Introduction
Rheumatoid arthritis (RA), known as "Wang Bi" in Traditional Chinese Medicine (TCM), is an autoimmune disease characterized by symmetrical polyarthritis as the main clinical manifestation, with chronic inflammation of the synovial joints and progressive joint destruction.1 Early symptoms include joint numbness, swelling, morning stiffness, and pain. If left untreated, progressive bone destruction may occur in the later stages. The prevalence of RA in China is 0.42%, with middle-aged women being more commonly affected. Error! Reference source not found. Due to the unclear etiology of RA, there is currently no definitive cure. Recent studies have highlighted the significant impact of the gastrointestinal microbiota on the onset and progression of RA. The gastrointestinal tract harbors the body’s largest microbial population and immune system, making it a crucial area for further investigation. Therefore, integrating recent research with a rational approach combining Western and Traditional Chinese Medicine treatment may enable effective management for the majority of patients, reducing joint deformities, functional disabilities, and even mortality.
Professor Ji Wei, MD, Chief Physician, and Doctoral Supervisor at Nanjing University of Chinese Medicine, is currently the Chairman of the Rheumatology Subcommittee of the Jiangsu Provincial Society of Traditional Chinese Medicine. He studied under Master of Traditional Chinese Medicine Zhu Liangchun and Professor Jin Shi, a renowned expert in the inheritance of TCM academic experience. Professor Ji has long been engaged in clinical practice, teaching, and research on rheumatic immune diseases in TCM, accumulating rich experience and unique insights, with a focus on the integration of both Western and TCM approaches.
Exploring the Pathogenesis of RA from the Perspective of the Spleen
In TCM, the spleen, stomach, small intestine, san jiao (triple burner), and bladder are considered the foundational organs for the storage and transformation of essential substances, with the spleen being the source of nourishment. The spleen opens to the mouth, and its manifestation is seen in the lips, which are key locations discussed in this context. The spleen governs the transportation and transformation of nutrients and is responsible for the ascending of clear qi. It is favorable to dryness and adverse to dampness. The spleen controls the four limbs and is interconnected through the pathways of the three jiaos (upper, middle, and lower burners), linking the ying (nutrient) and wei (defensive) qi of spleen-stomach qi transformation. As described in the Huangdi Neijing (Yellow Emperor's Inner Canon), "The central earth irrigates the four directions," meaning that disease often affects the extremities. This provides the physiological foundation for the present discussion.
Spleen deficiency leading to dampness is the intrinsic pathogenesis of RA. When the spleen is deficient and unable to ascend clear qi, the transformation and transportation functions of the spleen and stomach are impaired. This results in stagnation of ying and wei qi, and the internal and external dampness converge, obstructing the flow of qi. In TCM, RA is typically considered to involve a combination of wind, cold, and dampness, with wind-damp invading the joints. In clinical practice, the disease may manifest in different stages with changes in the balance of dampness, cold, and heat, which are considered the most typical features. When the spleen is weak and unable to transport dampness, dampness combined with wind, cold, and heat flows into the joints, causing swelling. If the condition persists, it may transform into heat, resulting in obstruction and pain, manifesting as red, swollen, hot, and painful joints. Long-term disease can affect the meridians, with dampness congealing into phlegm. Phlegm and blood stasis can obstruct the meridians, leading to joint morning stiffness and deformity. According to the Huangdi Neijing, "All forms of swelling due to dampness belong to the spleen." This highlights how the inability to stabilize the postnatal foundation can lead to the onset and progression of RA.
The Mechanism of the Gut-Joint Axis in RA
Gut Microbiota and Immunity
The gastrointestinal microbiota and mucosal immune system are mutually influencing and interact with each other. This interaction involves mechanisms such as microbiota homeostasis, cross-reactivity (molecular mimicry), and immune tolerance. Dysbiosis of the gut microbiota in patients with RA has been a focal point of research in recent years and is considered one of the key factors in the pathogenesis of the disease.3 Anti-citrullinated protein antibodies (ACPAs) are critical diagnostic markers for RA. Studies on ACPAs help understand the process of breaking immune tolerance and aid in the identification of strategies for addressing the disease.
