Effectiveness and Safety of Chinese Medicine Decoctions for Behcet's Disease: A Systematic Review and Meta-Analysis

Background Behcet's disease (BD) is an autoimmune disease of systemic vasculitis with an unclear pathogenesis. Although western medicines remain the mainstay interventions, effectiveness and safety are significant challenges. Complementary and alternative medicine, including herbal medicine, are gaining more attention. Chinese medicine decoctions, which have been used for centuries, are the most common form of traditional therapies. Objective The purpose of the review was to evaluate the effectiveness and safety of Chinese medicine decoctions in the treatment of BD. Methods Randomized controlled trials (RCTs) for BD treatment with Chinese medicine decoctions were searched in six electronic databases until March 2021. Primary outcomes were total effective rate, recovery rate, and recurrence rate. Secondary outcomes were clinical feature scores (oral ulcers, eye lesions, genital ulcers, skin lesions, arthropathies, fever, and pathergy reactions) and laboratory index levels (erythrocyte sedimentation rate, C-reactive protein, and immunoglobulin A). The risk of bias was assessed with the Cochrane Handbook, and a meta-analysis was performed with RevMan 5.4.1. Results Sixteen RCTs with 924 patients were included in the review. The meta-analysis indicated that Chinese medicine decoctions were effective for BD when compared with control groups for all the primary outcomes and 7/10 of the secondary outcomes. Adverse events were reported in 11 of the 16 RCTs, with the Chinese medicine decoctions possibly having fewer adverse events than western drugs. This review included a range of classical prescriptions. An additional meta-analysis of modified Gancao Xiexin Decoction for BD treatment was conducted. Gancao Xiexin decoction is also discussed as a representative prescription, as well as high-frequency herbs, and warrants further exploration for individualized medicine and pharmacology. Conclusion Chinese medicine decoctions have the potential to be effective and safe for treating BD. However, additional well-designed RCTs are needed to confirm the findings because of the unsatisfactory quality of the included studies.


Introduction
Behcet's disease (BD), also referred to as Behcet's syndrome, is a chronic inflammatory vasculitis with multiple systems involved. It is typically characterized by recurrent canker sores, genital ulcers, ocular lesions, and cutaneous lesions [1]. In most reports, the mean age of onset is 20 to 30 years, and the incidence of the disease is higher in males than females [2]. Although the etiology of BD is not yet clear [3], it is recognized as an autoimmune disease with a genetic predisposition and infection-associated triggering factors, mediated by immune cells, chemokines, and cytokines [4]. e homeostasis perturbation of T cells, especially 1 and 17, is now considered to be the main immunological basis of BD pathogenesis [5].
For treatment, corticosteroids, immunomodulatory agents, immunosuppressive agents, and tumor necrosis factor (TNF) alpha inhibitors are commonly used. e main goal of treatment is to prevent the effects of inflammation and inhibit the progression of the disease from reaching the point of target organ damage [6]. However, the long-term disadvantages of western medical treatment include side effects, drug resistance, and relapse after discontinuation of the medication [5]. For example, thalidomide is contraindicated in pregnant women because of teratogenicity [7]. Systemic steroids are associated with a number of adverse events (AEs) and can lead to tolerance [8]. For patients with severe clinical manifestations and intolerance or resistance to standard immunosuppression protocols, TNF blockade might be beneficial, but with relatively high costs [9]. us, for certain groups of BD patients, treatment options are limited.
Complementary and alternative medicine, including herbal medicine, are gaining more notice. Herbal medicines have been reported to reduce the risk of disease and improve the body's immunity, such that in the positive role they play in immune regulation in cancer patients [10]. ere is also evidence that some of the ingredients in herbal medicines act as anti-inflammatory agents, mimicking flavonoids, steroids, alkaloids, glycosides, polyphenols, curcumins, terpenoids, gamma linolenic acid, phenolic diterpenes, and harpagoside. Compared to synthetic steroid and nonsteroidal anti-inflammatory drugs, they have fewer side effects and lower cost [11].
In traditional Chinese medicine theory, Behcet's disease is similar to Huhuo disease in clinical manifestations and pathogenesis [12]. e presentation of Huhuo was first recorded in Jin-Kui-Yao-Lue (Synopsis of Golden Chamber). In this important reference, the classic treatment prescriptions, including Gancao Xiexin decoction and Chixiaodou Danggui powder, were addressed. After thousands of years of practical application and adjustment, a few more classical prescriptions have been developed that also deserve further attention. e aim of this systematic review is to provide clinical evidence of Chinese medicine decoctions in the treatment of BD. Although a few systematic reviews have been previously published on herbal medicine for BD, the number of included studies has been limited. Additionally, there is a lack of reviews on Chinese medicine decoctions, even though they are the most common form of traditional therapy. In this review, we conducted a comprehensive search for studies on Chinese medicine decoctions for BD, to provide evidence for using herbal medicine to treat BD, by analyzing effectiveness and safety data. Furthermore, an additional meta-analysis of modified Gancao Xiexin Decoction for BD treatment was also conducted.

