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The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study Min-Chien Yu a,b, Shun-Ku Lin b,d, Jung-Nien Lai b,c,n, James Cheng-Chung Wei e,f, Chieh-Yuan Cheng g a School of Medicine, Chung Shan Medical University, Department of Integrated Chinese and Western Medicine, Chung Shan Medical University Hospital, Taichung City, Taiwan b Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei City 112, Taiwan c Department of Chinese Medicine, Taipei City Hospital, Yangming Branch, Taipei City 111, Taiwan d Department of Chinese Medicine, Taipei City Hospital, Ren-Ai Chinese Medicine Branch, Taipei, Taipei City 106, Taiwan e Institute of Medicine, Chung Shan Medical University, Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chung Shan Medical University Hospital, Taiwan f Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan g Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, Taiwan
art ic l e i nf o Article history: Received 11 February 2014 Received in revised form 9 May 2014 Accepted 23 May 2014 Keywords: Sjögren's syndrome Chinese herbal product Qi-Ju-Di-Huang-Wan Prescription patterns National Health Insurance Research Database
a b s t r a c t Q2 Ethnopharmacological relevance: Traditional Chinese medicines (TCM), when given for symptom relief, have gained widespread popularity among Sjögren's patients. The aim of this study was to analyze the Q3 utilization of TCM among Sjögren's patients in Taiwan. Q4 Materials and methods: The usage, frequency of service, and the Chinese herbal products prescribed among Sjögren's patients were evaluated in a cohort of 1,000,000 beneficiaries recruited from the National Health Insurance Research Database. The logistic regression method was employed to estimate the odds ratios (ORs) for utilization of a TCM. Results: More than 90% of Sjögren's patients received TCM out-patient services at least once during the study period. Patients with secondary Sjögren's syndrome were more likely to seek TCM treatment than those with primary Sjögren's syndrome. The aOR for those suffering from at least one rheumatologic disease was 1.56 (95% CI: 1.26–1.93), those with two rheumatologic diseases was 1.98 (95% CI: 1.29–3.04), while those with three or more rheumatologic diseases was 7.86 (95% CI: 1.09–56.58). Compared to Sjögren's patients who used no medical treatment, the aOR for those who took one type of conventional medication was 1.55 (95% CI: 1.25–1.92), those who took two types was 1.98 (95% CI: 1.60–2.47) while those who took three or more types was 2.91 (95% CI: 2.20–3.84). Qi-Ju-Di-Huang-Wan (Lycium Berry, Chrysanthemum, and Rehmannia Pill) was the most frequently prescribed formula among Sjögren's patients. Conclusion: Qi-Ju-Di-Huang-Wan is the most commonly prescribed Chinese herbal formula for Sjögren's syndrome and its effects should be taken into account by healthcare providers. & 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Sjögren's syndrome is an incurable autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands that is characterized by hypofunction of the salivary and lacrimal glands (Chisholm and Mason, 1968; Coll et al., 1992; Fox, 2005; Ramos-Casals et al., 2012). Sjögren's syndrome is more frequent among women and its diagnosis involves three n Correspondence to: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong Road, Taipei 112, Taiwan. Tel.: þ 886 2 28223464; fax: þ886 2 28225044. E-mail address: [email protected] (J.-N. Lai).
areas of specialty: rheumatology, ophthalmology and oral medicine, which in each case can be classified as either primary or secondary disease, with the latter imposing more substantial individual and socioeconomic burdens (Shiboski, 2012). Although several studies have suggested that various symptomatic pharmacotherapies are effective ways of relieving discomfort and improving the sufferers' quality of life (al-Hashimi and Taylor, 2001; Iannuccelli et al., 2012; González et al., 2013; Mumcu et al., 2013), the long-term treatment for this incurable and complex illness is often difficult and less than optimal (Frost-Larsen et al., 1978; Ramos-Casals et al., 2010). Not surprisingly, complementary and alternative therapies have become increasingly popular as a treatment to relieve symptoms among Sjögren's patients.
http://dx.doi.org/10.1016/j.jep.2014.05.049 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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TCM, which includes acupuncture, traumatology, manipulative therapies and Chinese herbal products, has been an important part of health care in Taiwan for hundreds of years and is fully reimbursed under the current National Health Insurance (NHI) system. Previous studies using the NHI research database have reported that Chinese herbal remedies are the most common TCM modality used among the general population; this is followed by acupuncture, then traumatology and manipulative therapies. The unique approach of TCM used for diagnosis involves gathering clinical symptoms and signs and then a treatment principle is put forward in accordance with the aforementioned diagnostic process. In this situation, researchers in Taiwan have found that symptoms, signs and ill-defined conditions are the most common reasons for TCM visits across various different patient populations (Hsieh et al., 2008; Yang et al., 2009; Fang et al., 2012; Lai et al., 2012; Huang et al., 2013). Accordingly, the claims database, part of the Taiwan National Health Insurance Research Database, is able to provide a platform for understanding the utilization of TCM therapies by licensed TCM doctors (Hsieh et al., 2008). The aim of our study was to analyze a random sample from this comprehensive database and to determine the TCM utilization patterns of newly diagnosed Sjögren's patients in Taiwan. The results of this study should provide valuable information that will enable physicians to respond to patient use of TCM in an informed way. This will, in turn, strengthen further the patient-physician relationship when treating Sjögren's syndrome.
2. Materials and methods 2.1. Data resources This study was designed as a population-based study analyzing a sample of one million subjects from the 22 million beneficiaries of the National Health Insurance scheme of Taiwan. It was aimed at determining the prevalence of use of prescribed Chinese herbal products among Sjögren's patients between January 1, 1997, and December 31, 2008. All data were obtained from the National Health Insurance Research Database (NHIRD), which includes all of the reimbursement data of the NHI with the identification numbers of all individuals encrypted and transformed. This database is maintained by the National Health Research Institutes of Taiwan (Institutes. NHR. National Health Insurance Research database). The NHIRD database contained patient sex, date of birth, all records of clinical visits and hospitalizations, drugs prescribed and their dosages (including Chinese herbal products (CHPs) and three major diagnosis codes as included in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)). 2.2. Study subjects The selection of study subjects from the random sample of one million individuals was performed as follows (Fig. 1). All the registration and claim data of these 1,000,000 individuals were randomly selected by the National Health Research Institutes. There was no significant difference in the distribution of gender, age, and average insurance amount between the patients in the sample population and the original NHIRD (National Health Research Institute, Longitudinal Health Insurance Database). First, we excluded all beneficiaries without Sjögren's syndrome (n ¼ 989,822) or those without a catastrophic illness card (n ¼1206) to confirm the diagnosis of Sjögren's syndrome. Second, the prevalent cases of Sjögren's syndrome (n ¼663) that had been diagnosed before the end of 1996 and those without complete NHI reimbursement data (n ¼ 62) were also excluded to make sure that
all the subjects included were newly diagnosed with Sjögren's syndrome. Finally, 8247 study subjects were included in the study cohort. 2.3. Study variables To determine the key independent variables for utilization of TCM among Sjögren's patients, we selected a series of demographic factors including age, gender, insured salaries, and insured region based on previous studies (Coll et al., 1992; Fox, 2005; Fang et al., 2012; Huang et al., 2013). The subjects were categorized into seven groups according to age: r20, 21–30, 31–40, 41–50, 51–60, 61–70, Z71 years. Taiwan was divided into seven geographic regions: Taipei city, Kaohsiung city, Northern region, Central region, Southern region, Eastern region and Outlying islands. We sorted insured amount to four groups: new Taiwan dollars (NT$) 0, 1–19,999, 20,000-39,999, and Z40,000. We also searched the NHIRD database for clinical features and treatment records related to Sjögren's syndrome as independent variables. Sjögren's syndrome was classified as primary or secondary according to its existence as a disorder in its own right (primary Sjögren's syndrome) or the development years after the onset of an associated rheumatic disorder, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, primary biliary cirrhosis, polyarteritis nodosa and allied conditions such as multiple sclerosis, Graves' disease, Hashimoto's thyroiditis, and ankylosing spondylitis. The reimbursement database contains all details related to the prescription of conventional medicines for treating Sjögren's syndrome. Then, for the final analysis, we categorized the types of preparations into the following categories: artificial tears, prednisolone, hydroxychloroquine, azathioprine, cyclophosphamide, methotrexate, and pilocarpine. 2.4. Traditional Chinese medicine NHIRD recorded three TCM treatments including CHPs, acupuncture, and manipulative therapies. CHPs included several herbs that are most widely accepted by patients in Taiwan. According to Taiwan's laws, to ensure manufacturing quality, all CHPs must comply with good manufacturing practice (GMP) standards and can only be prescribed by licensed TCM doctors (Hsieh et al., 2008; Institutes. NHR. National Health Insurance Research Database). We downloaded all details of reimbursed CHPs, including the proportion of each single herbal, the date and period of drug approval, and the name of the manufacturer from the Department of Chinese Medicine and Pharmacy website, which is the competent authority of Chinese medicine in Taiwan. Because of strict production quality control, there were only minor differences between each type of CHP. We classified CHPs with the same components in the same category, regardless of slight variations between pharmaceutical manufacturing companies (Department of Chinese Medicine and Pharmacy, guideline of Drug administration and inspection).
