Characteristics of Traditional Chinese Medicine Use in Patients with Rheumatoid Arthritis in Taiwan: A Nationwide Population-Based Study
Ming-Cheng Huang1,2,*, Fu-Tzu Pai3,*, Che-Chen Lin4, Ching-Mao Chang5,6, Hen-Hong Chang2,7,8, Yu-Chen Lee2,7,9, Mao-Feng Sun2,7,8, Hung-Rong Yen 1,2,7,8 * These authors have equal contribution
1Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
2Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan
3Graduate Institute of Clinical Medical Sciences, School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
4Health Data Management Office, China Medical University Hospital, Taichung 404, Taiwan
5Center for Traditional Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
6Graduate Institute of Clinical Medicine, and Graduate Institute of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
7Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung 404, Taiwan
8School of Chinese Medicine, China Medical University, Taichung 404, Taiwan 9Graduate Institute of Acupuncture Science, China Medical University, Taichung 404, Taiwan.
Running Title: Traditional Chinese Medicine for Rheumatoid Arthritis Corresponding Author: Hung-Rong Yen, M.D., Ph.D.
Research Center for Traditional Chinese Medicine, Department of Medical Research, and Department of Chinese Medicine, China Medical University Hospital
2 Yude Road, North District, Taichung 404, Taiwan. Office: +886-4-2205-2121, ext. 7508
Fax: +886-4-2236-5141
ABSTRACT
Objective: Large-scale study of traditional Chinese medicine (TCM) usage among patients with rheumatoid arthritis (RA) is lacking. The aim of this study is to evaluate the TCM usage among RA patients in Taiwan.
Methods: We examined the “registry for catastrophic illness patient dataset” of the National Health Insurance Research Database (NHIRD; n=23 million people) in Taiwan. Patients (n=25,263) newly diagnosed as RA in 2001-2009 were included and then followed-up until the end of 2011. Based on the medical utilization, they were further categorized into TCM users (n=6,891; 27.3%) and non-TCM users (n=18,372; 72.7%). The demographic data, treatment modalities, disease distributions, comorbidities and core prescription pattern of the TCM users were analyzed.
Results: Compared to non-TCM user, TCM users were younger (mean age: 49.6 versus 54.0 years), had a higher female/male ratio (82.7%/17.3% versus 74.1%/25.9%), resided in more urbanized area. Herbal remedies were the most commonly used therapeutic approach (76.4%), followed by combining acupuncture (21.1%). The frequency of outpatient visits in TCM users was higher across all disease categories except circulatory system. The most commonly prescribed formula and herb was Shang-Jong-Shiah-Tong-Yong-Tong-Feng-Wan and Rhizoma Corydalis, respectively. RA patients who had anxiety and depression, allergic rhinitis, osteoporosis, menstrual disorder, and menopausal syndrome were prone to have more TCM visits compared to non-TCM users.
Conclusion: Our population-based study revealed the high prevalence and specific usage patterns of TCM in the RA patients in Taiwan. The information could be used for further pharmacological investigation and clinical trials.
Keywords: complementary and alternative medicine; epidemiology; national health insurance research database; rheumatoid arthritis; traditional Chinese medicine;
Introduction
Rheumatoid arthritis （RA ）is a common disorder among autoimmune diseases affecting approximately one percent of worldwide population [1]. Although the annual incidence in Taiwan was only 15.8 per 100,000 people [2], lower than the data extracted from other countries [3], it could lead to significant synovial inflammation, bone erosion and progressive disability. Even more, it also hampers somatic systems, resulting in cardiovascular disease, interstitial lung disease, osteoporosis [4-7] and mortality [8, 9]. Non-steroid anti-inflammation drugs (NSAIDs) and Disease-modifying antirheumatic drugs (DMARDs) are conventionally used to suppress inflammation and modulate immunity [5, 7, 10]. Biologic agents that inhibit tumor necrosis factor (TNF-), interleukin-1 (IL-1) and interleukin-6 (IL-6) are also available to reduce the ongoing inflammation that is refractory to conventional therapy [7]. Despite the fact that conventional and biological therapies are effective to inhibit the inflammation; there are still some unmet needs and concerns [11-13]. The economic burden of using biologic products may also delay the treatment if the patient could not afford it.
