Identifying Chinese herbal medicine network for treating acne: Implications from a nationwide database

Journal of Ethnopharmacology 179 (2016) 1–8

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Identifying Chinese herbal medicine network for treating acne: Implications from a nationwide database Hsing-Yu Chen a,b,c, Yi-Hsuan Lin a,b,c, Yu-Chun Chen d,e,f,n a

Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan Graduate Institute of Clinical Medical Sciences and Chang Gung University, Taoyuan, Taiwan c School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan d Department of Medical Research and Education, National Yang-Ming University Hospital, I-Lan, Taiwan e Faculty of Medicine and School of Medicine, National Yang-Ming University, Taipei, Taiwan f Institute of Hospital and Health Care Administration, School of Medicine, National Yang-Ming University, Taipei, Taiwan b

art ic l e i nf o

a b s t r a c t

Article history: Received 2 June 2015 Received in revised form 24 August 2015 Accepted 20 December 2015 Available online 22 December 2015

Ethno-pharmacological relevance: Acne is a highly prevalent inflammatory skin disease which causes patients great psychological stress, especially teenagers. Chinese herbal medicine (CHM) is commonly used to treat acne with personalized but complicated prescriptions. The aim of this study is to determine a CHM network and core CHM treatments for acne by analyzing a nationwide database. Materials and methods: From January 1st to December 31st, 2011, all CHM prescriptions made for acne (ICD-9-CM code: 706.0 or 706.1) were included in this study. Visits with acupuncture, manual therapy or other treatment modalities were excluded, and CHM visits with other diagnoses were also excluded in final analysis. Association rule mining (ARM) and social network analysis (SNA) were used to explore and demonstrate a CHM network. Results: A total of 91,129 patients used traditional Chinese medicine, and 99% of them chose CHM for acne treatment. Most CHM users were teenagers, and there were twice as many female patients as male patients. A total of 279,823 CHM prescriptions were made for acne in 2011. Qing-Shang-Fang-Feng-Tang was the most commonly used CHM (31.2% of all prescriptions), and Zhen-Ren-Huo-Ming-Yin combined with Forsythia suspensa (Thunb.) Vahl. (Lian Qiao) was the most commonly used CHM-CHM combination. Thirty-one important CHM-CHM combinations were identified, and the CHM network could be built. Extensive coverage of the known pathogenesis of acne could be found in the CHM network when incorporating CHM pharmacological mechanisms into the network. Anti-inflammatory and anti-bacterial effects were commonly found in the CHM network, and CHMs with anti-androgen, anti-depressive and skin whitening effects were frequently used in combination. Conclusions: The CHM combination patterns and core treatments for acne were disclosed in this study by applying network analysis to a CHM prescription database. These results may be beneficial for further bench or clinical studies when choosing target CHM. & 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Association rule mining Acne Chinese herbal medicine Social network analysis The National Health Insurance Research Database

1. Introduction Acne is the one of the most prevalent chronic inflammatory cutaneous disorders, and more than 70% of people report having acne during and after their teenage years, most of whom are

Abbreviations: Terms, Abbreviation; ARM, Association rule mining; CHM, Chinese herbal medicine; HF, Herbal formula; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; NHI, National Health Insurance; NHIRD, National Health Insurance Research Database; SHrb, Single he; SNAis, Social network analys; TCM, Traditional Chinese medicine n Corresponding author at: Department of Medical Research and Education National Yang-Ming University, Hospital No. 152, Xin Min Rd, 26042 I-Lan, Taiwan. E-mail address: [email protected] (Y.-C. Chen). http://dx.doi.org/10.1016/j.jep.2015.12.032 0378-8741/& 2015 Elsevier Ireland Ltd. All rights reserved.