Citrullination and Cross-Reactivity
Citrullination is a physiological post-translational modification in which arginine is converted to citrulline through the action of calcium-dependent peptidyl arginine deiminases. Protein modifications can create new epitopes, resulting in the formation of neoantigens that are distinct from self-antigens. This promotes the recognition and presentation of these new antigens by antigen-presenting cells, thereby enhancing the immunogenicity of the protein.4 ACPAs are a class of antibodies that recognize citrullinated antigens and engage in cross-reactivity (molecular mimicry), potentially mediating immune damage. These citrullinated proteins are recognized by the immune system as foreign antigens, leading to upregulation of inflammatory responses and triggering the production of autoantibodies.5 Studies have shown that citrullination facilitates the production of antibodies against citrullinated proteins generated by bacteria. In the preclinical stage of RA, there is a characteristic accumulation of citrullinated proteins in the joints along with the presence of autoimmune ACPAs.Error! Reference source not found.
Dysbiosis and Immune Tolerance
The most studied gut microbiota species include Prevotella and Porphyromonas gingivalis .Error! Reference source not found. Changes in these microbiota may influence the immune system via molecular mimicry, contributing to the development of RA. In early RA patients, the abundance of Prevotella in the gut increases, while the abundance of Porphyromonas gingivalis in the oral cavity decreases. The antibody response to Prevotella correlates with the presence of anti-citrullinated peptide antibodies and rheumatoid factor positivity.Error! Reference source not found. Porphyromonas gingivalis can induce citrullination of host proteins, breaking immune tolerance to citrullinated proteins and generating ACPAs. This bacterium can also disrupt the intestinal barrier and, through the oral-gut-joint axis, migrate to distant tissues, triggering cross-reaction in the joints and contributing to arthritis.Error! Reference source not found. Porphyromonas gingivalis can induce citrullination of host proteins, breaking immune tolerance to citrullinated proteins and generating ACPAs. This bacterium can also disrupt the intestinal barrier and, through the oral-gut-joint axis, migrate to distant tissues, triggering cross-reaction in the joints and contributing to arthritis.Error! Reference source not found.
Leaky Gut, Immune Cells, and Cytokines
Leaky gut, induced by poor dietary habits, dysbiosis, and intestinal environmental disruptions, is a key factor in the onset of autoimmune diseases.
Leaky Gut and Antigen Translocation
The intestinal surface is continuously exposed to antigens from food, pathogens, and commensal microorganisms. Damage to the epithelial barrier increases intestinal permeability, allowing potential antigens to translocate into the body, particularly into the joints.Error! Reference source not found.12 Gut microbiota can induce epithelial injury and open paracellular pathways, facilitating contact between the epithelium and immune cells beneath the epithelial layer, thereby triggering inflammation. Compared to healthy controls, early RA patients show an increased level of peripheral Th17 cells. Th17 cells secrete a variety of pro-inflammatory cytokines, including IL-17, TNF-α, GM-CSF, IL-21, and IL-22, all of which play significant roles in the pathogenesis of RA. Th17 cells produce IL-17 and IL-22 to combat extracellular bacterial, fungal, and mycobacterial infections and maintain a balance with regulatory T cells (Tregs), a balance that, when disrupted, contributes to the development of autoimmune diseases. Error! Reference source not found.
Leaky Gut and Immune Cell Migration
Specific immune cell trafficking originating from the gut and influenced by the microbiota may shape peripheral immunity in various ways.Error! Reference source not found. Under steady-state conditions, B cells, the major immune cell population, migrate extensively. Cells originating from the gut can migrate to lymphoid and non-lymphoid tissues within a day. The migrating T cell population is more differentiated compared to their counterparts in the spleen. Antibiotic interference with gut bacteria reduces the systemic spread of immune cells from the colon, suggesting that commensal microorganisms play a role in cell migration.Error! Reference source not found.
