Integrated Chinese and western medicine interventions for atopic dermatitis: a systematic review and meta-analysis

Background Atopic dermatitis (AD) is a chronic relapsing skin disease characterized by recurring episodes of itchiness with skin erythema and surface damages. Chinese medicine (CM) is widely used for the management of AD in China not only by its own, but also used in combination with conventional therapy (integrated Chinese-Western medicine, ICWM). Although many clinical trials on the effectiveness of ICWM on AD have been conducted, however, up to date, no sound evidence has been established on the clinical effectiveness and safety of ICWM for AD. Objectives To systematically review the currently available clinical evidence on the clinical effectiveness and safety of ICWM for AD. Methods Randomised and quasi-randomised controlled trials, which investigated ICWM interventions with at least one control group using the same conventional interventions, no treatment or placebo treatment, were included. Four English (CENTRAL, MEDLINE, EMBASE, AMED) and three Chinese (CNKI, CBM, WanFang Med) databases were searched. Risk of bias was assessed according to the Cochrane’s tool. Meta-analysis was performed to pool the data. Results From 1473 entries, 55 studies were included, involving 5953 participants aged between 35 days and 67 years old. Duration of treatment ranged from 1 to 24 weeks. Only 2 studies were judged to have low risk of bias, 3 studies had unclear risk of bias, and the other 50 studies were with high risk of bias. ICWM was found to be superior over WM alone in improving clinical severity of AD (measured by EASI, SCORAD), health-related quality of life (measured by CDLQI, DLQI), long term control of AD (recurrence rate), patients/investigator global score (clinical effectiveness rate), and serum IgE level. Adverse events associated with ICWM were found to be comparable with WM alone. Conclusion ICWM seems to produce superior treatment response than WM alone in managing AD without increased risk of adverse events. However, the current available evidence remains too weak to make a conclusive decision.

most significant clinical symptoms. It affects around 15% to 30% of children and 2% to 10% of adults worldwide [3,4]. In Hong Kong, the incidence rate of AD was 15% to 20% of the general population [5].
The pathogenesis of AD involves interactions among genetic and environmental factors, skin barrier dysfunction, microbial imbalance and immune dysregulation [6][7][8]. Multiple factors are believed to underlie dysfunctional T-helper (Th) cell type 1, Th2, and Th17 innate and adaptive immune responses in patients with AD [7,8]. Currently anti-inflammatory treatment with topical corticosteroids and/or topical calcineurin inhibitors is widely used for the management of mild to moderate form of AD, while systemic immunosuppressive agents, such as glucocorticoids, cyclosporine, or methotrexate, can be used in severe cases [8,9]. Long-term topical corticosteroid use is associated with side effects including stretch marks, small red or purple spots, telangiectasia (small, dilated blood vessels on the surface of the skin), skin thinning, atrophy and acne. Topical use of excessive corticosteroids can also cause hypothalamic-pituitary axis suppression [1,6]. The systemic immunosuppressive agents do not target specific points of immune dysregulation in AD, and may result in severe adverse events, including liver and kidney impairment. Ultraviolet phototherapy can be used for generalized AD, but it is contraindicated in children and young adults because of its long-term use is associated with the occurrence of skin cancer.
Complementary and alternative medicine has been increasingly used for the management of AD worldwide [10]. Chinese medicine (CM) is nowadays widely used for treating AD in East Asia and provides a valuable alternative treatment option. Many clinical studies have been conducted to evaluate the effectiveness of Chinese herbal medicines (CHMs) for the treatment of AD in recent decades [11,12]. Findings suggested that oral use of CHMs may improve health-related quality of life for children with moderate or severe atopic eczema. As integrated Chinese and Western medicine (ICWM) is a common way of clinical practice in mainland China, many clinical studies have been published on the effectiveness of ICWM on AD [13]. However, currently no solid evidence is available to support the effectiveness and safety of ICWM for AD treatment.
Since 1997, the Hong Kong Special Administrative Region Government has adopted an evidence-based approach in promoting the use of ICWM. High quality evidence on the use of ICWM is in urgent need. We would therefore like to fill in the gap by conducting a systematic review focusing on the use of ICWM for AD. The evidence synthesized would likely help develop a pragmatic collaborative care model for both WM and CM practitioners for the management of AD in Hong Kong.