Utilization of complementary and alternative medicine (CAM) was not uncommon in patients with RA [14]. However, current knowledge of the usage of CAM among RA patients is limited by research methodologies such as telephone interview and questionnaires. Although there are some international studies on RA, including the RAISE survey [13], as well as national studies including the Swedish Rheumatology Quality Register (SRQ) [15], the Consortium of Rheumatology Researchers of North America (CORRONA) registry [16, 17], the American Rochester Epidemiology Project (REP) [3], the Italian RAPSODIA study [12] and the Hong Kong study [9], there is a lack of large-scale surveys on the adjunctive CAM usage specifically among
RA patients.
Traditional Chinese medicine (TCM), including Chinese herbal remedies, acupuncture and manipulative therapies, is commonly used as an adjunctive therapy in different diseases in Asian countries [18]. In Chinese pollution, TCM has been used as an adjunctive therapy for autoimmune and rheumatologic diseases. RA was viewed as the Bi Syndrome (Impediment Syndrome) and treated according to the stages of the disease, onset symptoms, and condition of whole body [19]. For example, Chinese herbs might play a role in modulating cytokine networks in inflammatory response of RA [20] or have analgesic effects [21]. In Taiwan, more than 99% of the total population (23 million people) were enrolled in the mandatory National Health Insurance (NHI) program since 1995 [22]. Not only Western medicine, but also TCM treatment—including Chinese herbal products, acupuncture/moxibustion and manipulative therapy, were reimbursed by this program [23, 24]. We have also identified the specific pattern of TCM usage in patients with Sjögren's syndrome [25], asthma [26], allergic rhinitis [27] and rhinosinusitis [28].
To explore the characteristics of adjunctive TCM use in patients with RA, we analyzed the registry for catastrophic illness patients of the National Health Insurance Research Database (NHIRD) of Taiwan. This dataset comprehensively included all clinical and laboratory confirmed RA patients with long-term follow-up and thus could reduce the potential for sampling bias. The results of this study should provide valuable information for patients, rheumatologists, and the government concerning the healthcare of patients with RA. The Chinese herbal prescription patterns should also serve as a candidate list for further pharmacological investigation and clinical trial.
Methods Data Source
Taiwan established the NHI program in March 1995. Nearly all of the necessary Western medical services were reimbursed since 1995 and TCM services (Chinese herbal remedies, acupuncture/moxibustion, and manipulative therapy) since 1996. Any other treatment such as mediation, Qigong and tai chi were not covered. Only licensed TCM doctors are qualified for reimbursement. In 2010, there were 23 million people, equaled to 99.89% of the total population, enrolled in the NHI program [22]. The registry and original data comprising demographic characteristics, outpatient and inpatient visits, diagnostic codes, assessments, procedures, prescriptions and medical expenditure for reimbursement were included in the NHRID. The NHIRD also established a “registry for catastrophic illnesses patient database (RCIPD)", including about 30 disease categories such as cancer, schizophrenia, end-stage renal disease, lupus and rheumatoid arthritis. RA patients who received complete clinical and laboratory evaluation, followed by careful and routine review by rheumatologists commissioned by the National Health Insurance Administration, were granted for catastrophic illness certificates. This accuracy of the diagnosis of the RA patients enrolled in this study is thus highly reliable [29].
Data Availability Statement: All data are deposited in an appropriate public repository. The study’s datasets were from the NHIRD (http://w3.nhri.org.tw/nhird//date_01.html), which are maintained by National Health Research Institutes (http://nhird.nhri.org.tw/en/index.htm), Taiwan.
Study Subjects and Variables
The flow chart for selection of RA cases was shown in Figure 1. First, all the patients (n=47,809) with diagnosis of RA (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code: 714.0) in the RCIPD of
NHIRD were included in this study. Ultimately, individuals with newly diagnosed RA between January 2001 and December 2009 were included for this study (n=25,263) and then followed-up until the end of 2011. After a confirmed diagnosis of RA, those consulted with TCM doctors were grouped as TCM users (n=6,891), while the others non-TCM users (n=18,372). The demographic characteristics and claims data of this study cohort were collected and analyzed. Therapeutic actions and indication of TCM prescription was recorded based on TCM theory [30].
Urbanization of the residence areas was described previously [24, 31]. In brief, the residence area of Taiwan township were divided into 4 levels of urbanization which were defined by population density (people/km2), the population ratio of different educational level, ratio of elderly people, ratio of people of agriculture workers, and the number of physicians per 100,000 people. Level 1 had the highest degree of urbanization and level 4 had the lowest. Urbanization levels 1 and 2 were defined as urban areas, while levels 3 and 4 were classified as rural areas.
