Title:
From the Core Pattern Analysis on Chinese Herbal Medicine for Sjögren's
Syndrome to A Protocol of Randomized Control Trial: A Nationwide
Population-Based Study in Taiwan from Year 2002 to 2011
Running head:
Nationwide Survey of CHMs for Sjögren's Syndrome and a SS-1 Clinical Trial
Protocol
Authors:
Ching-Mao Chang 1,2, Hsueh-Ting Chu 3,4,d, Yau-Huei Wei 5,6, Fang-Pey Chen 2,
Shengwen Wang 7, Po-Chang Wu 8, Hung-Rong Yen 9,a,d, Tzeng-Ji Chen b,c,*,
Hen-Hong Chang 1,9,a,d,*
Grants/Financial Support:
This study was supported by the National Science and Technology Program for
Biotechnology and Pharmaceuticals, Ministry of Science and Technology [MOST
103-2325-B-039-009], Taiwan, and it was also supported by China Medical
University under the Aim for Top University Plan of the Ministry of Education,
Taiwan, R.O.C.
Corresponding author:
Prof. Hen-Hong Chang, M.D., Ph.D.
School of Chinese Medicine,
China Medical University,
Taichung 404, Taiwan, R.O.C
E-mail: tcmchh55@gmail.com
Co-corresponding author:
Prof. Tzeng-Ji Chen
Department of Family Medicine,
Taipei Veterans General Hospital,
Taipei 112, Taiwan, R.O.C.
Email: tjchen@vghtpe.gov.tw
Conflict of interest: The authors declare that they have no competing interests.
Word count: 3657
Abstract
Objectives. This large-scale survey aimed to evaluate frequencies and patterns of
Chinese herbal medicine (CHM) used for Sjögren's syndrome (SS) in Taiwan by
analyzing the National Health Insurance Research Database (NHIRD) while CHM has
been another alternative therapy of conventional western medication for improving
patients’ discomforts.
Methods. We analyzed the SS primary diagnosis (ICD-9:710.2) with catastrophic
illness certificate (CIC) in Traditional Chinese Medicine (TCM) outpatients’ clinics
from three cohorts of Longitudinal Health Insurance Database (LHID) in the NHIRD
between years 2002 and 2011. CHM prescription patterns for SS were evaluated from
claimed visiting files and corresponding prescription files.
Results. There were 15,914 SS patients with CIC (SS/CIC), only 683 SS/CIC in
LHID2000, 678 in LHID2005 and 635 in LHID2010 respectively. We found 130
SS/CIC visiting the TCM clinics in LHID2000, 133 in LHID2005 and 126 in
LHID2010, and duplicating data were removed. Hence, 366 SS/CIC and 4,867 visits
were performed in our study, and the ages between 50 and 59 years had the highest
ratio (29.51%) in both female and male. Qi-Ju-Di-Huang-Wan and Xuan-Can
(Scrophularia ningpoensis Hemsl.) was the most commonly-used formulae and single
herb. Qi-Ju-Di-Huang-Wan, Gan-Lu-Yin, Xuan-Can, Mai-Men-Dong (Ophiopogon
japonicus (L. f.) Ker-Gawl.) and Sheng-Di-Huang (raw Rehmannia glutinosa Libosch)
were the core pattern prescriptions in treating with SS/CIC.
Conclusions. Higher CHM utilization rates of SS/CIC were investigated in this
large-scale NHIRD in Taiwan from years 2002 to 2011. We also initiated a
well-defined, randomized, double-blind, placebo-controlled and crossover clinical
trial (Clinicaltrials.gov NCT02110446) to provide evidence-based clinical data in
TCM.
Keywords: Sjögren's syndrome, Traditional Chinese medicine, National Health
Insurance Research Database, Qi-Ju-Di-Huang-Wan, Xuan-Can, SS-1
Significance and Innovations


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The utilization-patterns of CHMs for Sjögren's syndrome with catastrophic
illness certificate were evaluated with a large-scale survey in Taiwan.
The CHMs descripting may have some potential effects on antioxidant capacity,
anti-inflammation and immune modulation.
“Qi-Ju-Di-Huang-Wan, Gan-Lu-Yin, Xuan-Can, Mai-Men-Dong and
Sheng-Di-Huang (raw Rehmannia glutinosa Libosch) were the core pattern
prescriptions in treating with SS from the network analysis.
A randomized, double-blind, placebo-controlled clinical trial (Clinicaltrials.gov
NCT02110446) was initiated to provide EBM in TCM.
Introduction
Sjögren's syndrome (SS) is an auto-immune disease which is mainly involved
with exocrine gland such as lacrimal and salivary glands, and it also causes gland
dysfunction through the manifestation of dry mouth and dry eye (1). SS can be
divided into primary and secondary types (2, 3). The former, primary Sjögren's
syndrome (pSS), presents SS alone, and the latter, secondary type, combines other
autoimmune diseases like rheumatoid arthritis (RA) (4), systemic lupus erythematosus
(SLE) (5) or systemic scleroderma (6). In Taiwan, the incidence of pSS from year
2005 to 2007 was 6.0 (per 100,000 inhabitants) with a female/male ratio of 9.9 (7).
And the prevalence and incidence of SS was the third autoimmune rheumatic diseases
in Taiwan form 2000 to 2008(8).
The pathogenesis of pSS is still unclear, but some clues support the thesis of
dysfunction of B cells and T cells, which lead to autoimmune epithelial cell
inflammation and maybe the mainstream concept of pathogenesis for pSS (9, 10). The
type I interferon and B-cell-activating factor were an important issue according to the
current point of view (11-13).
Because some SS patients treated with conventional western medication had
discomforts such as pain (14) and fatigue (15, 16), some SS had a high risk of
developing non-Hodgkin's lymphoma (17). Complementary and alternative medicine
(CAM) was another choice for improving the symptoms and signs.
Chinese herbal medicine (CHM) (18) and acupuncture (19) were common CAM
therapies widely accepted by SS patients, and many randomized control trials were
performed in treating SS (20). These studies had poor methodological quality of
included trials and high heterogeneity and complexity of interventions; no
recommendation for specific CHMs could be used in the clinical.