women (Collier et al., 2008). Although acne rarely causes death directly, psychological stress due to scars and pustule lesions on the face can have a high emotional impact on a patient's life, especially when up to 20% of teenagers may have lifelong scars due to acne (Misery, 2011; Williams et al., 2012). Multiple factors are associated with the pathogenesis of acne, including follicular hyperkeratinization, androgen-induced sebum hyper-production, follicles infected with Propionibacterium acnes and inflammation (Kurokawa et al., 2009). Multiple treatments including antibiotics, topical retinoid, oral isotretinoin, benzoyl peroxide, azelaic acid, salicylic acid, and hormone therapy are often used alone or in combination to control symptoms; nevertheless, there are still limitations with these treatments. In addition to potential gastrointestinal upset, the emergence of antimicrobial resistance in

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the community should be considered after the extended use of oral antibiotics (Williams et al., 2012). Oral isotretinoin is currently the only acne treatment that can alter the natural course of the disease; however, it is associated with teratogenicity, cheilitis, skin and mucosal dryness, eczema, liver toxicity, tiredness, epistaxis, desquamation, photosensitivity, and even inflammatory bowel disease (Etminan et al., 2013; Rademaker, 2010). Traditional Chinese medicine (TCM) is one of the most commonly used alternative medicines in Taiwan due to easy accessibility with full national health insurance coverage (Chen et al., 2007; Chen et al., 2012). Several modalities such as Chinese herbal medicine (CHM), acupuncture and cupping therapy are used, with CHM being the most common (Cao et al., 2015). CHM is often used to alleviate the severity of acne by clearing heat toxins and dampness, which are regarded as the main causes of acne from a TCM viewpoints (Cao et al., 2015). Nevertheless, the considerable complexity of CHM prescriptions makes it difficult to gain insights into CHM with regards to the mechanisms and application into clinical practice, since TCM doctors usually use several CHMs in combination to treat a disease. This may cause high heterogeneity when performing a meta-analysis on the efficacy of CHM, and may also account for substantial discrepancies between the CHM used in real clinical practice and research targets in bench studies (Hu et al., 2011). Moreover, this discrepancy may become greater if the study target is selected from a textbook or TCM classics due to the considerable differences in prescribing CHMs between practice and literature (Scheid et al., 2010). The aim of this study was to identify a CHM network for treating acne by analyzing a nationwide prescription database. It is difficult to analyze multiple CHMs used in a huge prescription database using conventional statistical methods. CHM network analysis, based on the most commonly used single CHM and CHM combinations, is crucial to understand what and why certain CHMs are prescribed and how TCM doctors treat a disease (Chen et al., 2015b; Poon, 2014).

2. Material and methods 2.1. Data source The National Health Insurance Research Database (NHIRD), which includes more than 99% of all medical records in Taiwan, was used as the prescription data source in this study. The NHIRD includes all medical information required by the National Health Insurance (NHI) program since 1995, and it is updated on a regular basis. Due to the high coverage, prescription analysis can be regarded as a form of consensus from all clinicians in Taiwan (Chen et al., 2012). Patient information including gender, birth date, place of residence, reasons for medical visits, medications, interventions, examinations, hospitalization and medical expenses are all digitized and stored in the database. The NHIRD is provided publicly for researchers, and the identification of each patient is encrypted to protect their privacy. The protocol of this study was approved by the Institutional Review Board of Chang Gung Memorial Foundation (No.: 104-4077B). 2.2. Study design and subjects Acne patients who had used at least one TCM from January 1 to December 31, 2011 were defined as TCM users. All medical care records with a single diagnosis of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 706.0 or 706.1 were included in this study. Acne is diagnosed mainly by skin manifestations, including open or closed comedones, inflammatory follicles, post-inflammatory scarring and