Statistical analysis
All statistical analyses were performed using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, U.S.A.). Univariate analysis was used to compare the TCM users with the non-TCM users. The chi-square test was performed to examine the relationship between the categorical variables and to examine the differences between TCM users and non-TCM users. Prevalence rate ratio indicated how large is the prevalence of a disease in the TCM user group relative to the non-TCM users. A P value <0.05 was considered as statistically significant. An open-sourced freeware NodeXL (http://nodexl.codeplex.com/) identified the core patterns of Chinese herb medicine used in treating RA patients, and all the selected two drugs combinations were applied in this network analysis. The thicker line width, defined as counts of
connections between formulas and herbs, indicated significant prescription patterns in the network figure [25].
Ethics Statement
The NHIRD was provided by the National Health Insurance Administration and managed by National Health Research Institutes, Taiwan. All of the released datasets were de-identified and scrambled for research. Therefore, it was not possible to identify individual patient by any means. This study was approved by the Research Ethics Committee of China Medical University and Hospital (CMU-REC-101-012).
Results
There were 47,809 patients diagnosed as RA with catastrophic illness certificates enrolled in this study (Figure 1). After excluding the prevalent cases, there were 25,263 newly diagnosed RA patients. Among them, 6,891 (27.3%) patients were TCM users while 18,372 (72.7%) subjects were non-TCM users. Demographic characteristics (Table 1) revealed a proportional difference among the age groups between TCM and non-TCM users. The mean age of TCM users were younger than non-TCM users (49.6±14.3 versus 54.0±16.0). Although there was a female predominance in both groups, there was a significantly higher female to male ratio in TCM users versus non-TCM users (82.7%/17.3% versus 74.1%/25.9%). Regarding the urbanization level of patients’ residence area, TCM users resided in more urbanized area. The interval between the confirmed diagnosis of RA and the first TCM visit was 23.4 months.
To understand the frequency of visits and therapeutic approaches utilized by these TCM users, we analyzed the distribution of clinical visits in TCM users (Table 2). A portion of the patients (n=3,024; 43.9%) visited TCM clinics less than 3 times, while 2,808 (40.7%) patients consulted TCM doctors more than 6 times. With regard
to the therapeutic approaches, majority (n=5,268; 76.4%) of the TCM users used Chinese herbal remedies. Only 2.5% of the patients used acupuncture or traumatology alone and 21.1% adapted both approaches.
We further analyzed the frequency distribution of clinical visits of TCM and non-TCM user by major disease categories (as the reasons for consultation) (Table 3). Other than musculoskeletal system and connective tissue disorders, RA patients most commonly visited TCM or non-TCM doctors due to concurrent illness in digestive system, respiratory system, nervous system, injury, skin and subcutaneous tissue, infectious diseases, genitourinary system, endocrine/immunity disorder, mental disorder and neoplasms. Comparing the TCM users and non-TCM users, we noticed that there is a statistically higher frequency of outpatient visits among TCM users across almost all disease categories except circulatory system (Table 3). The comorbid neoplasm drew our attention and we did an additional subtyping to further analyze the distribution of various benign and malignant tumor types among these patients (Table 4).
Furthermore, the ten most common herbal formulas and single herbs prescribed by licensed TCM doctors for the treatment of RA were analyzed and listed in Table 5. The most commonly used TCM formula and single herb were Shang-Jong-Shiah-Tong-Yong-Tong-Feng-Wan and Rhizoma Corydalis (Yan-Hu-Suo), respectively. We utilized the network analysis to demonstrate that Myrrha, Olibanum, Dang-Gui-Nian-Tong-Tang, Shu-Jing-Huo-Xie-Tang and Gui-Zhi-Shao-Yao-Zhi-Mu-Tang formed the core patterns of Chinese formulas and herbs prescribed for RA patients in Figure 2.
Comparing the disease prevalence rate ratio of TCM versus non-TCM group, we found that RA patients with certain diseases tended to receive treatment in TCM
clinics, rather than in non-TCM clinics (Table 6). Specifically, RA patients preferred to visit TCM doctors when they had anxiety and depression, allergic rhinitis, menstrual disorders, menopausal syndromes and osteoporosis.