National Health Insurance (NHI) covers both western medicine and Traditional
Chinese Medicine (TCM) medical care records in Taiwan since 1995 till this day (21).
Most of the general populations (98%) in Taiwan were covered in the NHI program at
the end of 2012. A recent large-scale investigation about TCM usage for SS in
Taiwan showed Qi-Ju-Di-Huang-Wan was the most commonly prescribed Chinese
herbal formula for SS (22). However, the report included only one cohort LHID (one
million random sample subjects) and the results may be overestimated in patient
recruited for TCM visiting and the average daily dose of Chinese formula for the
patients to take. Hence we conducted a national population-based study from three
cohorts LHID in Taiwan for Chinese herbal medicine (CHM) utilization of SS from
year 2002 to 2011 and focused on the SS patients with CIC and SS primary diagnosis
in TCM visits.
Methods
Data Sources
The National Health Insurance (NHI) program was a unique database which
implemented in Taiwan from 1995 and covered almost entire population. Nationwide
medical information was recorded as an electronic claim data in National Health
Insurance Research Database (NHIRD) that contains genders, ages, dates of
encounters, disease diagnosis of patients, and prescription of all beneficiaries (23).
Scrambling cryptogram was performed on these data for protecting patients and
institutional privacies. The study population with the diagnosis of diseases was
defined according to the International Classification of Diseases, Ninth Revision,
Clinical Modification (ICD-9-CM). Since this is a retrospective analysis of the
NHIRD and all the individual information data are de-identified, so we cannot get the
inform consent form from the including patients. This study was approved by the
Institutional Review Board of Taipei Veterans General Hospital
(VGHIRB-2013-04-005E).
Identification of Patients with Sjögren's Syndrome
We designed a national population-based study to analyze three cohorts of one
million random sample subjects selected from all the beneficiaries of the NHI
program in Taiwan, and we surveyed the CHM usage rate and patterns to determine
the utilization of the subjects with primary diagnosis of Sjögren's syndrome treated in
TCM outpatients’ clinics. SS Primary diagnosis in TCM visits can reduce the
statistical bias due to TCM visits for non-SS treatments.
Sjögren's syndrome is one of the 31 categories of major illnesses or injuries that
result in a patient holding a catastrophic illness certificate (CIC). Since Sjögren's
syndrome and Sicca syndrome had the same ICD-9 code “710.2”, we identified the
“true” Sjögren's syndrome from CIC holders between years 2002 and 2011. These
populations were matched with three cohorts of one million random samples from the
Longitudinal Health Insurance Database (LHID2000, LHID2005 and LHID2010),
which LHID extracted 1-million random sampling from 26-million individuals of the
NHIRD in the year 2000, 2005 and 2010. The SS subjects were included in this study
after duplicating data were removed. Figure 1 is the flowchart of recruitment of
subjects from the 3-million random samples for SS with CIC from the NHIRD in
Taiwan.
Data Analysis
Data linkage analysis and processing were set up with the Structure Query
Language (SQL server 2008, Microsoft Corp., Redmond, WA USA). Statistical
Package for Social Science version 19.0 (SPSS Inc., Chicago, IL USA) was applied to
analyze the frequency and patterns of formulae or single herbs and CHM utilization.
In addition, we identified core patterns of CHMs used in treating SS/CIC patients
through an open-sourced freeware NodeXL (http://nodexl.codeplex.com/), and all the
selected combinations were applied for the network analysis (24, 25). The line width
ranging from one to ten in the network figure was defined by counts of connections
between a certain CHM and co-prescribed CHMs, and thicker widths of line
connections indicated crucial prescription patterns. Top 5 core patterns of CHMs were
clearly identified within the network analysis of the CHM utilization.
Results
There were 15,914 Sjögren's syndrome patients with CIC (SS/CIC) in Taiwan
from year 2002 to 2011, but there were only 683 SS/CIC with primary diagnosis in
LHID2000, 678 in LHID2005 and 635 in LHID2010, respectively. In these three
LHID data, more than 90% SS outpatients had visited TCM clinics. However, not all
the patients visited TCM clinics for the Sjögren's syndrome, so we only included the
SS primary diagnosis in TCM visits. We found 130 SS patients in LHID2000, 133 in
LHID2005 and 126 in LHID2010, and we removed the 23 duplicating data. There
were 366 SS patients and 4,867 visits in total with the SS primary diagnosis in the
TCM clinics from year 2002 to 2011. The flowchart of recruitment of subjects treated
with CHM from the 3-million random samples for SS/CIC in the NHIRD in Taiwan
was shown in Figure 1.
There were 339 female and 27 male patients in 366 SS/CIC patients treated with
CHM, and female patients preferred using CHM for SS more than male patients
(Female: Male = 12.56: 1). The age-sex-specific frequency of CHM used in SS/CIC
patients is illustrated in Table 1, and the age and sex of SS/CIC were performed only
with the time of the first visit at TCM clinics. The ages between 50 and 59 years had
the highest ratio (29.79% and 25.93%) in female and male groups, and the mean ± SD
were 54.82 ± 13.00 in female and 57.96 ± 16.42 in male patients.
The mean ± SD of TCM clinic visits among 366 SS/CIC patients was 13.30 ±
20.09, most of SS/CIC patients visited TCM clinic less than 10 times, and the
maximum was 129. The mean ± SD of medical service provided from 472 TCM
doctors was 10.31 ± 19.15. Most of TCM doctors diagnosed and treated SS patients
for less than 10 times, and the maximum was 143. Table 2 was the visit distribution of
patients and doctors of Sjögren's syndrome in Taiwan.
Table 3 presents the top 10 formulae for treating SS among the total 26,733
CHM prescriptions. The most commonly-used formula was Qi-Ju-Di-Huang-Wan
(9.08%), and the average daily dosage was 4.78 ± 1.62 gram (g). The following ones
were Gan-Lu-Yin (8.16%), Jia-Wei-Xiao-Yao-San (6.02%), Zhi-Gan-Cao-Tang
(2.06%), Xue-Fu-Zhu-Yu-Decoction (2.03%) with the average daily dosage of 4.37 ±
1.78 g, 4.70 ± 1.49 g, 3.65 ± 2.23 g and 4.50 ± 2.21 g respectively.
