Hindawi

Evidence-Based Complementary and Alternative Medicine

Volume 2020, Article ID 4140692, 15 pages
https://doi.org/10.1155/2020/4140692

Review Article
Effectiveness and Safety of Herbal Medicine for Atopic Dermatitis:
An Overview of Systematic Reviews

Chan-Young Kwon ,1 Boram Lee ,2 Suran Kim,3 Jaesuk Lee,3 Minjung Park ,3
and Namkwen Kim 3,4
1
Department of Oriental Neuropsychiatry, Dong-eui University College of Korean Medicine, 62 Yangjeong-ro, Busanjin-gu,
Busan 47227, Republic of Korea
2
Clinical Medicine Division, Korea Institute of Oriental Medicine, 1672 Yuseongdae-ro, Yuseong-gu, Daejeon 34054,
Republic of Korea
3
Guideline Center for Korean Medicine, National Institute for Korean Medicine Development, 173 Toegye-ro, Jung-gu,
Seoul 04554, Republic of Korea
4
Department of Ophthalmology and Otolaryngology and Dermatology, School of Korean Medicine, Pusan National University,
20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do 50612, Republic of Korea

Correspondence should be addressed to Namkwen Kim; drkim@pusan.ac.kr

Received 8 January 2020; Accepted 11 June 2020; Published 17 July 2020

Academic Editor: Pratibha V. Nerurkar

Copyright © 2020 Chan-Young Kwon et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Objectives. Herbal medicine (HM) is attracting attention for treating atopic dermatitis (AD). This overview was conducted to
summarize and critically evaluate the current systematic reviews (SRs) on HM for the treatment of AD. Methods. Through
comprehensive searches, all relevant SRs on HM for AD published until May 2020 were included. The quality of included SRs was
assessed using the AMSTAR-2 tool. Moreover, original randomized controlled trials (RCTs) included in the SRs were resyn-
thesized to investigate the efficacy and safety of oral HM for AD. The quality of evidence for the main findings was evaluated using
the GRADE approach. Results. Nine SRs were included in this overview. HM showed significantly better efficacy in terms of total
effective rate (TER), itching and sleep symptom scores, quality of life, and the dose of topical treatment used compared with
placebo. HM as a monotherapy and/or an adjunctive therapy to conventional medication (CM) showed significantly better results
on the efficacy, symptom relief, and some laboratory parameters related to the inflammatory response. The methodological quality
was generally low. When 58 original RCTs were reanalyzed, HM showed significantly lower SCORing Atopic Dermatitis
(SCORAD) score and higher TER than the placebo or CM. In terms of the safety profile, HM was not significantly different from
the placebo and was better than CM. The quality of evidence ranged from “moderate” to “very low.” Conclusion. The results
suggested that HM as a monotherapy or an adjunctive therapy is promising for the treatment of AD. However, due to low
methodological quality and low quality of evidence, further rigorous, well-designed, high-quality SRs, and RCTs are needed to
make clinical recommendations on HM use.

1. Introduction tuberculosis), relations with microflora, duration of

breastfeeding, and social position of the parents are con-
Atopic dermatitis (AD) is a common, chronic, inflamma- sidered to be relevant [2]. Today, topical glucocorticoste-
tory, and refractory skin disease characterized by itching, dry roids, calcineurin inhibitors, tacrolimus, and pimecrolimus
skin, skin redness, and thickened skin. The prevalence of this as well as some adjuvant therapies including ultraviolet (UV)
disease is known to be around 2.1%–4.9% worldwide [1]. In irradiation, lifestyle modification, antimicrobial therapy,
addition to genetic causes, environmental factors such as the systemic anti-inflammatory treatment, and immunotherapy
history of prototypical infections (e.g., hepatitis and are recommended for the treatment of AD based on the
2 Evidence-Based Complementary and Alternative Medicine

international clinical guidelines [3–5]. However, the efficacy Oriental Medicine Advanced Searching Integrated System).
of a highly standardized treatment strategy is insufficient, The initial search date was June 14, 2019, and we conducted
and highly individualized treatment is recommended for the an updated search on May 24, 2020, to provide a more up-to-
management of AD, emphasizing the need for a tailored date and comprehensive evidence. There was no restriction
multimodal strategy [4]. In this regard, attempts to use on language, publication status (including gray literature), or
complementary and integrative medicine (CIM) in the publication country. In addition, the reference lists of the
management of AD are increasing [6]. included reviews were hand-searched to identify additional
East Asian traditional medicines (EATMs) such as tra- relevant reviews. The following terms were used when
ditional Chinese medicine, traditional Korean medicine, and searching PubMed: (Dermatitis, Atopic[MeSH] OR atopic
Kampo medicine have been used for health care in Asia for [tiab]) AND (Drugs, Chinese Herbal[MeSH] OR Medicine,
thousands of years. Recently, valuable CIM approaches such East Asian Traditional[MeSH] OR Herbal Medicine[MeSH]
as herbal medicine (HM) are known to be popular not only OR herbal[tiab]). The search strategy for each database is
in Asian countries but also in Western countries. Although presented in Supplement 1.
solid evidence is still needed, some HMs of both topical use
and oral administration have been shown to be effective in
skin diseases including AD [7–9]. Based on these accu- 2.2. Inclusion and Exclusion Criteria. This overview included
mulating evidences, in the Republic of Korea, a clinical SRs and/or meta-analyses that examined the efficacy and
practice guideline (CPG) on HM treatment for AD was safety of HM on AD by analyzing RCTs, quasi-RCTs, and/or
developed and published in 2016 [10]. controlled clinical trials (CCTs) regardless of age, gender,
In the treatment of diseases with complex pathological race/ethnicity, and disease duration of AD patients. HM was
mechanisms such as AD, HM with the so-called “multi- compared with no treatment, usual care, or active controls
component, multitarget, and multipathway” characteristic such as conventional medication (CM) in the treatment of
can be a suitable candidate [11]. Clinical evidences sup- AD, or the benefit of HM combined with other treatments
porting the efficacy and safety of HM as treatment for AD was compared with those of other treatments alone. In this
have been extensively accumulated, and some systematic study, HM included not only individual herbs but also
reviews (SRs) have summarized these clinical evidences. prescriptions composed of various herbs, and studies on
However, the evidence and methodological quality of SRs individual compounds extracted from herbs were also
regarding the use of HM for AD has not yet been sum- permitted. The following cases were excluded: (1) non-SRs,
marized and evaluated, and this should be conducted for (2) SRs that provided a comparison between multiple HMs,
clinical recommendations. Today, an overview of systematic and (3) SRs that analyzed the efficacy and safety of HM for
reviews, or umbrella reviews, has been considered as a new nonhuman studies, for example, SR for animal studies.
research strategy that described the current body of SR
evidence [12–14]. It provides a synthesis and integrates 2.3. Study Selection and Data Extraction. Two reviewers
information from multiple studies to reduce the uncer- (CYK and BL) independently assessed whether the searched
tainties in decision-making and to provide updated evi- articles met the inclusion criteria. The screening of the titles
dence, in situations where there are a large number and and abstracts of the searched literature was conducted for
various qualities of available information [15]. first inclusion, and the full texts of all eligible studies were
This overview aimed to assess the methodological quality reviewed for final inclusion. In case of disagreement, they
of the current SRs on the efficacy and safety of HM as a tried to resolve it through discussions.
treatment for AD. Moreover, we aimed to reanalyze and Using a standardized data extraction form in Excel 2016,
synthesize original randomized controlled clinical trials the following data were extracted from included SRs: first
(RCTs) from the included SRs on oral HM for AD to clarify author’s name, publication year, country, number of pri-
its efficacy and safety and to evaluate the quality of evidence mary studies included, total sample size, search period,
for the main findings. interventions of treatment group and control group, major
outcomes and results from meta-analysis, safety data, details
2. Methods on the assessment of methodological quality, the author’s
conclusions, and cautions in the interpretation of results.
We conducted the overview according to the guidelines Two reviewers (CYK and BL) independently extracted the
stated in the Cochrane handbook [16]. Ethics approval was abovementioned information from the included SRs, and in
not required as this is an overview. The protocol of this case of disagreement, they tried to resolve it through
overview was registered in PROSPERO (registration ID: discussions.
CRD42020150475).