Discussion
Our study is the first large-scale population-based investigation of TCM usage in RA patients. RA patients with a younger age, female gender, or residency in urbanized area had a tendency to consult TCM service. The most commonly adapted TCM therapeutic approach is Chinese herbal remedies. The frequency of outpatient visits in TCM users was higher across all disease categories except circulatory diseases. We also identified the prescription patterns of TCM formulas and herbs. Especially, the prevalence rate ratio of TCM versus non-TCM users was higher in diseases such as anxiety and depression, allergic rhinitis, osteoporosis, menstrual disorders, and menopausal syndromes. Overall, our study provided valuable information and added value to the existing knowledge regarding healthcare in RA patients.
The strength of this study at least included the following aspects: First, all residents of Taiwan can access the NHI system with low-cost and convenience [22], there was no bias regarding the accessibility of healthcare, either Western or Chinese medicine. Until 2012, there are approximately 59,017 Western medical doctors and 5,556 board-certified TCM doctors serving 23 million people in Taiwan. 93.7% of the hospitals/clinics are contracted with the NHI program [32]. Second, all RA patients with catastrophic illness certificates were included in this study. They were all diagnosed by rheumatologists with confirmed clinical and laboratory tests. This database is highly accurate and reliable for epidemiology study in RA patients [29].
Third, a couple unmet needs of RA patients do exist [12, 33]. Our experience of adjunctive use of TCM in RA patients may provide some thoughts in the design of future therapeutic strategy.
Consistent with previous data [14], female patients used CAM more frequently than did male patients, and those who used complementary therapy were younger than those who did not. Our and other’s studies also found that female with a higher socioeconomic status, higher educational level and self-perceived poor health status used TCM more often [34, 35]. It is surprising that even though RA has been a disease prevalent in female, there were much more female patients using TCM. Regarding the interval between RA diagnosis and the first consultation of TCM, our result is consistent with a previous study [36]—patients with disease duration more than two years were more likely to use CAM than those in early period of RA. It is probably most patients usually used western medicine as first choice initially. If unsatisfied with conventional therapy or disturbed by recurrence of symptoms, they might further seek adjunctive TCM consultation [14].
Unlike the tendency toward acupuncture in most of the Western countries, herbal remedies have been widely accepted in Taiwan. Western herbal products and dietary supplements taken orally was one of the most common forms of CAM used in Europe and America [37, 38]. However, herein the Chinese herbal remedies referred were not only for supplementary or complementary use. This is partly due to the long history of TCM usage in Chinese population. Fundamental principles such as “Yin and Yang” and “Qi and Blood” having been integrated as part of Chinese culture and lifestyle. Furthermore, the low cost and insurance coverage for TCM treatment also contributed to the widespread of TCM. Regarding the visiting frequency, a significant portion (43.9%) of RA patients might only sought for second opinion because they only
visited TCM clinics for 1-3 times. On the other hand, 40.7% of the RA patients used TCM service for more than 6 times, which might be due to the confidence in symptoms relief or effectiveness perceived by users.
RA is not a disease merely affecting joints. There is an increased prevalence of cardiovascular disease, incidence of infection, and the development of malignancies result in shortened life span in patients with RA. A previous investigation revealed that depression was the most frequently associated disease, followed by asthma, cardiovascular illness, solid tumors, and chronic obstructive pulmonary disease [39]. The result was consistent with our findings that RA patients had a broad spectrum of disease category in their clinical visits, either in TCM or non-TCM users. The finding that RA patients had a high prevalence of various comorbidities is in accordance with a previous international cross-sectional study (COMORA study) [39]
It is undoubted that biological agents, high-dose corticosteroid and DMARDs all can modulate the immunity to ameliorate the disease progression. However, many patients worried about the side effects or still had unmet needs [14, 40]. The TCM prescriptions from this nationwide survey could be used as a candidate list for further pharmacological investigation. The most commonly prescribed herbal formula, Shang-Jong-Shiah-Tong-Yong-Tong-Feng-Wan was used in TCM for arthritis and pain control. According to the TCM theory, it could dispel wind and dampness, promote blood circulation and clear heat. It has been used in relieve and cure the symptoms of Bi Syndrome (Impingement Syndrome) including stiffness, tenderness, swelling and deformity of the joints and limited range of motion [19]. Xiao-Huo-Luo-Dan consisted of Radix Aconiti Preparata, which was found to be an effective analgesic [41]. Liu-Wei-Di-Huang-Wan was found to inhibit both Th1- and Th2-type cytokine in human peripheral blood mononuclear cells in a previous study [42].