The top 10 single herbs for SS/CIC are listed in Table 4. Xuan-Can (Scrophularia
ningpoensis Hemsl., 2.98%) was the most commonly-used single herb, and the
average daily dosage was 1.86 ± 0.41 g, followed by Mai-Men-Dong (Ophiopogon
japonicus (L. f.) Ker-Gawl., 2.93%), Sheng-Di-Huang (raw Rehmannia glutinosa
Libosch., 21.7%), Tian-Hua-Fen (Trichosanthes kirilowii Maxim., 2.04%),
Huang-Qin (Scutellaria baicalensis Georgi, 1.95%) with the average daily dosage of
1.38 ± 0.58 g, 1.42 ± 0.52 g, 1.24 ± 0.46 g and 1.24 ± 0.46 g respectively.
Figure 2 shows that a SS/CIC patient was given an average item of 6.24 ± 2.47
CHMs in a single prescription, and five items of CHMs (16.85%) was the most
common prescription with the combination of formulae or single herbs. The following
ones were 6 CHMs (16.71%) and 7 CHMs (13.77%). Some SS patients, only at a very
low ratio (0.05%), were prescribed more than 20 CHMs.
Among these prescriptions, we evaluated the co-prescription pattern of formula
and single herb. Table 5 shows the most common prescription patterns of two
formulae combination and two single herbs combination. The most common item of
two formulae combination was “Qi-Ju-Di-Huang-Wan plus Gan-Lu-Yin”, followed
by “Jia-Wei-Xiao-Yao-San plus Qi-Ju-Di-Huang-Wan”, “Jia-Wei-Xiao-Yao-San plus
Ping-Wei-San”, “Jia-Wei-Xiao-Yao-San plus Zhi-Bo-Di-Huang-Wan” and
“Gan-Lu-Yin plus Sang-Ju-Yin.” And the most common items of two single herbs
were “Xuan-Can plus Mai-Men-Dong”, “Sheng-Di-Huang plus Mai-Men-Dong”,
“Xuan-Can plus Sheng-Di-Huang”, “Gou-Qi plus Mai-Men-Dong” and “Sha-Can
(Glehnia littoralis F. Schmidt ex Miq.)plus Mai-Men-Dong.”
Table 6 shows the most common prescription patterns of two and triple
formulae/single herbs combination. The most common combination of two
formulae/single herbs combination was “Qi-Ju-Di-Huang-Wan plus Gan-Lu-Yin”,
followed by “Xuan-Can plus Mai-Men-Dong”, “Sheng-Di-Huang plus
Mai-Men-Dong”, “Xuan-Can plus Sheng-Di-Huang” and “Xuan-Can and
Gan-Lu-Yin.” And the most common combination of triple formulae/single herbs
combination was “Xuan-Can, Sheng-Di-Huang plus Mai-Men-Dong”, followed by
“Nu-Zhen-Zi (Ligustrum lucidum Ait.), Jia-Wei-Xiao-Yao-San plus Gou-Qi”,
“Nu-Zhen-Zi, Wu-Wei-Zi (Schizandra chinensis (Turcz.) Baill.) plus
Jia-Wei-Xiao-Yao-San”, “Wu-Wei-Zi, Jia-Wei-Xiao-Yao-San and Gou-Qi” and
“Qi-Ju-Di-Huang-Wan, Gan-Lu-Yin plus Dan-Can.” The network analysis in Figure 3
demonstrated that “Qi-Ju-Di-Huang-Wan”, “Gan-Lu-Yin”, “Xuan-Can”,
“Mai-Men-Dong” and “Sheng-Di-Huang” formed the core pattern of Chinese formula
and other single herbs used to treat the Sjögren's syndrome patients with catastrophic
illness certificate.
Discussion
This study is the first nationwide population-based survey of the utilization and
core pattern analysis of CHM with Sjögren's syndrome patients with catastrophic
illness certificate from three LHID in Taiwan. Females SS/CIC patients had much
higher ratio of using CHM than males (12.56: 1); and the female and male groups
aged from 50 to 59 years both had the highest ratio of CHM use for SS/CIC. It may
have the correlation with a lack of both active estrogens and androgens, which leads
to apoptosis in epithelial salivary gland cells (26). A recent study demonstrated
different serum levels of endocrines regarding SS symptoms and discussed that oral
dryness may be related to a low level of androgens, while low level of estrogens were
expressed with ocular dryness (27).
The total numbers of SS/CIC were 15,914 (which 72,391 is the total patient
number of generalized autoimmune syndrome requiring lifelong treatment with CIC
(28)) in Taiwan from year 2002 to 2011, and the SS/CIC subjects treated with CHM
were 366 patients, including from three LHID with the duplicating data are removed.
The sample size in this study was not large enough; it could not represent the whole
view of SS/CIC with CHM treatment. The database could only represent the ratio of
one-million samplings/total 26-million total inhabitants (3.84%). We found that the
ratio of SS/CIC patients treated with CHM could be traced back to consider as
63.55% of the entire SS/CIC, the ratio could also match the nationwide survey of
TCM utilization (29).
There were 366 subjects with TCM clinic visits among 472 TCM doctors; four
subjects had visited over 100 times from year 2002 to 2011 while the 238 subjects
(65.03%) had visited less than 10 times. The situation also occurred in the TCM
doctor side; only three doctors had visited more over 100 times while 343 doctors
(72.67%) had visited less than 10 times. The phenomenon of doctor shopping among
patients with chronic illness may account for the observation that many SS/CIC
patients received treatment with CHM from different TCM doctors (30). The common
reasons for doctor shopping is that the health service of family doctors system in
Taiwan had not yet been well-established (31); therefore, patients who have been
bothered by persistent symptoms and medication side effects seek a second opinion
(32). The health care cost may be also wasted due to this doctor shopping in TCM
(33).
“Qi-Ju-Di-Huang-Wan” was the most commonly-used formula for SS/CIC; its
therapeutic function was “nourish the liver and brighten the eyes”, and it could be
used for SS and dry eye. Recent literatures reported that “Qi-Ju-Di-Huang-Wan” had
more effective effect than conventional medicine on SS, no matter whether using
“Qi-Ju-Di-Huang-Wan” alone (34) or “Qi-Ju-Di-Huang-Wan” plus acupuncture (35).
