Preliminary Study on Acupuncture Combined with Grain-sized Moxibustion for Treating Rheumatoid Arthritis with Finger Joint Pain

Based on the clinical trial, this study provides a standardized operational reference for treating RA with finger joint pain through acupuncture combined with grain-sized moxibustion by stimulating acupoints and warming. It can be used as an effective complementary therapy for RA pain management due to its efficacy and advantages.

Most patients with rheumatoid arthritis (RA) often start with pain and swelling in the joints of the extremities, especially the small joints of the hands. At present, the etiology of RA remains unclear, and its pathological process is difficult to control. In clinical treatment, Western medicine mostly uses non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, biologics, etc. While they can alleviate local joint symptoms and reduce inflammatory responses, long-term use may cause significant adverse effects and high costs. In recent years, there has been an increasing application of external Traditional Chinese Medicine (TCM) therapies for treating RA, with a growing number of related studies. In this study, we observed acupuncture combined with grain-sized moxibustion in the treatment of RA with finger joint pain, assessed the changes in tender joint counts (TJC), duration of morning stiffness, the visual analog scale (VAS), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level of the patients before and after treatment. The results indicated that acupuncture combined with grain-sized moxibustion was more effective in reducing finger joint pain compared to therapy with simple basic medication for treating RA. Guided by the theory of syndrome differentiation in TCM, this therapy exerts its effects primarily through the stimulation of acupoints and warmth. It offers advantages such as safety, simplicity, ease of operation, precise targeting, and low price, which makes it expected to become a potential complementary therapy to relieve finger joint pain associated with RA and further improve the quality of life for RA patients. The purpose of this study is to provide a standardized operational reference for treating RA with finger joint pain by acupuncture combined with grain-sized moxibustion based on the clinical trial.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with basic pathological features, including inflammatory cell infiltration, synovial fibroblast proliferation, and cartilage erosion, with a global prevalence rate of approximately 1%¹. Although the etiology and pathogenesis of RA have not been fully clarified, factors such as genetics, environment, and abnormal immune system response play a key role in the pathogenesis of RA². Clinically, RA patients often present with pain and swelling in the joints of the extremities (especially the small joints of the hands), most of which are accompanied by morning stiffness. With the progress of the disease, varying degrees of ankylosis and deformity occur in the joints during the middle and late stages, leading to restricted joint mobility and eventual complete loss of function, resulting in an inability to perform daily activities, in addition to multi-organ damage³. This leads to changes in depression and coping behaviors, severely impacting patients' quality of life and psychosocial well-being⁴. Therefore, early diagnosis and active treatment are particularly important².

Currently, the treatment of RA primarily relies on medications, with effective joint pain control and inflammation management being the main goals of treatment⁵. Non-steroidal anti-inflammatory drugs (NSAIDs) such as loxoprofen act rapidly and are used for the treatment of RA during the acute phase, alleviating pain by reducing inflammation. However, they do not possess disease-modifying properties, and long-term use may lead to gastrointestinal bleeding⁶. Disease-modifying anti-rheumatic drugs (DMARDs) are the cornerstone of RA treatment for controlling inflammation, preventing joint and organ damage, and reducing the risk of death⁷, and their use should be initiated as early as possible. It is worth noting that low-dose methotrexate remains the primary method for the initial treatment of RA⁸. The specific toxic effects and contraindications of most drugs have been properly described. For example, infliximab can induce the reactivation of tuberculosis and hepatitis B activation⁹. Glucocorticoids are most often used as bridging therapy when RA is diagnosed or episodes of high disease activity. Still, they have limited use in preventing disease progression. They are associated with numerous known side effects, including increased risk of infections, elevated blood pressure, osteoporosis, etc¹⁰. In the middle and later stages of the disease, when the results of strictly standardized drug treatment are unsatisfactory, the patient develops joint deformity, which seriously affects the function of the joints and the quality of life, surgical treatment (joint debridement, joint replacement, etc.) can be considered. It should be emphasized that surgery must be accompanied by drug treatment. Therefore, optimizing the therapeutic strategy of RA and adopting safe, effective, and promising therapeutic techniques are the focus of our attention.