Among the single herbs, Rhizoma Corydalis (Yan-Hu-Suo), has been used in TCM for pain relief for a long time. Its extracts has been found to exert anti-inflammatory activity in adjuvant-induced arthritis [43]. Clematichinenoside, a kind of triterpene saponin isolated from Radix Clematidis (Wei-Ling-Xian), had been proven its anti-inflammatory effect in collagen-induced-arthritis rats by decreasing nitric oxide and TNF, and inhibiting the expression of NF-kappaB p65 subunits, TNF- and cyclooxygenase-2 [44]. Radix Achyranthis Bidentatae (Niu-Xi), Cortex Phellodendri (Huang-Bo) and Semen Coicis (Yi-Yi-Ren) are the three ingredients of San-Miao-San, which could improve arthritis symptoms and lower level of inflammatory cytokine IL-18 [20, 21]. Fructus Chaenomelis (Mu-Gua) also reduced inflammation in adjuvant arthritis rats and inhibited of secretion of IL-1, TNF-α and prostaglandin E2 [45].
Other than joint symptoms, depression is more common in patients with RA than in healthy individuals. We found that the TCM prescriptions were not only for RA itself but also covered a broad range of comorbidities. It has been reported that vulnerable psychosocial status such as depression could be a predictor of negative effect of RA in the follow-up period [46]. Our data showed that RA patients with anxiety and depression were more likely to use TCM. Among the commonly prescribed herbal remedies, Jia-Wei-Xiao-Yao-San, Tian-Wang-Bu-Xin-Dan and Xiao-Chai-Hu-Tang, were usually used to bi-directionally adjust depressive and anxious mood resulted from Qi stagnation and blood insufficiency according to TCM theory [47, 48]. Women treated with Jia-Wei-Xiao-Yao-San had significantly decreased serum IL-6 concentration, which had been reported to be increased in major depressive disorders [49] and RA [50]. Among single herbs, Radix Salviae Miltiorrhizae (Dan-Shen) has been widely used in the treatment of cardiovascular and cerebrovascular diseases
attributing to its capability to decrease blood clotting [51]. However, the frequency of TCM user’s clinical visit due to disease of circulatory system was not higher than non-TCM user. It will be interesting to know whether it could help to prevent or treat the cardiovascular complications resulting from RA.
To explore the most frequently used combinations of these formulas and single herbs, we conduct network analysis of accumulative experiences of over five thousands TCM practitioners and found that the core pattern consisted of “Myrrha and Olibanum”,“Gui-Zhi-Shao-Yao-Zhi-Mu-Tang”, “Dang-Gui-Nian-Tong-Tang”, and “Shu-Jing-Huo-Xie-Tang”. Two formulas, Gui-Zhi-Shao-Yao-Zhi-Mu-Tang and Dang-Gui-Nian-Tong-Tang, were the center of connections and used to treat the inflammation, swelling and tenderness of joints. Phellodendri Chinensis Cortex, Atractylodis Lanceae Rhizoma and Achyranthis Bidentatae Radix composed San-Miao-San, which could reduce inflammation. Myrrha and Olibanum made a pair in quickening the blood and transform stasis correspond to poor periarticular circulation or remodeling of joints. These results implied that TCM practitioners’ thoughts in treating RA were similar to the pathophysiologic mechanism proposed by Western medicine.
Some caveats in this study merit comments. First, the laboratory data and imaging findings were unavailable and not provided in this database. It was impossible to judge the disease severity of the TCM users and non-TCM users. However, most of the patients seeking CAM [14] or TCM [34] treatment perceived themselves poor health status. It is possible these TCM users were at least not satisfied with the current treatment. Second, Qiqong exercise or tai chi was not covered by the NHI program. Although tai chi has been recommended in knee osteoarthriti by the American College of Rheumatology [52], it is deemed as one of
the suggestions in the TCM consultations and thus not reimbursed by the insurance. Except this, most of the TCM therapeutic approaches by licensed TCM doctors were covered in the NHI system.
In conclusion, this study is the first large-scale nationwide population-based investigation into TCM usage in RA patients. TCM use in RA patients was not uncommon. The information could be used for further pharmacological investigation and clinical trials. Additional basic and clinical studies on the use and mechanism of TCM are warranted.