Eligibility criteria
We included randomised controlled trials (RCTs) or quasi-RCTs using a superiority design, which evaluated the use of investigated WM & CM interventions or its variants on the patients with atopic dermatitis. The herbal medicines included single herb, classical formulae, new formulae, herb-derived products and combination products. The control group should receive the same WM interventions, no treatment or placebo. The WM medicine included both oral and topical application of chemical drugs such as antihistamines, corticosteroids and other modalities such as UV light therapy.
Studies on "chronic eczema", "subacute eczema" and "acute eczema" were generally excluded, except when they use a recognized diagnosis of AD such as the Hanifin and Rajka's criteria or the UK working group criteria explicitly [14]. Studies on other types of eczema such as anal eczema, genital eczema, dyshidrosis, eczema rhagadiforme, keratinized eczema were all excluded. Trials with co-morbidity other than allergy-related diseases (e.g. asthma) were also excluded.
The included studies should report one or more of the following primary and secondary outcomes. The primary outcome was the clinical severity of eczema, measured by a validated or objective tool, such as eczema area and severity index (EASI), scoring atopic dermatitis (SCO-RAD), six area, six sign atopic dermatitis (SASSAD) severity score, investigators' global assessment (IGA), and affected body surface area (BSA). The secondary outcomes included participant-reported symptoms, health-related quality of life, long-term control of atopic dermatitis (defined as the status of disease control at least 1 week after the end of intervention, such as recurrence rate), serum IgE level and adverse events. The percentage of trial participants with more than 50% improvement in terms of patients or investigator global score ("clinical effectiveness rate", further explained in "Results" section) was also accepted as one of secondary outcomes as it is widely used in the studies conducted in China based on national guidelines.
Participant-reported symptoms should be measured by a validated tool, such as patient-oriented eczema measure (POEM) and Pruritus Visual Analogue Scale (pruritus VAS). Health-related quality of life should also be measured by a validated measure, such as Dermatology Life Quality Index (DLQI) and Children's Dermatology Life Quality Index (CDLQI).

Search strategy
Literature search strategies were developed using medical subject headings and text words related to eczema. Various synonyms of the concepts of "eczema", "Chinese medicine", "integrative medicine" and "randomised controlled trials" were combined by "And" to construct the searching strategies. We searched the Cochrane Central Previous systematic reviews or meta-analyses on AD were also examined to identify potential trials eligible to be included.

Data extraction
The systematic review was conducted and reported according to the Cochrane Handbook for Systematic Review of Interventions (version 5.1) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15,16].
All titles and abstract of the entries returned by the search were imported into Covidence, an online collaboration tool designed to facilitate the work in different stages in systematic reviews, to remove duplicates and enable online screening. A review author (SCH) independently screened all the titles and abstracts against the original inclusion and exclusion criteria, and obtained full-texts of all entries that matched the inclusion criteria. Each of four reviewers (SCH, LMK, LCW, CPK) then screened part of the obtained full text articles and extracted characteristics of the studies. Another reviewer (LCW) rescreened the titles and abstracts classified as irrelevant to ensure completeness of inclusion, and a reviewer (SCH) rescreened the articles that did not explicitly describe atopic dermatitis (e.g. those articles that used "acute eczema", "subacute eczema" or "chronic eczema") to check whether AD's criteria were actually used for those studies. All questionable cases were referred to another reviewer (LZX) for decision. The final list of included articles was then determined. We resolved disagreement through discussion, and recorded the reasons for excluding articles/ studies. The review authors were not kept blind to the journal titles or to the study authors or institutions.
One review author (SCH) extracted outcome data in the included studies and input them onto an excel spreadsheet. The means, standard deviations of continuous outcomes and the numbers of events of dichotomous outcomes were recorded. Other information including age, diagnosis, type of intervention (including constituent component and dose), randomisation method, sample size, primary and secondary outcome types were also recorded.