Methods
is review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA): the PRISMA Statement [13].

Inclusion and Exclusion Criteria.
e inclusion criteria were as follows: (a) the studies on the treatment of BD with Chinese medicine decoctions had to be RCTs. (b) Interventions in the experimental group were orally administered Chinese medicine decoctions with or without topical decoctions. (c) e additional intervention (if any) in the experimental group must be the same (including dose, frequency, and route of administration) as the control group. (d) Interventions in the control group could be western drugs (such as thalidomide and prednisone) or placebos. (e) e studies had to report at least one primary outcome and one secondary outcome. (f ) e age and gender of patients were not limited. (g) No language restrictions were applied. e exclusion criteria were as follows: (a) duplicate publications, (b) studies with unavailable full-text, (c) protocols, (d) studies using nondecoction dosage forms (such as capsules, granules, tablets, and substituting tea drinking) or decoctions only by topical application in the experimental group, and (e) intervention combined with herbs in the control group.

Types of Outcome Measures.
Primary outcomes were (a) total effective rate: numbers of clinically cured, significant improvement, or improvement/total number; (b) recovery rate: number of clinically cured/total number; (c) recurrence rate. Secondary outcomes were (a) clinical feature scores (oral ulcers, eye lesions, genital ulcers, skin lesions, arthropathy, fever, and pathergy reactions); (b) laboratory index levels (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP], and immunoglobulin A (IgA)). In addition, we documented the AEs mentioned in all the included studies.

Data Extraction.
Two reviewing authors (Jingxian Yan and Yi Yan) performed the literature search, study selection, and data collection independently. Extracted data included the title, author, year of publication, type of grouping, type of blinding, sample size, general condition of the patients, intervention of the experimental and control group, treatment course, outcome measures, components of basic decoction, and modification of prescriptions. A third reviewer (Zhiyong Yan or Zhimin Yan) was invited to make an assessment if the two review authors could not reach a consensus.  [14]. e assessment criteria include seven domains: (1) random sequence generation (selection bias), (2) allocation concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome assessment (detection bias), (5) incomplete outcome data (attrition bias), (6) selective reporting (reporting bias), and (7) other bias. We described the degree of risk of bias for each domain as "low risk of bias," "unclear risk of bias," or "high risk of bias."

Data Analysis.
e efficacy of Chinese medicine decoctions on BD was evaluated using the RevMan 5.4.1 software. For dichotomous data, we chose the Mantel-Haenszel statistical method. Results were expressed as risk ratios (RR) together with the 95% confidence interval (CI) and plotted on a forest plot. For continuous data, we chose the inverse variance statistical method. Results were expressed as mean difference (MD) together with the 95% CI and plotted on a forest plot. e Q-test and I 2 were used to test for heterogeneity of the included studies. When there was no significant heterogeneity (P > 0.10, I 2 < 50%), the fixed effect analysis model was used; when there was obvious heterogeneity (P < 0.10, I 2 > 50%), the random effects analysis model was used. When the same outcome measure was reported in more than ten RCTs, a funnel plot was used to assess publication bias.