Dysbiosis of the gut microbiota not only affects its abundance but also influences the mucosal microenvironment, immune regulation, and the balance of inflammatory factors. While common probiotics may offer some hope, for patients who have already initiated an autoimmune process, comprehensive treatment strategies are needed to achieve therapeutic remission.
Professor Ji Wei emphasizes the importance of the postnatal foundation and believes that the pathogenic factor of spleen deficiency leading to dampness can be integrated into the diagnosis and treatment of Yang Bi (rheumatism) in both traditional Chinese medicine and Western medicine at various stages of treatment.
Case 1: Zhang, Male, 57 Years Old, Initial Diagnosis on February 21, 2024
Chief Complaint: "Joint pain in the limbs for 2 months."
Present Illness: The patient developed pain in the joints of both hands and knees without any obvious triggering factors, accompanied by swelling in some joints and morning stiffness lasting more than half an hour. He is currently taking 5mg of prednisone daily. There are no significant symptoms of dry mouth or dry eyes. Appetite and sleep are normal, and bowel movements are regular, though stools are not formed. On examination, the tongue is slightly red with a greasy coating, and the pulse is wiry and slippery. Laboratory Findings (February 7, 2024):
White blood cell count: 3.03 * 10⁹/L,C-reactive protein (CRP): 15 mg/L,Erythrocyte sedimentation rate (ESR): 15 mm/h,Rheumatoid factor (RF): 188 U/ml,ACPAs: >1000 RU/ml,Negative for total ANA, anti-SSA, and anti-SSB antibodies.
The patient has a history of smoking and drinking, and his younger brother has a history of ankylosing spondylitis.
Diagnosis: Based on the four diagnostic methods (inspection, auscultation, palpation, and inquiry), the condition is diagnosed as RAwith a pattern of spleen deficiency and damp-heat.
Pathogenesis: Spleen deficiency leads to dampness accumulation, which transforms into heat. This obstructs the flow of fluids to the joints, causing swelling and pain.
Treatment Strategy: Strengthen the spleen, promote diuresis, regulate Qi, invigorate blood, dry dampness, clear heat, detoxify, and alleviate pain.
Prescription: Cinnamon twig (Gui Zhi) 10g,Processed white peony root (Chao Bai Shao) 30g,Poria (Fu Ling) 10g,Dried tangerine peel (Chen Pi) 10g,Dried ginger and magnolia bark (Jiang Hou Po) 8g,Bupleurum (Chai Hu) 10g,Processed bitter orange (Fu Chao Zhi Ke) 10g,Licorice (Gan Cao) 5g,Xianhecao (Xian He Cao) 15g,Coptis (Huang Lian) 3g,Earthworm (Tu Fu Ling) 30g,Tripterygium wilfordii (Lei Gong Teng) 8g,Angelica (Dang Gui) 10g,Salvia (Dan Shen) 10g.
Dosage: 10 doses, taken 200ml after breakfast and dinner.
Additionally, the patient continues taking 5mg of prednisone daily and 0.3g of Duyu Shengbai tablets three times a day.
Follow-up (March 7, 2024): The patient reports significant improvement in symptoms, with reduced joint pain and swelling. The tongue coating has improved, and laboratory results show a normalization of white blood cell count, CRP 9 mg/L, and ESR 19 mm/h. Prednisone and Duyu Shengbai tablets were discontinued, and the formula was adjusted by removing magnolia bark and adding 10g of curcuma (Yu Jin) and 20g of Rehmannia (Sheng Di Huang). The patient continued to take the prescribed formula as before.