hyperpigmentation (Eichenfield et al., 2013). The accuracy and reliability of using ICD-9-CM codes as reasons for visits has been well validated in previous studies (Chen et al., 2010; Cheng et al., 2011). Visits for reasons other than CHM treatment, such as acupuncture and manual therapy were excluded. 2.3. CHM prescription dataset CHM prescriptions were extracted from all eligible visits for acne, and a new CHM prescription dataset was generated by integrating CHM prescriptions with CHM users’ information. A herbal formula (HF) and single herb (SH) are the only two kinds of CHM reimbursed by the NHI in Taiwan. A HF is made from a mixture of SHs with fixed a composition according to CHM classics, while a SH includes herbs, animals, insects, and minerals. According to CHM classics, every HF and SH has its own indications, which are usually aimed at treating certain TCM syndromes. All HFs and SHs are made into concentrated powder by the Good Manufacturing Pharmacy in Taiwan with strict regulation of heavy metals, insecticides and other possibly poisonous materials. 2.4. Bias assessment This dataset is unique and particularly suitable for CHM prescription analysis due to its high coverage of the general population in Taiwan and unbiased selection of CHM as a treatment option (Chen et al., 2015b). In addition, by using a nationwide database, potential selection bias and referral bias can be avoided as much as possible compared to the use of a hospital-based database (Pan et al., 2014). Although the use of a single diagnosis of acne to extract medical records may markedly decrease the number of cases, this may avoid possible confounding bias caused by other co-morbidities. In addition, the exclusion of visits for acupuncture, moxibustion, or manual therapy is helpful to avoid confounding bias with a possible influence on CHM prescriptions. 2.5. Statistical analysis Descriptive statistics were used to present the features of CHM users and prevalence of CHMs. Association rule mining (ARM) and social network analysis (SNA) were used to analyze and graphically demonstrate the combinations of CHMs. ARM is a novel data mining technique which has been widely used to explore important connections between subjects in a big database such as comorbidities, combination patterns of CHMs, relationships between TCM syndromes for allergic rhinitis, and DNA-protein binding patterns (Chen et al., 2015b; Feng et al., 2006; Leung et al., 2010; Lin et al., 2013; Tai and Chiu, 2009; Yang et al., 2012). Every possible CHM combination was evaluated using three parameters: support, confidence and lift. Support is similar to the prevalence of a certain CHM or CHM combination, while confidence and lift factors are used to evaluate the strength of connections between the CHM with a concept similar to conditional probability (Agrawal et al., 1993; Chen et al., 2014b; Yang et al., 2013a). Significant CHM combinations were identified from the entire CHM dataset only when the value of these three parameters was higher than a preset, and this was an iterative process to reveal the most significant CHM combinations. Furthermore, SNA was used to analyze the relationships between every CHM within all important CHM combinations with a graphical demonstration of the relationships and clusters of all CHMs. The detailed algorithm has been described in previous studies, and “R” and “NodelXL” software were used to perform ARM and SNA (Chen et al., 2015b; Wakita and Tsurumi, 2007; Yang et al., 2013b).

3

3.9

3.8

Heat toxin

Heat toxin

28,665 (10.2)

4.1 Liver qi stagnation with heat, spleen qi deficiency

28,762 (10.3)

4.2 Heat toxin

49,361 (17.6)

4.7 Wind heat and toxin

78,015 (27.9)

Dosage (gm/ day)

87,327 (31.2)

3. Results

TCM indications

3.1. Characteristics of TCM users From January 1st, 2011 to December 31st, 2011, a total of 91,129 patients used TCM to treat acne, 99% of whom (90,626) chose CHM as the primary treatment modality. The ratio of male to female patients was about 2:1 (28,500 versus 62,126 patients). Among all users, patients aged from 21 to 30 years used CHM most commonly (37,876 patients, 41.8% of all CHM users), followed by teenagers (11-20 years old, 27,188 patients, 30% of all CHM users).

