A Meta-Analysis of Randomized Clinical Trials of Runzao Zhiyang Capsule in Chronic Urticaria

Chinese herbal medicine has many advantages in the treatment of chronic urticaria (CU). Herein, we evaluated the efficacy and safety of the Runzao Zhiyang (RZZY, Chinese patent herbal medicine capsule) capsule for CU through a meta-analysis of randomized clinical trials (RCTs). This meta-analysis included 17 RCTs involving 1,760 patients. RZZY capsule combined with conventional drugs showed a better clinical total effective rate (risk ratio (RR) = 1.20, 95% confidence interval (CI) (1.15, 1.24), P < 0.00001), significantly reduced the adverse reaction rate [RR = 0.68, 95% CI (0.50, 0.92), P=0.01] and recurrence rate [RR = 0.29, 95% CI (0.18, 0.46), P < 0.00001], and improved the life quality of patients (mean difference (MD) = −2.95, 95% CI (−4.32, −1.57), P=0.0001). Meanwhile, the serum Interleukin-4 (IL-4) (MD = −13.83, 95% CI (−23.45, −4.20), P=0.005) and immunoglobulin E (IgE) (MD = −22.99, 95% CI (−31.48, −14.50), P < 0.00001) of patients in the intervention group decreased more significantly. In all, the RZZY capsule has potential therapeutic advantages and is relatively safe for CU. However, we are cautious about the conclusion, which needs to be further confirmed by more large samples, multicenter, and high-quality research in the later stage.


Introduction
Chronic urticaria (CU) is a common skin disorder characterized by recurring wheals or combined with angioedema, accompanied by an itching or burning sensation, which occurs repeatedly and lasts for more than 6 weeks. e skin usually returns to its normal appearance within one day after each attack [1,2]. According to statistics, CU affects 1% of the world's population, mainly youthful and middle-aged females, and it is more common in Asia than in Europe and North America [3,4]. Many patients with CU have anxiety, depression, sleep disorders, autoimmune thyroid diseases, and other comorbidities [5][6][7]. CU patients with low quality of life make hospitals and society bear great economic pressure [3,8,9]. e etiology of CU is unknown and rarely caused by allergen-mediated type I allergy. Studies have shown that histamine is the main mediator of CU. erefore, the guideline recommends that 2 nd -generation H 1 antihistamines (such as Ebastine, Cetirizine, and Loratadine) are the first-line therapy, while the second-line treatment is by increasing their dose [10]. However, relevant studies have reported that even at higher doses, more than a quarter of cases are resistant to H 1 antihistamines. For CU patients who did not respond to the 2 nd -generation H 1 antihistamines, the treatment of biological agents (such as Omalizumab) was proposed [10,11]. Nevertheless, the price of biological agents is relatively expensive, and the long-term risk is not clear, so it is difficult to use widely. In addition, the immunosuppressants (such as Cyclosporine A) can also be applied to patients who are insensitive or ineffective to the 2 nd -generation H 1 antihistamines. However, due to the high incidence of adverse reactions to immunosuppressants, it is not recommended as a standard treatment [12,13]. Chinese herbal medicine (CHM) is a great treasure of China. After millennium development, its therapeutic advantages have been gradually explored. Many Chinese herbal medicines (such as Runzao Zhiyang (RZZY) capsule, Danggui Yinzi, Siwu decoction, and Xiaofeng powder) have been proven to be effective in relieving symptoms of CU [14][15][16][17][18]. In the theoretical system of Chinese medicine, CU is related to wind evil outside and deficiency of yin ( e Yinyang concept is the basic concept of Chinese philosophy as well as traditional Chinese medicine) and blood inside erefore, the treatment of moistening dryness and enriching the blood, dispelling wind, and arresting itching should be adopted. e RZZY capsule is approved by the China National Medical Products Administration and has the functions of nourishing yin and blood, dispelling wind, relieving itching, moistening intestines, and defecating. At present, several randomized controlled trials (RCTs) [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] show that the RZZY capsule has better clinical efficacy in treating CU. e RZZY capsule consists of six kinds of traditional Chinese medicine (including Polygonum multiflorum, Radix polygoni multiflori preparata, Rehmannia glutinosa, mulberry leaves, Sophora flavescens, and red live hemp). From the perspective of modern pharmacology, Polygonum multiflorum has the effects of improving immunity, antiinflammatory, antibacterial, and adrenocortical hormones [36,37]. Radix polygoni multiflori preparata is a processed product of Polygonum multiflorum.
rough animal experiments, researchers have proved that the polysaccharide, the main pharmacodynamic component of Radix polygoni multiflori preparata, has an immunomodulatory effect. It can ameliorate the learning and memory situation of dementia mice and reduce the content of total cholesterol and low-density lipoprotein in rat blood [38]. Rehmannia glutinosa can inhibit the release of cytokines and inflammatory mediators with antioxidant and anticancer effects [39][40][41][42]. Mulberry leaves can have anti-inflammation, immune regulation, liver protection, antianxiety, antidopamine, and hypoglycemic effects [43,44]. Matrine, a component of Sophora flavescens, can inhibit the degranulation of mast cells and reduce the release of allergic mediators [21]. Su et al. conducted an in vitro experiment and proved that red live hemp has anti-inflammatory and analgesic effects, inhibits T lymphocyte proliferation, and inhibits the secretion of IL-2 and IFN-c [45]. In addition, an animal experiment has demonstrated that the total coumarin, as the main chemical component of red live hemp, can regulate the expression of proinflammatory/anti-inflammatory cytokines in mice and can be used for developing immunosuppressive drugs [46]. e RZZY capsule has been widely used in the CU market of China and has achieved good curative effects. erefore, several medical institutions have also conducted clinical research on it. However, the relatively small clinical samples and the lack of systematic and comprehensive evaluation exist in the single RCT, which is not enough to be effective evidence for the clinical application of the RZZY capsule. us, we conducted a meta-analysis, systematically analyzing and summarizing previous studies. Compared with the previous single study, by integrating all relevant studies, we can more accurately estimate the effect of the RZZY capsule on CU. is study is conducive to exploring the consistency of single-study evidence and the differences between studies and providing better evidence-based medical evidence for the RZZY capsule on CU.