2.4. Quality Assessment. The Assessing the Methodological

2.1. Search Strategy. One reviewer (CYK) conducted a Quality of Systematic Reviews- (AMSTAR-) 2 tool was used
comprehensive search on three English databases (Medline to assess the methodological quality of the included SRs by
(via PubMed), EMBASE (via Elsevier), and the Cochrane two independent reviewers (CYK and BL) [17]. This 16-item
Library), one Chinese database (the China National validated evaluation tool is used for evaluating the meth-
Knowledge Infrastructure), and one Korean database (the odological quality of an SR. All 16 items were evaluated and
Evidence-Based Complementary and Alternative Medicine 3

rated as “yes,” “partially yes,” or “no” [17]. AMSTAR-2 does disagreement, the two reviewers tried to resolve it through
not generate an overall score; however, the overall quality of discussions.
each SR was assessed and classified as either “high,”
“moderate,” “low,” or “critically low” by referencing the 3. Results
critical weakness and flaw of each SR [17]. In case of dis-
agreement in the result of quality assessment, the two re- 3.1. Description of Included Studies. We identified 1,832
viewers (CYK and BL) tried to resolve it through discussions. studies by searching five databases. After removing dupli-
cations, the titles and abstracts of the remaining 1,396
studies were screened. Then, the full texts of 31 potentially
2.5. Data Analysis relevant articles were reviewed for eligibility. Seventeen
articles that were identified as non-SRs, two that were the
2.5.1. Qualitative Synthesis of Included SRs. In the first step, previous version of Cochrane review, two that were not
a qualitative synthesis of the included SRs was performed related to HM, and one that used the same data (disserta-
using the abovementioned extracted data. The data obtained tion) were excluded. Finally, a total of 9 SRs [7, 21–28] were
from each SR was presented as odds ratio (OR) or risk ratio included in this overview (Figure 1).
(RR) for dichotomous data, and mean difference (MD) or
standardized mean difference (SMD) for continuous data,
with 95% confidence intervals (CIs). 3.2. Study Characteristics. All nine SRs [7, 21–28] included
in this overview conducted a meta-analysis of 6–37 RCTs.
Four reviews [7, 22, 25, 27] were published in English, and
2.5.2. Quantitative Synthesis of Original RCTs. In the sec- the remaining five [21, 23, 24, 26, 28] were published in
ond step, we obtained the full text of the original RCTs in Chinese. There was a Cochrane review [22] comparing the
the SRs included in this overview to comprehensively efficacy and safety of oral and/or external HM with placebo,
reevaluate the efficacy and safety of HM for AD using a no treatment, or active controls. Among the remaining SRs,
meta-analysis, particularly the oral HM. In addition, data one [21] compared oral HM with oral antihistamines; one
on the components of oral HM used were extracted from [7] compared oral HM with placebo, no treatment, or active
each RCT by the two independent reviewers (CYK and controls; one [23] compared oral HM alone or in combi-
BL). For the outcomes including the scoring atopic der- nation with CM with CM alone; one [24] compared oral or
matitis (SCORAD) score, total effective rate (TER), and external HM in combination with CM with CM alone; one
the incidence of adverse events (AEs), a meta-analysis of [25] compared EATM treatments including oral HM,
the following comparisons was conducted: (1) oral HM acupuncture, and moxibustion with placebo or CM; one [26]
versus placebo, (2) oral HM versus conventional medi- compared oral Jinpi (meaning tonifying spleen) HM alone
cine, and (3) oral HM combined with conventional or in combination with CM with CM alone; one [27]
medicine versus conventional medicine alone. The het- compared Tripterygium agents alone or in combination with
erogeneity of effect measures between the studies was CM with CM alone; one [28] compared oral or external HM
assessed using both the chi-square test and the I-squared with CM or placebo. Among the outcomes meta-analyzed,
statistic (I2). When the value of I2 is greater than 50% or TER was the most frequently used outcome in eight reviews
75%, the heterogeneity was considered to be substantial or [21–28], followed by recurrence rate in six reviews
high, respectively. When the heterogeneity was not high [21, 23, 25–28], and SCORAD score and serum level of
(I2 ≤ 75%) and when the number of studies included in immune-related substances such as immunoglobulin E
each meta-analysis was less than five [18, 19], a fixed- (IgE), interleukin (IL)-c, IL-4, and eosinophils (EOS) in four
effects model was used. Otherwise, a random-effects reviews [23, 26–28], respectively. The main characteristics of
model was used. We used the Review Manager version 5.3 the included SRs are shown in Table 1.
software (Cochrane, London, UK) to perform all statis-
tical analyses.
3.3. Methodological Quality. According to the AMSTAR-2
checklist, all reviews specified the research question and
2.6. Quality of Evidence. Using the grading of recommen- inclusion criteria including the components of PICO and
dations, assessment, development, and evaluation (GRADE) explained the selection of the study designs for inclusion.
approach, two reviewers (CYK and BL) independently However, only two reviews [22, 27] preregistered the study
assessed the quality of evidence for the main findings from protocol. The authors of most SRs [21–23, 25, 27, 28] in-
the quantitative synthesis of original RCTs. The GRADE dependently performed the study selection and data ex-
method is a validated tool for evaluating the quality of traction. Except for the Cochrane review [22], all other
evidence by assessing the following five key items: (1) risk of studies did not describe the excluded studies with reasons.
bias (RoB), (2) inconsistency, (3) indirectness, (4) impre- Except for one study [21], which did not even describe the
cision of results, and (5) probability of publication bias. For list of included RCTs, all other studies described the details
the assessment of the RoB item, we reassessed the quality of of included RCTs adequately [7, 22, 25, 27] or insufficiently
primary RCTs within the SRs using Cochrane’s RoB tool [23, 24, 26, 28]. Three reviews [21, 23, 24] that assessed the
[20]. The quality of evidence for the main findings was methodological quality of included RCTs using only the
judged as “very low,” “low,” “moderate,” or “high.” In case of Jadad scale were evaluated using an unsatisfactory quality
4 Evidence-Based Complementary and Alternative Medicine

Records identified through

5 databases searching (n = 1,832)
Cochrane Library: 77, PubMed: 373,
EMBASE: 889, CNKI: 491, OASIS: 2

Records after duplicates

removed
(n = 1,396)

Titles and abstracts

screened Records excluded (n = 1,365)
(n = 1,396)

Records excluded (n = 22)

(i) Not systematic review: 17
Full-text articles assessed (ii) Previous version of
for eligibility Cochrane review: 2
(n= 31) (iii) Not related to herbal
medicine: 2
(iv) Use of duplicate data: 1
Studies included
in this overview
(n = 9)

Figure 1: PRISMA flow chart of the study selection process.