Key Messages:
1. Traditional Chinese medicine usage, especially herbal remedies, among RA patients is not uncommon in Taiwan.
2. TCM users were younger, had a higher female/male ratio and resided in more urbanized area.
3. RA patients who had anxiety and depression, allergic rhinitis, osteoporosis, menstrual disorder, and menopausal syndrome were prone to have more TCM visits.
Acknowledgments
This study was based in part on data from the National Health Insurance Research Database, provided by the National Health Insurance Administration, Ministry of Health and Welfare, and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of National Health Insurance Administration, Ministry of Health and Welfare, or National Health Research Institutes.
Funding: This study was supported by China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan ( Ａ -1-2-a (10343TU5)). This study was also supported in part by China Medical University Hospital
(DMR-104-003) and the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002). Yen H-R. was supported by a career-developing grant (EX101-10124SC, EX102-10124SC, NHRI-EX103-10124SC and NHRI-EX104-10124SC) from the National Health Research Institutes, Taiwan.
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Table 1. Demographic characteristics of the patients newly diagnosed with rheumatic arthritis in Taiwan in 2001-2009 Variable Non-TCM user N= 18372 (72.7%) TCM user N = 6891 (27.3%) p value* Sex <0.0001 Female 13606 (74.1) 5697 (82.7) Male 4766 (25.9) 1194 (17.3) Age at baseline
mean age (years ± SD) 54.0 ± 16.0 49.6 ± 14.3 <0.0001
<20 604 (3.3) 228 (3.3) 20-39 2592 (14.1) 1322 (19.2) 40-59 8515 (46.3) 3752 (54.4) ≧60 6661 (36.3) 1589 (23.1) Urbanization <0.0001 1 (most urbanized) 5008 (27.3) 1983 (28.8) 2 5429 (29.6) 2190 (31.8) 3 3003 (16.3) 1119 (16.2) 4 (least urbanized) 4932 (26.8) 1599 (23.2) Interval between the diagnosis and
initial TCM use, median (months) 23.4
* P value between TCM and non TCM-user TCM: traditional Chinese medicine
Table 2. The frequency distribution of therapeutic approaches in TCM users Number of TCM visits Only Chinese herbal remedies N = 5268 (%) Only Acupuncture or traumatology N = 170 (%) Combination of both treatment N = 1453 (%) Total N = 6891 (%) 1-3 2575 (48.9) 151 (88.8) 298 (20.5) 3024 (43.9) 4-6 803 (15.2) 13 (7.6) 243 (16.7) 1059 (15.4) >6 1890 (35.9) 6 (3.5) 912 (62.8) 2808 (40.7)
Table 3. The frequency distribution of TCM and non-TCM user by major disease categories Disease (ICD-9-CM) Non-TCM user
N= 18372 (%) TCM user N = 6891 (%) Total N=25263 (%) p value*
Infectious and parasitic disease (001-139)
11421 (62.2) 4995 (72.5) 16416 (65.0) <0.0001
HBV (070.2, 070.3, and V02.61)
1098 (6.0) 529 (7.7) 1627 (6.4) <0.0001
Endocrine, nutritional and metabolic disease and immunity disorder (240-279)
10022 (54.6) 4117 (59.7) 14139 (56.0) <0.0001