Risk of bias assessment
Two review authors (SCH and LCW) independently assessed potential risks of bias in all included studies using the Cochrane's tool for assessing the risk of bias [15]. They assessed all six domains (sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias) in each study and assigned a scale of high, low, or unclear risk of bias. The discrepancy in judgment was resolved by another author (ZHW).

Data synthesis and statistical analysis
We used risk ratio (RR) with 95% confidence intervals (CI) to summarize dichotomous outcome data of individual studies, and used Mantel-Haenszel randomeffects model to pool the results across studies. We used the mean difference (MD) with 95% CI to summarize continuous outcome data at the end of treatment or follow-up within studies, and used the inverse-variance random-effects model to pool the results. For meta-analysis, we used random-effects model because of the expected heterogeneity of the studies. RevMan 5.1 software was used for data analyses. Forest plots were made to assess the effect size and corresponding 95% CI using random-effects models. Heterogeneity was assessed using the I 2 test with the significance level set at I 2 over 50% or P < 0.1.
We planned to perform subgroup analyses based on patients' age (less or more than 12); however, this was eventually found to be infeasible as the majority of included studies (31 out of 56) contained patients of both age groups. We assessed the possibility of publication bias by using funnel plots when at least 10 studies reported the outcomes. Sensitivity analyses were performed to evaluate the influence of study methodological quality and that of using change from baseline data (with missing standard deviation imputed) instead of post-intervention data, when the imputation of standard deviation could be made based on available data.

Study selection
The electronic database search returned 1473 records. A total of 998 records remained after duplicates were removed. After the title and abstract screening, 650 irrelevant records were excluded and 348 full-text records were assessed for eligibility. And 6 additional records were identified from previous systematic reviews and trial summaries. Eventually, a total of 55 trials (in 61 search records ) were included. (Fig. 1, flow of study selection).

Study characteristics
All 55 included studies were randomised controlled trials (RCTs). Among them, 5 studies were published in English and the remaining ones in Chinese. The included studies involved 5953 participants. antibiotics: 9 studies, 588 participants; phototherapy: 6 studies, 479 participants) within certain period (7 days to 2 months before screening) from participating in the trials.
All the included trials compared the use of Chinese herbal medicine combined with Western medicine to the use of same Western medicine alone (baseline treatment). CHMs included oral and topical use of Chinese herbal medicine in the form of decoction, granules or proprietary Chinese medicine (pCm).
Western medicine treatment included oral and topical medicines (such as emollients, antihistamines, topical corticosteroids, topical calcineurin inhibitors, urea-containing cream, antibiotics, anti-septic solutions, vitamin C or non-pharmacological therapy such as UV light therapy). The duration of treatment ranged from 1 to 24 weeks.

Chinese medicine syndromes and Chinese herbal medicines
Twenty-seven studies mentioned some types of Chinese medicine syndrome 證候, and totally 15 syndromes were identified in those studies ( Table 1). The four most common syndrome types were damp-heat 濕熱 (566 Fig. 1 Flow of study selection participants), spleen deficiency with dampness accumu-lation脾虛濕蘊 (377 participants), spleen deficiency 脾 虛 (309 participants) and blood deficiency and wind-dryness 血虛風燥 (304 participants).
From the Chinese medicine perspective, the herbs used in the formulae generally have at least one of the following functions: The frequency of usage, functions and classifications of the top 20 most frequently used CHMs in the included studies were summarised in Table 2. These 20 CHMs can be classified into 11 categories according to their main functions in Chinese medicine. They are, in descending order of their prescribing frequency: qi-tonifying 補氣藥, heat-clearing and dampness-drying 清熱燥濕藥, waterdraining and swelling-dispersing 利水消腫藥, wind-colddispersing 發散風寒藥, dampness-resolving 化濕藥, blood tonifying 補血藥, heat-clearing and blood-cooling 清熱涼血藥, stranguria-relieving diuretics 利尿通淋藥, qi-regulating 理氣藥, liver-pacifying 平抑肝陽藥, and heat-clearing and detoxicating 清熱解毒藥. These match well with the pathophysiology of AD in CM theory, i.e. accumulating dampness, heat and wind and the associated spleen qi deficiency that could result in blood deficiency if it persists into the chronic stage.
A total of 42 herbal formulae with specific names were identified in the included studies. The most commonly used formulae was Danggui Yinzi 當歸飲子, a blood tonifying and wind dispersing (養血祛風) formula designed to resolve blood deficiency and wind-dryness (血虛風燥, which is a common CM syndrome in the chronic stage of AD), with 4 studies using it as the main intervention.