assessment tool. All other reviews using Cochrane’s RoB tool [22] reported that oral or external HM showed better results
were evaluated using a satisfactory quality assessment tool. in terms of TER (RR: 2.09, 95% CI: 1.32 to 3.32, 2 studies, 85
With regard to the sources of funding for the included RCTs, participants), itching score (which was rated using a visual
only the Cochrane review [22] reported the details. Most analog scale (VAS)) (SMD: −1.53, 95% CI: −2.64 to −0.41, 2
reviews [7, 21, 22, 24, 25, 27, 28] included were considered to studies, 94 participants), overall severity score (SMD: −0.88,
use the appropriate method for the statistical combination of 95% CI −1.67 to −0.09, 4 studies, 239 participants), and
results. The two reviews [23, 26] rated “no” did not provide a children’s dermatology life quality index (CDLQI) score
definition of the use of the random-effects model or the (MD: −2.50, 95% CI: −4.77 to −0.23, 1 study, 85 participants)
fixed-effects model or distinguish their use according to compared with placebo. They planned to perform sensitivity
statistical heterogeneity. Three reviews [21, 22, 25] consid- analysis by excluding studies with low methodological
ered the effect of RoB of the included RCTs on the synthesis quality; however, they failed to do due to the lack of enough
results. Among them, two reviews [21, 22] performed a studies. Tan et al. [7] reported that oral HM showed sig-
sensitivity analysis according to methodological quality, and nificant benefits compared with placebo based on the ery-
the other one [25] used a methodological quality as selection thema score (SMD: −0.76, 95% CI: −1.05 to −0.47, 3 studies,
criteria for their analysis. Except for one review [21], all the 245 participants), surface damage score (SMD: −1.08, 95%
remaining reviews noted the effect of RoB of the included CI: −1.59 to −0.56, 3 studies, 245 participants), itching score
RCTs on the reliability of their results. Except for the two (MD: −1.10, 95% CI: −1.59 to −0.61, 1 study, 71 participants),
reviews [23, 26], the remaining reviews did not show sta- sleep score (MD −0.80, 95% CI: −1.12 to −0.48, 1 study, 71
tistically significant heterogeneity in their meta-analysis or participants), CDLQI score (MD: −2.50, 95% CI: −4.77 to
described an explanation to clarify the heterogeneity that −0.23, 1 study, 85 participants), and a dose of topical
occurred. With regard to reporting bias, except for one treatment used (MD: −24.50, 95% CI: −27.92 to −21.08, 1
review [25], the investigation of publication bias was con- study, 91 participants). However, both of these reviews were
ducted. All included reviews had no potential sources of based on a small number of and low-quality RCTs; therefore,
conflicts of interest. The overall quality of one Cochrane caution should be taken when interpreting our results
review [22] was high without a critical flaw. However, the (Table 1).
remaining reviews had low or critically low quality (Table 2).
3.4.2. HM versus CM
3.4. What Do the SRs Say about HM for AD?
(1) Efficacy and Symptom Relief. In most reviews
3.4.1. HM versus Placebo. Two reviews [7, 22] reported the [7, 21–24, 26–28], HM as a monotherapy and/or an ad-
efficacy of HM on AD compared with the placebo. Gu et al. junctive therapy to CM showed significantly better results on
Evidence-Based Complementary and Alternative Medicine 5

Table 1: Characteristics of included systematic reviews.

First Studies
First author Search Control Main results
author’s (sample Key conclusion
(year) duration intervention (meta-analysis)
country size)
(I) Oral HM vs. oral Meta-analysis showed that
antihistamines HM is effective in treating AD,
(1) TER∗ and its curative effect is
Gong 11 RCTs Inception- Oral 11 RCTs, n � 1479; OR 5.64, superior to antihistamine. The
China
(2009) [21] (1,479) 2007.12. antihistamines 95% CI 4.07 to 7.81, I2 � 0% conclusion of this study is
(2) Recurrence rate+ credible, suggesting that HM
11 RCTs, n � 1436; OR 0.38, treatment of AD has positive
95% CI 0.29 to 0.49, I2 � 0% prospects.
(I) Oral or external HM vs.
placebo
(1) TER∗
2 RCTs, n � 85; RR 2.09, 95% CI
1.32 to 3.32, I2 � 0%
(2) Itching VAS+
2 RCTs, n � 94; SMD −1.53, 95%
CI −2.64 to −0.41, I2 � 74%
(3) Overall severity+
4 RCTs, n � 239; SMD −0.88,
95% CI −1.67 to −0.09, I2 � 87%
(4) CDLQI score+
1 RCT, n � 85; MD −2.50, 95%
CI −4.77 to −0.23
(II) Oral or external HM vs. CM We could not find conclusive
(1) TER∗ evidence that oral or external
21 RCTs, n � 1868; RR 1.43, 95% HM could reduce the severity
CI 1.27 to 1.61, I2 � 65% of eczema in children or
(2) Itching VAS+ adults. We assessed most of
Placebo, no 7 RCTs, n � 465; SMD −0.83, the studies as high risk of bias,
Gu (2013) 28 RCTs Inception-
China treatment, or 95% CI −1.43 to −0.22, I2 � 89% particularly in blinding of
[22] (2,306) 2012.9.
active controls (3) Overall severity+ participants and personnel,
15 RCTs, n � 1062; SMD −0.97, and there was substantial
95% CI −1.23 to −0.71, I2 � 74% inconsistency between
(III) Oral or external HM vs. oral studies, so any positive effect
HM of HM must be interpreted
(1) TER∗ with caution.
1 RCT, n � 20; RR 1.13, 95% CI
0.78 to 1.63
2) Itching VAS+
1 RCT, n � 23; MD −1.05, 95%
CI −1.75 to −0.35
(3) Skin lesion score+
1 RCT, n � 23; MD −1.59, 95%
CI −2.92 to −0.26
(4) Overall severity+
1 RCT, n�20; MD -3.43, 95% CI
-7.01 to 0.15
5) CDLQI score+
1 RCT, n � 20; MD 0.90, 95% CI
−2.89 to 4.69
6 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.
First Studies
First author Search Control Main results
author’s (sample Key conclusion
(year) duration intervention (meta-analysis)
country size)
(I) Oral HM vs. placebo
(1) Erythema score+
3 RCTs, n � 245; SMD −0.76,
95% CI −1.05 to −0.47, the value
of I2 was not presented.
(2) Surface damage score+
3 RCTs, n � 245; SMD −1.08,
95% CI −1.59 to −0.56, the value
of I2 was not presented.
HM significantly improved
(3) Itching score+
symptom severity of AD and it
1 RCT, n � 71; MD −1.10, 95%
was reported as well-tolerated.
CI −1.59 to −0.61
Placebo, no The overall risk of bias
Tan (2013) 6 RCTs Inception- (4) Sleep score+
China treatment, or assessment found that the
[7] (432) 2011. 1 RCT, n � 71; MD −0.80, 95%
active controls quality of studies was poor;
CI −1.12 to −0.48
therefore, the results from the
(5) CDLQI score+
meta-analysis have to be
1 RCT, n � 85; MD −2.50, 95%
interpreted with caution.
CI −4.77 to −0.23
(6) Dose of topical treatment
used+
1 RCT, n � 91; MD −24.50, 95%
CI −27.92 to −21.08
(II) Oral HM + CM vs. CM
(1) Overall severity score+
1 RCT, n � 98; MD −2.56, 95%
CI −3.46 to −1.66
(I) Oral HM (or oral HM + CM)
vs. CM
(1) TER∗
13 RCTs, n � 1232; OR 4.86,
The current clinical evidence
95% CI 3.44 to 6.87, I2 � 0%
showed that HM treatment
(2) SCORAD score+
for AD has better clinical
4 RCTs, n � 390; MD −15.51,
effect. Due to poor
Yang 13 RCTs 2000.01.01- 95% CI −20.15 to −10.87,
China CM methodological quality of
(2016) [23] (1,232) 2015.10.31 I2 � 73%
existing trials, the future need
(3) Serum IgE+
more high quality, large-
2 RCTs, n � 181; MD −67.10,
sample RCTs to get more
95% CI −179.63 to 45.43,
reliable clinical conclusions.
I2 � 87%
(4) Recurrence rate+
4 RCTs, n � 326; OR 0.21, 95%
CI 0.07 to 0.60, I2 � 58%
(I) Oral or external HM + CM vs. The present study suggests
CM that combination of HM and
(1) Cure rate∗ CM has curative effect with
11 RCTs, n � 757; OR 2.94, 95% lower incidence of adverse
CI 2.08 to 4.16, I2 � 0% reactions in the treatment of
Ma (2017) 14 RCTs Inception- (2) TER∗ AD. The search results are
China CM
[24] (976) 2016.9. 12 RCTs, n � 733; OR 4.86, 95%limited to domestic literature,
CI 3.13 to 7.56, I2 � 0% the clinical evidence level is
(3) Recurrence rate+ low, and there is a lack of
high-quality, standardized
3 RCTs, n � 251; OR 0.74, 95%
2 RCT. Further RCTs are
CI 0.36 to 1.53, I � 0%
required to confirm it.
Evidence-Based Complementary and Alternative Medicine 7

