Clinical Effective Evaluation of Tongren Dahuoluo Pill(同仁大活络丸) on Knee Osteoarthritis by Musculoskeletal Ultrasound

WANG Yan-yan (王炎焱), ZHANG Hong (张 红), QI Yan (齐 岩), SHI Cheng (史 成)

1. Department of Rheumatology, First Medical Center of PLA General Hospital, Beijing 100853, China

2. Department of Rheumatology, Beijing Tongrentang Hospital of Traditional Chinese Medicine, Beijing 100051, China

ABSTRACT Objective:To evaluate the clinical effect of Tongren Dahuoluo Pill (同仁大活络丸) on knee osteoarthritis by musculoskeletal ultrasonography.Methods:From March 2019 to December 2019, 45 patients with knee osteoarthritis were collected from the outpatient department of the First Medical Center of PLA General Hospital. Tongren Dahuoluo Pill (同仁大活络丸) was given oral treatment for 12 weeks. VAS score, Lequesne score and WOMAC score were recorded before and after treatment, and the changes of knee joint effusion and synovial hyperplasia were observed by musculoskeletal ultrasonography.Results:Among the 45 patients, 18 were male and 27 were female, with the average age of (62.07±9.08) years old, and average disease course of (6.83±7.01) years. The VAS score, Lequesne score and WOMAC score were significantly reduced compared with before treatment, and the difference was statistically significant (P＜0.01). We observed that joint effusion range and joint synovial hyperplasia thickness of knee osteoarthritis significantly reduced with Tongren Dahuoluo Pill (同仁大活络丸) treatment by musculoskeletal ultrasonography, and the difference were statistically significant (P＜0.01).Conclusion:Tongren Dahuoluo Pill (同仁大活络丸) can not only relieve the clinical symptoms of knee osteoarthritis, but also effectively inhibit synovitis hyperplasia of knee joint.

KEYWORDS Knee osteoarthritis; Tongren Dahuoluo Pill (同仁大活络丸); Musculoskeletal ultrasonography;Joint effusion; Synovial hyperplasia

Osteoarthritis (OA) is a joint degenerative disease that has joint pain as the main symptom and seriously affects the patient's quality of life.It involves knees, hips, ankles, hands, and spine(cervical and lumbar) joints. Among them, knee osteoarthritis (KOA) is the most common. KOA is one of the important causes of chronic knee pain in the elderly. The course of osteoarthritis is progressive. It is one of the main reasons for the disability of the elderly. China is the country with the largest elderly population in the world. The entire country is rapidly aging with the proportion of aging population (60 years old) estimated to be 14.9% in 2013 and is expected to be 25.3% in 2030, and will exceed 30%. According to reports, about 30%-50%of people over 60 years old suffer from KOA, of which about 80% of patients can be diagnosed by imaging, and 60% of patients have clinical manifestations[1]. According to a 2016 Chinese epidemiological survey data, the prevalence rate of symptomatic KOA in China is 8.1%, and there are currently about 110 million KOA patients in China[2]. The imaging examinations of KOA mainly include X-ray, MRI and musculoskeletal ultrasound.Musculoskeletal ultrasound is simple to operate and highly sensitive to joint synovium, effusion and cartilage, which can help evaluate the changes in KOA joint inflammation and is widely used in clinical observation.

Tongren Dahuoluo Pill (同仁大活络丸) is a traditional Chinese patent medicine with a history of 300 years. It has the effects on expelling wind,relaxing muscles, activating collaterals, and removing dampness. The clinical main treatment is to treat liver and kidney deficiency, Qi (气) and blood disorders, and limb and joint pain caused by cold and dampness, numbness of hands and feet,constriction of meridians, stroke, hemiplegia, and other common symptoms of old age. Our previous studies have shown that Tongren Dahuoluo Pill(同仁大活络丸) can effectively relieve the clinical symptoms of KOA. In this study, musculoskeletal ultrasound was used to observe the changes in knee joint effusion and synovial hyperplasia before and after the treatment of KOA with Tongren Dahuoluo Pill (同仁大活络丸), and to evaluate its improvement effect on KOA arthritis. The report is as follows.