Risk of bias within studies
About a third of included studies described an appropriate way of generating a random sequence (e.g. generation by computer software, coin tossing, random number table) and deemed to have low risk of bias in the domain of random sequence generation. Only 3 studies described  Fig. 3b, effects of ICWM on the clinical severity of AD measured by EASI when compared with WM alone). High heterogeneity was evidenced and possibly due to the varied interventions in these studies. Furthermore, sensitivity analysis was conducted to examine the influence of study quality (including only study of low risk of bias) and that of using the change of score from the baseline rather than post-intervention scores as the outcome. The only study of low risk of bias [17] reported no significant difference between the ICWM and WM alone groups in the term of EASI change. When the change of score from baseline was used, with the missing SD of EASI imputed from figures reported in Gu et al. [17] and that of SCORAD imputed from Chen et al. [22], ICWM was still superior to WM alone (SCORAD: MD = − 8.15, 95% CI − 12.89 to − 3.41; EASI: MD = − 2.59, 95% CI − 4.48 to − 0.70).
Other measures included IGA [20], SASSAD [35,36], Skin Severity Score by Japanese Dermatological Association [18] and 3 different kinds of author-defined clinical lesion/symptom scores [19,33,64]. Except for the Qi-tonifying 補氣藥 Japanese study applying IGA, which showed no significant difference between ICWM and WM groups in terms of IGA (with the amount of topical agents used in the WM group substantial higher than in ICWM group), all other studies indicated that ICWM was superior to WM in their respective measures.

Secondary outcomes
Participant-reported symptoms Six studies measured participant-reported symptoms by validated measurement scales. Among these, 5 used pruritus visual analogue scale (VAS) [20,27,28,39,46], of which 3 were included in the meta-analysis [27,28,39]. The result of meta-analysis showed no significant difference between the ICWM and Health-related quality of life Seven studies measured health-related quality of life by validated measure scales. Among these, 3 used only CDLQI [17,24,55], 3 used only DLQI [23,54,70], and one used a score combined from both CDLQI and DLQI [31]. Two studies using only CDLQI [17,55] and 3 studies using only DLQI were included in the meta-analysis. The study with combined score was not included for the meta-analysis as the scores were combined in an unspecified way and not separately available. In both measures, ICWM was superior to WM alone (CDLIQ: MD = − 2.12, 95% CI − 3.93 to − 0.31, participants = 125, I 2 = 1%; DLQI: MD = − 3.12, 95% CI − 5.03 to − 1.22, participants = 206, I 2 = 94%). However, sensitivity analysis showed no significant difference between groups in terms of CDLQI (MD = − 1.41, 95% CI − 3.84 to 1.02) when using change from baseline instead of post-intervention data, with missing SD imputed from Gu et al. [17].
Apart from the above, one English study [18] reported "prominent efficacy rate" (defined as the rate of subject with skin severity scoring 0 at the end of study). The difference between ICWM and WM alone groups was not significant (ICWM: 19%, 7 of 37; WM alone: 5%, 2 of 40; P = 0.06).
Funnel plots were made for the outcomes that have at least 10 studies included in the meta-analysis. The pooled data on SCORAD, the percentages of trial participants with more than 50% improvement in terms of SCORAD or "other measures" as defined above, and serum IgE level were examined by funnel plots. Apart from the one with SCORAD, the plots were all highly asymmetrical, suggesting a significant risk in publication bias. (Fig. 5, funnel plots).