Blood and blood-forming organs (280-289) 4009 (21.8) 1922 (27.9) 5931 (23.4) <0.0001 Anemia (280.9,285.9) 3025 (16.5) 1483 (21.5) 3208 (12.7) <0.0001 Mental disorder (290-319) 7141 (38.9) 3306 (48.0) 10447 (41.4) <0.0001 Nervous system (320-389) 15076 (82.1) 6182 (89.7) 21258 (84.1) <0.0001 Circulatory system (390-459) 11640 (63.4) 4444 (64.5) 16084 (63.7) 0.0955 Respiratory system (460-519) 17083 (93) 6660 (96.6) 23743 (94.0) <0.0001 Digestive system (520-579) 17502 (95.3) 6792 (98.6) 24294 (96.1) <0.0001 Genitourinary system (580-629) 12421 (67.6) 5473 (79.4) 17894 (71.0) <0.0001 Menstruation disorder and other abnormal bleeding from female genital tract (626)
2815 (20.7) 1765 (31.0) 4580 (18.1) <0.0001
Menopausal and postmenopausal
disorders (627)
Female infertility (628) 118 (0.9) 98 (1.7) 216 (0.9) <0.0001 Complications of
pregnancy, childbirth and the puerperium (630-676)
512 (2.8) 376 (5.5) 888 (3.5) <0.0001
Skin and subcutaneous tissue (680-709)
14009 (76.3) 5872 (85.2) 19881 (78.7) <0.0001
Musculoskeletal system and connective tissue (710-739)
18284 (99.5) 6891 (100.0) 25175 (99.7) <0.0001
Symptoms, signs and ill-defined conditions (780-799)
16005 (87.1) 6481 (94.1) 22486 (89.0) <0.0001
Injury and poisoning (800-999)
14127 (76.9) 5880 (85.3) 20007 (79.2) <0.0001
Others** 1216 (6.6) 786 (11.4) 2002 (7.9) <0.0001
* p value between TCM and non TCM-user
**Others included ICD-9-CM code range 630–677, 740–759, 760–779, and missing/error data TCM: traditional Chinese medicine; HBV: Viral hepatitis B
Table 4. The frequency distribution of TCM and non-TCM user by various tumor types
Disease (ICD-9-CM) Non-TCM user
N= 18372 (%) TCM user N = 6891 (%) Total N=25263 (%) Neoplasms (140-239)* 6442 (35.1) 3160 (45.9) 9602 (38.0) Malignant 1624 (8.8) 514 (7.4) 2138 (8.5)
Female genital organs (**) 213 (1.2) 87 (1.2) 300 (1.2)
Thyroid gland (193) 62 (0.3) 22 (0.3) 84 (0.3)
Benign 4818 (26.2) 2646 (38.4) 7464 (29.5)
Lip, oral cavity and pharynx (210)
212 (1.2) 116 (1.7) 328 (1.3)
Other digestive system (211) 781 (4.3) 400 (5.8) 1181 (4.7)
Respiratory organs (212) 99 (0.5) 52 (0.8) 151 (0.6)
Bone and articular cartilage (213)
73 (0.4) 40 (0.6) 113 (0.4)
Lipoma (214) 154 (0.8) 82 (1.2) 236 (0.9)
Other connective/soft tissue (215)
579 (3.2) 314 (4.6) 893 (3.5)
Skin (216) 1285 (7.0) 743 (10.8) 2028 (8.0)
Breast (217) 836 (4.6) 531 (7.7) 1367 (5.4)
Uterine leiomyoma (218) 996 (5.4) 721 (10.5) 1717 (6.8) Uterus, excluding leiomyoma
(219)
318 (1.7) 222 (3.2) 540 (2.1)
Ovary (220) 511 (2.8) 356 (5.2) 867 (3.4)
Other female genital organs (221 )
34 (0.2) 27 (0.4) 61 (0.2)
Male genital organs (222) 27 (0.1) 6 (0.1) 33 (0.1)
Kidney/other urinary organs (223)
43 (0.2) 29 (0.4) 72 (0.3)
Eye (224) 16 (0.1) 10 (0.1) 26 (0.1)
Brain/other nervous system (225)
125 (0.7) 70 (1.0) 195 (0.8)
Thyroid glands (226) 75 (0.4) 46 (0.7) 121 (0.5)
(228)
Others (229) 208 (1.1) 106 (1.5) 314 (1.2)
* p value between TCM and non-TCM users: <0.0001
** Female genital organs (ICD-9-CM) included uterus-unspecified part (179), cervix uteri (180), placenta (181), body of uterus (182), ovary and other uterine adnexa (183) and unspecified female genital organs (184)
Table 5. Ten most common herbal formulas and single herbs prescribed for patients with rheumatoid arthritis
TCM prescription Therapeutic actions/