Study Characteristics.
Seven theses and nine journal articles were included. All the included studies were conducted in China. A total of 924 patients were enrolled in the 16 studies. All 16 included studies were RCTs. Seven RCTs described specific randomization methods including random number tables and statistical software random allocation. Two RCTs explicitly used blinding, and both were single-blind designs. e basic characteristics of the included studies are presented in Table 1. For the control group, western medicine was used in all the included studies. For the experimental group, eight RCTs used only Chinese medicine decoctions, and eight RCTs used Chinese medicine decoctions combined with the same treatment as the control group. Treatment course ranged from two to four months. In each study, the experimental group had the same treatment course as the control group. e interventions and treatment course are presented in Table 2. e outcome measures and AEs are presented in Table 3. All 16 RCTs had a basic decoction in the experimental group, and 12 RCTs revised the prescription according to the patient's condition. ere were 102 herbs mentioned in the 16 RCTs. e components of basic decoction and modification of prescriptions are presented in Table S2 in the Supplementary Material.

3.7.
AEs. AEs were reported in 11 out of 16 RCTs. For eight RCTs [15, 16, 21, 23-25, 27, 28], the incidence of AEs in the experimental group was lower than in the control group. For one RCT [18], no AEs occurred in the experimental or control groups. For one RCT [17], the incidence of AEs in the control group was lower than that in the experimental group. For one RCT [30], diarrhea occurred in three patients in the experimental group, and no AEs occurred in the control group. Generally, the major AEs of Chinese medicine decoctions were gastrointestinal reactions, sleepiness, and dizziness; no severe kidney or liver damage was  reported. Five RCTs did not mention AEs. Specific AEs are presented in Table 3.

Publication Bias.
A funnel plot was drawn for the total effective rate of 16 RCTs through the RevMan 5.4.1 software (see Figure 11). Visual inspection of the funnel plot showed asymmetry, suggesting a potential publication bias. For this reason, the Stata 14.0 software was used to conduct a sensitivity analysis by the trim and fill method [31]. e imputed studies formed a symmetrical funnel plot (see Figure 12). Without trim and fill, the combined effect sizes calculated by the fixed effect model and the random effects model were the same, RR � e RR values were similar, and the effects of intervention were both statistically significant before and after trim and fill. is indicated that publication bias had little effect on the conclusion.

Summary of Main Results.
e meta-analysis of the 16 RCTs indicates that Chinese medicine decoctions have, compared to controls, a significantly higher total effective rate and recovery rate and significantly lower recurrence rate, clinical feature scores (oral ulcers, eye lesions, genital ulcers, skin lesions, arthropathy, and pathergy reaction), and laboratory index levels (ESR). However, the evidence is inadequate to support that Chinese medicine decoctions are effective in lowering fever, and CRP and IgA levels. As for safety, in one RCT, diarrhea occurred in three patients after the use of Chinese medicine decoctions, which might be related to the gastrointestinal motility adjustment caused by herbs. In the other eight studies that reported adverse events, the incidence of adverse events in the experimental group was lower than in the control group, which indicated Chinese medicine decoctions may have lower incidences of adverse events than western drugs. In summary, Chinese medicine decoctions are valuable as a complementary and Gong  e review covered a range of classical prescriptions, such as Gancao Xiexin decoction, Huanglian Wendan decoction, and Zhigancao decoction. Gancao Xiexin decoction and the high frequency herbs will be discussed from the perspective of individualized medicine and pharmacology. It may provide a reference for the exploration of more targeted treatment of BD with herbs.

Agreements and Disagreements with Another Relevant
Review. Compared to the latest published meta-analysis on the treatment of BD with herbal medicine [32], 11     (fever and pathergy reaction) and one new laboratory index (IgA) were added to the analysis. From the results, it was concluded that Chinese medicine decoctions were effective and safe in the treatment of BD.

