). Peptide arginine deaminase type 4 (PADI4) has been recognized as a non-MHC genetic risk factor associated with RA.

In RA, immune cells tend to aggregate locally in the affected areas. The cellular components of our immune system consist of a variety of different types of cells. Among them are innate immune cells, including dendritic cells, monocytes, mast cells, and innate lymphocytes. Alongside these are adaptive immune cells, such as helper T-1 and helper T-17 cells, B cells, plasma cells, and plasma cells. Dendritic cells (DCs) can be activated by various environmental or genetic factors, leading to the initiation of innate immune responses. These specialized cells play a crucial role in recruiting and activating T cells, stimulating B cells, macrophages, synovial cells, chondrocytes, and osteoclasts. Additionally, they secrete inflammatory cytokines like TNF-α, IL-1β, IL-6, and matrix metalloproteinases (MMPs), which contribute to bone damage (21, 22). Hence, the interaction between innate and acquired immune mechanisms fosters tissue degradation and restructuring in the neighboring bone marrow and synovium (23). The chronic inflammation seen in RA triggers a series of interconnected reactions, leading to the migration of white blood cells to inflamed joints. Notably, this cascade reaction necessitates the presence of proangiogenic factors, which stimulate the formation of new blood vessels and ensure a steady supply of nutrients and oxygen to the swollen joints (24, 25). The fibroblast like synovial cells (FLSs) found in the synovial membrane possess a distinctive invasive behavior, which contributes to the invasion of the extracellular matrix and worsens joint damage (26).

In the presence of RA-induced inflammatory conditions, the characteristics of FLSs are dramatically altered, transforming them from innocuous mesenchymal cells into aggressive and infiltrating tumor like cells. The altered RA-FLSs assume a pivotal role in the development and advancement of RA, exerting a distinctive phenotype marked by diminished susceptibility to cell apoptosis, heightened expression of adhesion molecules, and aberrant generation of cytokines, chemokines, and MMPs (27, 28). The intricate network of cytokines and chemokines exerts a significant regulatory impact on the inflammatory milieu within the synovial cavity; Cytokines and chemokines play a crucial role in driving inflammation through their ability to activate endothelial cells, recruit immune cells to the synovial chamber, stimulate fibroblasts, and facilitate the accumulation of activated T and B cells. The intricate network of cytokines and chemokines exerts a significant regulatory impact on the inflammatory milieu within the synovial cavity; Cytokines and chemokines play a crucial role in driving inflammation through their ability to activate endothelial cells, recruit immune cells to the synovial chamber, stimulate fibroblasts, and facilitate the accumulation of activated T and B cells (see Figure 1).

Various approaches have been employed to attenuate, with Chinese herbal medicine being recognized as a significant approach. Chinese herbal medicine, encompassing Chinese herbs, acupuncture, and massage, has been widely studied for its potentially alleviative effects on RA. The exploration of the mechanism is currently underway. Numerous anti-rheumatic Chinese herbs have been discovered to contain potent ingredients that effectively hinder the progression of RA. These ingredients have been extensively studied and their efficacy has been scientifically confirmed (Figure 2).

Currently, in the clinical management of RA, there are four primary classifications of Western medicines being employed: NSAIDs, anti-rheumatic drugs, glucocorticoids and biological agents (77, 78). NSAIDs, known for their rapid and targeted effects, can swiftly reach the affected areas and alleviate the pain experienced by RA patients (77). As to its therapy, DMARDs are most commonly used. However, these drugs are not entirely satisfactory in terms of treatment effectiveness. They come with significant toxicity and side effects, low patient tolerance and compliance, among other factors. Consequently, recent research and development efforts have focused on harnessing the advantages of natural medicine. Chinese herbal medicines, in particular, has emerged as an important source for identifying and exploring new potential drugs (79, 80). According to the theory of TCM, herbs with “cool” or “cold” properties are employed to eliminate “heat” and may exhibit the function of replenishing “Qi” deficiency, relieving patients of severe symptoms such as pain caused by inflammation. Contrarily, herbs that possess “warm” or “hot” properties, such as “Fuzi,” have consistently been recognized as “interior-warming medicine” that can be used to ward off internal and external “cold.” Meanwhile, given the critical significance of oxidative stress in the development of RA, this study also summarized the treatment methods of Chinese herbal medicine with antioxidant activity for RA. Many natural drugs, like GTE, TAN, NIP, ASE and PCA, have observable antioxidant impacts on RA. Some examples of medicinal herbs that have garnered attention in the search for potential remissions for RA are Radix Stephaniae Tetrandrae, Radix Gentianae Macrophyllae, Caulis Lonicerae and Caulis Sinomenii. These plants have been the focus of research aimed at identifying and studying new alleviative agents for RA. Furthermore, extensive scientific research has proven the extraordinary anti-RA properties possessed by the active compounds present in these traditional Chinese herbal medicines (81, 82). It is worth noting that the development of new remission options for RA is an ongoing process, and the utilization of natural medicine, particularly Chinese herbal medicines, is an important trend in this field. By capitalizing on the unique benefits provided by natural remedies, researchers are making significant strides in finding more effective and safer remission approaches for RA patients.