Chang (36) used “Qi-Ju-Di-Huang-Wan” with a randomized, double-masked, parallel
grouped and controlled study to treat dry eyes, and the result showed that
abnormalities of corneal epithelium reduction and it also could be an alternative drug
for topical eye drops. However, the included subjects in Chang’s study were dry eye
syndrome not SS, “Qi-Ju-Di-Huang-Wan” may have the potential therapeutic effect
for the dry eye symptom of SS.
“Gan-Lu-Yin” was the second commonly-used formulae in our database; its
therapeutic function was “enrich yin and clear heat”, and it could be used for the
treatment of SS and dry month. A study used “Gan-Lu-Yin” in post-radiotherapy
NPC patients to alleviate the mucositis and dry mouth (37). “Jia-Wei-Xiao-Yao-San”
can “course the liver and resolve depression”, and Yi et al. (38) used it to treat
xerophthalmia in perimenopausal women with significant improvement of visual
fatigue sensation, red eye, dryness, foreign body sensation, burning sensation and
photophobia. “Zhi-Gan-Cao-Tang” features “boost qi and enrich yin”; however, no
literature discusses it for treating SS related symptoms. “Xue-Fu-Zhu-Yu-Decoction”
can “quicken the blood and dispel stasis”, it can modulate the immune function of B
cells and T cells (39) and alleviate tissue fibrosis (40).
“Xuan-Can” was the most commonly-used single herb with the function of
“enrich yin and clear heat”, and it had some positive effects on anti-inflammation and
tumor cell apoptosis (41). “Mai-Men-Dong” was the second commonly-used single
herb to “nourish yin and moisten dryness”, it can down-regulate the mRNA
expression of TGF-β1 and had potential antioxidant activity (42). “Sheng-Di-Huang”
can “enrich yin and clear heat”, it also reduced eosinophil cationic proteins level
which was positively correlated with "heat zheng" (43). “Tian-Hua-Fen” can “clear
heat and engender liquid”, and it can inhibit Nitrogen oxide activity and elevate
anti-inflammation effects (44). “Huang-Qin” can “clear heat and drain fire” and it has
the function of scavenging reactive oxygen species.(45)
Figure 3 includes the top 50 Chinese formula and single herbs for the Sjögren's
syndrome patients with catastrophic illness certificate and shows the core pattern of
these CHMs. This figure implies that Qi-Ju-Di-Huang-Wan, Gan-Lu-Yin, Xuan-Can,
Mai-Men-Dong and Sheng-Di-Huang are among the most frequently used
combinations. Although these items may have some potential effects on antioxidant
capacity, anti-inflammation and immune modulation, they were rarely applied in
clinical trials. Furthermore, these five CHMs of the core pattern identified in the
figure did not have the function of alleviating tissue fibrosis. For this purpose, we
initiated a randomized, double-blind, placebo-controlled, cross-over design clinical
trial (Clinicaltrials.gov NCT02110446) for the SS/CIC patients in order to evaluate
the effect of CHM (SS-1) on the regulation of oxidative stress-related cytokines and
the antioxidant capacity. “Gan-Lu-Yin, Sang-Ju-Yin and Xue-Fu-Zhu-Yu-Decoction”
with the ratio of 2:1:1 is the composition of SS-1, and its therapeutic functions include
antioxidant capacity, anti-inflammation, immune modulation and anti-fibrosis. We
expect the quality of patients’ life and clinical manifestation will be improved by
reducing the oxidative stress. And we also plan to use a SS cell model to elucidate the
antioxidant effect and the mechanism of action of SS-1.
Our analysis shows different results from a recent SS report surveying the CHM
prescription patterns in Taiwan from 1997 to 2008 (22): (1) We included the SS/CIC
subjects from three LHID between year 2002 to 2011 for a comprehensive and
up-to-date nationwide survey. (2) We only included the primary diagnosis with
SS/CIC in TCM visits, so as to reduce the statistical bias due to TCM visits for
non-SS treatments. (3) The statistics of SS/CIC patient number and the dosage of top
10 Chinese formulae demonstrated more rational and significant results in this study.
However, there are some limitations in this study: (1) Many potential SS patients
accepted the conventional therapy or TCM, but they were not CIC holders due to
incompatibility of histopathology or autoantibody criteria. Since the SS subjects
included in this study are required to have the CIC, the CHM utilization of SS patients
may be underestimated. (2) The sample size in this study was not large enough; hence,
we should conduct another larger survey on this issue in the future. (3) Since the
subjects included in this study were extracted from three LHIDs, the multivariate
logistic regression model was not conducted to evaluate the correlated factors in the
CHM utilization. (4) We studied the utilization of CHM only in the recruited SS/CIC
patients; however, we did not investigate the utilization of acupuncture, Chinese tuina
or other CAMs which they might be applied in SS therapies as well.
Clinical Trial Protocol
A Protocol of Chinese Herbal Medicine SS-1 Randomized Control Trial for
Sjögren's Syndrome
We initiated a randomized, double-blind, placebo-controlled, cross-over design
clinical trial (Clinicaltrials.gov NCT02110446) to evaluate the effect of Chinese
herbal medicine (SS-1) on the regulation of oxidative-related cytokines and the
antioxidant capacity for the SS/CIC patients from April 2014 and recruited the
subjects from July 2014. Through the oxidative stress reduction, the quality of
patients’ life and clinical manifestation will be improved. And we will also use a SS
cell model to elucidate the antioxidant mechanism of SS-1. This study was approved
by the Institutional Review Board and ethics committee of Chang Gung Memorial
Hospital in Taiwan (103-4180C). All the participants who were included in this study
provided their written informed consent to participate.