indications in TCM Number Average daily dose (g) Herbal formula 169525 6.5 Shang-Jong-Shiah-Tong-Yong-Tong-Feng-Wan Dispel wind-damp 4310 7.3
Jia-Wei-Xiao-Yao-San Rectify Qi and nourish
blood 3514 5.5
Liu-Wei-Di-Huang-Wan Enrich Yin 2716 6.3
Xiao-Huo-Luo-Dan Dispel wind-damp 2309 6.5
Ban-Xia-Xie-Xin-Tang Relieve GI upset 2218 3.5
Ping-Wei-San Dry dampness 1519 3.8
Xiao-Chai-Hu-Tang Harmonize Qi 1266 7.9
Tian-Wang-Bu-Xin-Dan Enrich Yin 1247 4
Zuo-Gui-Wan Enrich Yin 1024 4.9
Xiao-Qing-Long-Tang Suppress cough and clam
panting 704 3.3
Single herbs 264577 2.2
Rhizoma Corydalis (Yan-Hu-Suo) Relieve pain 7087 1.6
Radix Clematidis (Wei-Ling-Xian) Dispel wind-damp 5623 1.6
Caulis Spatholobi (Ji-Xue-Teng) Move the blood 5525 1.9
Semen Coicis (Yi-Yi-Ren) Clear dampness 5199 1.9
Radix Achyranthis Bidentatae (Niu-Xi) Strengthen sinew and bone 5187 2.7 Radix Salviae Miltiorrhizae (Dan-Shen) Transform stasis 5068 1.4 Cortex Phellodendri (Huang-Bo) Clear heat and dampness 4809 2.9
Ramulus Mori (Sang-Zhi) Free the channels 4643 2
Ramulus Cinnamomi (Gui-Zhi) Free the channels 4275 2.9
Fructus Chaenomelis (Mu-Gua) Soothe the sinews 3885 1.7
Table 6. Prevalence rate ratio of diseases between non-TCM and TCM user Disease (ICD-9-CM)
Age group (year)
Non-TCM user TCM user
PRR (95% CI)
N (%) N (%)
Anxiety (300) and depression (311)
All 4233 (23.0) 2267 (32.9) 1.18(1.12-1.24) <20 37 (6.1) 19 (8.3) 1.16(0.67-2.02) 20-39 430 (16.6) 330 (25.0) 1.32(1.15-1.53) 40-59 2072 (24.3) 1334 (35.6) 1.24(1.16-1.33) ≧60 1694 (25.4) 584 (36.8) 1.13(1.03-1.24) Allergic rhinitis (477.9) All 4135 (22.5) 2198 (31.9) 1.17(1.11-1.23) <20 248 (41.1) 111 (48.7) 1.02(0.81-1.27) 20-39 646 (24.9) 455 (34.4) 1.21(1.08-1.37) 40-59 1987 (23.3) 1174 (31.3) 1.14(1.06-1.23) ≧60 1254 (18.8) 458 (28.8) 1.20(1.08-1.33) Osteoporosis (733) All 3612 (19.7) 1749 (25.4) 1.07(1.01-1.13) <20 10 (1.7) 10 (4.4) 2.27(0.94-5.45) 20-39 143 (5.5) 97 (7.3) 1.17(0.90-1.51) 40-59 1356 (15.9) 936 (25.0) 1.33(1.23-1.45) ≧60 2103 (31.6) 706 (44.4) 1.10(1.01-1.20) Menstrual disorder (626) All 2815 (20.7) 1765 (31.0) 1.25(1.18-1.33) <20 103 (33.9) 61 (50.8) 1.33(0.97-1.82) 20-39 1214 (58.5) 789 (67.9) 1.02(0.93-1.11) 40-59 1410 (21.6) 880 (27.7) 1.10(1.01-1.19) ≧60 88 (1.9) 35 (2.8) 1.20(0.81-1.78) Menopausal syndrome (627) All 3062 (22.5) 1984 (34.8) 1.29(1.22-1.37) 20-39 111 (5.4) 90 (7.8) 1.27(0.96-1.68) 40-59 2188 (33.5) 1548 (48.7) 1.24(1.16-1.33) 60 ≧ 761 (16.2) 346 (28.0) 1.38(1.21-1.56)
*PRR: prevalence rate ratio: the prevalence of a disease in the TCM user group relative to the non-TCM user
CI: confidential interval
Figure Legend
Figure 1. Flow recruitment chart of subjects from the registry for catastrophic illness patient database (RCIPD) obtained from the National Health Insurance Research Database (NHIRD) in Taiwan. TCM: traditional Chinese medicine.
Figure 2: The top 50 herbal formulas and single herbs for rheumatoid arthritis patients were analyzed through open-sourced freeware NodeXL, and the core pattern of these Chinese herbal medicine showed that Myrrha, Olibanum, Dang-Gui-Nian-Tong-Tang Shu-Jing-Huo-Xie-Tang, and Gui-Zhi-Shao-Yao-Zhi-Mu-Tang were among the most frequently used combinations.