Analysis of TCM Prescription: The treatment of Wangbi (chronic rheumatic pain) is mentioned in the classical Chinese medical text Jinkui Yaolue, which dates back nearly 2,000 years to the Han Dynasty: "For pain in the limbs and joints, weakness in the body, swelling in the feet, dizziness, shortness of breath, and a sensation of warmth with nausea, Gui Zhi Shao Yao Zhi Mu Tang (Cinnamon Twig, white Peony, and Anemarrhena Decoction) is the prescribed formula." In the clinical presentation, the main issues are joint swelling and pain, and the internal accumulation of water and dampness, with stagnation of fluids in the middle burner. This condition is linked to spleen and kidney yang deficiency, which causes a loss of transformation and transportation functions, leading to the failure of fluid metabolism and the accumulation of dampness in the joints.
In this case, the patient’s condition involves spleen deficiency leading to dampness accumulation, which in turn causes obstruction in the middle burner and transformation of dampness into heat, resulting in joint swelling and pain. Therefore, the treatment is modeled on Gui Zhi Shao Yao Zhi Mu Tang, with Gui Zhi (Cinnamon Twig) and Bai Shao (White Peony) as the chief herbs to harmonize the middle, regulate the Qi, and promote the transformation of the spleen and stomach. This formula helps the Qi to flow and circulate throughout the body, unblocking the limbs and joints. Given the patient's marked damp-heat accumulation, the treatment is adjusted to include herbs that clear heat and dry dampness, such as Fu Ling (Poria), Hou Po (Magnolia Bark), and Huang Lian (Coptis), which strengthen the spleen and expel dampness. Additionally, Dang Gui (Angelica Sinensis) and Dan Shen (Salvia Miltiorrhiza) are used to nourish and invigorate the blood and promote the circulation of Qi and blood in the joints.
Xian He Cao (Agrimonia pilosa) is included to tonify the Qi and strengthen the spleen, addressing the root cause of Taiyin Spleen Dampness, which is vital for supporting the post-natal Qi. To resolve Qi stagnation and dampness, the formula also includes Chai Hu (Bupleurum), Zhi Ke (Aged Bitter Orange), and Bai Shao, which help to clear the Shaoyang stagnation and regulate the San Jiao (Triple Burner) to alleviate dampness obstruction. This helps to restore the smooth movement of Qi and its normal rising and descending functions. Xian He Cao, Huang Lian, and Tu Fu Ling (Smilax) are added to further resolve dampness, stop diarrhea, and clear heat and toxins.
In the second visit, Sheng Di Huang (Rehmannia) is added to nourish and tonify the liver and kidneys, working synergistically with Lei Gong Teng(Tripterygium wilfordii) to reduce toxicity while enhancing its therapeutic efficacy.16
Case 2: Liu, Female, 64 Years Old, Initial Diagnosis on May 28, 2024
Chief Complaint: "Joint pain in the limbs for more than 10 years."
Present Illness: The patient has experienced chronic joint pain with swelling for over 10 years, previously treated with methotrexate, anbutine, and celecoxib (which was discontinued due to a skin rash). She is currently taking 5mg of prednisone daily and 25mg of elamomide twice daily. She has scattered skin rashes, fatigue, moderate appetite, poor sleep, and loose stools. On examination, the tongue is dark red with a white, greasy coating, and there are tooth marks on the edges. The pulse is wiry and slippery.
Laboratory Findings (May 31, 2024):CRP: 21.2 mg/L,ACPAs: >500 RU/ml,ESR: 37 mm/h
Diagnosis: This patient presents with long-standing joint pain, swelling, and a history of treatment for RA. The diagnosis is spleen deficiency with dampness accumulation and wind-damp obstruction in the joints, complicated by blood dryness and wind.
Pathogenesis: The prolonged illness has led to blood stasis, Qi stagnation, and phlegm accumulation, which obstruct the joints and disturb the heart. Dampness has accumulated, transforming into heat, which flows into the joints.
Treatment Strategy: Strengthen the spleen, promote diuresis, invigorate blood, regulate Qi, clear heat, detoxify, and relieve pain.