Data Sources and Search Strategy. China National
Knowledge Infrastructure (CNKI), Wanfang Data, VIP database, SinoMed, PubMed, EMbase, Cochrane Library, and Web of Science were searched for RCTs of RZZY capsule or combined with conventional drug for CU from the inception to July 30, 2021. ere was no limitation on language. We searched using different combinations of keywords, including "urticaria," "chronic urticaria," "Runzao Zhiyang capsule," and "randomized clinical trials." e search strategies of PubMed and CNKI are displayed in supplementary materials, respectively.

Study Registration and Inclusion/Exclusion Criteria.
Study registration: this study followed the PRISMA statement [47], and the protocol was registered at PROSPERO (NO: CRD42021274429). e inclusion criteria were as follows: (1) type of study: the RCTs were qualified. (2) Participants: participants had been diagnosed with CU according to the Chinese guidelines for the diagnosis and treatment of urticaria (2018 Edition) [48]. (3) Intervention and comparison: the patients in the intervention group were treated with RZZY capsules combined with conventional drugs, while the patients in the control group were treated with conventional drugs (the course of treatment in both groups was at least 4 weeks). e exclusion criteria were as follows: (1) case report, animal experiment, experience summary, and other research types; (2) repeated publications; (3) unable to obtain full-text literature; (4) the research design is not rigorous; and (5) unable to extract valid outcome data or inconsistent outcome indicators.

Methodological Quality Assessment.
e methodological quality of each study was evaluated by two authors (S. Z. Ye and D. Huang) using the Cochrane Handbook for Systematic Review of Intervention Version 5.1.0 [49]. It included the following items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Each item makes a judgment of low risk, high risk, or unclear risk according to the literature. Any disagreement can be solved by consensus or by a third researcher (M. L. Chen).
2.6. Statistical Analysis. RevMan 5.3 software was used for meta-analysis. Mean difference (MD) and risk ratio (RR) were evaluated for continuous data and dichotomous data, respectively. e statistical heterogeneity of the study was determined by the standard chi-square test and I 2 statistics. When the risk of heterogeneity between studies is low, the chi-square test P ≥ 0.10 and I 2 ≤ 50%, the fixed effect model should be used. Otherwise, the random effect model will be used.

Description of Included
Studies. 148 related articles were retrieved. Among them, 100 duplicate articles were excluded, and 39 studies were obtained after reading the titles and abstracts. After screening according to the relevant criteria, 17 studies were finally included in the meta-analysis. Figure 1 shows the flow chart of the study selection process.