Table 1: Continued.
First Studies
First author Search Control Main results
author’s (sample Key conclusion
(year) duration intervention (meta-analysis)
country size)
(I) Oral HM, acupuncture,
moxibustion, etc. vs. placebo or
CM
(1) TER∗ We need to make conclusion
8 RCTs, n � 667; RR 1.10, 95% cautiously for the efficacy and
CI 0.99 to 1.21, I2 � 65% safety of HM and related
(2) SCORAD score+ treatment on AD. Articles
Shi (2017) 24 RCTs Inception-
China Placebo or CM 4 RCTs, n � 173; SMD 0.89, 95% having good quality based on
[25] (1,618) 2016.12.
CI −0.24 to 2.02, I2 � 86% the Cochrane Collaboration’s
(3) decrease of EASI score∗ risk of bias tool were included
2 RCTs, n � 50; MD 3.22, 95% ensuring the results
CI 0.41 to 6.03, I2 � 0% trustworthy.
(4) decrease of SSRI score∗
2 RCTs, n � 105; SMD −0.36,
95% CI −1.16 to 0.45, I2 � 76%
(1) Oral Jinpi HM (or oral Jinpi
HM + CM) vs. CM
(1) TER∗
30 RCTs, n � 2333; OR 4.05,
95% CI 3.27 to 5.03, I2 � 0%
(2) SCORAD score+
15 RCTs, n � 1282; MD −9.82,
95% CI −13.31 to −6.33,
I2 � 90%
(3) EASI score+
3 RCTs, n � 232; MD −2.80, 95%
CI −3.54 to −2.07, I2 � 0%
(4) Itching VAS+
7 RCTs, n � 448; MD −0.79, 95% Studies have shown that HM
CI −1.10 to −0.47, I2 � 24% Jianpi therapy had
(5) Serum IgE+ significantly higher clinical
6 RCTs, n � 534; MD −34.92, efficacy than CM in the
95% CI −86.07 to 16.22, treatment of AD. Due to the
I2 � 97% publication bias and low
Liu 2018 37 RCTs Inception-
China CM (6) Serum IFN-c∗ quality of included RCTs in
[26] (2,973) 2017.12.
4 RCTs, n � 346; MD 1.75, 95% this study, more multicenter,
CI 1.14 to 2.35, I2 � 0% high quality, large-sample,
(7) Serum IL-4+ randomized double-blind
4 RCTs, n � 346; MD −3.15, 95% controlled trials are needed to
CI −4.16 to −2.15, I2 � 75% further demonstrate the
(8) Serum EOS+ conclusion.
5 RCTs, n � 410; MD −0.11, 95%
CI −0.20 to −0.02, I2 � 0%
(9) Recurrence rate+
4 RCTs, n � 283; OR 0.36, 95%
CI 0.21 to 0.60, I2 � 0%
(II) Oral Jinpi HM vs. CM
(1) TER∗
21 RCTs, n � 1355; OR 4.81, 95%
CI 3.63 to 6.36, I2 � 0%
(III) Oral Jinpi HM + CM vs. CM
(1) TER∗
9 RCTs, n � 832; OR 2.94, 95%
CI 2.11 to 4.11, I2 � 0%
8 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.
First Studies
First author Search Control Main results
author’s (sample Key conclusion
(year) duration intervention (meta-analysis)
country size)
(I) Tripterygium agents (or
Tripterygium agents + CM) vs.
CM
(1) TER∗
13 RCTs, n � 1361; RR 1.59, 95%
CI 1.26 to 2.00, I2 � 93%
(2) Serum IL-2∗
2 RCTs, n � 178; SMD 11.09,
95% CI −13.41 to 35.58,
I2 � 99%
Tripterygium agents appear to
(3) Serum IL-4+
be effective when treating
1 RCT, n � 160; SMD −0.64,
patients with atopic eczema,
95% CI −0.96 to −0.33
but with apparent side effects.
(4) Serum IFN-c∗
It cannot be concluded that
1 RCT, n � 160; SMD 0.69, 95%
Tripterygium agents can be
CI 0.37 to 1.01
generally used for eczema in
Liu (2019) 13 RCTs Inception- (5) Serum CRP+
China CM the clinic because of the small
[27] (1385) 2018.10.2. 1 RCT, n � 118; SMD −20.01,
sample size. Further multi-
95% CI −22.64 to −17.39
center studies with large
(6) Serum IgE+
samples, and high-quality
1 RCT, n � 220; SMD −0.57,
should be conducted to clarify
95% CI −1.11 to −0.03
the efficacy and safety of
(7) Recurrence rate+
Tripterygium agents for
2 RCTs, n � 149; RR 0.44, 95%
treating eczema.
CI 0.06 to 3.00, I2 � 89%
(II) Tripterygium agents vs. CM
(1) TER∗
4 RCTs, n � 367; RR 1.19, 95%
CI 0.96 to 1.48, I2 � 85%
(III) Tripterygium agents + CM vs.
CM
(1) TER∗
9 RCTs, n � 994; RR 1.78, 95%
CI 1.40 to 2.25, I2 � 84%
(I) Oral or external HM vs. CM
(1) Cure rate∗
16 RCTs, n � 1727; RR 1.79, 95%
CI 1.35 to 2.39, I2 � 60%
(2) TER∗
16 RCTs, n � 1727; RR 1.19, 95%
CI 1.08 to 1.31, I2 � 90%
(3) SCORAD score+
4 RCTs, n � 292; MD −14.67,
95% CI −19.52 to −9.82,
HM have certain advantages
I2 � 77%
Wang 19 RCTs 1980.1.1.- Placebo or in treating atopic dermatitis
China (4) Recurrence rate+
(2019) [28] (2178) 2019.3.31. active controls and have relatively lower
7 RCTs, n � 906; RR 0.57, 95%
incidents of adverse reaction.
CI 0.32 to 1.02, I2 � 76%
(5) Adverse events rate+
14 RCTs, n � 1735; RR 0.49, 95%
CI 0.36 to 0.66, I2 � 42%
(II) Oral or external HM vs. CM or
Placebo
(1) Serum IgE+
5 RCTs, n � 464; MD −119.19,
95% CI −177.93 to −60.45,
I2 � 0%
∗
Higher score indicates better results, +lower score indicates better results. AD, atopic dermatitis; CDLQI, children’s dermatology life quality index; CI,
confidence interval; CM, conventional medication; CRP, C-reactive protein; EASI, eczema area and severity index; EOS, eosinophil count; HM, herbal medicine;
IFN, inteferon; IL, interleukin; IgE, immunoglobulin E; MD, mean difference; OR, odds ratio; RCT, randomized controlled trial; RR, risk ratio; SCORAD, scoring
atopic dermatitis; SMD, standardized mean difference; SSRI, symptom score reducing index; TER, total effective rate; VAS, visual analogue scale.
Evidence-Based Complementary and Alternative Medicine 9