Prescription: Cinnamon twig (Gui Zhi) 10g,Processed white peony root (Chao Bai Shao) 30g,Poria (Fu Ling) 15g,Dried tangerine peel (Chen Pi) 10g,Stephania (Fang Ji) 10g,Astragalus (Huang Qi) 20g,Angelica (Dang Gui) 10g,Salvia (Dan Shen) 10g, Radix Heterosmilacis (Xu Chang Qing) 20g, Poria cocos (Tu Fu Ling) 30g,Coix seed (Yi Yi Ren) 30g,Albizia (He Huan Pi) 10g,Polygala (Yuan Zhi) 10g,Uncaria (Ye Jiao Teng) 15g,Vinegar processed Corydalis (Cu Yan Hu Suo) 10g,Licorice (Gan Cao) 5g.
Dosage: 10 doses, taken after breakfast and dinner. The patient continues with prednisone and Elamomide.
Follow-up (June 11, 2024): The patient reports improvement in joint pain, though skin rashes persist, and sleep has slightly improved.
Prescription Adjustment: Added 10g of DiFuzi, 15g of Dijincao, and 6g of Buddha's hand (Fo Shou). Removed Astragalus, Albizia, and Polygala, and adjusted the formula for the next 15 doses.
Third Visit (June 25, 2024): The patient's CRP dropped to 5.15 mg/L, and ESR to 31 mm/h. Joint swelling reduced, pain alleviated, morning stiffness improved, and skin rash subsided. Stools became more formed.
Analysis of TCM Prescription: The patient presented with spleen deficiency and dampness accumulation, leading to dampness flowing into the joints. The long-term illness had affected the meridians, causing the formation of phlegm and blood stasis, which obstructed the heart and mind. Additionally, there was dryness of the blood resulting in wind and pruritic rashes. Therefore, during the treatment process, the strategy was based on strengthening the spleen, benefiting Qi, and eliminating dampness, along with regulating Qi and nourishing blood. The prescription was further modified by adding Fang Ji (Stephania), Xu Changqing (Herba Siegesbeckiae), Di Fu Zi (Kochia fruit), Di Jin Cao (Earth hemp), and Yi Yi Ren (Job's tears) to expel wind, eliminate dampness, clear heat, detoxify, and alleviate itching. He Huan Mi (Mimosa seeds), Yuan Zhi (Polygala), and Ye Jiao Teng (Fleeceflower stem) were added to relieve depression and calm the mind.
After the condition had stabilized, in the third prescription, Zhi Mu (Anemarrhena), Jiang Huang (Turmeric), and Qiang Huo (Notopterygium) were added. These herbs, combined with Gui Zhi (Cinnamon Twig) and Bai Shao (White Peony), followed the principles of Gui Zhi Shao Yao Zhi Mu Tang to promote the circulation of the defensive Qi and reach the surface, while Fu Ling (Poria), Chen Pi (Tangerine Peel), Fo Shou (Buddha's Hand), Fang Ji, and Tu Fu Ling (Smilax) focused on draining dampness and regulating Qi. Dang Gui (Angelica), Dan Shen (Salvia), Sheng Di Huang (Rehmannia), and Yan Hu Suo (Corydalis) were used to nourish the blood and Qi. Lei Gong Teng (Tripterygium) was added to invigorate the Qi, enhance the efficacy, and reduce toxicity.
Regarding the use of low-dose steroids, Professor Jiwei believed that traditional Chinese herbal formulas and disease-modifying antirheumatic drugs (DMARDs) could not immediately replace steroid use in the short term. Therefore, maintaining a low steroid dose was necessary to serve as a bridge while the herbal formula and DMARDs gradually took effect. The steroid dosage could then be reduced gradually, minimizing fluctuations in the patient's condition. This is a common challenge in clinical practice with traditional Chinese medicine.
Professor Ji Wei’s Inheritance and Development of TCM Experience fromTCM,Master Zhu Liangchun, in Treating RA Patients with Systemic Symptoms
In cases of RA, patients often experience additional systemic symptoms, and commonly used RA medications may not sufficiently alleviate these manifestations. In contrast, TCM offers a wealth of clinical experience, particularly from renowned veteran practitioners. Below is an exploration of how the herbal formulations and principles used by TCM Master, Zhu Liangchun, are applied in the aforementioned cases.