Discussion of Precision Medicine.
Precision medicine is a medical model for prevention, diagnosis, and treatment that aims to achieve an optimal therapeutic regimen for an individual. Treatment based on TCM syndrome differentiation meets this requirement and is a good example of this concept. In the theory of TCM, a syndrome is composed of several subjective symptoms and objective signs, and individual differences in patients are taken into account. As in precision treatment, the most appropriate decoction is then sought for each individual. In TCM, there are several guiding principles by which syndromes are differentiated: the Zangfu viscera syndrome differentiation, six-meridian syndrome differentiation, and eight-principle syndrome differentiation. It can be helpful to discuss them in the context of deficiency syndrome and sthenia syndrome (two syndromes based on eight-principle syndrome differentiation). Damp-heat syndrome is one type of sthenia syndrome, commonly seen in patients with BD [33]. It is similar to the acute episodes of BD, in which ulcers present as red in color, swollen in form, and severe in pain, and may be accompanied by fever [34]. Damp-heat syndrome is closely related to immunity, inflammatory response, intestinal flora, and glucolipid metabolism [35]. In the decoctions in this review, Gancao Xiexin decoction includes a combination of herbs with Rhizoma Pinelliae, Rhizoma Zingiberis, Rhizoma Coptidis, and Radix Scutellariae for the treatment of dampheat syndrome. Modified Gancao Xiexin decoction was used in five RCTs. e potential mechanism of action of Gancao Xiexin decoction is worth exploring and is discussed in Section 4.4.
Deficiency syndrome is opposite to sthenia syndrome and is related to immune dysfunction or decreased immune function [36]. e ulcers are light in color, flat or sunken in form, with healing difficulty and slightly painful [34]. e symptoms of BD are recurrent in a long course and thus require higher energy expenditure from the body. Astragalus membranaceus is an example of the tonic herbs and was applied in six RCTs. In fact, deficiency syndrome and sthenia syndrome do not exist in isolation, and the two can occur alternately in the same patient. A patient may even show deficiency in some aspects, but sthenia in others. Clinical treatment based on syndrome differentiation is therefore adjustable.
e specific herbs that are effective against particular syndromes may in fact suggest more targeted exploration into possible pharmacological mechanisms.