In traditional Chinese medicine (TCM), RA is classified under the category of Bi syndrome, which arises from weakened qi and blood, deficiency of the liver and kidney, reduced bodily resistance, and recurrent infections by wind, cold, and dampness pathogens¹¹. These pathogens accumulate in the muscles, tendons, bones, and joints, leading to impaired qi and blood circulation, obstructed meridians and blood vessels, and blocked tendons and vessels, ultimately resulting in the onset of the disease. The treatment of RA in TCM encompasses a variety of methods, including internal or external application of traditional Chinese herbs, acupuncture, tuina massage, acupoint injection, wax therapy, and hot compress¹². Among them, acupuncture can be subdivided into needle acupuncture and moxibustion, both of which are used to stimulate specific areas on the surface of the human body through physical stimulation, thereby triggering a systemic response that regulates body functions and ultimately achieves therapeutic goals. Needle acupuncture is mainly to insert needles into specific points in the skin and subcutaneous tissue, while moxibustion typically transfers the heat generated by burning moxa to specific areas under the skin¹³. The specific acupoints or specific areas described therein have a high density of mast cells and an abundance of nerve endings within their structure and appear to be distinct from other skin areas¹⁴. In general, an acupuncture needle is inserted into the acupoint, followed by mechanical stimulation with the hand, which induces the twisting of subcutaneous collagen fibers around the needle. This operation triggers mast cell degranulation via the mechanically sensitive transient receptor potential vanilloid-2 (TRPV2) channel proteins on mast cell membranes¹⁵, which then mediators such as histamine, 5-hydroxytryptamine (5-HT), adenosine, and adenosine triphosphate (ATP) are released, producing analgesic effects and the activation of anti-inflammatory cascades. The TRPV2 channel can also be activated by mechanical, thermal, and red-light laser stimulation¹⁶, which may also be the basis of the mechanism of moxibustion activating mast cells. These two kinds of green external therapy, with traditional Chinese characteristics, offer advantages such as simplicity, cheapness, no need for oral administration, and fewer toxic side effects.

Rheumatoid arthritis synovial fibroblasts (RA-FLS) are a critical component of the synovium membrane and play a major role in joint destruction caused by proliferation and inflammatory invasion of the RA synovial membrane¹⁷. RA-FLS interact with various immune cells within the synovium and continuously secrete multiple inflammatory cytokines, such as interleukins (ILs), tumor necrosis factor-α (TNF-α), along with matrix metalloproteinases (MMPs), thereby inducing and exacerbating synovial inflammation and bone erosion. After acupuncture intervention¹⁸, pro-inflammatory factors interleukin-1β (IL-1β) and interleukin-6 (IL-6) in joint fluid and peripheral blood of RA patients decrease, while anti-inflammatory factors interleukin-4 (IL-4) and interleukin-10 (IL-10) increase, which improve the internal environment contributing to slow down the onset and progression of RA. The synovial membrane of the joint is hypoxic under the infiltration of inflammatory cells, leading to the accumulation of hypoxia-inducible factor-1α (HIF-1α) in the joint cavity, which stimulates the secretion of vascular endothelial growth factor (VEGF) by synovial tissues and induces vascular proliferation, which in turn promotes the extravasation of inflammatory factors, further stimulates the formation of neovascularization, aggravates the inflammation of the synovial membrane and the formation of tendon sheaths, and ultimately leads to joint pain, swelling, and deformity¹⁹. Clinically, RA patients exhibit elevated VEGF levels in serum and synovial fluid compared to healthy individuals, and VEGF levels correlate with RA disease activity. Research²⁰ indicates that moxibustion can downregulate the levels of IL-1β, TNF-α, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-3 (MMP-3), and HIF-1α/VEGF, thereby inhibiting angiogenesis and demonstrating potential bone-protective effects.