Xianhecao (Herba Agrimoniae)
Xianhecao, also known as Tuo Li Cao, is an herb highly regarded by Master Zhu Liangchun for its ability to strengthen the body’s defensive Qi and expel dampness. It is considered both invigorating and stabilizing, with actions that promote blood circulation and stop bleeding, suggesting it not only enhances vitality but also treats abscesses and toxic swellings. Zhu Liangchun emphasized its dual efficacy in both strengthening the body and managing toxicity.17 Animal studies have demonstrated that Xianhecao can significantly elevate white blood cell counts in immunosuppressed mice, suggesting its potential to support immune function in cases of leukopenia. 18
Fangji (Stephania Tetrandra)
Fangji is known for its ability to resolve blood stasis, promote diuresis, and alleviate joint pain and swelling. It is commonly used in the treatment of rheumatism, edema, and painful obstruction syndromes. Fangji is frequently combined with other herbs like Xu Changqing, Di Fu Zi, and Bai Xian Pi to treat wind-damp-heat, especially when it causes skin conditions like allergic dermatitis. Its role in facilitating the resolution of wind-damp obstructions is critical in managing rheumatic conditions associated with both pain and skin rashes.
Xu Changqing (Radix Heterosmilacis)
As recorded in the Shen Nong’s Materia Medica, Xu Changqing is known for its ability to address epidemic diseases, toxic qi, and malaria. It is particularly effective in regulating Qi, relieving pain, detoxifying, and reducing swelling. Xu Changqing is often employed in the treatment of wind-damp-induced joint pain and itching, as well as snakebites. It is particularly noted for its dual ability to expel wind and calm the spirit, making it an excellent choice for conditions such as hidden rashes or itching. When combined with Bai Xian Pi, Xu Changqing enhances its therapeutic effects on dermatological issues in TCM formulations. Additionally, when paired with turmeric (Jiang Huang), Xu Changqing can help move Qi, invigorate blood circulation, and relieve pain—making it a useful addition to formulas for chronic wind-damp conditions with concurrent skin disorders.
Zhong Jie Feng (Radix Corallii)
Zhong Jie Feng is derived from the dried whole plant of Coral Root and is used to expel wind, invigorate blood, and dissipate blood stasis and swelling.19 It is particularly useful for conditions such as rheumatoid arthritis, lupus erythematosus, and dermatomyositis, where there is chronic inflammation and swelling of the joints. It has a cooling effect, especially when used in high doses, to clear heat and toxins, resolve masses, and expel stasis. During periods of active immune response or acute infections, Zhong Jie Feng can be combined with other herbs to clear heat, detoxify, and resolve stagnation.
Zhimu (Anemarrhena Asphodeloides)
According to the Shen Nong’s Materia Medica, Zhimu is described as having the ability to "expel pathogenic Qi, reduce edema, promote urination, replenish deficiencies, and tonify Qi." In Jin Kui Yao Lue, Zhimu is used in the Gui Zhi Shao Yao Zhi Mu Tang formula, with a typical dosage of 120g (four taels). In the treatment of heat bi (heat-induced arthritis) with symptoms such as joint redness, swelling, and pain, Master Zhu Liangchun often combines Zhimu with Han Shui Shi (cold water stone), along with Gui Zhi (cinnamon twig), Bai Shao (white peony root), and Lao Guancao (Old Stork Grass) to clear heat from the meridians and alleviate pain, thereby helping to reduce the ESR.