Saposhnikovia divaricata (Turcz.) Schisch., Coptis chinensis Franch., Coptis deltoidea C. Y. Cheng et Hsiao, or Coptis teeta Wall., Ligusticum chuanxiong Hort., Platycodon grandiflorum (Jacq.) A. DC., Forsythia suspensa (Thunb.) Vahl., Scutellaria baicalensis Georgi, Mentha haplocalyx Briq., Angelica dahurica Benth. et Hood. F. or Angelica dahurica Benth. et Hook. F. var. formosana Shan et Yuan, Schizonepeta tenuifolia (Benth.) Briq., Glycyrrhiza uralensis Fisch., Citrus aurantium L.. Zhen-Ren-Huo-Ming-Yin Lonicera japonica Thunb., Lonicera hypoglauca Miq., Lonicera confusa DC., or Lonicera dasystyla Rehd., Saposhnikovia divaricata (Turcz.) Schisch., Angelica dahurica Benth. et Hood. F. or Angelica dahurica Benth. et Hook. F. var. formosana Shan et Yuan, Angelica sinensis (Oliv.) Diels., Paeonia lactiflora Pall. Boswellia carterii Birdw., Commiphora myrrha Engl., Fritillaria thunbergii Miq., Trichosanthes kirilowii Maxim. or Trichosanthes japonica Regel, Gleditsia sinensis Lam., Citrus reticulata Blanco, Glycyrrhiza uralensis Fisch. Jia-Wei-Xiao-Yao-San Paeonia lactiflora Pall., Bupleurum chinense DC., Atractylodes macrocephala Koidz., Poria cocos (Schw.) Wolf, Angelica sinensis (Oliv.) Diels., Mentha haplocalyx Briq., Glycyrrhiza uralensis Fisch., Zingiber officinale Rosc., Paeonia suffruticosa Andr., Gardenia jasminoides Ellis.. Wu-Wei-Xiao-Du-Yin Lonicera japonica Thunb., Lonicera hypoglauca Miq., Lonicera confusa DC., or Lonicera dasystyla Rehd., Chrysanthemum morifolium Ramat., Taraxacum mongolicum Hand.-Mazz., Viola prionantha Bunge., Huang-Lian-Jie-Du-Tang Gardenia jasminoides Ellis.., Scutellaria baicalensis Georgi., Coptis chinensis Franch., Phellodendron chinense Schneid. or Phellodendron amurense Rupr.

3.2. CHMs commonly used to treat acne

Qing-Shang-Fang-FengTang

Ingredients Herbal formula

Table 1 The top five single herbal formulas (HFs) used to treat acne during 2011 (Total prescriptions ¼ 279,823).

Number of prescriptions (%)