RA is an immune response-mediated inflammatory disease. Acupuncture can improve immune function by up-regulating the expression level of vasoactive intestinal peptide (VIP) in synovial tissues and then regulating the brain-gut axis²¹. The pathogenesis of RA also involves T cells, especially regulatory T cells (Treg)/helper T cells (Th) imbalance²². Moxibustion regulates the microRNA-221/suppressor of cytokine signaling 3 axis to the balance of T-regulatory/T-helper 17 cell, thereby relieving RA²³.

Moxibustion, as physical therapy, offers a variety of forms of treatment. Grain-sized moxibustion is one such approach, categorized under direct moxibustion with small moxa cones. The operator manually rolls moxa wool into small, grain-shaped cones placed directly on the skin for moxibustion. Leveraging the warming, penetrating, and tonifying properties of moxa fire and mugwort, combine with the specific functions of the acupoint to warm meridians and disperse cold, unblock collaterals and alleviate pain, reduce inflammation and swelling, strengthen vital energy (Zheng) while expelling pathogenic factors (Xie), regulate the balance of Yin and Yang²⁴. Due to its small size, precise positioning, strong thermal penetration, and effective pain relief, grain-sized moxibustion is highly compatible with the clinical characteristics of RA and is particularly suitable for the treatment of small arthritic joints in both hands.

In summary, as an autoimmune-mediated chronic inflammatory disease, RA requires long-term treatment. However, long-term use of Western medications is associated with many contraindications, high toxicity and side effects, the risk of drug resistance, and a heavy economic burden, leading to poor patient compliance and difficulty in adherence. In contrast, the combination of acupuncture and grain-sized moxibustion for RA treatment has the advantages of safety and simplicity, easy operation, accurate positioning, low price, and do-on compared to simple Western medication treatment. This approach is more acceptable and cooperative for patients and is worth promoting vigorously. Therefore, this article has proposed a specific reference protocol for the standardized operation of acupuncture combined with grain-sized moxibustion for the treatment of RA with finger joint pain, which will be explicitly described below.

The study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Traditional Chinese Medicine Hospital of Dianjiang
Chongqing (cord:2022-KY-NO074-1). Comprehensive information about the study was explained to all recruited participants, and written informed consent was obtained from each participant.