Table 2: Methodological quality assessment of the included reviews using the AMSTAR-2 tool.
Included studies Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14 Q15 Q16 Overall quality
Gong [21] Yes No Yes No Yes Yes No No No No Yes Yes No Yes Yes Yes Critically low
Gu et al. [22] Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes High
Tan et al. [7] Yes No Yes Partial yes No Yes No Yes Yes No Yes No Yes Yes Yes Yes Critically low
Yang et al. [23] Yes No Yes No Yes Yes No Partial yes No No No No Yes No Yes Yes Critically low
Ma et al. [24] Yes No Yes Partial yes No Yes No Partial yes No No Yes No Yes Yes Yes Yes Critically low
Shi et al. [25] Yes No Yes Partial yes Yes Yes No Yes Yes No Yes Yes Yes Yes No Yes Critically low
Liu et al. [26] Yes No Yes Partial yes No No No Partial yes Yes No No No Yes No Yes Yes Critically low
Liu et al. [27] Yes Yes Yes Yes Yes Yes No Yes Yes No Yes No Yes Yes Yes Yes Low
Wang et al. [28] Yes No Yes Partial yes Yes Yes No Partial yes Yes No Yes No Yes Yes Yes Yes Critically low
Q1: did the research questions and inclusion criteria for the review include the components of PICO? Q2: did the report of the review contain an explicit
statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?
Q3: did the review authors explain their selection of the study designs for inclusion in the review? Q4: did the review authors use a comprehensive literature
search strategy? Q5: did the review authors perform study selection in duplicate? Q6: did the review authors perform data extraction in duplicate? Q7: did the
review authors provide a list of excluded studies and justify the exclusions? Q8: did the review authors describe the included studies in adequate detail? Q9: did
the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? Q10: did the review
authors report on the sources of funding for the studies included in the review? Q11: if meta-analysis was performed, did the review authors use appropriate
methods for statistical combination of results? Q12: if meta-analysis was performed, did the review authors assess the potential impact of RoB in individual
studies on the results of the meta-analysis or other evidence synthesis? Q13: did the review authors account for RoB in individual studies when interpreting/
discussing the results of the review? Q14: did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the
results of the review? Q15: if they performed quantitative synthesis, did the review authors carry out an adequate investigation of publication bias (small study
bias) and discuss its likely impact on the results of the review? Q16: did the review authors report any potential sources of conflicts of interest, including any
funding they received for conducting the review?

the efficacy and symptom relief. Gong [21] reported that oral Index (EASI) score (MD: −2.80, 95% CI: −3.54 to −2.07, 3
HM showed significantly better results on TER compared studies, 232 participants), and itching score (MD: −0.79,
with oral antihistamines (OR: 5.64, 95% CI: 4.07 to 7.81, 11 95% CI: −1.10 to −0.47, 7 studies, 448 participants) com-
studies, 1479 participants). Through sensitivity analysis pared with CM alone. Moreover, on TER, oral Jinpi HM as
according to study quality, and sensitivity analysis between a monotherapy (OR: 4.81, 95% CI: 3.63 to 6.36, 21 studies,
the random-effects model and fixed-effect model, consis- 1355 participants) and an adjunctive therapy to CM (OR:
tent conclusions were reached showing that the conclu- 2.94, 95% CI: 2.11 to 4.11, 9 studies, 832 participants)
sions of the study were credible. Gu et al. [22] reported that showed significantly better results compared with CM
oral or external HM showed significantly better results on alone. Liu et al. [27] reported that Tripterygium agents as a
TER (RR: 1.43, 95% CI: 1.27 to 1.61, 21 studies, 1868 monotherapy or an adjunctive therapy to CM showed
participants), itching score (SMD: −0.83, 95% CI: −1.43 to significantly better results on TER (RR: 1.59, 95% CI: 1.26 to
−0.22, 7 studies, 465 participants), and overall severity 2.00, 13 studies, 1361 participants) compared with CM
(SMD: −0.97, 95% CI: −1.23 to −0.71, 15 studies, 1062 alone. However, Tripterygium agents as a monotherapy did
participants) compared with CM. They planned to perform not show significant benefits compared with CM (RR: 1.19,
sensitivity analysis by excluding studies with low meth- 95% CI: 0.96 to 1.48, 4 studies, 367 participants), while
odological quality; however, they failed to do due to the lack Tripterygium agents as an adjunctive therapy to CM
of data. Tan et al. [7] reported that oral HM as an adjunctive showed significant benefits (RR: 1.78, 95% CI: 1.40 to 2.25, 9
therapy to CM showed significantly better overall severity studies, 994 participants) on TER. Wang et al. [28] showed
score (MD: −2.56, 95% CI: −3.46 to −1.66, 1 study, 98 that oral or external HM showed significantly better results
participants) compared with CM alone. Yang et al. [23] on cure rate (RR: 1.79, 95% CI: 1.35 to 2.39, 16 studies, 1727
reported that oral HM as a monotherapy or an adjunctive participants), TER (RR: 1.19, 95% CI: 1.08 to 1.31, 16
therapy to CM showed significantly better results on TER studies, 1727 participants), and SCORAD score (MD:
(OR: 4.86, 95% CI: 3.44 to 6.87, 13 studies, 1232 partici- −14.67, 95% CI: −19.52 to −9.82, 4 studies, 292 participants)
pants) and SCORAD score (MD: −15.51, 95% CI: −20.15 to compared with CM (Table 1).
−10.87, 4 studies, 390 participants) compared with CM
alone. Ma et al. [24] reported that oral or external HM as an (2) Recurrence Rate. For the recurrence rate, mixed results
adjunctive therapy to CM showed significantly better re- were reported according to reviews. Gong [21] reported that
sults on cure rate (OR: 2.94, 95% CI: 2.08 to 4.16, 11 studies, oral HM showed a significantly lower recurrence rate than
757 participants) and TER (OR: 4.86, 95% CI: 3.13 to 7.56, oral antihistamines (OR: 0.38, 95% CI: 0.29 to 0.49, 11
12 studies, 733 participants). Liu et al. [26] reported that studies, 1436 participants). Yang et al. [23] reported that oral
oral Jinpi HM as a monotherapy or an adjunctive therapy to HM as a monotherapy or an adjunctive therapy to CM
CM showed significantly better results on TER (OR: 4.05, showed significantly lower recurrence rate (OR: 0.21, 95%
95% CI: 3.27 to 5.03, 30 studies, 2333 participants), CI: 0.07 to 0.60, 4 studies, 326 participants) compared with
SCORAD score (MD: −9.82, 95% CI: −13.31 to −6.33, 15 CM alone. Liu et al. [26] reported that oral Jinpi HM as a
studies, 1282 participants), Eczema Area and Severity monotherapy or an adjunctive therapy to CM showed
10 Evidence-Based Complementary and Alternative Medicine