Discussion of Pharmacology.
Research on the potential mechanisms of the herbal drugs has been somewhat limited because of the unclear pathogenesis of BD. e anti-inflammatory and immunomodulatory effects of traditional Chinese medicine, as well as the effects of its promotion of ulcer healing, deserve more attention. Gastrointestinal manifestations of BD are important as they are closely associated with morbidity and mortality [37]. Although the ileocecum is the region most commonly involved, BD may affect any part of the digestive tract and a variety of gastrointestinal organs [38,39]. Interestingly, Gancao Xiexin decoction is more widely used in digestive system diseases, such as oral ulcers, gastric ulcers, and ulcerative colitis. Gancao Xiexin decoction is a classic prescription recorded in Shang-Han-Lun (Treatise on Cold Pathogenic Diseases) and Jin-Kui-Yao-Lue (Synopsis of Golden Chamber). It has been inherited and developed in different clinical areas because of its classic herbal combination and considerable clinical effect. It has been shown to exert an antireflux esophagitis effect, antiulcerative colitis effect, antioral ulcer effect, and protective effect against liver damage. It has also been shown to regulate gastric mucus secretion, enhance immune function, and improve antihypoxia ability [40]. In clinical studies on treating recurrent aphthous ulcers, Gancao Xiexin decoction was found to regulate the imbalance of T lymphocyte subsets including the ratio of CD4 + /CD8 + and the number of CD3 + , CD4 + , and CD8 + [41][42][43]. T cells are the main lymphocytes involved in the pathogenesis of BD, also have an activated phenotype, and can produce inflammatory cytokines [44,45]. In clinical studies on treatments for ulcerative colitis and gastric ulcers, Gancao Xiexin decoction was proved to adjust the level of serum  inflammatory factors including TNF-α, IFN-c, IL-8, IL-12,  IL-17, and IL-23 [46][47][48]. Among them, the IL-17/IL-23 pathway may play an important role in the mechanism of BD [49], and 1 cell infiltrates including IL-8, IL-12, TNF-α, and IFN-c were reported in gastrointestinal manifestations of BD [5]. erefore, Gancao Xiexin decoction might be a potential treatment for the gastrointestinal lesions and recurrent aphthous ulcer lesions of BD.
Although other decoctions are not as frequently reported as Gancao Xiexin decoction, some key herbs are noteworthy. Radix Glycyrrhizae is the most widely used herb, appearing in almost every decoction. e active compounds isolated from Radix Glycyrrhizae have anti-inflammatory, antiviral, antimicrobial, antitumor, and immunoregulatory effects [50]. Among them, mainly glycyrrhizin mediates the antiinflammatory activity of liquorice and promotes the healing of stomach and oral ulcers. Its anti-inflammatory effect is similar to mineralocorticoids and glucocorticoids [51]. Glucocorticoids are one class of drugs used to treat BD. is means that Chinese medicine may play a similar pharmacological role to western drugs, but with fewer adverse events.
Radix Astragali seu Hedysari, the most frequent tonic herb in the included studies, is considered to have immunoregulatory, anti-inflammatory, and antioxidative effects, as well as antiviral and antihyperglycemic activity [52]. A systematic review showed that Astragalus membranaceus may have an immunomodulatory effect on the 17/Treg axis [53], and 17 cells are considered to play an important part in BD pathogenesis [49].
Rhizoma Coptidis was used in eight RCTs. Berberine (BBR) is the abundant and main active ingredient of Rhizoma Coptidis [54] and widely used in the treatment and research of inflammatory diseases. Yang et al. reported that BBR may reduce STAT3 phosphorylation to inhibit the 17 response in the patients with ocular BD [55]. Recently, Li et al. discovered that its natural oxoderivative, oxyberberine, has greater anti-inflammatory activity than BBR and a promising future in the area of inflammation [56].
In this review, Radix Angelicae Sinensis, Radix Scutellariae, Rhizoma Pinelliae (including Rhizoma Pinelliae Preparata), and Rhizoma Zingiberis (including Rhizoma Zingiberis Recens) were used in more than half of included RCTs. eir extracts have been demonstrated to have antiinflammatory effects, which can suppress the expression of inflammatory cytokines such as TNF-α [57][58][59][60]. Interestingly, by comparing the phytochemicals and anti-inflammatory and antioxidant properties of sun-, freeze-and ovendried ginger extracts, it was concluded that the drying process had a positive effect on ginger bioactivities, especially sun-dried ginger [61]. is reflects the superiority of traditional processing methods for herbs. In general, TNF-α is an important target of pharmacological action of herbs, and TNF blockade is an essential therapeutic progress for treating BD [9], suggesting that these herbs have the potential to be more targeted treatments for BD.
Radix Ginseng can exert anti-inflammatory and immunomodulatory effects, and the terpenoid saponins have some structural similarities to steroids [62]. Fructus Jujubae was considered protective of the gastrointestinal tract against intense inflammatory stimulation, alleviating inflammatory bowel disease [63], and played bidirectional immunoregulatory roles [64]. e other five ingredients of Gancao Xiexin have already been discussed above.

Limitations and Prospects.
Although all the included studies were RCTs, some did not report their specific randomization methods. e blinding methods were also unsatisfactory. Lastly, solid conclusions cannot be drawn due to small sample sizes and poor methodological quality. erefore, well-designed, multicenter, RCTs with large sample sizes are needed.
Differences in the types and dosages of herbs may also be a source of statistical heterogeneity. We did not find large numbers of clinical studies of similar classical prescriptions, although modified Gancao Xiexin decoction was used in five RCTs. For this reason, more research should be done on the herbs and decoctions of high frequency in treating BD and their pharmacological effect. e criteria of TCM syndrome determination are not completely uniform. Different studies have developed different criteria for syndrome differentiation. Even for the same type of syndrome, subjective symptoms and objective signs may not be identical. is makes it difficult to carry out large-scale clinical studies on a single syndrome. us, an authoritative, standardized, and unified standard of TCM syndrome diagnosis is necessary for clinical research.

Conclusion
From this systematic review and meta-analysis, it was concluded that Chinese medicine decoctions had the potential to be effective and safe treatments for BD. However, more large-scale, well-designed, double-blinded RCTs are needed to further investigate the effectiveness and safety of Chinese medicine decoctions in the treatment to BD.
Data Availability e data supporting this systematic review and metaanalysis are from previous studies and datasets, which have been cited. e processed data are available from the corresponding author upon reasonable request.

Conflicts of Interest
e authors declare that they have no conflicts of interest. Table S1: retrieval strategy of the Cochrane database. Table  S2: components of basic decoction and modification of prescriptions.