1. Sample collection

1. The randomized controlled trial enrolled 20 patients with RA with finger joint pain from Traditional Chinese Medicine Hospital of Dianjiang, Chongqing, China. Rigorously screen participants based on the following diagnostic, inclusion, and exclusion criteria. Use the RAND function in the spreadsheet to generate two groups of random data, namely the observation group and the control group, with 10 cases in each group. For demographic data, see Table 1.
2. Use the following diagnostic criteria for patient screening.
   1. Western medicine diagnostic criteria: Follow the new RA classification criteria and scoring system proposed by the American College of Rheumatology/European League Against (ACR/EULAR) in 2010, with a total score of 6 or above indicating RA²⁵.
   2. TCM diagnostic criteria: Follow the Rheumatoid Arthritis Syndrome Combined Diagnosis and Treatment Guide issued by the Rheumatism Branch of the China Association of Chinese Medicine (CACM) in 2018, which must conform to the TCM diagnosis of Bi syndrome and syndrome differentiation of cold and damp Bi syndrome¹².
   3. Inclusion criteria: Include participants who meet the following four criteria at the same time in this study. Patients with RA with finger joint pain, tenderness, and morning stiffness who meet the diagnostic criteria of both TCM and Western medicine diagnostic criteria; Patients >18 years old; Patients who had not received anti-inflammatory, analgesic, and anti-rheumatic treatment (including NSAIDs, DMARDs, glucocorticoids, proprietary Chinese medicines and TCM decoctions) within 1 week before enrollment, and who have not used biologics in the past 3 months without taking therapeutic measures for RA; Patients who voluntarily participated in this trial and signed the informed consent.
   4. Exclusion criteria: Exclude those who meet any of the following criteria and cannot participate in this study. Patients who do not meet the above inclusion criteria; Patients who need treatment for hand joint infection or skin lesion; Patients with other types of rheumatic diseases, complications of which may appear as hand joint symptoms, such as systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), gouty arthritis, psoriatic arthritis, etc.; Patients with severe concomitant diseases in other systems such as the heart, respiratory, liver, and kidney; Patients with psychiatric diseases and sensory decline or disappearance; Patients who were allergic to the drugs used in this study, as well as those with severe allergies to acupuncture and moxibustion; Pregnant and lactating women, and patients who are not able to cooperate.
   5. Withdrawal criteria: Withdraw those who meet any of the following criteria and no longer want to participate in this study. Patients who did not carry out the prescribed course of treatment gave up halfway or lost contact after inclusion; Patients who have experienced significant allergic reactions or disease changes in the body or may or have had serious adverse events. During the study, if the subject develops certain comorbid or complicating conditions in the form of specific physiological changes, the continuation of the participant may be inappropriate.
3. Perform randomization and blinding as described below.
   1. Divide subjects into observation and control groups using a computer-based randomization technique and the spreadsheet's RAND function.
   2. Hide allocations in sealed, opaque, sequentially numbered envelopes; number envelopes from 1 to 20 integers; and then assign screened RA patients' envelopes with the appropriate serial numbers in order of treatment.
      NOTE: The purpose of this research is to study the mechanism of the synergistic effect of acupuncture combined with grain-sized moxibustion on conventional medicine, as it is easy to know whether the patient has received treatment or not after we collected serum indicators twice; it is impossible to blind the patients and the operating doctors. To eliminate potential bias, we have blinded the recruitment doctors, data collectors, and data statisticians.
4. Perform the following interventions.
   1. Control group: Carry out conventional drug treatment, including methotrexate tablets²⁶ (10 mg, once a week), folic acid tablets²⁶ [(taken 24 h after oral methotrexate) 5 mg, once a week], loxoprofen sodium tablets²⁷ (60 mg, 2x a day), for a total of 4 weeks.
   2. Observation group: Carry out conventional drug treatment + acupuncture + grain-sized moxibustion. Perform conventional drug treatment as done for the control group. Perform acupuncture + grain-sized moxibustion treatment 5x per week (treatment from Monday to Friday, rest on Saturday and Sunday), for a total of 4 weeks, as described in step 2.

2. Acupuncture combined with grain-sized moxibustion treatment

NOTE: For a simple flow chart of the experiment, see Figure 1. Details of the reagents, equipment, and software used in this study can be found in the Table of Materials.