significantly lower recurrence rate (OR: 0.36, 95% CI: 0.21 to CI: −86.07 to 16.22, 6 studies, 534 participants) compared
0.60, 4 studies, 283 participants) compared with CM alone. with CM alone (Table 1).
However, Liu et al. [27] reported that Tripterygium agents as
a monotherapy or an adjunctive therapy to CM showed no
significant difference in terms of recurrence rate (RR: 0.44, 3.4.3. Other Comparisons. Shi et al. [25] reported that oral
95% CI: 0.06 to 3.00, 2 studies, 149 participants) compared HM, acupuncture, moxibustion, and so on were associated
with CM alone. Ma et al. [24] reported that oral or external with a decrease in the EASI score (MD: 3.22, 95% CI: 0.41 to
HM as an adjunctive therapy to CM showed no significant 6.03, 2 studies, 50 participants). However, there was no
difference in terms of recurrence rate (OR 0.74, 95% CI 0.36 significant difference between groups in terms of TER (RR:
to 1.53, 3 studies, 251 participants) compared with CM 1.10, 95% CI: 0.99 to 1.21, 8 studies, 667 participants),
alone. In addition, Wang et al. [28] reported that there was SCORAD score (SMD: 0.89, 95% CI: −0.24 to 2.02, 4 studies,
no difference between HM and CM in terms of recurrence 173 participants), and reduction of symptom scores or index
rate (RR: 0.57, 95% CI: 0.32 to 1.02, 7 studies, 906 partic- scores (SMD: −0.36, 95% CI: −1.16 to 0.45, 2 studies, 105
ipants) (Table 1). participants). However, the review is based on a small
number of and low-quality RCTs; therefore, caution must be
(3) Laboratory Results. The effect of HM on laboratory re- taken when interpreting our results (Table 1).
sults was dependent on the outcomes. First, the positive
effects of HM on interferon-gamma (IFN-c) and IL-4 have 3.5. Is Oral HM Effective and Safe for Treating AD? We
been reported consistently in two reviews. Liu et al. [26] collected and reanalyzed the original RCTs that matched
reported that oral Jinpi HM as a monotherapy or an ad- each comparison from each SR: (1) oral HM versus placebo
junctive therapy to CM showed significantly higher serum (4 RCTs), (2) oral HM versus active controls (37 RCTs), and
IFN-c (MD: 1.75, 95% CI: 1.14 to 2.35, 4 studies, 346 (3) oral HM combined with active controls versus active
participants) and lower serum IL-4 (MD: −3.15, 95% CI: controls (17 RCTs). We also assessed the quality of evidence
−4.16 to −2.15, 4 studies, 346 participants). In addition, Liu using the GRADE approach based on the reanalyzed data on
et al. [27] reported that Tripterygium agents as a mono- efficacy and safety. The list of the included original RCTs is
therapy or an adjunctive therapy to CM showed signifi- described in Supplement 2.
cantly higher serum IFN-c (SMD: 0.69, 95% CI: 0.37 to
1.01, 1 study, 160 participants) and lower serum IL-4 (SMD:
−0.64, 95% CI: −0.96 to −0.33, 1 study, 160 participants). 3.5.1. HM versus Placebo. Compared with the placebo
Second, the positive effects of HM on EOS and C-reactive group, the oral HM group showed significantly lower
protein (CRP) have been reported. Liu et al. [26] reported SCORAD score (MD: −10.65, 95% CI: −16.24 to −5.06, 1
that oral Jinpi HM as a monotherapy or an adjunctive study, 25 participants, low-quality evidence) and higher TER
therapy to CM showed significantly lower serum EOS (MD: (RR: 9.43, 95% CI: 1.44 to 61.85, 1 study, 25 participants,
−0.11, 95% CI: −0.20 to −0.02, 5 studies, 410 participants) low-quality evidence). Moreover, there was no significant
compared with CM alone. Liu et al. [27] reported that difference between the groups in terms of the incidence of
Tripterygium agents as a monotherapy or an adjunctive AEs (RR: 1.23, 95% CI: 0.65 to 2.35, 3 studies, 178 partic-
therapy to CM showed significantly lower serum CRP ipants, low-quality evidence). The levels of evidence for the
(SMD: −20.01, 95% CI: −22.64 to −17.39, 1 study, 118 results evaluated by the GRADE approach were all “low”
participants) compared with CM alone. Third, HM had no because of the presence of RoB in the included RCTs and
significant effects on IL-2. Liu et al. [27] reported that imprecision of the results (Table 3).
Tripterygium agents as a monotherapy or an adjunctive
therapy to CM showed no significant difference in terms of 3.5.2. HM versus Active Controls . Compared with active
serum IL-2 (SMD 11.09, 95% CI −13.41 to 35.58, 2 studies, controls, the oral HM group showed significantly lower
178 participants) compared with CM alone. Fourth, mixed SCORAD score (MD: −11.39, 95% CI: −14.21 to −8.57, 17
results have been reported for IgE. Liu et al. [27] reported studies, 1285 participants, low-quality evidence) and higher
that Tripterygium agents as a monotherapy or an ad- TER (RR: 1.31, 95% CI: 1.23 to 1.40, 33 studies, 2812 par-
junctive therapy to CM showed significantly lower serum ticipants, moderate-quality evidence). Moreover, oral HM
IgE (SMD -0.57, 95% CI −1.11 to −0.03, 1 study, 220 showed a significantly lower incidence of AEs than active
participants) compared with CM alone. In addition, Wang controls (RR: 0.40, 95% CI: 0.26 to 0.64, 19 studies, 1507
et al. [28] reported that oral or external HM showed sig- participants, low-quality evidence). The levels of evidence
nificantly lower serum IgE (MD: −119.19, 95% CI: −177.93 to for the SCORAD score and the incidence of AEs were “low,”
−60.45, 5 studies, 464 participants) compared with CM or while the level of evidence for TER was “moderate” (Table 3).
placebo. However, Yang et al. [23] reported that oral HM as a
monotherapy or an adjunctive therapy to CM showed no
significant difference in terms of serum IgE (MD: −67.10, 95% 3.5.3. HM Combined with Active Controls versus Active
CI: −179.63 to 45.43, 2 studies, 181 participants) compared Controls Alone. Compared with active controls, oral HM
with CM alone. Liu et al. [26] reported that oral Jinpi HM as a combined with active controls showed significantly lower
monotherapy or an adjunctive therapy to CM showed no SCORAD score (MD: −6.05, 95% CI: −7.86 to −4.25, 4
significant difference in terms of serum IgE (MD: −34.92, 95% studies, 333 participants, moderate-quality evidence) and
Evidence-Based Complementary and Alternative Medicine 11

Table 3: Quality of evidence for the main findings.