3. Statistical analysis Data analysis consisted of descriptive statistics, including the prescription rates of the CHP users stratified by patient's demographic characteristics, indications for the prescription of the CHP, and the most frequently prescribed herbal formulae for treating Sjögren's syndrome. Primary indications were classified according to their ICD-9 code. The diagnoses were coded according to the ICD-9 and grouped into a series of distinct broad disease categories. Multiple logistic regression was conducted to evaluate the factors that correlated with CHP use. A significance level of α ¼0.05 was selected. The statistical software SAS 9.13 was used for data management and analysis.
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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One million random sample of NHIRD N = 1,000,000
Exclusion of cases without Sjögren's syndrome, N = 989,822
All Sjögren's patients N = 10,178
Exclusion of cases without catastrophic illness card, N = 1,206
All Sjögren's patients with catastrophic Illness card, N = 8,972 Exclusion of prevalent cases of Sjögren's syndromes before the end of 1996, N = 663 Newly diagnosed Sjögren's patients, N = 8,309 Exclusion of cases with missing data, N = 62 Newly diagnosed Sjögren's patients, N = 8,247
TCM users,
TCM non-users, N =
N = 7,524
723
Fig. 1. Flowchart of recruitment of subjects from the 1-million random sample of the National Health Insurance Research Database (NHIRD) from 1997 to 2008 in Taiwan.
4. Results From 1997 to 2008, the database claims identified 8247 newly diagnosed Sjögren's patients with a catastrophic illness card which was issued to patients who had a severe disease that required strict medical attention by a specialist. Prevalence of primary and secondary Sjögren's syndrome was 0.6% and 0.2%, respectively. 7524 (91.2% ) Sjögren's patients received TCM out-patient services at least once during the study period. Among all Sjögren's patients, 1074 (13%) did not use any conventional medication for treating Sjögren's syndrome even though they experienced suffering from this chronic, incurable, progressive inflammatory disease, the diagnosis of which was confirmed by the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan.
Details on the demographic distribution of TCM users and nonusers are provided in Table 1. The mean age of non-users was slightly higher than that of TCM users. There were more non-users than TCM users who were diagnosed with primary Sjögren's syndrome or who were residing in Taipei city and Northern Taiwan. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) obtained by multiple logistic regression are shown in Table 1. Compared with the age group ≦20 years (aOR ¼1.00), those aged 61 years and above were more likely to be TCM non-users. Compared with the patients with no income level (aOR ¼1.00), patients with a high income level were more likely to be TCM users. After adjusting for other factors, patients with secondary Sjögren's syndrome were more likely to seek TCM treatment than
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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Table 1 Demographic characteristics and results of multiple logistic regression showing the adjusted odds ratio (aOR) and 95% CI (confidence interval) of patients with primary Sjögren's syndrome (SS) from 1997 to 2008 in Taiwan. aORb (95% CIc)
Characteristics
TCM user (%)
TCMa nonuser (%)
No. of cases Age at diagnosis (years) Mean 7 SD ≦20 21–30 31–40 41–50 51–60 61–70 ≧71
7524
723
–
40.2 7 16.8 982(13.1) 1122(14.9) 1553(20.6) 1637(21.8) 1117(14.8) 839(11.2) 274(3.6)
43.8 7 19.2 88(12.2) 90(12.5) 120(16.6) 134(18.5) 104(14.4) 124(17.2) 63(8.7)
– 1 0.99(0.70–1.39) 1.08(0.81–1.44) 1.03(0.78–1.37) 0.90(0.67–1.21) 0.64(0.48–0.86) 0.45(0.32–0.65)
Sex Female Male
5747(76.4) 1777(23.6)
433(59.9) 290(40.1)
1 0.48(0.41–0.57)
Insured salaries (NT$/month) 0d 1–19,999 20,000–39,999 ≧40,000
2106(28.0) 2317(30.8) 2155(28.6) 946(12.6)
218(30.2) 194(26.8) 211(29.2) 100(13.8)
1 1.37(1.09–1.73) 1.13(0.89–1.43) 1.12(0.83–1.5)
Insured region Taipei City Kaohsiung City Northern Taiwan Central Taiwan Southern Taiwan East Taiwan Out Island
1818(24.2) 211(2.8) 1654(22.0) 2236(29.7) 1325(17.6) 234(3.1) 46(0.6)
210(29.1) 16(2.2) 207(28.6) 100(13.8) 164(22.7) 16(2.2) 10(1.4)
1 1.58(0.93–2.70) 0.95(0.77–1.17) 2.64(2.06–3.38) 1.00(0.80–1.24) 1.69(0.99–2.87) 0.59(0.29–1.20)
Number of another systemic autoimmune disease Primary Sjögren's syndrome 0 Secondary Sjögren's syndrome 1 Rheumatoid arthritis Systemic lupus erythematosus Systemic sclerosis Polymyositis Primary biliary cirrhosis Polyarteritis nodosa and allied conditions Multiple sclerosis Graves' disease Hashimoto's thyroiditis Ankylosing spondylitis 2 ≧3
5498(73.1)
593(82.0)
1
1530(20.3) 787 205 11 41 7 32 10 138 35 264 423(5.6) 73(1.0)
106(14.7) 50 12 0 2 1 2 0 11 3 25 23(3.2) 1(0.1)
1.56(1.26–1.93)
Number of medication for SS 0 1
921(12.2%) 2417(32.1%)
153(21.2%) 259(35.8%) 140 112 6 0 0 0 1 226(31.3%) 85(11.8%)
1 1.55(1.25–1.92)
Artificial tears Prednisolone Hydroxychloroquine Azathioprine Cyclophosphamide Methotrexate Pilocarpine 2 ≧3
1338 997 66 1 5 2 8 2699(35.9%) 1487(19.8%)
1.98(1.29–3.04) 7.86(1.09–56.58)
1.98(1.60–2.47) 2.91(2.20–3.84)
Primary Sjögren's syndrome occurs in people with no other rheumatologic disease. Secondary Sjögren's occurs in people who have another rheumatologic disease. d
30 NT$ convert 1 US dollars.
those with primary Sjögren's syndrome. The aOR for those suffering from at least one rheumatologic disease was 1.56 (95% CI: 1.26–1.93), those with two rheumatologic diseases was 1.98 (95% CI: 1.29–3.04), while those with three or more rheumatologic diseases was 7.86 (95% CI: 1.09–56.58). Compared to Sjögren's patients who used no medical treatment, Sjögren's patients who took conventional medications for relieving their Sjögren's syndrome were more likely to be TCM users. The aOR for those who took one type of conventional medication was 1.55 (95%
CI: 1.25–1.92), those who took two types was 1.98 (95% CI: 1.60– 2.47) while those who took three or more types was 2.91 (95% CI: 2.20–3.84). Of the Sjögren's patients visiting TCM doctors, 199,409(74.83%) of the persons were treated with the prescription of Chinese herbal remedies, while the rest were prescribed acupuncture and traumatology manipulative therapies. Analyses of the major disease categories for all TCM visits are summarized in Table 2, which show that “symptoms, signs, and ill-defined conditions”
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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Table 2 Frequency distribution of traditional Chinese medicine (TCM) visits by major disease categories (according to 9th ICD codes) in patient with Sjögren's syndrome from 1997 to 2008 in Taiwan. Major disease category
ICD-9-CM codes
Infectious and parasitic diseases Neoplasms Endocrine, nutritional and metabolic diseases, and immunity disorders Diseases of the nervous system and sense organs and Mental disorders Diseases of the circulatory system Diseases of the respiratory system Diseases of the digestive system Diseases of the genitourinary system Diseases of the skin and subcutaneous tissue Diseases of the musculoskeletal system and connective tissue Symptoms, signs, and ill-defined conditions Injury and poisoning Supplementary classificationa Othersb
No. of visits N (%) Chinese herbal remedies
Acupuncture and manipulative therapies
Total of TCM
001–139 140–239 240–289
1049(0.39) 1258(0.47) 4190(1.57)
8(0.003) 28(0.01) 111(0.04)
1057(0.40) 1286(0.48) 4301(1.61)
290–389
11,254(4.22)
1340(0.50)
12,594(4.73)
390–459 460–519 520–579 580–629 680–709 710–739 780–799 800–999 V01–V82, E800–E999
5426(2.04) 43,734(16.41) 31,511(11.83) 21,993(8.25) 7629(2.86) 21,081(7.91) 46,712(17.53) 1541(0.58) 35(0.01) 3572(1.34)
336(0.13) 438(0.16) 313(0.12) 331(0.12) 101(0.04) 26,638(10.00) 951(0.36) 31,309(11.75) 12(0.00) 5142(1.93)
5762(2.16) 44,172(16.58) 31,824(11.94) 22,324(8.38) 7730(2.90) 46,143(17.32) 47,663(17.89) 32,850(12.33) 47(0.02) 8714(3.27)
199,409(74.83)
67,058(25.17)
266,467(100.00)
Total a b
Supplementary classification of factors influencing health status and contact with health service, external causes of injury and poisoning Others include ICD-9-CM codes, 630-677, 740-759, 760-779 and missing/error data.