1. Instrument preparation
   1. Prepare disposable sterile acupuncture needles (size 0.25 mm x 25 mm), moxa, petroleum jelly, incense sticks, lighter, tweezer, water tray, iodophor swabs, cotton swabs, and sterile dry cotton balls (see Figure 2).
   2. Inspect that all medical consumables are within their expiration dates, and check whether the needles are bent, broken, burred, or barbed.
2. Doctor preparation
   1. Wash hands with soapy water, dry thoroughly, and use a 75% ethanol hand sanitizer gel to disinfect hands before handling the needle. Perform the seven-step washing technique²⁸. Wear a surgical mask and cap.
3. Patient preparation
   1. Conduct a correct and comprehensive assessment of the patient's condition, taking into account their specific health status. Measure the patient's blood pressure, heart rate, respiratory rate, and oxygen saturation levels. Examine the patient's skin to ensure there are no injuries, infections, or other skin conditions.
   2. Position the patient in a seated position to fully expose the acupuncture points. Instruct the patient to promptly notify the doctor if they experience any discomfort during the procedure.
4. Acupuncture procedures
   1. Carry out acupoint selection (with International Code²⁹). Select the acupuncture point Baxie (EX-UE9; see Figure 3, and Table 2).
   2. Check the acupoints again. For spiral disinfection, use iodophor swabs from the center of the acupoint outward. Ensure that the diameter of the disinfection site is greater than 3 cm. Leave it for a few seconds until all the iodophor has evaporated.
   3. Use the thumb and index finger of the right hand to hold the needle handle and place the pulp of the middle finger against the lower part of the needle body. When the thumb and index finger apply downward force, the middle finger also flexes concurrently.
   4. Hold the needle at an inclination of 45° to the skin and stab centripetally into the Baxie point, with a depth of approximately 12 mm³⁰ (see Figure 3).
   5. Rotate the needle handle approximately 180° or less back and forth along the angle of insertion, with a frequency of about 60 times/min³¹, until the patient feels Deqi^32,33,34,35 (Figure 4).
      1. Deqi has two criteria. First is the subjective criterion that refers to the sensation under the needle. Assess this as follows for the patient: The patient feels acid reflux, numbness, swelling, pain, or ant crawling sensation at the acupuncture site. Sometimes, the sensation may conduct or diffuse along specific directions and regions. Assess this as follows for the doctor: The doctor has a sense of tightness or a fish-biting-the-bait sensation as the needle sinks in.
      2. Use the following for the objective criteria.
      3. Check for redness of the skin at the acupuncture site: redness appears gradually with the process of Deqi, the range can be large or small, with an irregular circular shape. This redness typically fades after needle removal.
      4. Check for slight needle stagnation phenomenon: During needle retention, the skin around the needle tightens slightly and may rise slightly above the surrounding skin.
      5. Assess based on the MGH Acupuncture Sensation Scale (MASS): This includes a primary scale and two subscales. Use the primary scale to record the intensity of acupuncture sensation using a 10 cm Visual Analog Scale (VAS)³⁶. Use the subscales to measure the diffusion of the sensation and associated emotional responses.
      6. Perform surface electromyography (sEMG): This may be the earliest objective indicator of Deqi. When Deqi occurs, check that significant electromyographic activity is observed at the acupuncture point, characterized by low amplitude and low density. This activity persists during needle retention, and the EMG amplitude and the number of EMG are positively correlated with the intensity of the Deqi³⁵.
   6. Retain the needle for 30 min³⁷. Press the skin around the needle hole with the sterile dry cotton ball in the left hand. Hold the needle handle with the thumb and index finger of the right hand, slowly withdrawing the needle under the skin and quickly exiting the skin.
   7. Disinfect the needle holes with iodophor swabs.
5. Grain-sized moxibustion
   1. Joint localization: Select finger joint pain points (Ashi points) as the operation site of grain-sized moxibustion, namely the metacarpophalangeal joints, thumb interphalangeal joints, and proximal interphalangeal joints (see Figure 3 and Table 2).
   2. Roll moxa into conical moxa cones the size of wheat grains by hand.
   3. Apply a small amount of petroleum jelly with a dry cotton swab to the back of the metacarpophalangeal joints or (and) proximal interphalangeal joints.
   4. Hold the middle of the moxa cone with tweezers in the right hand and fix it to the joint of the hand smeared with petroleum jelly.
   5. Use a lighter to light the incense stick, then use the incense stick to light the top of the moxa cone (see Figure 5).
   6. Hold the tweezer and wait. When the moxa cone has burned down to 1/5-2/5 of its original size, and the patient reports a burning sensation at the joint that is unbearable, quickly remove the unburned moxa cone with the tweezers and put it in the water tray to extinguish it.
   7. Repeat the above procedures until each affected finger joint is treated with moxibustion 5x²⁴.

3. Cautions during acupuncture combined with grain-sized moxibustion

1. Grain-sized moxibustion uses an open flame and will produce smoke and odor. Choose a safe and well-ventilated environment to avoid accidents.
2. Adhere to the principle of asepsis. Carry out strict sterilization before and after treatment, including articles and utensils, the patient's acupuncture points, and the doctor's hands.
3. Do not repeat needling and avoid excessive force at the same acupoint to reduce the risk of needle sticking and bleeding.
4. After the operation, ask patients to refrain from taking a bath or touching cold water immediately to prevent wound infection and virus invasion, which may aggravate the condition.
5. Properly dispose of used needles and other waste materials to prevent cross-infection. This operation is not suitable for patients with high fever, fasting, full stomach, over-exertion, mental stress, and impaired skin sensation.