H.-Y. Chen et al. / Journal of Ethnopharmacology 179 (2016) 1–8

A total of 279,823 CHM prescriptions were made to treat acne, and about 642 kinds of CHM were used for these prescriptions. TCM doctors often combined 5-6 CHMs in one prescription, and on average there were 5.6 CHMs in each prescription. Qing-ShangFang-Feng-Tang was the most commonly used HF (31.2% of all prescriptions), followed by Zhen-Ren-Huo-Ming-Yin (27.9%) and Jia-Wei-Xiao-Yao-San (17.6%) (Table 1). For SH, Forsythia suspensa (Thunb.) Vahl., Lian Qiao, was used most frequently (22.3% of all prescriptions), followed by Taraxacum mongolicum Hand.-Mazz. (19.2%) and Lonicera japonica Thunb., Jin Yin Hua, (13.4%) (Table 2). In general, a HF was the major component of each prescription with a higher dosage than a SH (about 4 g/day for a HF, and 1–2 g/ day for a SH). 3.3. CHM network to treat acne A total of 31 important CHM combinations were identified by applying ARM and SNA on the CHM prescription dataset. ZhenRen-Huo-Ming-Yin with Forsythia suspensa (Thunb.) Vahl. was the most commonly used CHM-CHM combination, accounting for 7.2% of all prescriptions, followed by Qing-Shang-Fang-Feng-Tang with Taraxacum mongolicum Hand.-Mazz. (7.1%) and Zhen-Ren-HuoMing-Yin with Taraxacum mongolicum Hand.-Mazz. (6.6%) (Table 3). CHM-CHM combinations were clustered and graphically demonstrated using SNA. Strong adjuvant relationships between the centers of each CHM cluster were clearly seen in the graphical demonstration (Fig. 1). Five clusters with their own trends for TCM indication were found when summarizing the indications for each CHM, and heat syndrome seemed to be the most important indication for treating acne (Fig. 1b). For example, Zhen-Ren-Huo-Ming-Yin is the core of cluster 1, which was mainly prescribed for “heat-toxin with hardness/phlegm syndrome”, Forsythia suspensa (Thunb.) Vahl. is the core of cluster 3 (heat-toxin syndrome), and Qing-Shang-FangFeng-Tang is the core of cluster 4 (heat-toxin syndrome). All of these clusters were connected directly or through other CHMs. Cluster 5 was special since this cluster was isolated from other CHMs with strong inter-connections, although the prevalence was lower (Fig. 1(a), thin but dark connections with medium-sized CHM circles). Multiple mechanisms of action were found among the CHM treatments, including anti-inflammation, anti-bacterial infection, mood modification, skin whitening and hormone therapy, especially when multiple CHMs were used in combination (Fig. 1c). An anti-inflammation effect was found exclusively among CHMs, and the detailed pharmacological mechanisms are summarized in Appendix A (last assessed in PubMed: May 30, 2015). Almost all of the SHs have been studied in the treatment of acne, whereas studies on the HFs are lacking, although their role in treating acne may be more important than SHs according to their central role in clusters (Fig. 1c, grey circles represent no studies on the target CHM). Cluster 5, the isolated cluster around the left lower corner,

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Table 2 The top 10 most commonly used single herbs (SHs) used to treat acne (Total prescriptions ¼ 279,823). Latin name

English name

Forsythia suspensa (Thunb.) Vahl. Taraxacum mongolicum Hand.-Mazz. Lonicera japonica Thunb., Lonicera hypoglauca Miq., Lonicera confusa DC., or Lonicera dasystyla Rehd. Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf Rheum palmatum L., Rheum tanguticum Maxim. ex Balf., or Rheum officinale Baill. Angelica dahurica Benth. et Hood. F. or Angelica dahurica Benth. et Hook. F. var. formosana Shan et Yuan Scutellaria baicalensis Georgi Paeonia suffruticosa Andr. Salvia miltiorrhiza Bge. Morus alba L.

Lian Qiao Heat toxin Pu Gong Ying Heat toxin Jin Yin Hua Heat toxin

covered nearly all of the mechanisms of action to treat acne by combining six SHs.

4. Discussion To the best of our knowledge, this is the first study on CHM prescription analysis for the treatment of acne. CHM is the most commonly used TCM modality to treat acne, accounting for more than 99% of all TCM users. The CHM prescriptions were extremely complicated, with more than 600 kinds of CHM used. On average, one prescription was composed of 5–6 kinds of CHM. By combing ARM and SNA, a large number of CHM prescriptions can be analyzed and a CHM network identified. Through the graphical demonstration of a CHM network, the relationships between disease-TCM indications/syndrome-CHM treatment and core CHM treatments can be clearly identified. The phenomenon “complex disease, multiple targets” can also be investigated when treating acne as with other skin diseases (Li and Zhang, 2013). Only when using network analysis can the whole picture of a CHM treatment strategy be viewed, rather than fragments of information gained from the analysis of a single CHM (Chen et al., 2015a; Chen et al., 2015b). The CHM network revealed that “heat syndrome” was the most common treatment target, combined with other minor TCM syndromes including dampness or hardness, and most of the CHMs had anti-inflammation effects (Fig. 1b–c). Overall, the CHM treatment strategy was rather similar to Western medicine therapy, and focused on anti-inflammation, anti-bacteria, anti-hyperkeratinization and decreasing sebum production (Eichenfield et al., 2013). The usefulness of anti-inflammatory and anti-bacterial effects has been widely studied in CHMs aiming at treating “heat syndrome”, such as Forsythia suspensa (Thunb.) Vahl. and