Table 3 Top 10 herbal formulas prescribed by TCM doctors for treating patient with Sjögren's syndrome from 1997 to 2008 in Taiwan. Herbal Formulae
English name
Frequency of prescriptions
Average duration for prescriptions (day)
Average daily dose (g)
Qi-Ju-Di-Huang-Wan Gan-Lu-Yin Jia-Wei-Xiao-Yao-San Zhi-Gan-Cao-Tang Ma-Zi-Ren-Wan Zhi-Bai-Di-Huang-Wan Shen-Tong-Zhu-Yu-Tang Tian-Wang-Bu-Xin-Dan Sang-Ju-Yin Mai-Men-Don-Tang
Lycium Berry, Chrysanthemum, and Rehmannia Pill Sweet Dew Beverage Supplemented Free Wanderer Powder Honey-Fried Licorice Decoction Cannabis Fruit Pill Anemarrhena, Phellodendron, and Rehmannia Pill Generalized Pain Stasis-Expelling Decoction Celestial Emperor Heart-Supplementing Elixir Mulberry Leaf and Chrysanthemum Beverage Ophiopogon Decoction
285 282 159 68 84 93 29 65 45 31
50.2 47.1 51.3 81.2 61.3 28.3 162.3 41.0 50.6 12.3
16.2 38.4 5.9 5.6 3.6 7.1 3.0 5.3 8.8 4.4
was the most common reason for using a CHP, followed by “diseases of the respiratory system”, and “diseases of the digestive system”. Details of the most frequently prescribed CHP by TCM doctors are provided in Table 3, which demonstrates that Qi-Ju-DiHuang-Wan (Lycium Berry, Chrysanthemum, and Rehmannia Pill) was the most frequently prescribed CHP, followed by Gan-Lu-Yin (Sweet Dew Beverage), and Jia-Wei-Xiao-Yao-San (Supplemented Free Wanderer Powder). The potential effects of the top 10 most commonly prescribed Chinese herbal formulae in Sjögren's patients are summarized in Table 4.
5. Discussion To the best of our knowledge, this study is the first of its kind to use a nationwide sample to document the utilization characteristics of traditional Chinese medicine in Sjögren's patients who have sought to obtain help via TCM therapies. The prevalence of Sjögren's syndrome in Taiwan over the 11 years in the study was 0.8%, which appears to be high compared with the estimates given by previous surveys (Alamanos et al., 2006; Haugen et al., 2008). All of the patients with Sjögren's syndrome were included in the study, and the diagnosis was verified by the NHI catastrophic
illnesses registry during 1997–2008. Because all patients who are confirmed to have a catastrophic illness are exempt from all copayments, the presence of Sjögren's syndrome must be diagnosed by the attending physician and be formally reviewed by a committee to qualify for the registry and therefore we can rule out the possibility of recall bias. The present study includes all patients who were newly diagnosed with Sjögren's syndrome from a nationwide sample of one million subjects among the insured general population. Importantly, the rate of insured individuals has been consistently above 96% since 1997 and therefore we can rule out the possibility of selection bias. The present study found that Sjögren's syndrome occurs predominately in women in Taiwan, with the female to male ratio about 3:1 and the mean age at physician-diagnosed Sjögren's syndrome was 40.5 years. The difference in results between the present study and previously reported studies (Jacobsson et al., 1989; Tomsic et al., 1999) is probably due to disparities in the scale of the survey and the definitions of Sjögren's syndrome between patients and qualified conventional physicians. Previous studies collected information on Sjögren's syndrome via self-reported questionnaires, which represent the patients' own perceptions and expectations from any healing practice that does not fall within the realm of conventional medicine. In Taiwan, physicians
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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Table 4 Ingredients of the herbs contained in the 10 most common herbal formulae prescribed for treating patient with Sjögren's syndrome. Herbal Formulae
Number of herbs
Qi-Ju-Di-HuangWan Gan-Lu-Yin
8 10
Jia-Wei-Xiao-Yao- 10 San Zhi-Gan-Cao-Tang 9
Ma-Zi-Ren-Wan
6
Zhi-Bai-DiHuang-Wan Shen-Tong-ZhuYu-Tang
8 12
Tian-Wang-BuXin-Dan
13
Sang-Ju-Yin
8
Mai-Men-DonTang
6
Contain drug Moutan Cortex (Mu-Dan-Pi), Alismatis Rhizoma (Ze-Xie), Dioscoreae RhizomaA (Shan-Yao), PoriaAC (Fu-Ling), Rehmanniae Radix PraeparataAC (Shu-Di-Huang), Corni Fructus (Shan-Zhu-Yu), Lycii FructusA (Gou-Qi-Zi), Chrysanthemi FlosAC (Ju-Hua) Rehmanniae Radix PraeparataAC (Shu-Di-Huang), Rehmanniae Radix (Sheng-Di-Huang), Artemisiae Scopariae Herba (Yin-Chen), Scutellariae Radix (Huang-Qin), Aurantii Fructus (Zhi-Ke), Eriobotryae Folium (Pi-Pa-Ye), Dendrobii HerbaAE (Shi-Hu), Glycyrrhizae RadixC (Gan-Cao), Asparagi Radix (Tian-Men-Dong), Ophiopogonis RadixD (Mai-Men-Dong) Angelicae Sinensis RadixAC (Dang-Gui), Paeoniae Radix AlbaBC (Bai-Shao), Bupleuri Radix (Chai-Hu), PoriaAC (Fu-Ling), Atractylodis Macrocephalae Rhizoma (Bai-Zhu), Glycyrrhizae RadixC (Gan-Cao), Zingiberis Rhizoma Tostum (Wei-Jiang), Menthae Herba (Bo-He), Gardeniae Fructus (Zhi-Zi), Moutan Cortex (Mu-Dan-Pi) Rehmanniae RadixAC (Sheng-Di-Huang), Ophiopogonis RadixD (Mai-Men-Dong), Glycyrrhizae Radix cum Liquido FrictaC (Zhi-GanCao), Ginseng RadixA (Ren-Shen), Cinnamomi Ramulus (Gui-Zhi), Zingiberis Rhizoma Recens (Sheng-Jiang), Asini Corii Colla (A-Jiao), Jujubae Fructus (Da-Zao), Cannabis Fructus (Ma-Zi-Ren) Cannabis Fructus (Ma-Zi-Ren), Paeoniae Radix Alba (Bai-Shao), Aurantii Fructus Immaturus (Zhi-Shi), Rhei Radix et Rhizoma (DaHuang), Magnoliae Officinalis Cortex (Hou-Po), Armeniacae Semen (Xing-Ren) Moutan Cortex (Mu-Dan-Pi), Alismatis Rhizoma (Ze-Xie), Dioscoreae RhizomaA (Shan-Yao), Poria (Fu-Ling), Rehmanniae Radix PraeparataAC (Shu-Di-Huang), Corni Fructus (Shan-Zhu-Yu), Anemarrhenae Rhizoma (Zhi-Mu), Phellodendri Cortex (Huang-Bo) Angelicae Sinensis RadixAC (Dang-Gui), Persicae Semen (Tao-Ren), Carthami Flos (Hong-Hua), Achyranthis Bidentatae Radix (Niu-Xi), Chuanxiong Rhizoma (Chuan-Xiong), Pheretima (Di-Long), Myrrha (Mo-Yao), Trogopteri Faeces (Wu-Ling-Zhi), Gentianae Macrophyllae Radix (Qin-Jiao), Notopterygii Rhizoma et Radix (Qiang-Huo), Cyperi Rhizoma (Xiang-Fu), Glycyrrhizae RadixC (GanCao) Rehmanniae RadixAC (Sheng-Di-Huang), Angelicae Sinensis RadixAC (Dang-Gui), Ziziphi Spinosi Semen (Suan-Zao-Ren), Ophiopogonis RadixD (Mai-Men-Dong), Asparagi Radix (Tian-Men-Dong), Platycladi Semen (Bai-Zi-Ren), Schisandrae Fructus (Wu-Wei-Zi), PoriaAC (Fu-Ling), Platycodonis Radix (Jie-Geng), Polygalae Radix (Yuan-Zhi), Ginseng RadixA (Ren-Shen), Salviae Miltiorrhizae Radix (DanShen), Scrophulariae Radix (Xuan-Shen) Mori Folium (Sang-Ye), Chrysanthemi FlosAC (Ju-Hua), Forsythiae Fructus (Lian-Qiao), Menthae Herba (Bo-He), Armeniacae Semen (Xing-Ren), Platycodonis Radix (Jie-Geng), Glycyrrhizae RadixC (Gan-Cao), Phragmitis Rhizoma (Wei-Gen) Ophiopogonis RadixD (Mai-Men-Dong), Pinelliae Rhizoma (Ban-Xia), Ginseng RadixA (Ren-Shen), Oryzae Semen (Jing-Mi), Glycyrrhizae RadixC (Gan-Cao), Jujubae Fructus (Da-Zao)
A
Modulation of cytokines expression. Down regulate the antibodies productions. Anti-inflammatory effects. D Prevent epithelial injury. E Increase body fluid production. B C