MATERIALS AND METHODS

Case Selection

A total of 45 knee osteoarthritis patients who were treated at the Rheumatology Clinic of the PLA General Hospital between the ages of 38 and 80 from March 3, 2019 to December 2019. They were in line with KOA diagnostic criteria in the 2010 version Guidelines for the diagnosis and treatment of osteoarthritis (《骨关节炎诊断及治疗指南》)of Chinese Medical Association Rheumatology Branch[3], and excluded secondary osteoarthritis such as acute traumatic osteochondral injury,ligament injury, psoriatic arthritis, rheumatoid arthritis, septic arthritis, gout, and hemophilic joints inflammation, etc., without severe heart failure,asthma, chronic obstructive pulmonary disease, liver and kidney damage. Those who have not received relevant treatment, used relevant medicine, or other drug treatments without effectiveness in the past month, and sign an informed consent form.

Treatment Methods

Tongren Dahuoluo Pill (同仁大活络丸) was given orally, 2 pills each time, 2 times a day; the specification of Tongren Dahuoluo Pill (同仁大活络丸) was 0.36g×6 pills/box, which was manufactured by Beijing Tongrentang Co., Ltd. (Approval number:Z11020090). The patients were observed for 12 weeks to evaluate the treatment effect and record adverse reactions.

Evaluation of Clinical Efficacy

①The pain score was scored by the visual analogue scale (VAS). A 10cm scale was used to represent the degree of pain. 0 represented no pain, and 10 represented severe pain; the middle part represented different degrees of pain, and the patient was asked to record the pain score according to self-feeling, indicating the degree of pain. 0 point:no pain; 3 points or less: slight pain, tolerable; 4-6 points: pain affects sleep, but still tolerable; 7-10 points: strong pain, unbearable pain.

②Lequesne index scoring system scored the pain and discomfort, walking ability, and the degree of involvement in daily life. A total score of 1-4 was mild, 5-7 was moderate, 8-10 was severe, 11-13 was very severe, and greater than 14 was extremely severe. Scores were performed before treatment and 12 weeks after treatment.

③The Osteoarthritis Index (WOMAC) had 24 items for scoring. Among them, 5 were pain scores,2 were stiffness scores, and 17 were functional scores. The higher the score, the worse the function.Scores were performed before treatment and 12 weeks after treatment.

Musculoskeletal Ultrasound Evaluation

Philips HD7 color Doppler ultrasound diagnostic apparatus was used. The probe frequency was set to 3-12 MHz. The unilateral knee joint with severe clinical symptoms was selected for musculoskeletal ultrasound examination.The patient was lying or sitting with the knee flexed by 20°-30°, sliding the probe close to the patient's skin, and starting the examination above the patient's patella. The joints were scanned longitudinally and laterally to determine the patient's suprapatellar sac effusion status, effusion range, maximum effusion depth, etc., and the thickness of the synovial membrane is determined to understand the knee joint synovitis.

Statistical Analysis

SATA16 statistical software was used for statistical analysis, and the measurement data of each group were expressed as (mean±standard)deviation. VAS score, Lequesne score and WOMAC score were evaluated by analysis of variance, and P＜0.05 indicated that the difference was statistically significant. The paired Wilcoxon signed-rank test was used to compare joint effusion and joint synovial hyperplasia. P＜0.05 indicated that the difference was statistically significant.

RESULTS

A total of 45 KOA patients were enrolled in this study, including 18 males and 27 females, aged 41 to 78 years old, with an average age of (61.8±9.13) years old, and a medical history of 2-12 years, with an average of (6.83±7.01) years. The weight was (67.7±9.40) kg,and the average BMI was (24.8±2.47) kg/m2.

Improvement of Knee Function Score

Comparison of VAS scores before and after treatment

The VAS score of the knee joint of 45 patients after 12 weeks of treatment was significantly decreased than before treatment, and the difference was statistically significant (P＜0.01). The results were shown in Table 1.

Comparison of Lequesne score before and after treatment

Compared with before treatment, the Lequesne score of 45 patients after 12 weeks of treatment was significantly decreased, and the difference was statistically significant (P＜0.01). The results were shown in Table 1.

Comparison of WOMAC scores before and after treatment

The WOMAC score of 45 patients after 12 weeks of treatment decreased significantly compared with before treatment, and the difference was statistically significant (P＜0.01). The results were shown in Table 1.