TCM indications Dosage (gm/day) Number of prescriptions (%) 1.8 1.6 1.4

62,309 53,749 37,556

(22.3) (19.2) (13.4)

Yi Yi Ren Da Huang Bai Zhi

Dampness heat 1.5 Heat toxin 2.1 Wind dampness 1.7

32,883 31,061 30,656

(11.7) (11.1) (11.0)

Huang Qin Mu Dan Pi Dan Shen Sang Bai Pi

Heat toxin Blood heat Blood stasis Heat

23,351 21,937 18,628 16,980

(8.3) (7.8) (6.7) (6.1)

2.4 2.3 1.6 1.2

Scutellaria baicalensis Georgi (Muluye et al., 2014). From a TCM viewpoint, in contrast to a single CHM, combinations of CHMs are thought to have more effective anti-inflammation/anti-bacteria effects but less adverse events (Che et al., 2013). The strong intercluster connections (ex: Zhen-Ren-Huo-Ming-Yin with Forsythia suspensa (Thunb.) Vahl.) and within-cluster connections (ex: Forsythia suspensa (Thunb.) Vahl. with Lonicera japonica Thunb.) revealed how the TCM doctors combined CHMs to achieve a greater anti-inflammation effect, known as the principle of “Jun-ChenZuo-Shi” (Fan et al., 2006). Interestingly, the CHM network revealed that the TCM doctors usually took the patient's overall mental and physical condition into consideration when making a prescription. Although hormone therapy and mood modification therapy did not form new clusters, they were frequently included in clusters with tight connections to core CHMs (Fig. 1c). Hormone therapy is an interesting issue when treating acne, since androgen-related sebum hypersecretion is an important therapeutic target, especially for severe acne (Eichenfield et al., 2013). Scutellaria baicalensis Georgi. (Huang Qin), Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf (Yi Yi Ren) and Glycyrrhiza uralensis Fisch. (Gan Cao) have been reported to have an anti-androgen effect, and an estrogenic effect has also been reported with Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf (Armanini et al., 1999; Hsia et al., 2009; Hsia et al., 2007; Kim et al., 2014). This unique hormonal therapy and subsequent decrease in sebum secretion may be the reason why Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf has been used to “eliminate dampness” for hundreds of years, where dampness refers to abnormal liquid secretion from the body. An anti-bacterial effect was also a feature of CHM treatment, and was found among clusters indicating heat syndrome. In addition to directly destroying bacteria as with conventional antibiotics, enhancing innate immunity was extensively found in CHM

Table 3 The top ten most commonly used two CHM combinations. Combinations of CHM

Number of prescriptions (%) Confidence Lift

Zhen-Ren-Huo-Ming-Yin Qing-Shang-Fang-Feng-Tang Zhen-Ren-Huo-Ming-Yin Forsythia suspensa (Thunb.) Vahl.

with with with with

Qing-Shang-Fang-Feng-Tang

with

Qing-Shang-Fang-Feng-Tang Forsythia suspensa (Thunb.) Vahl. Qing-Shang-Fang-Feng-Tang Taraxacum mongolicum Hand.Mazz. Forsythia suspensa (Thunb.) Vahl.

with with with with

Forsythia suspensa (Thunb.) Vahl. Taraxacum mongolicum Hand.-Mazz. Taraxacum mongolicum Hand.-Mazz. Lonicera japonica Thunb., Lonicera hypoglauca Miq., Lonicera confusa DC., or Lonicera dasystyla Rehd. Lonicera japonica Thunb., Lonicera hypoglauca Miq., Lonicera confusa DC., or Lonicera dasystyla Rehd. Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf Huang-Lian-Jie-Du-Tang Viola prionantha Bunge.

with Morus alba L.