Ninety of SS patients in this clinical trial will be screened and be referred from
the out-patient department (OPD) of the Rheumatology Department of Chang Gung
Memorial Hospital. The 60 of the included patients will be randomly divided into two
groups (A and B) and all of them will keep receiving the routine treatment in the
rheumatology OPD. Group A patients will first receive a 12-week SS-1 treatment and
then stop the SS-1 for 4 weeks in order to enter the wash-out phase; at last, they will
receive a 12-week placebo treatment. Group B patients will receive a 12-week
placebo first and then stop the placebo treatment for 4 weeks in order to enter the
wash-out phase; afterwards, they will receive a 12-week SS-1 treatment. SS-1 is
composed of the powder of “Gan-Lu-Yin, Sang-Ju-Yin and
Xue-Fu-Zhu-Yu-Decoction” in the ratio of 2:1:1; while the placebo is composed of
corn starch, pigment and 1/100 SS-1. Patients in both groups will take 6 grams of
experimental medicine three times per day. We plan to evaluate the associated
parameters at the time just before treatment (V1), after the first treatment (V2), at the
end of wash-out phase (V3) and when the crossover treatment is completed (V4).
Primary Outcome Measure: Clinical manifestation and quality of life
SS-1 may improve the clinical manifestation (EULAR Sjogren's Syndrome
Patient Reported Index, Ocular Surface Disease Index, SS symptoms Questionnaire,
Schirmer's test, salivary scintigraphy) and the quality of life (SF-36) for the patients
with Sjögren's syndrome.
Secondary Outcome Measures: Oxidative stress, antioxidant capacity and
regulatory effect on cytokine
SS-1 may reduce the oxidative stress (8-OHdG) and elevate the antioxidant
capacity (TAC, GSH, SOD, GPX, CAT). Moreover, SS-1 may have the regulatory
effect on related cytokine secretion of immune function.
Other Pre-specified Outcome Measures: Patient safety, adverse effect and tongue
diagnosis
We will monitor the patient safety and adverse effect (ADR) during the SS-1
trial, and monitor Liver, Kidney and Blood function (RBC, WBC, Hb, PLT, AST,
ALT, BUN, Cre) during the SS-1 trial. Besides, SS-1 may have effect on the tongue
diagnosis before and after the treatment.
Statistical methods for efficacy/safety evaluations
We will analyze the study population with an intent-to-treat model, and a
generalized estimating equation will be used to evaluate the difference of the primary,
secondary outcomes, drug safety monitor and tongue diagnosis between two groups.
The statistical difference was considered to be significant at p value < 0.05 and both
with a 95% confidence interval.
Conclusions
Qi-Ju-Di-Huang-Wan was the most commonly-used formula while Xuan-Can was
the most commonly-used single herb in our database. Among different age groups, the
highest utilization of CHM was found between ages 50 and 59 in both female and
male. The most commonly-used two formulae combination was
“Qi-Ju-Di-Huang-Wan plus Gan-Lu-Yin”, and the most commonly-used two single
herbs combination was “Xuan-Can plus Mai-Men-Dong.” The core pattern
prescriptions were Qi-Ju-Di-Huang-Wan, Gan-Lu-Yin, Xuan-Can, Sheng-Di-Huang
and Mai-Men-Dong. However, the therapeutic effects and safety of these
commonly-used CHMs treated for Sjögren's syndrome in this study have not been
clearly elaborated, so well-designed clinical trials for this purpose are required in the
future.
Author’s contributions
CMC, TJC and HHC were responsible for study concept and design,
modification of study design, and review and interpretation of data. CMC, TJC and
HHC were also responsible for drafting the manuscript. HTC, SWW and PCW
provided modifications of study design and revisited the manuscript. YHW, FPC and
HRY contributed to collection, analysis and interpretation of data and revisited the
manuscript. All authors read and approved the final manuscript.
Conflict of interests
The authors declare that they have no competing interests.
Acknowledgments
This study was a portion of data that were extracted from the National Health
Insurance Research Database provided by the Bureau of National Health Insurance,
Ministry of Health and Welfare in Taiwan. This study was supported by the National
Science and Technology Program for Biotechnology and Pharmaceuticals, Ministry of
Science and Technology [MOST 103-2325-B-039-009], Taiwan, and it was also
supported by China Medical University under the Aim for Top University Plan of the
Ministry of Education, Taiwan, R.O.C.
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Authors:
Ching-Mao Chang 1,2, Hsueh-Ting Chu 3,4,d, Yau-Huei Wei 5,6, Fang-Pey Chen 2,
Shengwen Wang 7, Po-Chang Wu 8, Hung-Rong Yen 9,a,d, Tzeng-Ji Chen b,c,*,
Hen-Hong Chang 1,9,a,d,*
Affiliation:
1
Graduate Institute of Clinical Medicine, and Graduate Institute of Traditional
Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33378,
Taiwan
2
Center for Traditional Medicine, Taipei Veterans General Hospital, Taipei 11217,
Taiwan
3
Department of Computer Science and Information Engineering, Asia University,
Taichung 41354, Taiwan
4
Department of Medical Research, China Medical University Hospital, China Medical
University, Taichung 40447, Taiwan
5
Department of Biochemistry and Molecular Biology, School of Life Sciences,
National Yang-Ming University, Taipei 11221, Taiwan
6
Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan
7
Cloud Computing and System Integration Division, National Center for
High-Performance Computing, Taichung 40763, Taiwan
8
Division of Rheumatology and Immunology and Department of Education, China
Medical University Hospital, Taichung 40447, Taiwan
9
Research Center for Traditional Chinese Medicine, Department of Chinese Medicine
and Department of Medical Research, China Medical University Hospital, Taichung
40447, Taiwan
a
School of Chinese Medicine, China Medical University, Taichung 40447, Taiwan
b
Department of Family Medicine, Taipei Veterans General Hospital, Taipei 11217,
Taiwan
c
Institute of Hospital and Health Care Administration, School of Medicine, National
Yang-Ming University, Taipei 11217, Taiwan
d
Research Center for Chinese Medicine & Acupuncture, China Medical University,
Taichung 40447, Taiwan
*
Correspondence and co-correspondence to: Prof. Hen-Hong Chang and Prof.