who are involved in the treatment of Sjögren's syndrome must prescribe according to the requirements of the NHI and code accurately the diagnosis when claiming reimbursement from the NHI bureau. The present study provides information on cases in a nationwide health survey (96% of the population) rather than results from previous small-scale community surveys which may have seriously under-reported the number of cases with Sjögren's syndrome (Alamanos et al., 2006; Haugen et al., 2008). It is worth noting that the utilization of TCM among patients with Sjögren's syndrome in Taiwan during the study period was 91.2%. TCM is a unique traditional therapy approach for various ailments that has been used in Taiwan for over hundreds of years and this long period of use may have contributed significantly to the high prevalence of TCM usage among Sjögren's patients. Among all TCM users, nearly 88% of them continued receiving conventional treatment for relieving their Sjögren's syndrome. Hence, we suggest that when TCM is used to treat Sjögren's syndrome in Taiwan, this is generally an adjunct to the treatment of Sjögren's syndrome rather than a replacement for it. The present study describes only the utilization of TCM, which involves therapies that are also becoming popular in many other counties. Although the present findings cannot be generalized to a comprehensive analysis of the usage of various types of complementary and alternative medicine, the present study used a nationwide sample that reveals the prevalence in use of a TCM for the treatment of Sjögren's syndrome as prescribed by licensed TCM doctors. The present findings show that, among Sjögren's patients, females and those aged 21–30 years were more likely to be TCM users than males and other age groups as shown in Table 1. Possibly, because the pathogenesis of Sjögren's syndrome is not well understood, uncertainties about the progression of the disease, together with the high co-occurrence rate of other types of autoimmune diseases is perhaps a motivation for young adult
women to use a TCM in Taiwan. The present findings corroborate the results of the earlier studies (Hsieh et al., 2008; Yang et al., 2009; Fang et al., 2012; Lai et al., 2012; Huang et al., 2013), which demonstrated that Sjögren's patients who were living in central Taiwan (statistical significance) are more likely to be a TCM users. The main reason is there are more TCM physicians and institutes per person in central Taiwan than in other regions (Lin, 2008) resulting in a higher rate of TCM use. Qi-Ju-Di-Huang-Wan, which is one of the derivatives of Liu-WeiDi-Huang-Wan, was the most frequently prescribed formula for Sjögren's patients in Taiwan, as is shown in Table 3. Liu-Wei-DiHuang-Wan is said to nourish yin and to invigorate the kidney which was first documented in the classical Chinese text Xiao Er Yao Zheng Zhi Jue (Key to Therapeutics of Children's Diseases) ca. 1119 A.D. Its effect in relieving dryness, burning, and a sandy-gritty eye irritation that gets worse on windy days were improved after adding Gou-Qi-Zi (Lycii Fructus) and Ju-Hua (Chrysanthemi Flos). Previous studies have revealed that some Chinese herbs have immunomodulatory properties that act via increase in the levels of interleukin-2 and immunoglobulin G (Zhu et al., 2007) or alternating the dynamic regulation of cytokines (Yu and Tseng, 1996; Choi et al., 2004; Spelman et al., 2006; Liu et al., 2009). These modes of action are a reasonable explanation for the higher frequency of prescription of formulae containing these Chinese herbs in the present study (Roescher et al., 2010). However, no matter how popular the use of Qi-Ju-Di-Huang-Wan is in the markets of China, Japan, South Korea, and Taiwan, which are countries having a similar history of traditional Chinese medicine (TCM), no randomised controlled trial has been conducted yet. We therefore are unable to draw any conclusion about the effectiveness of Qi-Ju-Di-Huang-Wan in relieving the dry eye syndrome for lack of actual clinical data. The remaining most
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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frequently prescribed formulas (Gan-Lu-Yin or Sweet Dew Beverage and Jia-Wei-Xiao-Yao-San or Augmented Rambling Powder) are associated with eye irritation, dry eyes and mouth (Lin et al., 2011; Xiao et al., 2011). It is apparent from this study that TCM doctors in Taiwan prescribed herbal therapies that reduce Sjögren's syndrome based on gathering the clinical symptoms and signs via the four diagnostic methods (inspection; listening and smelling; inquiry; pulse-feeling and palpation) and then differentiate the pattern of the Sjögren's syndrome in order to reach a specific type of zheng (a pathological summary of the body's health condition at a certain stage in the disease process). After the aforementioned diagnostic process, treatment formulae are prescribed in accordance with the different stages of Sjögren's syndrome. The major drawback of this syndrome-differentiation when treating dry eye or dry mouth is the lack of consideration of the etiology and risk factors of Sjögren's syndrome. Without taking aforementioned potential confounders into consideration, a TCM doctor will prescribe the same herbal formula to either Sjögren's patients or patients with chronic conjunctivitis who present with similar symptoms. These individuals might have symptoms that are caused by different pathogens and this might lead to TCM therapies having unpredictable effects (Zheng et al., 2011; Luo et al., 2012). Further studies are warranted to assess the formulae found to be generally used by TCM practitioners in this study and to determine whether they form a potential complementary for Sjögren's patients who have long-term morbidities even under regular standard conventional treatment (Murphy et al., 2013). A major limitation of our study is that it is a retrospective observational study and that it lacks a randomized placebo control group. Thus great caution is necessary when interpreting the results with respect to the most commonly prescribed Chinese formula used as there is a high likelihood of a placebo effect of some sort. Furthermore, this study does not include Chinese herbal remedies purchased directly from TCM herbal pharmacies nor have we included health foods containing herbs. Thus, the frequency of CHP utilization might have been underestimated. However, because the NHI system has a comprehensive coverage for TCM prescriptions, which is generally less costly than the cost of herbs sold in Taiwan's markets, the likelihood is that subjects have not purchased large quantities of other herbs outside the NHI database.
6. Conclusions It is apparent that our findings may have implications for physicians treating Sjögren's patients. Our results suggest that, under the co-existence of the conventional medical treatments and TCM, most Sjögren's patients consumed herbal therapies with the intention of relieving a wide variety of symptoms caused by this incurable autoimmune disorder. Qi-Ju-Di-Huang-Wan is the most frequent prescribed formula by TCM doctors in Taiwan for Sjögren's patients. However, the results from the current study could have been confounded by the placebo effect. This possibility emphasizes the need for well conducted, double-blind, randomized; placebo-controlled studies that can be used to further evaluate the efficacy of TCM formulas on the different patterns of Sjögren's syndrome.
Acknowledgments This research was conducted at the Institute of Traditional Medicine at the School of Medicine, National Yang-Ming University, Taipei. The authors would like to express sincere gratitude for the partial support provided for this project in the form of grants from the Department of Health, Taipei City Government (38), the Committee on Chinese Medicine and Pharmacy (CCMP100-RD-
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033) and the National Science Council Taiwan (NSC 99-2320-B010–011-MY2).