20178 19764 18368 17036

(7.2) (7.1) (6.6) (6.1)

32.4 36.8 34.2 45.4

1.2 1.2 1.2 2.0

14422 (5.2)

38.4

1.2

11727 11397 9346 7729

(4.2) (4.1) (3.3) (2.8)

35.7 34.7 32.6 53.4

1.1 1.6 1.0 2.8

6721 (2.4)

39.7

1.8

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5

Fig. 1. (a) Chinese herbal medicine (CHM) network for treating acne. (b) Network with TCM syndrome mapping. (c) Network with potential pharmacological mechanisms. The width of connecting lines indicates the confidence of each combination, and the depth of color indicates the prevalence. A thicker line means a higher prevalence, and a wider line means a stronger relationship between connected CHMs. The size of a circle indicates the prevalence of each CHM, and a CHM with a higher prevalence has a larger circle.

networks. Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf has been reported to increase natural killer cells and peripheral cytotoxic T lymphocytes, and Angelica dahurica Benth. has been reported to be able to enhance dendritic cells (Hidaka et al., 1992; Kim et al., 2013). Through enhancing innate immunity to bacterial infection, concerns with regards to drug resistance caused by the frequent or long-term use of conventional antibiotics may be reduced. Consequently, similar to treatment strategies in Western medicine, an add-on anti-bacterial effect may also improve the effectiveness of anti-inflammation CHMs, for example, Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf combined with Forsythia suspensa (Thunb.) Vahl. (Fig. 1c). As an adjuvant CHM, Jia-Wei-Xiao-Yao-San, the third most commonly used HF, and Gardenia jasminoides Ellis. are two CHMs with an anti-depression effect, which is unique in CHM treatment (Oh et al., 2007; Zhang et al., 2015). Emotional stress caused by acne has a great impact on the quality of life, especially in adolescents, and it may be associated with a high suicide rate (Hull and D’Arcy, 2005). Moreover, a depressive mood may be precipitated by receiving isotretinoin treatment, and this may limit its use (Marqueling and Zane, 2007). An add-on CHM may be able to complement the lack of mood modification when using only antiinflammation and anti-bacterial CHMs, or even Western medicine alone. Jia-Wei-Xiao-Yao-San may be especially suitable for

adolescent girls since it is commonly used for premenstrual syndrome, and acne is one of the most prevalent skin manifestations (Chen et al., 2014a; Itsekson et al., 2004). Post-inflammatory skin hyperpigmentation is a common and bothersome cosmetic problem among acne patients. Angelica dahurica Benth. et Hood. F. and Morus alba L. have been reported to have a potential skin whitening effect through blocking melanin release (Cho et al., 2006; Oh et al., 2010). When used with antiinflammation, anti-bacterial, and anti-androgen CHMs, coverage of the pathogenesis of acne and the symptoms may be more comprehensive, and the likelihood of hyperpigmentation may be decreased.

5. Conclusion The CHM network revealed prevalent CHM combinations with trends of CHM indications and pharmacological mechanisms. In contrast to Western medicine, CHMs are prescribed based on the patient's individual condition, and TCM doctors usually combine several CHMs with different pharmacological mechanisms in order to cover the pathogenesis of acne as needed. The results of the CHM network analysis are important for TCM doctors and researchers, since they provide not only a great reference for the

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choice and combination of CHMs in their practice, but also important guidance for researchers when choosing study candidates. Since these results are acquired from a nationwide database, the core CHM treatments and CHM combinations revealed in this study may be a form of consensus of the majority of TCM doctors in Taiwan. Therefore, the attrition rate may be improved when discovering new drugs from CHMs, and an understanding of complicated CHM prescriptions may become easier through the application of the findings of this study.

Conflict of Interest None.