4. Response measures for adverse events

1. Needle breakage: If the needle breaks and its tip remains within the skin, pick it out with sterile tweezers. If the broken needle is embedded deeply, locate it under X-ray fluoroscopy and remove it through surgical intervention.
2. Acupuncture fainting: If fainting occurs, stop acupuncture immediately and pull out all the needles. Let the patient lie flat, pay attention to warmth, and monitor vital signs. Patients with mild symptoms rest for a while, drink warm or sugar water, and can gradually return to normal; for patients with serious symptoms, take emergency measures.
3. Skin burns: If skin burns are observed in the patient, promptly disinfect the affected area and apply burn ointment. In the case of blisters, do not puncture small blisters as much as possible to make the blisters self-absorb. For larger blisters that are difficult to self-absorb, first disinfect the area, then puncture the blister with a disposable sterile syringe needle and instruct the patient to maintain local skin hygiene to prevent infection.

5. Assessment of observed indicators

1. Perform physical examination, VAS scores, and collection of fasting blood early in the morning of day 0 and day 29 of treatment after patient enrollment.
2. Perform joint assessment as described below.
   1. Tender joint counts (TJC): Examine and record the number of tenderness in 20 joints of the patient's hands, including 10 metacarpophalangeal joints, 8 proximal interphalangeal joints, and two thumb interphalangeal joints.
   2. Duration of morning stiffness: Ask and record the time between occurrence and resolution of stiffness and discomfort in both hands after the patient wakes up in the morning.
   3. Visual analog scale (VAS)³⁶: Draw a line segment 10 cm in length on the paper, and specify the values of 0 and 10 at the two ends of the line segment, respectively, representing no pain and severe pain. From left to right, it represents the gradual increase in the degree of pain. Ask the patient to perform a self-evaluation by marking the appropriate place on the line segment according to their pain status to indicate their pain level.
      NOTE: Specific scores represent the meaning: 0 means no pain; 1-3 means mild pain, but one can still engage in normal activities; 4-6 means moderate pain that affects normal work but can still be managed; 7-9 means more serious pain, and daily life can not be managed; 10 means severe pain, intolerable.
3. Check the following laboratory-tested serum inflammatory indicators.
   1. Erythrocyte sedimentation rate (ESR)³⁸: It refers to the rate of erythrocyte sedimentation under certain conditions, which can reflect the activity of RA disease as a sensitive indicator of acute inflammation. Collect fasting blood samples of patients before and after treatment and then analyze them with the automated erythrocyte sedimentation rate analyzer. Normal reference value range: male < 15 mm/h, female < 20 mm/h.
   2. C-reactive protein (CRP)³⁸: It refers to some proteins (acute proteins) that rise sharply in plasma when the body is infected or damaged by tissue and is widely used to monitor systemic inflammation and disease activity in RA patients. Collect fasting blood samples of patients before and after treatment and then test using an automatic biochemical analyzer. Normal reference value range: 0-10 mg/L.

6. Statistical analysis

1. Collect and analyze the data using SPSS 22.0. Express measurement data conforming to a normal distribution as mean ± standard ( ± s). Use independent sample t-test to compare between the observation group and the control group, and paired samples t-test for comparison before and after treatment in the group. Values of p < 0.05 were considered statistically significant.

The comparison of TJC before and after treatment between the two groups is shown in Table 3. Before treatment, there was no statistical significance in the number of joint tenderness between the observation and control groups (p > 0.05), which was comparable. After treatment, the number of patients with joint tenderness in the observation group and the control group was reduced, and the observation group and the control group were compared before and after treatment, respectively, and the two groups ...

RA is a complex and refractory disease, and once diagnosed, it should be given timely and standardized treatment. Currently, Western medicine cannot eliminate the cause but are also accompanied by various toxic side effects. In addition to conventional drug treatments, promising emerging technologies are worth looking forward to, such as Mesenchymal Stem Cell Transplantation (MSCT)⁴¹, and new approaches targeting Toll-like receptor (TLR) function that are being tested⁴²

The authors have no conflicts of interest to declare.

My sincere thanks to Ms. Luo and Ms. Li for their filming help.