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The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study Min-Chien Yu a,b, Shun-Ku Lin b,d, Jung-Nien Lai b,c,n, James Cheng-Chung Wei e,f, Chieh-Yuan Cheng g a School of Medicine, Chung Shan Medical University, Department of Integrated Chinese and Western Medicine, Chung Shan Medical University Hospital, Taichung City, Taiwan b Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei City 112, Taiwan c Department of Chinese Medicine, Taipei City Hospital, Yangming Branch, Taipei City 111, Taiwan d Department of Chinese Medicine, Taipei City Hospital, Ren-Ai Chinese Medicine Branch, Taipei, Taipei City 106, Taiwan e Institute of Medicine, Chung Shan Medical University, Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chung Shan Medical University Hospital, Taiwan f Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan g Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, Taiwan
art ic l e i nf o Article history: Received 11 February 2014 Received in revised form 9 May 2014 Accepted 23 May 2014 Keywords: Sjögren's syndrome Chinese herbal product Qi-Ju-Di-Huang-Wan Prescription patterns National Health Insurance Research Database
a b s t r a c t Q2 Ethnopharmacological relevance: Traditional Chinese medicines (TCM), when given for symptom relief, have gained widespread popularity among Sjögren's patients. The aim of this study was to analyze the Q3 utilization of TCM among Sjögren's patients in Taiwan. Q4 Materials and methods: The usage, frequency of service, and the Chinese herbal products prescribed among Sjögren's patients were evaluated in a cohort of 1,000,000 beneficiaries recruited from the National Health Insurance Research Database. The logistic regression method was employed to estimate the odds ratios (ORs) for utilization of a TCM. Results: More than 90% of Sjögren's patients received TCM out-patient services at least once during the study period. Patients with secondary Sjögren's syndrome were more likely to seek TCM treatment than those with primary Sjögren's syndrome. The aOR for those suffering from at least one rheumatologic disease was 1.56 (95% CI: 1.26–1.93), those with two rheumatologic diseases was 1.98 (95% CI: 1.29–3.04), while those with three or more rheumatologic diseases was 7.86 (95% CI: 1.09–56.58). Compared to Sjögren's patients who used no medical treatment, the aOR for those who took one type of conventional medication was 1.55 (95% CI: 1.25–1.92), those who took two types was 1.98 (95% CI: 1.60–2.47) while those who took three or more types was 2.91 (95% CI: 2.20–3.84). Qi-Ju-Di-Huang-Wan (Lycium Berry, Chrysanthemum, and Rehmannia Pill) was the most frequently prescribed formula among Sjögren's patients. Conclusion: Qi-Ju-Di-Huang-Wan is the most commonly prescribed Chinese herbal formula for Sjögren's syndrome and its effects should be taken into account by healthcare providers. & 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Sjögren's syndrome is an incurable autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands that is characterized by hypofunction of the salivary and lacrimal glands (Chisholm and Mason, 1968; Coll et al., 1992; Fox, 2005; Ramos-Casals et al., 2012). Sjögren's syndrome is more frequent among women and its diagnosis involves three n Correspondence to: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong Road, Taipei 112, Taiwan. Tel.: þ 886 2 28223464; fax: þ886 2 28225044. E-mail address: [email protected] (J.-N. Lai).
areas of specialty: rheumatology, ophthalmology and oral medicine, which in each case can be classified as either primary or secondary disease, with the latter imposing more substantial individual and socioeconomic burdens (Shiboski, 2012). Although several studies have suggested that various symptomatic pharmacotherapies are effective ways of relieving discomfort and improving the sufferers' quality of life (al-Hashimi and Taylor, 2001; Iannuccelli et al., 2012; González et al., 2013; Mumcu et al., 2013), the long-term treatment for this incurable and complex illness is often difficult and less than optimal (Frost-Larsen et al., 1978; Ramos-Casals et al., 2010). Not surprisingly, complementary and alternative therapies have become increasingly popular as a treatment to relieve symptoms among Sjögren's patients.
http://dx.doi.org/10.1016/j.jep.2014.05.049 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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TCM, which includes acupuncture, traumatology, manipulative therapies and Chinese herbal products, has been an important part of health care in Taiwan for hundreds of years and is fully reimbursed under the current National Health Insurance (NHI) system. Previous studies using the NHI research database have reported that Chinese herbal remedies are the most common TCM modality used among the general population; this is followed by acupuncture, then traumatology and manipulative therapies. The unique approach of TCM used for diagnosis involves gathering clinical symptoms and signs and then a treatment principle is put forward in accordance with the aforementioned diagnostic process. In this situation, researchers in Taiwan have found that symptoms, signs and ill-defined conditions are the most common reasons for TCM visits across various different patient populations (Hsieh et al., 2008; Yang et al., 2009; Fang et al., 2012; Lai et al., 2012; Huang et al., 2013). Accordingly, the claims database, part of the Taiwan National Health Insurance Research Database, is able to provide a platform for understanding the utilization of TCM therapies by licensed TCM doctors (Hsieh et al., 2008). The aim of our study was to analyze a random sample from this comprehensive database and to determine the TCM utilization patterns of newly diagnosed Sjögren's patients in Taiwan. The results of this study should provide valuable information that will enable physicians to respond to patient use of TCM in an informed way. This will, in turn, strengthen further the patient-physician relationship when treating Sjögren's syndrome.
2. Materials and methods 2.1. Data resources This study was designed as a population-based study analyzing a sample of one million subjects from the 22 million beneficiaries of the National Health Insurance scheme of Taiwan. It was aimed at determining the prevalence of use of prescribed Chinese herbal products among Sjögren's patients between January 1, 1997, and December 31, 2008. All data were obtained from the National Health Insurance Research Database (NHIRD), which includes all of the reimbursement data of the NHI with the identification numbers of all individuals encrypted and transformed. This database is maintained by the National Health Research Institutes of Taiwan (Institutes. NHR. National Health Insurance Research database). The NHIRD database contained patient sex, date of birth, all records of clinical visits and hospitalizations, drugs prescribed and their dosages (including Chinese herbal products (CHPs) and three major diagnosis codes as included in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)). 2.2. Study subjects The selection of study subjects from the random sample of one million individuals was performed as follows (Fig. 1). All the registration and claim data of these 1,000,000 individuals were randomly selected by the National Health Research Institutes. There was no significant difference in the distribution of gender, age, and average insurance amount between the patients in the sample population and the original NHIRD (National Health Research Institute, Longitudinal Health Insurance Database). First, we excluded all beneficiaries without Sjögren's syndrome (n ¼ 989,822) or those without a catastrophic illness card (n ¼1206) to confirm the diagnosis of Sjögren's syndrome. Second, the prevalent cases of Sjögren's syndrome (n ¼663) that had been diagnosed before the end of 1996 and those without complete NHI reimbursement data (n ¼ 62) were also excluded to make sure that
all the subjects included were newly diagnosed with Sjögren's syndrome. Finally, 8247 study subjects were included in the study cohort. 2.3. Study variables To determine the key independent variables for utilization of TCM among Sjögren's patients, we selected a series of demographic factors including age, gender, insured salaries, and insured region based on previous studies (Coll et al., 1992; Fox, 2005; Fang et al., 2012; Huang et al., 2013). The subjects were categorized into seven groups according to age: r20, 21–30, 31–40, 41–50, 51–60, 61–70, Z71 years. Taiwan was divided into seven geographic regions: Taipei city, Kaohsiung city, Northern region, Central region, Southern region, Eastern region and Outlying islands. We sorted insured amount to four groups: new Taiwan dollars (NT$) 0, 1–19,999, 20,000-39,999, and Z40,000. We also searched the NHIRD database for clinical features and treatment records related to Sjögren's syndrome as independent variables. Sjögren's syndrome was classified as primary or secondary according to its existence as a disorder in its own right (primary Sjögren's syndrome) or the development years after the onset of an associated rheumatic disorder, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, primary biliary cirrhosis, polyarteritis nodosa and allied conditions such as multiple sclerosis, Graves' disease, Hashimoto's thyroiditis, and ankylosing spondylitis. The reimbursement database contains all details related to the prescription of conventional medicines for treating Sjögren's syndrome. Then, for the final analysis, we categorized the types of preparations into the following categories: artificial tears, prednisolone, hydroxychloroquine, azathioprine, cyclophosphamide, methotrexate, and pilocarpine. 2.4. Traditional Chinese medicine NHIRD recorded three TCM treatments including CHPs, acupuncture, and manipulative therapies. CHPs included several herbs that are most widely accepted by patients in Taiwan. According to Taiwan's laws, to ensure manufacturing quality, all CHPs must comply with good manufacturing practice (GMP) standards and can only be prescribed by licensed TCM doctors (Hsieh et al., 2008; Institutes. NHR. National Health Insurance Research Database). We downloaded all details of reimbursed CHPs, including the proportion of each single herbal, the date and period of drug approval, and the name of the manufacturer from the Department of Chinese Medicine and Pharmacy website, which is the competent authority of Chinese medicine in Taiwan. Because of strict production quality control, there were only minor differences between each type of CHP. We classified CHPs with the same components in the same category, regardless of slight variations between pharmaceutical manufacturing companies (Department of Chinese Medicine and Pharmacy, guideline of Drug administration and inspection).