Tzeng-Ji Chen
Table 1. Age distribution of Sjögren's syndrome patients with catastrophic
illness certificate treated with Chinese herbal medicine
Total
Number
Age
< 20
20-29
30-39
40-49
Female
Male
Female/Male
Ratio
366
339
27
12.56
1 (0.27%)
9 (2.46%)
38 (10.38%)
72 (19.67%)
1 (0.29%)
7 (2.06%)
36 (10.62%)
68 (20.06%)
0 (0.00%)
2 (7.41%)
2 (7.41%)
4 (14.81%)
3.5
18
17
50-59
60-69
70-79
≧ 80
108 (29.51%)
86 (23.50%)
40 (10.93%)
12 (3.28%)
101 (29.79%)
81 (23.89%)
36 (10.62%)
9 (2.65%)
7 (25.93%)
5 (18.52%)
4 (14.81%)
3 (11.11%)
14.43
16.2
9
3
Mean ± SD
Max
Min
Range
55.05 ± 13.28
90
16
74
54.82 ± 13.00
90
16
74
57.96 ± 16.42
85
28
57
Table 2. Visit distribution of patients and doctors of Sjögren's syndrome with
catastrophic illness certificate in the treatment of Chinese herbal medicine
Patient
Number
Total
Visit
< 10
10-19
20-29
30-39
Doctor
366
4867
472
4867
238 (65.03%)
55 (15.03%)
19 (5.19%)
19 (5.19%)
343 (72.67%)
66 (13.98%)
26 (5.51%)
9 (1.91%)
40-49
50-59
60-69
70-79
10 (2.73%)
11 (3.01%)
1 (0.27%)
5 (1.37%)
6 (1.27%)
5 (1.06%)
2 (0.42%)
2 (0.42%)
80-89
90-99
100-109
110-119
120-129
130-139
≧ 140
3 (0.82%)
1 (0.27%)
2 (0.55%)
1 (0.27%)
1 (0.27%)
0 (0.00%)
4 (0.85%)
6 (1.27%)
1 (0.21%)
0 (0.00%)
0 (0.00%)
0 (0.00%)
0 (0.00%)
13.30 ± 20.09
129
1
128
2 (0.42%)
10.31 ± 19.15
143
1
142
Mean ± SD
Max
Min
Range
Table 3. The top 10 formulae of Sjögren's syndrome with catastrophic illness certificate in Taiwan (total prescription numbers =26,733)
TCM prescription
1
2
Qi-Ju-Di-Huang-Wan
Gan-Lu-Yin
Therapeutic actions and
indications (46)
Frequency of
prescription N
(%)
Average daily
dosage (g)
(Mean ± SD)
Ju-Hua (Chrysanthemum morifolium
Nourish the liver and
834 (9.08%)
4.78 ± 1.62
(Ramat.) Tzvel.), Gou-Qi (Lycium
barbarum L.), Shou-Di-Huang (Rehmannia
glutinosa Libosch.), Shan-Zhu-Yu (Cornus
officinalis Sieb. et Zucc.), Shan-Yao
(Dioscorea opposita Thunb.), Ze-Xie
(Alisma orientalis (Sam.) Juzep.), Fu-Ling
(Poria cocos (Schw.) Wolff), Mu-Dan-Pi
brighten the eyes
750 (8.16%)
4.37 ± 1.78
Ingredients
(Paeonia suffruticosa Andr.)
Sheng-Di-Huang (raw Rehmannia glutinosa
Libosch.), Shou-Di-Huang (Rehmannia
glutinosa Libosch.), Tian-Men-Dong
(Asparagus cochinchinensis (Lour.) Merr.),
Mai-Men-Dong (Ophiopogon japonicus (L.
f.) Ker-Gawl.), Shi-Hu (Dendrobium
chrysanthum Wall.), Yin-Chen-Hao
(Artemisia capillaris Thunb.), Huang-Qin
(Scutellaria baicalensis Georgi), Zhi-Ke
Enrich yin and clear heat
3
Jia-Wei-Xiao-Yao-San
(Citrus aurantium L.), Pi-Pa-Ye (Eriobotrya
japonica (Thunb.) Lindl.), Zhi-Gan-Cao
(Glycyrrhiza glabra L.)
Zhi-Gan-Cao (Glycyrrhiza glabra L.),
Course the liver and
Dang-Gui (Angelica sinensis (Oliv.) Diels), resolve depression
553 (6.02%)
4.70 ± 1.49
Boost qi and enrich yin
189 (2.06%)
3.65 ± 2.23
Mai-Men-Dong (Ophiopogon japonicus (L.
f.) Ker-Gawl.), Ma-Zi-Ren (Cannabis sativa
L.), Da-Zao (Ziziphus jujuba Mill.)
Xue-Fu-Zhu-Yu-Decoction Dang-Gui (Angelica sinensis (Oliv.) Diels), Quicken the blood and
187 (2.03%)
4.50 ± 2.21
Fu-Ling (Poria cocos (Schw.) Wolff),
Bai-Shao-Yao (Paeonia lactiflora Pall.) ,
Bai-Zhu (Atractylodes macrocephala
Koidz.), Chai-Hu (Bupleurum chinense
DC.), Sheng-Jiang (Zingiber officinale
Rosc.), Bo-He (Mentha haplocalyx Briq.),
Mu-Dan-Pi (Paeonia suffruticosa Andr.),
4
Zhi-Gan-Cao-Tang
Zhi-Zi (Gardenia jasminoides Ellis)
Zhi-Gan-Cao (Glycyrrhiza glabra L.),
Sheng-Jiang (Zingiber officinale Rosc.),
Ren-Can (Panax ginseng C. A. Meyer),
Sheng-Di-Huang (raw Rehmannia glutinosa
Libosch.), Gui-Zhi (Cinnamomun cassia
Presl), A-Jiao (Equus asinus L.),
5
Sheng-Di-Huang (raw Rehmannia glutinosa dispel stasis
Libosch.), Tao-Ren (Prunus persica (L.)
Batsch), Hong-Hua (Carthamus tinctorius
L.), Zhi-Ke (Citrus aurantium L.), Chi-Shao
(red Paeonia lactiflora Pall.), Chai-Hu
6
Yi-Guan-Jian
(Bupleurum chinense DC.), Zhi-Gan-Cao
(Glycyrrhiza glabra L.), Jie-Geng
(Platycodon grandiflorum (Jacq.) A. DC.),
Chuan-Qiong (Ligusticum chuanxiong
Hortorum), Niu-Xi (Achyranthes bidentata
Blume)
Dang-Gui (Angelica sinensis (Oliv.) Diels),
Bai-Zhu (Atractylodes macrocephala
Koidz.), Fu-Ling (Poria cocos (Schw.)