Professor Ji Wei's Experience with Traditional Chinese Medicine in Rheumatic Diseases and Pharmacological Research
Clinical Experience and Research Progress in Using Common TCM Herbs for the Treatment of RA
Bai Shao (White Peony Root)
Bai Shao is a blood-tonifying herb with a bitter, sour, and mildly cold nature, which enters the liver and spleen meridians. Professor Ji Wei frequently uses Bai Shao in doses up to 30g in the treatment of Wangbi (chronic rheumatic pain), often combined with Gui Zhi (Cinnamon Twig), Gan Cao (Licorice), and Huang Qi (Astragalus) to both nourish and tonify the body, ease acute pain, and supplement deficiencies. Clinically, Bai Shao is also used in treating conditions such as Sjögren’s syndrome, ankylosing spondylitis, and fibromyalgia. 20 Pharmacological studies have shown that the total glycosides of Bai Shao have anti-inflammatory, analgesic, and immunomodulatory effects, as well as hepatoprotective properties. It is often combined with other drugs in the treatment of RA.1 Research indicates that Bai Shao may increase the expression of tight junction proteins in intestinal cells, reduce the production of IL-17A, induce Foxp3 expression, and improve intestinal barrier integrity.Error! Reference source not found.
Lei Gong Teng (Tripterygium wilfordii)
The Lei Gong Teng (also known as Thunder God Vine) and its active compound tripterygium glycosides have anti-inflammatory, analgesic, and immunosuppressive effects. However, due to its potential toxicity, caution is advised when used in patients with reproductive needs. According to the International Clinical Practice Guidelines for RA, Lei Gong Teng preparations (including Lei Gong Teng Glycosides and Kunxian Capsules) are recommended as A-level evidence for use in RA. [1] Professor Ji Wei has also employed Lei Gong Teng in treating various autoimmune and rheumatic diseases, such as systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, Sjögren’s syndrome, and scleroderma, at a dose of 5-15g. It is usually decocted for 2 hours to reduce potential toxicity.2223
Dan Shen (Salvia miltiorrhiza)
Professor Ji Wei frequently uses Dan Shen in combination with Dang Gui (Angelica Sinensis) to nourish the blood, invigorate circulation, and relieve pain in RA. Animal studies have shown that Dan Shen and its active compound danshenone IIA can inhibit the proliferation of fibroblast-like synoviocytes induced by TNF-α in RA and reduce the production of inflammatory cytokines, thus alleviating joint inflammation. Error! Reference source not found. In vitro studies have also suggested that danshenone IIA effectively mitigates bone destruction in RA, possibly by covalently binding to lactate dehydrogenase C and inhibiting its enzymatic activity, thereby reducing oxidative stress and inflammation.25
Progress in Research on TCM Herbs for Strengthening the Spleen, Expelling Dampness, and Regulating Intestinal Microbiota
Professor Ji Wei believes that spleen deficiency and dampness accumulation are key pathological mechanisms in Wangbi, and that treatment should focus on strengthening the spleen, expelling dampness, and regulating Qi. Commonly used herbs for this purpose include Fu Ling (Poria), Chen Pi (Dried Tangerine Peel), Fo Shou (Buddha's Hand), Zhi Shi (Unripe Bitter Orange), Hou Po (Magnolia Bark), and Huang Lian (Coptis).
Fu Ling (Poria)
Fu Ling is known for its antioxidant, immunomodulatory, neuroregulatory, anticancer, hepatoprotective, and gut microbiota-modulating properties.Error! Reference source not found. Research has shown that a decoction of Fu Ling significantly improves the structural integrity of the colon in animal models by increasing the expression of tight junction proteins and their mRNA. Fu Ling also enhances the diversity and abundance of intestinal microbiota. It modulates microbial communities to influence gut mucosal barrier function, host immune responses, and metabolic processes. Further experiments have indicated that Fu Ling regulates immune and metabolic functions by modulating the expression of Forkhead box protein 3 (Foxp3) and G protein-coupled receptor 41 (GPR41) mRNA.Error! Reference source not found.