3. Statistical analysis Data analysis consisted of descriptive statistics, including the prescription rates of the CHP users stratified by patient's demographic characteristics, indications for the prescription of the CHP, and the most frequently prescribed herbal formulae for treating Sjögren's syndrome. Primary indications were classified according to their ICD-9 code. The diagnoses were coded according to the ICD-9 and grouped into a series of distinct broad disease categories. Multiple logistic regression was conducted to evaluate the factors that correlated with CHP use. A significance level of α ¼0.05 was selected. The statistical software SAS 9.13 was used for data management and analysis.
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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One million random sample of NHIRD N = 1,000,000
Exclusion of cases without Sjögren's syndrome, N = 989,822
All Sjögren's patients N = 10,178
Exclusion of cases without catastrophic illness card, N = 1,206
All Sjögren's patients with catastrophic Illness card, N = 8,972 Exclusion of prevalent cases of Sjögren's syndromes before the end of 1996, N = 663 Newly diagnosed Sjögren's patients, N = 8,309 Exclusion of cases with missing data, N = 62 Newly diagnosed Sjögren's patients, N = 8,247
TCM users,
TCM non-users, N =
N = 7,524
723
Fig. 1. Flowchart of recruitment of subjects from the 1-million random sample of the National Health Insurance Research Database (NHIRD) from 1997 to 2008 in Taiwan.
4. Results From 1997 to 2008, the database claims identified 8247 newly diagnosed Sjögren's patients with a catastrophic illness card which was issued to patients who had a severe disease that required strict medical attention by a specialist. Prevalence of primary and secondary Sjögren's syndrome was 0.6% and 0.2%, respectively. 7524 (91.2% ) Sjögren's patients received TCM out-patient services at least once during the study period. Among all Sjögren's patients, 1074 (13%) did not use any conventional medication for treating Sjögren's syndrome even though they experienced suffering from this chronic, incurable, progressive inflammatory disease, the diagnosis of which was confirmed by the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan.
Details on the demographic distribution of TCM users and nonusers are provided in Table 1. The mean age of non-users was slightly higher than that of TCM users. There were more non-users than TCM users who were diagnosed with primary Sjögren's syndrome or who were residing in Taipei city and Northern Taiwan. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) obtained by multiple logistic regression are shown in Table 1. Compared with the age group ≦20 years (aOR ¼1.00), those aged 61 years and above were more likely to be TCM non-users. Compared with the patients with no income level (aOR ¼1.00), patients with a high income level were more likely to be TCM users. After adjusting for other factors, patients with secondary Sjögren's syndrome were more likely to seek TCM treatment than
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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1 2 3Q11 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66
Table 1 Demographic characteristics and results of multiple logistic regression showing the adjusted odds ratio (aOR) and 95% CI (confidence interval) of patients with primary Sjögren's syndrome (SS) from 1997 to 2008 in Taiwan. aORb (95% CIc)
Characteristics
TCM user (%)
TCMa nonuser (%)
No. of cases Age at diagnosis (years) Mean 7 SD ≦20 21–30 31–40 41–50 51–60 61–70 ≧71
7524
723
–
40.2 7 16.8 982(13.1) 1122(14.9) 1553(20.6) 1637(21.8) 1117(14.8) 839(11.2) 274(3.6)
43.8 7 19.2 88(12.2) 90(12.5) 120(16.6) 134(18.5) 104(14.4) 124(17.2) 63(8.7)
– 1 0.99(0.70–1.39) 1.08(0.81–1.44) 1.03(0.78–1.37) 0.90(0.67–1.21) 0.64(0.48–0.86) 0.45(0.32–0.65)
Sex Female Male
5747(76.4) 1777(23.6)
433(59.9) 290(40.1)
1 0.48(0.41–0.57)
Insured salaries (NT$/month) 0d 1–19,999 20,000–39,999 ≧40,000
2106(28.0) 2317(30.8) 2155(28.6) 946(12.6)
218(30.2) 194(26.8) 211(29.2) 100(13.8)
1 1.37(1.09–1.73) 1.13(0.89–1.43) 1.12(0.83–1.5)
Insured region Taipei City Kaohsiung City Northern Taiwan Central Taiwan Southern Taiwan East Taiwan Out Island
1818(24.2) 211(2.8) 1654(22.0) 2236(29.7) 1325(17.6) 234(3.1) 46(0.6)
210(29.1) 16(2.2) 207(28.6) 100(13.8) 164(22.7) 16(2.2) 10(1.4)
1 1.58(0.93–2.70) 0.95(0.77–1.17) 2.64(2.06–3.38) 1.00(0.80–1.24) 1.69(0.99–2.87) 0.59(0.29–1.20)
Number of another systemic autoimmune disease Primary Sjögren's syndrome 0 Secondary Sjögren's syndrome 1 Rheumatoid arthritis Systemic lupus erythematosus Systemic sclerosis Polymyositis Primary biliary cirrhosis Polyarteritis nodosa and allied conditions Multiple sclerosis Graves' disease Hashimoto's thyroiditis Ankylosing spondylitis 2 ≧3
5498(73.1)
593(82.0)
1
1530(20.3) 787 205 11 41 7 32 10 138 35 264 423(5.6) 73(1.0)
106(14.7) 50 12 0 2 1 2 0 11 3 25 23(3.2) 1(0.1)
1.56(1.26–1.93)
Number of medication for SS 0 1
921(12.2%) 2417(32.1%)
153(21.2%) 259(35.8%) 140 112 6 0 0 0 1 226(31.3%) 85(11.8%)
1 1.55(1.25–1.92)
Artificial tears Prednisolone Hydroxychloroquine Azathioprine Cyclophosphamide Methotrexate Pilocarpine 2 ≧3
1338 997 66 1 5 2 8 2699(35.9%) 1487(19.8%)
1.98(1.29–3.04) 7.86(1.09–56.58)
1.98(1.60–2.47) 2.91(2.20–3.84)
Primary Sjögren's syndrome occurs in people with no other rheumatologic disease. Secondary Sjögren's occurs in people who have another rheumatologic disease. d
30 NT$ convert 1 US dollars.
those with primary Sjögren's syndrome. The aOR for those suffering from at least one rheumatologic disease was 1.56 (95% CI: 1.26–1.93), those with two rheumatologic diseases was 1.98 (95% CI: 1.29–3.04), while those with three or more rheumatologic diseases was 7.86 (95% CI: 1.09–56.58). Compared to Sjögren's patients who used no medical treatment, Sjögren's patients who took conventional medications for relieving their Sjögren's syndrome were more likely to be TCM users. The aOR for those who took one type of conventional medication was 1.55 (95%
CI: 1.25–1.92), those who took two types was 1.98 (95% CI: 1.60– 2.47) while those who took three or more types was 2.91 (95% CI: 2.20–3.84). Of the Sjögren's patients visiting TCM doctors, 199,409(74.83%) of the persons were treated with the prescription of Chinese herbal remedies, while the rest were prescribed acupuncture and traumatology manipulative therapies. Analyses of the major disease categories for all TCM visits are summarized in Table 2, which show that “symptoms, signs, and ill-defined conditions”
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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Table 2 Frequency distribution of traditional Chinese medicine (TCM) visits by major disease categories (according to 9th ICD codes) in patient with Sjögren's syndrome from 1997 to 2008 in Taiwan. Major disease category
ICD-9-CM codes
Infectious and parasitic diseases Neoplasms Endocrine, nutritional and metabolic diseases, and immunity disorders Diseases of the nervous system and sense organs and Mental disorders Diseases of the circulatory system Diseases of the respiratory system Diseases of the digestive system Diseases of the genitourinary system Diseases of the skin and subcutaneous tissue Diseases of the musculoskeletal system and connective tissue Symptoms, signs, and ill-defined conditions Injury and poisoning Supplementary classificationa Othersb
No. of visits N (%) Chinese herbal remedies
Acupuncture and manipulative therapies
Total of TCM
001–139 140–239 240–289
1049(0.39) 1258(0.47) 4190(1.57)
8(0.003) 28(0.01) 111(0.04)
1057(0.40) 1286(0.48) 4301(1.61)
290–389
11,254(4.22)
1340(0.50)
12,594(4.73)
390–459 460–519 520–579 580–629 680–709 710–739 780–799 800–999 V01–V82, E800–E999
5426(2.04) 43,734(16.41) 31,511(11.83) 21,993(8.25) 7629(2.86) 21,081(7.91) 46,712(17.53) 1541(0.58) 35(0.01) 3572(1.34)
336(0.13) 438(0.16) 313(0.12) 331(0.12) 101(0.04) 26,638(10.00) 951(0.36) 31,309(11.75) 12(0.00) 5142(1.93)
5762(2.16) 44,172(16.58) 31,824(11.94) 22,324(8.38) 7730(2.90) 46,143(17.32) 47,663(17.89) 32,850(12.33) 47(0.02) 8714(3.27)
199,409(74.83)
67,058(25.17)
266,467(100.00)
Total a b
Supplementary classification of factors influencing health status and contact with health service, external causes of injury and poisoning Others include ICD-9-CM codes, 630-677, 740-759, 760-779 and missing/error data.