Financial disclosure None.

Appendix A. Possible mechanisms of Chinese herbal medicine (CHM) for treating acne. (Last assessed in Pubmed: May 30, 2015).

English name

Latin name

Single herb (SH) Lian Qiao

Forsythia suspensa (Thunb.) Vahl.

Possible mechanisms

Anti-inflammation (Dai et al., 2009) Anti-bacteria (Qu et al., 2012; Qu et al., 2008) Pu Gong Ying Taraxacum mongolicum Hand.-Mazz. Anti-inflammation (Koh et al., 2010; Zhang et al., 2012) Jin Yin Hua Lonicera japonica Thunb., Lonicera hypoglauca Miq., Lonicera confusa Anti-inflammation (Cheng et al., 2014; Kang DC.,or Lonicera dasystyla Rehd. et al., 2010; Kwak et al., 2003) Anti-bacteria (Han et al., 2014; Xiong et al., 2013) Yi Yi Ren Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf Anti-inflammation (Huang et al., 2014; Zhao et al., 2014) Anti-bacteria (Hidaka et al., 1992) Hormone therapy (Hsia et al., 2009) Bai Zhi Angelica dahurica Benth. et Hood. F. or Angelica dahurica Benth. et Anti-inflammation (Lee et al., 2011) Hook. F. var. formosana Shan et Yuan Anti-bacteria (Kim et al., 2013) Skin whitening (Cho et al., 2006) Da Huang Rheum palmatum L.,Rheum tanguticum Maxim. ex Balf., or Rheum Anti-inflammation (Wang et al., 2010) officinale Baill. Zi Hua Di Ding Viola prionantha Bunge. Anti-bacteria (Xie et al., 2004) Gan Cao Glycyrrhiza uralensis Fisch. Anti-inflammation (Wu et al., 2011) Anti-bacteria (He et al., 2006) Hormone therapy (Hajirahimkhan et al., 2013; Hu et al., 2009) Sang Bai Pi Morus alba L. Anti-inflammation (Zelova et al., 2014) Anti-bacteria (Park et al., 2003; Wang et al., 2012) Skin whitening (Oh et al., 2010; Park et al., 2011) Huang Qin Scutellaria baicalensis Georgi Anti-inflammation (Choi et al., 2014) Anti-bacteria (Lu et al., 2011) Hormone therapy (Kim et al., 2014) Tu Fu Ling Smilax glabra Roxb. Anti-inflammation (Lu et al., 2015) Anti-bacteria (Xu et al., 2013) Zao Jiao Gleditsia sinensis Lam. Anti-inflammation (Dai et al., 2002) Anti-bacteria (Zhou et al., 2007) Zhi Zi Gardenia jasminoides Ellis. Anti-inflammation (Fu et al., 2012; Zheng et al., 2010) Anti-depression (Zhang et al., 2015) Tian Hua Fen Trichosanthes kirilowii Maxim. or Trichosanthes japonica Regel Anti-bacteria (Li et al., 2006) Bai Xian Pi Dictamnus dasycarpus Turcz. Anti-inflammation (Han et al., 2015) Xia Ku Cao Prunella vulgaris L. Anti-inflammation (Hwang et al., 2013) Pi Pa Ye Eriobotrya japonica (Thunb.) Lindl. Anti-inflammation (Cha et al., 2011; Lee et al., 2008) Xuan Shen Scrophularia ningpoensis Hemsl. Anti-bacteria (Li et al., 2009) Zi Cao Arnebia euchroma (Royle) Johnst., Lithospermum erythrorhizon Sieb. Anti-bacteria (Damianakos et al., 2012; Li et al., et Zucc., or Arnebia gutfata Bunge 2012a) Herbal formula (HF) Huang-LianAnti-inflammation (Li et al., 2012b; Wu et al., Jie-Du-Tang 2012) Anti-bacteria (Wei et al., 2013)

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