Anticipated absolute effects (95% CI)
No. of Quality of
Relative risk Risk with
Outcome participants evidence Risk with control Comments
(95% CI) treatment
(RCTs) (GRADE) intervention
intervention
HM versus placebo
SCORAD ⊕⊕○○ MD 10.65 lower Risk of bias (−1)
25 (1 RCT) — —
score LOW [-16.24, -5.06] Imprecision (−1)
⊕⊕○○ RR 9.43 857 per 1,000 Risk of bias (−1)
TER 25 (1 RCT) 91 per 1,000
LOW [1.44, 61.85] [131, 1,091] Imprecision (−1)
Adverse ⊕⊕○○ RR 1.23 189 per 1,000 Risk of bias (−1)
178 (3 RCTs) 154 per 1,000
events rate LOW [0.65, 2.35] [100, 362] Imprecision (−1)
HM versus active controls
SCORAD ⊕⊕○○ MD 11.39 lower Risk of bias (−1)
1,285 (17 RCTs) — —
score LOW [-14.21, -8.57] Inconsistency (−1)
⊕⊕⊕○ RR 1.31 921 per 1,000
TER 2,812 (33 RCTs) 703 per 1,000 Risk of bias (−1)
MODERATE [1.23, 1.40] [864, 984]
Adverse ⊕⊕○○ RR 0.40 39 per 1,000 Risk of bias (−1)
1,507 (19 RCTs) 98 per 1,000
events rate LOW [0.26, 0.64] [25, 63] Imprecision (−1)
HM combined with active controls versus active controls alone
SCORAD ⊕⊕⊕○ MD 6.05 lower
333 (4 RCTs) — — Risk of bias (−1)
score MODERATE [-7.86, -4.25]
⊕⊕○○ RR 1.19 948 per 1,000 Risk of bias (−1)
TER 1,329 (17 RCTs) 797 per 1,000
LOW [1.06, 1.34] [845, 1,068] Publication bias (−1)
Risk of bias (−1)
Adverse ⊕○○○ RR 1.21 94 per 1,000
558 (8 RCTs) 78 per 1,000 Inconsistency (−1)
events rate VERY LOW [0.43, 3.39] [33, 265]
Imprecision (−1)
CI, confidence interval; GRADE, grading of recommendations assessment, development, and evaluation; HM, herbal medicine; MD, mean difference; RCT,
randomized controlled trial; RR, risk ratio; SCORAD, scoring atopic dermatitis; TER, total effective rate.

higher TER (RR: 1.19, 95% CI: 1.06 to 1.34, 17 studies, 1329 SRs. Through a comprehensive search in five major medical
participants, low-quality evidence). There was no significant databases, a total of 9 SRs [7, 21–28] including 6–37 RCTs
difference between the groups in terms of the incidence of were included in this overview.
AEs (RR: 1.21, 95% CI: 0.43 to 3.39, 8 studies, 558 partic-
ipants, very low-quality evidence). The levels of evidence for
SCORAD score, TER, and the incidence of AEs were 4.1. Summary of Evidences. The overview has the advantage
“moderate,” “low,” and “very low,” respectively (Table 3). of summarizing and analyzing studies that have been ex-
cluded from each SR due to various reasons such as dif-
ferences in research questions. Moreover, we resynthesized
3.6. Components of Oral HM for AD. Of the original RCTs, the evidence for efficacy and safety of HM on AD by
the components of oral HM used in 55 RCTs were analyzed, extracting the original RCTs of each SR, to provide updated
except for one study that did not provide the components of and more comprehensive evidence. First, we summarized
oral HM used and two studies that did not provide basic the results from the included SRs. Two reviews [7, 22]
prescriptions. As a result, a total of 110 kinds of components evaluated the anti-AD effects of HM compared with the
including 109 herbs and 1 ingredient of herb, Tripterygium placebo. They found that HM showed significantly better
glycosides, were found. The most frequently used herb was efficacy in terms of TER, symptom scores including itching
Glycyrrhizae Radix et Rhizoma (39/55, 70.91%), followed by and sleep symptom, quality of life (QOL), and a dose of
Atractylodis Rhizoma Alba (37/55, 67.27%), Poria (Hoelen) topical treatment used compared with placebo. However, all
(32/55, 58.18%), Angelicae Gigantis Radix (22/55, 40.0%), meta-analyses included four or fewer RCTs, and the included
Dictamni Radicis Cortex (22/55, 40.0%), Atractylodis Rhi- RCTs had mostly uncertain or high RoB. Therefore, the
zoma (19/55, 34.55%), Saposhnikoviae Radix (19/55, reliability of the results could be limited. In addition, HM as
34.55%), Citri Unshius Pericarpium (18/55, 32.73%), and a monotherapy and/or an adjunctive therapy to CM showed
Astragali Radix (16/55, 29.09%). The frequency of the herbs significantly better clinical outcomes, symptom relief, and
used is shown in Supplement 3. results on some laboratory parameters including serum IFN-
c, IL-4, EOS, and CRP. In addition, mixed results were found
4. Discussion on the recurrence rate and serum IgE. The methodological
quality of each SR assessed using the AMSTAR-2 tool was
This overview aimed to summarize and critically evaluate the generally low except for one Cochrane review [22]. In
efficacy and safety of HM on AD, based on current available particular, only one study [22] reported the review methods
12 Evidence-Based Complementary and Alternative Medicine

prior to the conduct of the review and provided a list of studies; for example, the most frequently used prescription for
excluded studies. This means that most included reviews recalcitrant AD treatment in Japan was Hochu-ekki-to, a
might not provide an accurate and comprehensive summary tonifying qi HM [33], and in Taiwan, Xiao-Feng-San, a
of the included RCTs. Second, we obtained the full texts of 58 clearing heat-dampness HM. Moreover, Dictamni Radicis
original RCTs from each SR to resynthesize the results, Cortex has been found to be frequently used [34–36]. There
especially on efficacy and safety data including the SCORAD are also experimental evidences supporting that these herbs
score, TER, and the incidence of AEs. As a result, oral HM have anti-inflammatory and antiallergic effects, which may
showed a significantly lower SCORAD score and higher TER help with AD treatment. Angelicae Gigantis Radix and the
than the placebo. In addition, oral HM as a monotherapy or main component (glycyrrhizin) and derivatives (dipotas-
an adjunctive therapy to CM showed lower SCORAD score sium glycyrrhizinate) of Glycyrrhizae Radix et Rhizoma
and higher TER compared with CM alone. Moreover, in showed excellent anti-inflammatory effects in the in vitro
terms of the safety profile, oral HM was not significantly and in vivo AD models [37–39]. Moreover, these two herbs
different from the placebo and was better than CM. How- have shown to reduce inflammation and improve AD
ever, the quality of evidence for each finding assessed using symptoms such as itching in the AD model even in topical
the GRADE approach ranged from “moderate” to “very use [40, 41]. Atractylodis Rhizoma Alba and Poria (Hoelen)
low,” and there was no high-quality evidence provided. We are frequently used herb combinations, which demonstrated
downgraded the quality of evidence because of the high RoB anti-allergic and immunomodulatory effects in AD models,
in the included RCTs and the imprecision of the meta-an- respectively [42–44]. Dictamni Radicis Cortex is a herb with
alyzed data. Therefore, limited evidence suggested a positive potent anti-inflammatory and antiallergic effects and is of
efficacy of HM on AD, but it is difficult to draw definite interest in allergic diseases clinically and experimentally
conclusions owing to the low methodological quality of each [36, 45, 46]. However, the safety profiles of HM as an ad-
review and poor quality of the evidence. juvant therapy in terms of herb-drug interaction need
further studies. Although some studies have reported that
the combination of CM such as oral antihistamines and HM
4.2. Clinical Implications. Recently, HM has attracted at- in AD treatment was effective and safe [47], the interactions
tention as a promising alternative treatment for AD. between herbs and CMs used in AD were largely under-
According to a cross-sectional survey conducted in the studied. For example, in the case of systemic immunosup-
United States in the early 2000s, CIM use in AD patients was pressive agents such as cyclosporine for severe AD, the
very common at about 50% [29]; in a recent population- administration of HM metabolized by the cytochrome P450
based study of the 2007 National Health Interview Survey, (CYP) system may affect its efficacy by changing the bio-
47% of pediatric patients with eczema used CIM [30]. availability of the drug. Some herbs including St. John’s wort,
However, since abuse of unproven CIM approaches can be a ginger, liquorice, Scutellariae radix, and quercetin have been
barrier to optimal management of AD [31], evidence-based known to decrease the bioavailability of cyclosporine, while
and rationality-based use of CIM is required. The important other herbs including grapefruit juice, cannabidiol, cham-
findings of this overview are as follows: HM may be used as omile, resveratrol, Serenoa repens, Echinacea, and berberine
an adjunctive therapy in AD patients who are receiving have been known to increase the bioavailability [48]. This
conventional treatments and HM may be used as a mon- herb-drug interaction is an important issue in current
otherapy in AD patients who do not want to or cannot apply clinical settings, especially in terms of CIM, and should be
conventional treatments. This has the clinical significance of taken into account when establishing an optimal holistic
presenting a new evidence-based treatment option for pa- treatment strategy [49]. The results of meta-analysis suggest
tients with this intractable skin disease that severely affects that there was no difference in the incidence of AEs between
their QOL. In particular, the results of this overview showed HM combined with CM and CM alone, but the level of
that, in the treatment of AD, HM may have immuno- evidence evaluated by GRADE was very low. This finding
modulatory and anti-inflammatory effects, as evidenced by suggests that studies evaluating their interaction should be
improvements in IFN-c, IL-4, EOS, and CRP. These findings conducted, given the priority interaction between the drugs
are consistent with those of previous studies, which reported currently used and the HMs frequently used in treating AD,
that HM can prevent the development of AD, through as proposed in this overview. Additionally, these studies
complex mechanisms mainly related to inflammation and should be particularly important in terms of immunomo-
skin function improvement [32]. Interestingly, in the dulation and common drug metabolic systems.
component analysis of 55 original RCTs using oral HM, the
EATM theory indicated that frequently used herbs have
tonifying effects or clearing heat-dampness effects. Among 4.3. Limitations and Suggestions for Future Studies. Our
them, Glycyrrhizae Radix et Rhizoma, Atractylodis Rhizoma overview has some limitations. First, all included SRs as well
Alba, Poria (Hoelen), Angelicae Gigantis Radix, Atractylodis as most of the original RCTs were published in China. This
Rhizoma, and Astragali Radix are commonly used to tonify may seem reasonable because HM is primarily used in
qi and blood and to treat spleen-stomach dampness and China. However, this can still lead to reporting biases and
weakness. Meanwhile, Dictamni Radicis Cortex is a herb well barriers to generalizing HM in other countries. Second, most
known for its clearing heat-dampness effect. The frequent of the reviews included had low methodological quality.
use of these herbs is consistent with previous epidemiological Although our overview included a high-quality SR, such as
Evidence-Based Complementary and Alternative Medicine 13