Table 3 Top 10 herbal formulas prescribed by TCM doctors for treating patient with Sjögren's syndrome from 1997 to 2008 in Taiwan. Herbal Formulae
English name
Frequency of prescriptions
Average duration for prescriptions (day)
Average daily dose (g)
Qi-Ju-Di-Huang-Wan Gan-Lu-Yin Jia-Wei-Xiao-Yao-San Zhi-Gan-Cao-Tang Ma-Zi-Ren-Wan Zhi-Bai-Di-Huang-Wan Shen-Tong-Zhu-Yu-Tang Tian-Wang-Bu-Xin-Dan Sang-Ju-Yin Mai-Men-Don-Tang
Lycium Berry, Chrysanthemum, and Rehmannia Pill Sweet Dew Beverage Supplemented Free Wanderer Powder Honey-Fried Licorice Decoction Cannabis Fruit Pill Anemarrhena, Phellodendron, and Rehmannia Pill Generalized Pain Stasis-Expelling Decoction Celestial Emperor Heart-Supplementing Elixir Mulberry Leaf and Chrysanthemum Beverage Ophiopogon Decoction
285 282 159 68 84 93 29 65 45 31
50.2 47.1 51.3 81.2 61.3 28.3 162.3 41.0 50.6 12.3
16.2 38.4 5.9 5.6 3.6 7.1 3.0 5.3 8.8 4.4
was the most common reason for using a CHP, followed by “diseases of the respiratory system”, and “diseases of the digestive system”. Details of the most frequently prescribed CHP by TCM doctors are provided in Table 3, which demonstrates that Qi-Ju-DiHuang-Wan (Lycium Berry, Chrysanthemum, and Rehmannia Pill) was the most frequently prescribed CHP, followed by Gan-Lu-Yin (Sweet Dew Beverage), and Jia-Wei-Xiao-Yao-San (Supplemented Free Wanderer Powder). The potential effects of the top 10 most commonly prescribed Chinese herbal formulae in Sjögren's patients are summarized in Table 4.
5. Discussion To the best of our knowledge, this study is the first of its kind to use a nationwide sample to document the utilization characteristics of traditional Chinese medicine in Sjögren's patients who have sought to obtain help via TCM therapies. The prevalence of Sjögren's syndrome in Taiwan over the 11 years in the study was 0.8%, which appears to be high compared with the estimates given by previous surveys (Alamanos et al., 2006; Haugen et al., 2008). All of the patients with Sjögren's syndrome were included in the study, and the diagnosis was verified by the NHI catastrophic
illnesses registry during 1997–2008. Because all patients who are confirmed to have a catastrophic illness are exempt from all copayments, the presence of Sjögren's syndrome must be diagnosed by the attending physician and be formally reviewed by a committee to qualify for the registry and therefore we can rule out the possibility of recall bias. The present study includes all patients who were newly diagnosed with Sjögren's syndrome from a nationwide sample of one million subjects among the insured general population. Importantly, the rate of insured individuals has been consistently above 96% since 1997 and therefore we can rule out the possibility of selection bias. The present study found that Sjögren's syndrome occurs predominately in women in Taiwan, with the female to male ratio about 3:1 and the mean age at physician-diagnosed Sjögren's syndrome was 40.5 years. The difference in results between the present study and previously reported studies (Jacobsson et al., 1989; Tomsic et al., 1999) is probably due to disparities in the scale of the survey and the definitions of Sjögren's syndrome between patients and qualified conventional physicians. Previous studies collected information on Sjögren's syndrome via self-reported questionnaires, which represent the patients' own perceptions and expectations from any healing practice that does not fall within the realm of conventional medicine. In Taiwan, physicians
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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Table 4 Ingredients of the herbs contained in the 10 most common herbal formulae prescribed for treating patient with Sjögren's syndrome. Herbal Formulae
Number of herbs
Qi-Ju-Di-HuangWan Gan-Lu-Yin
8 10
Jia-Wei-Xiao-Yao- 10 San Zhi-Gan-Cao-Tang 9
Ma-Zi-Ren-Wan
6
Zhi-Bai-DiHuang-Wan Shen-Tong-ZhuYu-Tang
8 12
Tian-Wang-BuXin-Dan
13
Sang-Ju-Yin
8
Mai-Men-DonTang
6
Contain drug Moutan Cortex (Mu-Dan-Pi), Alismatis Rhizoma (Ze-Xie), Dioscoreae RhizomaA (Shan-Yao), PoriaAC (Fu-Ling), Rehmanniae Radix PraeparataAC (Shu-Di-Huang), Corni Fructus (Shan-Zhu-Yu), Lycii FructusA (Gou-Qi-Zi), Chrysanthemi FlosAC (Ju-Hua) Rehmanniae Radix PraeparataAC (Shu-Di-Huang), Rehmanniae Radix (Sheng-Di-Huang), Artemisiae Scopariae Herba (Yin-Chen), Scutellariae Radix (Huang-Qin), Aurantii Fructus (Zhi-Ke), Eriobotryae Folium (Pi-Pa-Ye), Dendrobii HerbaAE (Shi-Hu), Glycyrrhizae RadixC (Gan-Cao), Asparagi Radix (Tian-Men-Dong), Ophiopogonis RadixD (Mai-Men-Dong) Angelicae Sinensis RadixAC (Dang-Gui), Paeoniae Radix AlbaBC (Bai-Shao), Bupleuri Radix (Chai-Hu), PoriaAC (Fu-Ling), Atractylodis Macrocephalae Rhizoma (Bai-Zhu), Glycyrrhizae RadixC (Gan-Cao), Zingiberis Rhizoma Tostum (Wei-Jiang), Menthae Herba (Bo-He), Gardeniae Fructus (Zhi-Zi), Moutan Cortex (Mu-Dan-Pi) Rehmanniae RadixAC (Sheng-Di-Huang), Ophiopogonis RadixD (Mai-Men-Dong), Glycyrrhizae Radix cum Liquido FrictaC (Zhi-GanCao), Ginseng RadixA (Ren-Shen), Cinnamomi Ramulus (Gui-Zhi), Zingiberis Rhizoma Recens (Sheng-Jiang), Asini Corii Colla (A-Jiao), Jujubae Fructus (Da-Zao), Cannabis Fructus (Ma-Zi-Ren) Cannabis Fructus (Ma-Zi-Ren), Paeoniae Radix Alba (Bai-Shao), Aurantii Fructus Immaturus (Zhi-Shi), Rhei Radix et Rhizoma (DaHuang), Magnoliae Officinalis Cortex (Hou-Po), Armeniacae Semen (Xing-Ren) Moutan Cortex (Mu-Dan-Pi), Alismatis Rhizoma (Ze-Xie), Dioscoreae RhizomaA (Shan-Yao), Poria (Fu-Ling), Rehmanniae Radix PraeparataAC (Shu-Di-Huang), Corni Fructus (Shan-Zhu-Yu), Anemarrhenae Rhizoma (Zhi-Mu), Phellodendri Cortex (Huang-Bo) Angelicae Sinensis RadixAC (Dang-Gui), Persicae Semen (Tao-Ren), Carthami Flos (Hong-Hua), Achyranthis Bidentatae Radix (Niu-Xi), Chuanxiong Rhizoma (Chuan-Xiong), Pheretima (Di-Long), Myrrha (Mo-Yao), Trogopteri Faeces (Wu-Ling-Zhi), Gentianae Macrophyllae Radix (Qin-Jiao), Notopterygii Rhizoma et Radix (Qiang-Huo), Cyperi Rhizoma (Xiang-Fu), Glycyrrhizae RadixC (GanCao) Rehmanniae RadixAC (Sheng-Di-Huang), Angelicae Sinensis RadixAC (Dang-Gui), Ziziphi Spinosi Semen (Suan-Zao-Ren), Ophiopogonis RadixD (Mai-Men-Dong), Asparagi Radix (Tian-Men-Dong), Platycladi Semen (Bai-Zi-Ren), Schisandrae Fructus (Wu-Wei-Zi), PoriaAC (Fu-Ling), Platycodonis Radix (Jie-Geng), Polygalae Radix (Yuan-Zhi), Ginseng RadixA (Ren-Shen), Salviae Miltiorrhizae Radix (DanShen), Scrophulariae Radix (Xuan-Shen) Mori Folium (Sang-Ye), Chrysanthemi FlosAC (Ju-Hua), Forsythiae Fructus (Lian-Qiao), Menthae Herba (Bo-He), Armeniacae Semen (Xing-Ren), Platycodonis Radix (Jie-Geng), Glycyrrhizae RadixC (Gan-Cao), Phragmitis Rhizoma (Wei-Gen) Ophiopogonis RadixD (Mai-Men-Dong), Pinelliae Rhizoma (Ban-Xia), Ginseng RadixA (Ren-Shen), Oryzae Semen (Jing-Mi), Glycyrrhizae RadixC (Gan-Cao), Jujubae Fructus (Da-Zao)
A
Modulation of cytokines expression. Down regulate the antibodies productions. Anti-inflammatory effects. D Prevent epithelial injury. E Increase body fluid production. B C