Now, the options for clinical remission of RA are limited to a few natural remedies, with the majority of them still undergoing in the preclinical research phase. Sinomenine, tripterygium glycosides, and total glucosides of paeony have received official approval for their clinical application in the RA treatment. Resveratrol, a highly regarded natural medicine, has shown promising effects in attenuating various diseases, including RA, making it a subject of extensive research for its therapeutic potential. The remarkable effectiveness of tripterygium, the primary active component found in tripterygium glycosides tablet, in the remission of RA can be attributed to its potent immunosuppressive and anti-inflammatory properties. Nevertheless, it should be taken regularly, and excessive use can cause toxicity and various adverse reactions, especially affecting the gastrointestinal system, reproductive health, and effects on liver, kidney, and cardiovascular function. To enhance the benefits of natural remedies, the exploration of derivatives has become a prominent area of research. These derivatives, compared to their parent compounds, exhibit stronger pharmacological effects, generating considerable interest. For instance, derivatives such as 7,3′-dimethoxyhesperidin derived from hesperidin, pentaacetyl geniposide derived from geniposide, and paeoniflorin-6′-o-benzenesulfonate derived from paeoniflorin have garnered attention in the field.

Recent studies have shown that Chinese herbal medicines have potential in treating RA through various mechanisms, with a key focus on their anti-inflammatory properties (9, 79, 83). These Chinese herbal medicines have the ability to regulate the balance between pro-inflammatory and anti-inflammatory factors in the body, thereby reducing the infiltration of inflammatory cells in RA (84). They achieve this by targeting well-known inflammatory signaling pathways such as NF-κB and MAPK (22). Additionally, Chinese herbal medicines play a vital role in restoring immune balance by modulating the function of immune cells, including T cells, macrophages, and dendritic cells (85, 86). Furthermore, Chinese herbal medicines contribute to the repair and protection of articular cartilage, a major concern in RA. They promote apoptosis and inhibit the uncontrolled proliferation of RA-FLSs, leading to an improvement in the regenerative processes of damaged cartilage (87). Moreover, Chinese herbal medicines exhibit the ability to prevent bone destruction by inhibiting the differentiation of osteoclasts, which are responsible for bone resorption. These multi-faceted effects highlight the promising alleviative potential of Chinese herbal medicines in RA. Another noteworthy aspect is the regulation of microRNAs (miRNAs) associated with RA. Chinese herbal medicines demonstrate the capability to influence miRNA expression, thereby exerting a profound impact on the pathological processes underlying RA (88). Additionally, Chinese herbal medicines have been found to possess antiangiogenic properties by decreasing the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α), thereby hindering the formation of new blood vessels (89). Furthermore, Chinese herbal medicines help restore oxidative balance by enhancing the activity of antioxidant enzymes such as GSH, SOD, and CAT, while also modulating related biochemical pathways (90). But there are potential problems with excessive antioxidant, namely a potential barrier to fighting certain infections, and an increased risk of cancer cell metastasis, among others.

To summarize, the investigation into potent and low-toxic active compounds sourced from Chinese herbal medicines for attenuating rheumatoid diseases remains a crucial and continual area of emphasis in both present and forthcoming medical studies. Furthermore, there is immense potential in the field of managing RA through the development of enhanced and meticulously regulated medications derived from Chinese herbal medicines. Looking ahead, as we allocate more resources to thorough research and stringent clinical trials, we can expect the broader adoption of natural medicines, such as dietary interventions and herbal remedies, in the remission of RA. These natural approaches hold the potential to be utilized independently or in conjunction with traditional therapies, offering patients a comprehensive range of options. Several Chinese herbal medicines have been found to possess comparable properties to NSAIDs in terms of effectively reducing inflammation and relieving associated symptoms. With the continuous advancement in the field of medicine, it becomes increasingly crucial to explore and discover methods that not only provide effective results but also minimize adverse reactions and remain cost-effective. This pursuit has become an unavoidable trend within the medical community. Chinese herbal medicines possess distinct advantages owing to their unique composition of multiple active components and remarkable capacity to effectively target and modulate multiple pathways simultaneously. Nevertheless, the progress of Chinese herbal medicines is impeded by the absence of clear elucidation on their mechanisms of action and the limited comprehension of these intricate substances. Therefore, further efforts are needed to identify and confirm the active ingredients of Chinese herbal medicines with anti-RA properties, with a focus on fully elucidating their complete mechanism of action.

XW: Data curation, Formal analysis, Investigation, Methodology, Resources, Writing – original draft. YK: Writing – original draft. ZL: Project administration, Supervision, Writing – review & editing.