Study Characteristics. All the RCTs were published in
China from 2013 to 2020, involving a total of 1,760 participants. Before treatment, there was no significant difference in age, gender, and course of disease between the two groups. Patients in the control group were treated with simple conventional drugs, and the patients in the intervention group were treated with RZZY capsules based on the control group. e duration of treatment for both intervention and control groups ranged from 4 to 8 weeks. 17 trails [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] [19,[25][26][27][28][29] only mentioned the word "random" without any description in detail. One study [35] used SAS system random number table allocation, and other studies did not mention allocation concealment. 7 studies [20,25,27,29,30,32,34] did not explain whether the blind method was used, and the rest did not use the blind method. 2 cases were lost to follow-up in one study [32], and there was no case shedding in other studies. Both primary and secondary outcome indicators were reported, and there was no risk of selective reporting or other bias. e risk of bias is summarized in Figures 2 and 3 and Table 2.

Quality of
Life. e quality of life was evaluated by DLQI. e pooled data of 3 RCTs [19,21,33] reported the improvement of quality of life in patients with CU after treatment. It is obtained by the random effect model that the improvement of quality of life in the intervention group was better than that in the control group (MD � −2.95, 95% CI −4.32, −1.57], I 2 � 95%, P < 0.00001) (Figure 7).

IL-4 and IgE Level.
e changes of serum IL-4 level before and after treatment were evaluated by three studies [21,22,28]. e pooled data demonstrated that the level of serum IL-4 in the RZZY capsule group decreased more

Sensitivity Analysis and Publication Bias.
A sensitivity analysis was performed based on the results of high heterogeneity. After removing the articles one by one, the heterogeneity results did not change significantly, indicating that the sensitivity of the whole analysis result is low. e funnel plot of the total effective rate is incompletely symmetrical, suggesting that there may be potential publication bias ( Figure 10) and the funnel plot of the adverse reaction rate is roughly symmetrical (Figure 11).

Certainty of Evidence.
e certainty of evidence was moderate, low, and very low. e result of the adverse reaction rate was moderate, and the total effective rate, recurrence rate, and IgE were low. e results of DLQI and IL-4 were very low. e main reasons for the downgrade were an unclear risk of bias and a small sample size. Details of the results are shown in Table 3.

Discussion
In the past, the systematic reviews of Chinese medicine in the treatment of CU focused more on acupuncture, while the clinical studies of Chinese medicine decoction or Chinese patent medicine were mostly small sample and single-center studies [50][51][52]. is may be related to the simple and easy operation of acupuncture. Acupuncture has a good effect on urticaria and is one of the treatment methods that many patients choose. Meanwhile, some patients worry about the pain and fear caused by acupuncture and choose Chinese herbal medicine for treatment. e RZZY capsule studied in this paper belongs to Chinese patent medicine. It not only has the effect of Chinese medicine decoction but also avoids the complexity of carrying Chinese medicine decoction.

Evidence-Based Complementary and Alternative Medicine
Systematic evaluation is helpful for further clinical application of Chinese patent medicine. e routine medication method of the RZZY capsule is oral administration, 4 pills (0.5 g/pill) each time, three times a day for two weeks as a course of treatment. e above results suggested that the combined use of the RZZY capsule in the traditional treatment scheme is more beneficial for shortening the symptom duration of CU than simple conventional drugs, as well as obtaining better clinical efficacy, more effectively reducing the recurrence rate, and more significantly improving the quality of life of patients with a range (4-8 weeks) of treatment. erefore, on the basis of antihistamines, combining RZZY capsule treatment could be a promising complementary therapy. Besides, relatively high safety is one of the potential advantages of CHM. In addition, IL-4 and IgE, as key substances causing    Chinese and Western medicine treatment will be the most effective treatment for patients with CU.
Although this work has achieved some valuable results, there are several potential limitations in this review. Ai

Evidence-Based Complementary and Alternative Medicine
In view of the above-mentioned issues, the following suggestions are proposed: (a) the low quality of literature is mainly due to the defects of experimental design, such as random method, blind method, and sample size. Multicenter, large sample, and double-blind design should be adopted in future research, which is more meaningful to the systematic review. (b) Some articles did not have a clear follow-up time, which will be reported more clearly in future studies. (c) After the detailed study plan is formulated, it should be registered on the relevant website in advance and obtain research approval. Related

Conclusion
Our study systematically evaluated the treatment of CU by the RZZY capsule, which will help more dermatologists to have a further understanding of traditional Chinese medicine and also provide more evidence-based medical evidence for the clinical use of the RZZY capsule. Despite the potential limitations of this review, meaningful conclusions were drawn through systematic reviews and meta-analyses based on randomized controlled trials. is will provide a reference for the clinical promotion and use of the Chinese patent medicine RZZY capsule and promote the treatment of CU. Future research still needs to be further confirmed by more large samples, multicenters, and high-quality articles.
Data Availability e data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest
e authors declare that they have no conflicts of interest.