who are involved in the treatment of Sjögren's syndrome must prescribe according to the requirements of the NHI and code accurately the diagnosis when claiming reimbursement from the NHI bureau. The present study provides information on cases in a nationwide health survey (96% of the population) rather than results from previous small-scale community surveys which may have seriously under-reported the number of cases with Sjögren's syndrome (Alamanos et al., 2006; Haugen et al., 2008). It is worth noting that the utilization of TCM among patients with Sjögren's syndrome in Taiwan during the study period was 91.2%. TCM is a unique traditional therapy approach for various ailments that has been used in Taiwan for over hundreds of years and this long period of use may have contributed significantly to the high prevalence of TCM usage among Sjögren's patients. Among all TCM users, nearly 88% of them continued receiving conventional treatment for relieving their Sjögren's syndrome. Hence, we suggest that when TCM is used to treat Sjögren's syndrome in Taiwan, this is generally an adjunct to the treatment of Sjögren's syndrome rather than a replacement for it. The present study describes only the utilization of TCM, which involves therapies that are also becoming popular in many other counties. Although the present findings cannot be generalized to a comprehensive analysis of the usage of various types of complementary and alternative medicine, the present study used a nationwide sample that reveals the prevalence in use of a TCM for the treatment of Sjögren's syndrome as prescribed by licensed TCM doctors. The present findings show that, among Sjögren's patients, females and those aged 21–30 years were more likely to be TCM users than males and other age groups as shown in Table 1. Possibly, because the pathogenesis of Sjögren's syndrome is not well understood, uncertainties about the progression of the disease, together with the high co-occurrence rate of other types of autoimmune diseases is perhaps a motivation for young adult
women to use a TCM in Taiwan. The present findings corroborate the results of the earlier studies (Hsieh et al., 2008; Yang et al., 2009; Fang et al., 2012; Lai et al., 2012; Huang et al., 2013), which demonstrated that Sjögren's patients who were living in central Taiwan (statistical significance) are more likely to be a TCM users. The main reason is there are more TCM physicians and institutes per person in central Taiwan than in other regions (Lin, 2008) resulting in a higher rate of TCM use. Qi-Ju-Di-Huang-Wan, which is one of the derivatives of Liu-WeiDi-Huang-Wan, was the most frequently prescribed formula for Sjögren's patients in Taiwan, as is shown in Table 3. Liu-Wei-DiHuang-Wan is said to nourish yin and to invigorate the kidney which was first documented in the classical Chinese text Xiao Er Yao Zheng Zhi Jue (Key to Therapeutics of Children's Diseases) ca. 1119 A.D. Its effect in relieving dryness, burning, and a sandy-gritty eye irritation that gets worse on windy days were improved after adding Gou-Qi-Zi (Lycii Fructus) and Ju-Hua (Chrysanthemi Flos). Previous studies have revealed that some Chinese herbs have immunomodulatory properties that act via increase in the levels of interleukin-2 and immunoglobulin G (Zhu et al., 2007) or alternating the dynamic regulation of cytokines (Yu and Tseng, 1996; Choi et al., 2004; Spelman et al., 2006; Liu et al., 2009). These modes of action are a reasonable explanation for the higher frequency of prescription of formulae containing these Chinese herbs in the present study (Roescher et al., 2010). However, no matter how popular the use of Qi-Ju-Di-Huang-Wan is in the markets of China, Japan, South Korea, and Taiwan, which are countries having a similar history of traditional Chinese medicine (TCM), no randomised controlled trial has been conducted yet. We therefore are unable to draw any conclusion about the effectiveness of Qi-Ju-Di-Huang-Wan in relieving the dry eye syndrome for lack of actual clinical data. The remaining most
Please cite this article as: Yu, M.-C., et al., The traditional Chinese medicine prescription patterns of Sjögren's patients in Taiwan: A population-based study. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.049i
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frequently prescribed formulas (Gan-Lu-Yin or Sweet Dew Beverage and Jia-Wei-Xiao-Yao-San or Augmented Rambling Powder) are associated with eye irritation, dry eyes and mouth (Lin et al., 2011; Xiao et al., 2011). It is apparent from this study that TCM doctors in Taiwan prescribed herbal therapies that reduce Sjögren's syndrome based on gathering the clinical symptoms and signs via the four diagnostic methods (inspection; listening and smelling; inquiry; pulse-feeling and palpation) and then differentiate the pattern of the Sjögren's syndrome in order to reach a specific type of zheng (a pathological summary of the body's health condition at a certain stage in the disease process). After the aforementioned diagnostic process, treatment formulae are prescribed in accordance with the different stages of Sjögren's syndrome. The major drawback of this syndrome-differentiation when treating dry eye or dry mouth is the lack of consideration of the etiology and risk factors of Sjögren's syndrome. Without taking aforementioned potential confounders into consideration, a TCM doctor will prescribe the same herbal formula to either Sjögren's patients or patients with chronic conjunctivitis who present with similar symptoms. These individuals might have symptoms that are caused by different pathogens and this might lead to TCM therapies having unpredictable effects (Zheng et al., 2011; Luo et al., 2012). Further studies are warranted to assess the formulae found to be generally used by TCM practitioners in this study and to determine whether they form a potential complementary for Sjögren's patients who have long-term morbidities even under regular standard conventional treatment (Murphy et al., 2013). A major limitation of our study is that it is a retrospective observational study and that it lacks a randomized placebo control group. Thus great caution is necessary when interpreting the results with respect to the most commonly prescribed Chinese formula used as there is a high likelihood of a placebo effect of some sort. Furthermore, this study does not include Chinese herbal remedies purchased directly from TCM herbal pharmacies nor have we included health foods containing herbs. Thus, the frequency of CHP utilization might have been underestimated. However, because the NHI system has a comprehensive coverage for TCM prescriptions, which is generally less costly than the cost of herbs sold in Taiwan's markets, the likelihood is that subjects have not purchased large quantities of other herbs outside the NHI database.
6. Conclusions It is apparent that our findings may have implications for physicians treating Sjögren's patients. Our results suggest that, under the co-existence of the conventional medical treatments and TCM, most Sjögren's patients consumed herbal therapies with the intention of relieving a wide variety of symptoms caused by this incurable autoimmune disorder. Qi-Ju-Di-Huang-Wan is the most frequent prescribed formula by TCM doctors in Taiwan for Sjögren's patients. However, the results from the current study could have been confounded by the placebo effect. This possibility emphasizes the need for well conducted, double-blind, randomized; placebo-controlled studies that can be used to further evaluate the efficacy of TCM formulas on the different patterns of Sjögren's syndrome.
Acknowledgments This research was conducted at the Institute of Traditional Medicine at the School of Medicine, National Yang-Ming University, Taipei. The authors would like to express sincere gratitude for the partial support provided for this project in the form of grants from the Department of Health, Taipei City Government (38), the Committee on Chinese Medicine and Pharmacy (CCMP100-RD-
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033) and the National Science Council Taiwan (NSC 99-2320-B010–011-MY2).
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