Coursing the liver and
185 (2.01%)
3.58 ± 1.44
183 (1.99%)
4.27 ± 1.56
fortify the spleen
Wolff), Gou-Teng (Uncaria rhynchophylla
(Miq.) Jacks.), Chuan-Qiong (Ligusticum
chuanxiong Hortorum), Chai-Hu
(Bupleurum chinense DC.), Zhi-Gan-Cao
(Glycyrrhiza glabra L.)
7
Zhi-Bo-Di-Huang-Wan
Zhi-Mu (Anemarrhena asphodeloides
Bunge), Huang-Bo (Phellodendron
chinense Schneid.), Shou-Di-Huang
(Rehmannia glutinosa Libosch.),
Enrich yin and clear heat
Shan-Zhu-Yu (Cornus officinalis Sieb. et
Zucc.), Shan-Yao (Dioscorea opposita
Thunb.), Ze-Xie (Alisma orientalis (Sam.)
Juzep.), Fu-Ling (Poria cocos (Schw.)
Wolff), Mu-Dan-Pi (Paeonia suffruticosa
8
Ping-Wei-San
9
Sha-Can-Mai-Dong-Tang
Andr.)
Cang-Zhu (Atractylodes lancea (Thunb.)
DC.), Hou-Po (Magnolia officinalis Rehd.
et Wils.), Chen-Pi (Citrus reticulata
Blanco), Zhi-Gan-Cao (Glycyrrhiza glabra
L.)
Sha-Can (Glehnia littoralis F. Schmidt ex
Miq.), Yu-Zhu (Polygonatum odoratum
(Mill.) Druce), Sheng-Gan-Cao ( raw
Dry dampness and fortify
the spleen
183 (1.99%)
2.56 ± 1.09
Nourish yin and engender
174 (1.89%)
4.31 ± 1.93
165 (1.80%)
2.78 ± 1.59
liquid
Glycyrrhiza glabra L.), Sang-Ye (Morus
alba L.), Mai-Men-Dong (Ophiopogon
japonicus (L. f.) Ker-Gawl.), Bian-Dou
(Dolichos lablab L.), Tian-Hua-Fen
(Trichosanthes kirilowii Maxim.)
10
Ma-Zi-Ren-Wan
Ma-Zi-Ren (Cannabis sativa L.),
Bai-Shao-Yao (Paeonia lactiflora Pall.),
Zhi-Shi (Citrus aurantium L.), Da-Huang
(Rheum tanguticum Maxim. ex Balf.),
Moisten the intestines and
drain fire
29
Sang-Ju-Yin
Hou-Po (Magnolia officinalis Rehd. et
Wils.), Xing-Ren (Prunus armeniaca L.)
Sang-Ye (Morus alba L.), Ju-Hua
(Chrysanthemum morifolium (Ramat.)
Tzvel.), Xing-Ren (Prunus armeniaca L.),
Lian-Qiao (Forsythia suspense (Thunb.)
Vahl), Bo-He (Mentha haplocalyx Briq.),
Jie-Geng (Platycodon grandiflorum (Jacq.)
A. DC.), Zhi-Gan-Cao (Glycyrrhiza glabra
L.), Lu-Gen (Phragmites communis Trinus)
Course wind and
discharge heat
89 (0.97%)
3.75 ± 1.26
Table 4. The top 10 single herbs of Sjögren's syndrome with catastrophic illness certificate in Taiwan (total prescription numbers
=26,733)
TCM prescription
Xuan-Can
Mai-Men-Dong
Sheng-Di-Huang
Tian-Hua-Fen
Huang-Qin
Gou-Qi
Da-Huang
Ju-Hua
Dan-Can
Shi-Hu
Therapeutic actions and indications (47)
Frequency of
prescription N
(%)
Scrophularia ningpoensis Hemsl.
Ophiopogon japonicus (L. f.)
Ker-Gawl.
raw Rehmannia glutinosa Libosch.
Trichosanthes kirilowii Maxim.
Scutellaria baicalensis Georgi
Lycium barbarum L.
Enrich yin and clear heat
Nourish yin and moisten dryness
522 (2.98%)
514 (2.93%)
1.86 ± 0.41
1.38 ± 0.58
Enrich yin and clear heat
Clear heat and engender liquid
Clear heat and drain fire
Boost essence and brighten the eyes
380 (2.17%)
357 (2.04%)
342 (1.95%)
322 (1.84%)
1.42 ± 0.52
1.24 ± 0.46
1.24 ± 0.46
1.27 ± 0.59
Rheum tanguticum Maxim. ex Balf.
Chrysanthemum morifolium (Ramat.)
Tzvel.
Salvia miltiorrhiza Bge.
Dendrobium chrysanthum Wall.
Clear heat and drain fire
Course wind and discharge heat
294 (1.68%)
292 (1.66%)
1.07 ± 0.73
1.18 ± 0.38
Cool the blood and clear heat
Enrich yin and clear heat
289 (1.65%)
282 (1.61%)
1.20 ± 0.44
1.23 ± 0.46
Ingredients
Average daily
dosage (g)
(Mean ± SD)
Table 5. The most common prescription patterns for two formulae and two
single herbs combination in a single prescription of Sjögren's syndrome with
catastrophic illness certificate
Number of
prescriptions
N (%)
Name
Two formulae combination
1
Qi-Ju-Di-Huang-Wan
2
Jia-Wei-Xiao-Yao-San
3
Jia-Wei-Xiao-Yao-San
Gan-Lu-Yin
Qi-Ju-Di-Huang-Wan
Ping-Wei-San
268 (3.34%)
102 (1.27%)
68 (0.85%)
4
5
6
7
Jia-Wei-Xiao-Yao-San
Gan-Lu-Yin
Jia-Wei-Xiao-Yao-San
Qi-Ju-Di-Huang-Wan
Zhi-Bo-Di-Huang-Wan
Sang-Ju-Yin
Gan-Lu-Yin
Shen-Tong-Zhu-Yu-Tang
57 (0.71%)
56 (0.70%)
55 (0.69%)
53 (0.66%)
8
9
10
Jia-Wei-Xiao-Yao-San
Jia-Wei-Xiao-Yao-San
Qi-Ju-Di-Huang-Wan
Huang-Lian-Jie-Du-Tang
Ma-Zi-Ren-Wan
Xin-Yi-Qing-Fei-Tang
51 (0.64%)
49 (0.61%)
42 (0.52%)
Two single herbs combination
1
Xuan-Can
Mai-Men-Dong
2
Sheng-Di-Huang
Mai-Men-Dong
3
4
5
6
7
8
9
10
#
Xuan-Can
Gou-Qi
Sha-Can
Tian-Men-Dong
Mu-Dan-Pi
Wu-Wei-Zi
Tian-Hua-Fen
Nu-Zhen-Zi
Sheng-Di-Huang
Mai-Men-Dong
Mai-Men-Dong
Mai-Men-Dong
Huang-Qin
Gou-Qi
Mai-Men-Dong
Wu-Wei-Zi
176 (0.41%)
160 (0.37%)
152 (0.35%)
93 (0.22%)
92 (0.21%)
88 (0.20%)
88 (0.20%)
79 (0.18%)
79 (0.18%)
75 (0.17%)
Nu-Zhen-Zi: Ligustrum lucidum Ait., Wu-Wei-Zi: Schizandra chinensis (Turcz.)