Discussion
The present research findings suggested that ICWM was superior over WM alone in improving clinical severity of AD (as measured by EASI, SCORAD), health-related quality of life (as measured by CDLQI, DLQI), long term control of AD (recurrence rate), patients/investigator global score (effectiveness rate), and serum IgE level. We found no more adverse events associated with ICWM when compared with WM alone. However, some issues related to study quality weakened the strength of evidence, such as most studies having high risk of bias, conflicting results in some sensitivity analyses and potential publication bias. The pathogenesis of AD is a complex interplay of multiple contributing factors, such as skin barrier defects, infections, immunological factors, susceptible genes (e.g., filaggrin genes) and environmental factors (e.g., food and aeroallergens, seasonal and climatic change) [7][8][9]. CM also considers different influencing factors when making syndrome diagnosis of AD, albeit using different terminologies, such as damp-heat accumulation or spleen deficiency. A herbal formula is composed of herbs with different therapeutic functions to exert synergistic therapeutic actions. Experimental studies [78][79][80][81][82] have shown that many bioactive herbal ingredients from CHMs, including Poria (Fuling, 茯苓), Atractylodis Macrocephalae Rhizoma (Baizhu, 白朮), Angelicae Sinensis Radix (Danggui, 當歸), Atractylodis Lancea Rhizoma (Cangzhu, 蒼朮) and Dictamni Cortex (Baixianpi, 白鮮皮), exert anti-inflammatory, anti-allergic, antioxidative, and antiangiogenic effects. These active ingredients have been demonstrated to attenuate AD through diverse mechanisms such as restoring skin barriers, balancing Th1/Th2 cells levels, as well as regulating cytokine and chemokine expression, while have few side-effects [83,84]. The possible interaction between Chinese medicines and WM is one of the serious concerns about clinical safety. In this review, we found no significant difference in the occurrence of AEs between ICWM and WM. Our finding is congruent with previous reports that the combination of ICWM did not evoke additional adverse events [85]. It has also been reported that adding CHMs might have reduced the occurrence of adverse events of conventional pharmacotherapy such as skin dryness, skin itchiness, dry mouth/lips, and dry/scaly skin [86]. Different herbs and pharmacotherapies may be involved in the possible interaction. As CHMs can affect the pharmacokinetic properties of WMs, close attention should be paid to the possible interactions between CHMs and WMs.
To the best of our knowledge, this review is the first of its kind to systematically summarise and analyse the ICWM for AD. The comprehensive search strategy, scientifically robust way to assess risk of bias and the subsequent meta-analysis made the generation of findings more reliable. The low methodological quality and poor reporting are the main problems associated with many included studies which weakened the evidence. No proper blinding is another main methodological problem found in many included studies. As the main outcomes for evaluating the treatment effect for AD are most subjective, the blinding is a very important strategy to reduce possible bias and subjective influences. Additionally, no clear description of random generation and allocation concealment were commonly found in most of the included studies. Further clinical studies with high methodological quality are badly needed to consolidate the evidence about the ICWM for AD management.

Conclusions
Adopting ICWM was found to be superior to using WM alone in improving clinical symptoms and quality of life, and reducing the recurrence rate in the patients with atopic dermatitis. In addition, addition of CHMs to conventional western treatment presented no more adverse effect than WM alone. However, due to the methodological limitations in the included studies and possible publication bias, we could not draw a definitive conclusion about the effectiveness and safety of ICWM for the treatment of AD. In this connection, more methodologically rigorous clinical trials are urgently needed to generate quality clinical evidence about the routine use of ICWM in the management of atopic dermatitis.