the Cochrane review, the overall quality of included SRs and given that the impact on the microbiome is one of the
appeared to be low based on the AMSTAR-2 assessment complex therapeutic mechanisms of HM [51], anti-AD ef-
results. Literature review, including the SR, can be con- fects of HM via the gut-skin axis should be further
sidered as a kind of secondary analysis of the original ar- elucidated.
ticles. Therefore, it is necessary to exclude the bias of the Despite these limitations, to the best of our knowledge,
researcher as much as possible. This may include pre- this is the first overview to systematically summarize and
protocol registration and predefined analysis methods. evaluate the efficacy and safety HM on AD from current SRs.
There is also a need to use a multifaceted approach to explain In addition, we reextracted and resynthesized the infor-
significant heterogeneity, with proper methods. Like most mation related to efficacy and safety from the RCTs included
SRs included in this overview, the interventions used in in each SR to provide more updated and comprehensive
many SRs of HM have a great variety in their composition. information. This overview provided an evidence-based
This is thought to be a feature of EATM that uses different assessment and object summary on the efficacy and safety of
treatments for the same disease or vice versa, which has led HM on AD. We believe that this overview will facilitate the
to heterogeneity in many SRs. Recently, however, as a way to evidence-based use of HM as a way to optimize tailored care
solve this problem, analyses limited to HM with specific for healthcare practitioners who treat AD and policymakers.
therapeutic properties have also been conducted, like the The results of this overview will also provide researchers with
review by Liu et al. [26]. In addition, as in Liu et al. [27], insights on the urgent research challenges in this area.
analyses of HM focused on a specific herb can be conducted.
In particular, in the former case, the pattern identification
5. Conclusion
system of EATM can be used, and the contents of the
previously published CPG may be utilized. For example, the In conclusion, most of the included reviews and resynthesized
CPG of HM treatment for AD, published in 2014 in Korea, results suggested that HM might be effective for the treatment
classified the patterns of AD as follows [10]: dampness-heat of AD. In particular, HM generally appears to have immu-
(濕熱), fetal heat (胎熱), syndrome of spleen deficiency with nomodulatory and anti-inflammatory effects. However, the
wind-dryness (脾虛風燥), wind-dampness skin syndrome methodological quality of the included reviews and original
(風濕蘊膚), syndrome of damp-heat gluing each other (濕 RCTs and the quality of evidence for the main findings were
熱互結), spleen deficient with dampness (脾虛濕蘊), and generally low. In addition, since most included RCTs were not
syndrome of blood deficiency and wind-dryness (血虛風 strict in reporting AE, it might not sufficiently report the
燥). Some HMs corresponding to each pattern may have safety issues of HM and the herb-drug interactions. Therefore,
common therapeutic characteristics, and it is thought that it further rigorous, well-designed, high-quality SRs and RCTs
can be integrated into intervention condition or separated by are needed to draw a firm conclusion.
subgroup analysis in future SR. Through these studies, it is
necessary to conduct research for the standardization of HM
for AD and reflect it in the updated CPG. In addition, Disclosure
comparative effectiveness between various HMs should be Chan-Young Kwon and Boram Lee are co-first authors.
explored using a network meta-analysis in future studies.
Third, the overall quality of the original RCTs included was
also poor. In addition, the quality of evidence assessed using Conflicts of Interest
GRADE ranged from very low to moderate. For HM, a
double-blind and placebo-controlled RCT is essential to The authors declare that they have no conflicts of interest.
confirm its efficacy and safety. However, the number of such
studies included in our reanalysis was very limited. This Authors’ Contributions
suggests that high-quality, large, rigorous RCTs should be
performed in order for HM to be recognized as a solid The study was conceptualized by CYK. CYK and BL
treatment for AD. Fourth, there was a lack of strict AE searched and selected the trials and extracted, analyzed, and
reporting in the original RCTs included. As described above, interpreted the data. SK and JL analyzed the components of
the generalization of HM in medical choice requires the oral HM from original RCTs. CYK and BL drafted the
establishment of a clear basis for HM safety profile, par- manuscript. SK, JL, MP, and NK helped with the study
ticularly the herb-drug interaction. Given that many AD design and critically reviewed the manuscript. CYK and BL
patients already use CIM therapies including HM [29, 30], contributed equally to this work. All authors read and ap-
evaluations of the herb-drug interaction between the drugs proved the final version of the manuscript.
currently used and the HMs frequently used in treating AD
are highly needed. Furthermore, for HM to be considered a Acknowledgments
policy for the treatment of AD, it is necessary to conduct a
study evaluating the cost-effectiveness of HM for AD. Fi- This study was supported by the Traditional Korean Med-
nally, the therapeutic mechanism of HM for AD needs to be icine R&D program funded by the Ministry of Health and
further elucidated. For example, the gut-skin axis has been Welfare through the Korea Health Industry Development
found to play an important role in the pathology of AD [50], Institute (KHIDI) (HI16C0275).
14 Evidence-Based Complementary and Alternative Medicine

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