Chen Pi (Dried Tangerine Peel) and Fo Shou (Buddha's Hand)
Flavonoid compounds in Chen Pi have been found to improve symptoms of spleen deficiency by modulating the gut microbiota.Error! Reference source not found. Chen Pi enzymes can regulate gut microbiota homeostasis and repair intestinal mucosa via the Nrf2/NLRP3 signaling pathway. 29 Studies have shown that aged Chen Pi (5 years) exhibits significantly stronger gut immune activity compared to younger (1-year-old) tangerine peel.30 Fo Shou is rich in fo shou gan polysaccharides, which reduce inflammation and enhance gut tight junction proteins and mucin expression by modulating the intestinal microbiota and metabolic processes. Error! Reference source not found. Research has found that Fo Shou fo shou gan can reduce pro-inflammatory mediators in a temporomandibular joint osteoarthritis mouse model, increase type II collagen, bone mass, and trabecular bone number, and decrease serum reactive oxygen species (ROS) levels, thereby protecting cartilage.Error! Reference source not found.
Cang Zhu (Atractylodes Lancea) and Bai Zhu (Atractylodes Macrocephala)
Studies have shown that Cang Zhu inhibits the abundance of Helicobacter pylori while increasing beneficial bacteria, thereby improving symptoms of spleen deficiency-related diarrhea.Error! Reference source not found. Bai Zhu contains Cang Zhu Glycoside A, which protects the intestinal mucosal barrier by inhibiting the p38 MAPK pathway, thereby improving gastrointestinal function.Error! Reference source not found. Bai Zhu polysaccharides have been shown to protect the intestinal mucosal barrier and enhance immune function, alleviating immune suppression and intestinal damage induced by cyclophosphamide in mice by restoring gut microbiota balance and short-chain fatty acid metabolism. Error! Reference source not found.
Huang Lian (Coptis chinensis)
The active compound berberine in Huang Lian has well-established anti-inflammatory properties and is widely used in gastrointestinal and autoimmune diseases. Clinical studies have shown that berberine significantly downregulates gene expression and production of pro-inflammatory cytokines such as TNF-α and IL-1β in RA patients’ monocytes, without affecting immune cell activity in healthy individuals.Error! Reference source not found. Berberine exerts its therapeutic effects in RA by regulating multiple signaling pathways involved in inflammation, inhibiting the proliferative activity of fibroblast-like synoviocytes, suppressing dendritic cell activation, and modulating the Th17/Treg balance to prevent cartilage and bone destruction. Error! Reference source not found. Animal studies have also shown that berberine regulates the RAS/MAPK/FOXO/HIF-1 signaling pathway to suppress the proliferation and adhesion of synovial fibroblasts in RA.Error! Reference source not found. In terms of gut microbiota, in vitro studies suggest that berberine can adjust the diversity and richness of gut bacteria, reduce the abundance of Prevotella, and increase the abundance of butyrate-producing bacteria, thus improving collagen-induced arthritis. Error! Reference source not found.
Conclusion
The pathogenesis of RA is complex, and the concept of the "gut-joint axis" provides a new avenue for understanding the disease. By focusing on the imbalance of gut microbiota and immune regulation, a more comprehensive approach to treatment can be achieved. From a TCM perspective, understanding the relationship between the spleen and kidneys—particularly how spleen deficiency can lead to bone disease—provides a foundation for preventing bone destruction. Given the chronic nature of RA, treating spleen deficiency and dampness accumulation remains central to therapeutic strategies. Strengthening the spleen, tonifying Qi, expelling dampness, and unblocking the meridians are core principles in the management of RA. Combining these principles with the application of renowned TCM herbal formulations and expert clinical experiences has proven to be an effective approach in achieving favorable clinical outcomes.
Authors' Contributions
Both authors prepared the concepts, wrote the proposal, collected data in the field, reviewed and edited the proposal and manuscript, analyzed and wrote the full manuscript. Both authors contributed equally.
Data availability
All data analyzed in this study are available in the text, and raw data can be obtained from the corresponding author upon request.
Competing Interests
The authors declare no conflict of interest
Funding
Project of Jiangsu Provincial Administration of Traditional Chinese Medicine (ZD202218); Training Program for Key Talents in Clinical Traditional Chinese Medicine Techniques under the Pengcheng Qihuang Project, Shenzhen.