Baill.,
Table 6 The most common prescription patterns for two and triple drugs
combination in a single prescription of Sjögren's syndrome with catastrophic
illness certificate
Number of
prescriptions
N (%)
Name
Two combination
1 Qi-Ju-Di-Huang-Wan
2 Xuan-Can
3 Sheng-Di-Huang
4
5
6
7
8
9
10
3
4
5
6
7
8
9
10
#
Mai-Men-Dong
Mai-Men-Dong
Xuan-Can
Sheng-Di-Huang
Xuan-Can
Gan-Lu-Yin
Qi-Ju-Di-Huang-Wan
Mai-Men-Dong
Tian-Hua-Fen
Gan-Lu-Yin
Xuan-Can
Qi-Ju-Di-Huang-Wan
Jia-Wei-Xiao-Yao-San
Qi-Ju-Di-Huang-Wan
Sheng-Di-Huang
Qi-Ju-Di-Huang-Wan
Triple combination
1 Xuan-Can
2 Nu-Zhen-Zi
268 (0.322%)
176 (0.212%)
160 (0.193%)
Gan-Lu-Yin
152 (0.183%)
130 (0.156%)
123 (0.148%)
113 (0.136%)
110 (0.132%)
102 (0.123%)
95 (0.114%)
Sheng-Di-Huang
Mai-Men-Dong
Jia-Wei-Xiao-Yao-San
Gou-Qi
Nu-Zhen-Zi
Wu-Wei-Zi
Jia-Wei-Xiao-Yao-San
Wu-Wei-Zi
Jia-Wei-Xiao-Yao-San
Gou-Qi
Qi-Ju-Di-Huang-Wan
Gan-Lu-Yin
Dan-Can
Nu-Zhen-Zi
Wu-Wei-Zi
Gou-Qi
Jia-Wei-Xiao-Yao-San
Ping-Wei-San
Bai-Ji
Da-Huang
Bai-Hua-She-She-Cao
Mei-Yao
Jia-Wei-Xiao-Yao-San
Gou-Qi
Hai-Piao-Xiao
Xuan-Can
Gan-Lu-Yin
Qi-Ju-Di-Huang-Wan
96 (0.055%)
66 (0.038%)
66 (0.038%)
64 (0.037%)
63 (0.036%)
59 (0.034%)
52 (0.030%)
49 (0.028%)
47 (0.027%)
47 (0.027%)
Bai-Ji: Bletilla striata (Thunb.) Rechib. f., Mei-Yao: Commiphora myrrha Engler,
Hai-Piao-Xiao: Sepia esculenta Hoyle
Figure Legends
Figure 1. Flowchart of recruitment of Sjögren's syndrome with catastrophic
illness certificate from the 3-million random sample. We identified the Sjögren's
syndrome with ICD-9 code “710.2” with catastrophic illness certificate in Taiwan
between years 2002, and they were matched with three cohorts of one million random
samples from the LHID2000, LHID2005 and LHID2010. And the subjects with
catastrophic illness certificate were included in this study after duplicating data were
removed.
Figure 2. Relationship between the numbers of Chinese formula and single herbs
for the Sjögren's syndrome patients. Sjögren's syndrome patients with catastrophic
illness certificate was given an average item of 6.24 ± 2.47 CHMs in a single
prescription, and five items of CHMs (16.85%) was the most common prescription
with the combination of formulae or single herbs.
Figure 3. The core pattern of Chinese formula and single herbs for the Sjögren's
syndrome patients. The top 50 Chinese formula and single herbs for the Sjögren's
syndrome patients with catastrophic illness certificate were analyzed through an
open-sourced freeware NodeXL and the core pattern of these CHMs showed that
Qi-Ju-Di-Huang-Wan, Gan-Lu-Yin, Xuan-Can, Mai-Men-Dong and Sheng-Di-Huang
are among the most frequently used combinations.
Figure 1. Flowchart of recruitment of Sjögren's syndrome with catastrophic
illness certificate from the 3-million random sample. We identified the Sjögren's
syndrome with ICD-9 code “710.2” with catastrophic illness certificate in Taiwan
between years 2002, and they were matched with three cohorts of one million random
samples from the LHID2000, LHID2005 and LHID2010. And the subjects with
catastrophic illness certificate were included in this study after duplicating data were
removed.
Figure 2. Relationship between the numbers of Chinese formula and single herbs
for the Sjögren's syndrome patients. Sjögren's syndrome patients with catastrophic
illness certificate was given an average item of 6.24 ± 2.47 CHMs in a single
prescription, and five items of CHMs (16.85%) was the most common prescription
with the combination of formulae or single herbs.
Figure 3. The core pattern of Chinese formula and single herbs for the Sjögren's
syndrome patients. The top 50 Chinese formula and single herbs for the Sjögren's
syndrome patients with catastrophic illness certificate were analyzed through an
open-sourced freeware NodeXL and the core pattern of these CHMs showed that
Qi-Ju-Di-Huang-Wan, Gan-Lu-Yin, Xuan-Can, Mai-Men-Dong and Sheng-Di-Huang
are among the most frequently used combinations.