Evaluation of Knee Joint Effusion and Synovial Hyperplasia by Musculoskeletal Ultrasound

Musculoskeletal ultrasound was used to observe changes in the depth of knee joint effusion and synovial thickness in 45 patients with KOA before and after treatment. After 12 weeks of treatment, the range of knee joint effusion in KOA patients was significantly smaller than that before treatment, and the difference was statistically significant (P＜0.001), indicating that Tongren Dahuoluo Pill (同仁大活络丸) can help relieve KOA joint effusion (Table 2). After 12 weeks of treatment,the synovial hyperplasia of the KOA knee joint was significantly reduced compared with that before the treatment, and the difference was statistically significant (P＜0.001), indicating that Tongren Dahuoluo Pill (同仁大活络丸) can help alleviate the synovial hyperplasia of KOA (shown in Table 3).

DISCUSSION

KOA is one of the important causes of chronic knee pain in the elderly. KOA ranks 11th among 291 disabling diseases in the world[4]. It is currentlybelieved that chondrocytes cannot maintain the stable state of synthesis and degradation between the extracellular matrix and subchondral bone,leading to osteoarthritis[5], resulting in joint stiffness,swelling and joint instability, impaired motor function,muscle weakness, and imbalance, frequent falls and other dysfunctions, therefore leading to a decline in the quality of life. Due to increased life expectancy and obesity, the prevalence of KOA continues to rise. It has become a major health problem due to the loss of labor and the increase in medical expenses.

Table 1. Comparison of VAS Score, Lequesne Score and WOMAC Score Before and After Treatment (, Point)

Table 1. Comparison of VAS Score, Lequesne Score and WOMAC Score Before and After Treatment (, Point)

Note:**Compared with before treatment, there was a very significant difference (P＜0.01)

Knee Function Score 0 week 4 weeks 8 weeks 12 weeks VAS 6.95±1.70 4.74±1.71 2.80±1.34 1.87±0.84 Lequesne 9.00±3.79 5.04±2.99 2.46±2.05 1.65±1.83 WOMAC 24.13±11.18 14.20±8.59 6.39±5.50 4.90±4.75

Table 2. Evaluation of Changes in Knee Joint Effusion Before and After Treatment by Musculoskeletal Ultrasound

Table 3. Evaluation of Changes in Knee Synovial Hyperplasia Before and After Treatment by Musculoskeletal Ultrasound

In the Framingham osteoarthritis study, with a follow-up of 8.1 years, the incidence of symptomatic KOA was 6.7% (an increase of 0.8% per year)[6].A 4-year follow-up study recently published in my country showed that symptomatic KOA among people45 years old in my country reached 8.5% (an increase of 2.1% per year)[7], which was higher than the Framingham osteoarthritis study.The incidence of symptomatic KOA in women is significantly higher, considering that this may be related to decreased bone density in women. The older the age, the greater the risk of symptomatic KOA. The incidence of KOA is the highest between the ages of 60 and 69, and the incidence decreases after the age of 70. This may be because the elderly generally has less physical activity after the age of 70. Studies have also shown that hypertension,heart disease, kidney disease, and digestive system diseases are associated with an increased risk of symptomatic knee osteoarthritis[8-10].

Musculoskeletal ultrasound is used for KOA diagnosis and judgment. Compared with CT and magnetic resonance imaging, it has the characteristics of non-radiation, simple and convenient operation. Ultrasound highfrequency probes have a good ability to display the inflammatory changes of the joint synovium.Because it can scan the bone cortex and surrounding soft tissue lesions at the same time,it can comprehensively evaluate the synovial hyperplasia, joint cavity effusion, cartilage and bone erosion, inflammatory changes in the soft tissue around the joint, and can be compared with the contralateral or other joints. In osteoarthritis,musculoskeletal ultrasound can be used to evaluate joint inflammatory changes, such as joint effusion and synovial thickening[11]. Therefore, this study chose musculoskeletal ultrasound to evaluate Tongren Dahuoluo Pill (同仁大活络丸) in the treatment of KOA joint inflammation changes.

Regarding the treatment and management of KOA, the purpose of treatment is to relieve pain,prevent and delay disease progression, protect joint function, and improve quality of life. The International Osteoarthritis Society (OARSI) recommends conservative treatment as the first-line treatment for KOA. Among the conservative treatment methods,drug treatment is a method widely used in clinical practice and a method recommended by clinical guidelines.

In the treatment of OA drugs, non-steroidal anti-inflammatory drugs (NSAIDs) that improve symptoms have both analgesic and antiinflammatory effects. They are the most commonly used medicines to control OA symptoms. They mainly reduce the prostate by inhibiting the activity of cyclooxygenase. It is synthesized to reduce the pain and swelling caused by joint inflammation and improve joint movement. However, the main adverse reactions include gastrointestinal ulcers, liver and kidney damage, platelet function,and increase the risk of cardiovascular adverse events. Especially in the elderly, long-term use will increase the risk. Diseases modifying osteoarthritis drugs (DMOAD) and chondroprotective agents,commonly used medicines such as glucosamine,diacerein, chondroitin sulfate, etc. may have a certain improvement effect on early OA. However,these medicines generally have a slower onset,and the clinical efficacy of advanced osteoarthritis is controversial. Therefore, there is currently no medicine to reverse the progression of OA, and advanced patients require joint replacement surgery.

KOA belongs to the category of "Bi syndrome(痹症)" in traditional Chinese medicine. "Bi" means closed. The Inner Canon of Yellow · Emperor Plain Questions (《黄帝内经·素问》) records: "The interaction of wind, cold and dampness causes Bi(痹)." and "Bi syndrome in winter is called bone stagnation; Bi syndrome in spring is called sinew stagnation... Prolonged illness leads to transmission of disease to the parts that are connected with the five zang organs. So if bone stagnation is not cured and complicated by re-invasion of pathogen, it deepens into the kidney. If sinew stagnation is not cured and complicated by re-invasion of pathogen,it deepens into the liver." It conforms to the characteristics of aggravation of cold in most KOA patients, and also suggests that the main cause of KOA is related to liver and kidney deficiency and insufficient Qi (气) and blood.

Tongren Dahuoluo Pill (同仁大活络丸) is a traditional famous medicine. In 1470, the imperial physician in Ming Dynasty DONG Su's Miraculous Prescriptions (《奇效良方》) Volume 2 records Dashenxiao Huoluo Pill (大神效活络丹) cures dampness Bi syndrome, muscle and bone pain,clearing away heart-fire and improves eyesight,widens the chest and benefits blood, nourishes Qi (气) and warms the knees, relieves waist and arm pain, treats facial paralysis, difficulty to walk,tendons and veins convulsions. Patients over forty years old take one pill every time, and you will not get wind sickness till elderly." The composition of its prescriptions is comprehensive, including 50 medicines of Agkistrodon, Zaocys, Radix Clematidis, Scorpio, Bombyx Batryticatus, Rhizoma Anemones Raddeanae, Radix Aconiti Kusnezoffii,Radix Rehmanniae Preparata, Carapaxet Plastrum Testudinis, Herba Ephedrae, etc.. The whole prescription nourishes the liver and kidney Qi (气)and blood, expels wind and dampness, promotes blood circulation and dredges collaterals, with comprehensive effects. It is used for KOA treatment,for both treating pathogens and health Qi (气), and both symptoms and root causes. Our research also shows that Tongren Dahuoluo Pill (同仁大活络丸)significantly reduces VAS score, Lequesne score and WOMAC score after 12 weeks of treatment of KOA, which has a good effect on KOA in improving clinical symptoms and joint function. In this study,it was also observed through musculoskeletal ultrasound that Tongren Dahuoluo Pill (同仁大活络丸) had a good inhibitory effect on KOA's knee synovial hyperplasia and joint effusion after 12 weeks of treatment, suggesting that Tongren Dahuoluo Pill (同仁大活络丸) can not only improve symptoms, but also have obvious anti-inflammatory effect (Figure A, Figure B).

Figure A. Obvious Synovial Hyperplasia of the Right Knee Joint Before Treatment

Figure B. Synovial Hyperplasia of the Right Knee Joint After 12 Weeks of Treatment with Tongren Dahuoluo Pill (同仁大活络丸) was Significantly Reduced Compared with Before Treatment

There are many shortcomings in this study.There is no control group in this study, and the sample size is small, and the observation period for ultrasound imaging is relatively short. Therefore,on the basis of this study in the future, it is still necessary to design a larger-sample multi-center randomized controlled study of higher quality to verified the results.