CHEN Wen-ting, XIANG cong-lian, YAN yu-hong, LU chuan-jian,3,4

1.Guangzhou University of Traditional Chinese Medicine,Guangzhou 510405 Guangdong,China

2. Guangdong Provincial Hospital of Traditional Chinese Medicine,Guangzhou 510120 Guangdong,China

3. State Key Laboratory of Dampness Syndrome of Chinese Medicine,Guangzhou 510120 Guangdong,China

4. Key Laboratory of TCM Syndrome Clinical Research of Guangdong Province,Guangzhou 510120, Guangdong,China

Keywords:Psoriasis vulgaris Dampness-removing therapy Randomized controlled trial Meta-analysis

ABSTRACT Objective: To systematically evaluate the clinical effect and safety of dampness-removing therapy in the treatment of psoriasis vulgaris by Meta analysis. Methods: The clinical studies on the treatment of psoriasis with removing dampness therapy in CNKI, Wanfang, VIP,SinoMed, Medline, Embase and Cochrane Library were searched from the establishment of the database to June 2021. After screening, data extraction and bias risk assessment, the retrieved literature was statistically analyzed by Revman5.3 software. Results: A total of 2063 subjects were included in 24 clinical studies. The results of Meta analysis showed that the experimental group was superior to the control group in terms of total effective rate of treatment (OR=3.31, 95%CI [2.55, 4.31]), reducing PASI score (MD=-2.57, 95%CI [-3.08,-2.06]) and improving quality of life (MD=-3.23, 95%CI [- 3.70, -2.76]). The adverse reactions in the experimental group were slighter than those in the control group (OR=0.42,95%CI [0.29,0.61]). Conclusion: The method of removing dampness in traditional Chinese medicine is safe and effective in the treatment of psoriasis vulgaris, but in view of the low overall quality of the included research, larger samples and higher quality clinical trials are still needed to obtain more sufficient evidence.?Corresponding author: Lu Chuanjian, Professor, M.D., PhD Supervisor.E-mail: lcj@gzucm.edu.cn.

1. Introduction

Psoriasis as a chronic, inflammatory and recurrent skin disease caused by immunity or inflammation, psoriasis vulgaris(PV) is the most common, with red papules, white scales, shiny film and punctate bleeding as its typical characteristics. and the nail spot depression can be seen, and most of the disease shows the seasonal change of aggravation in winter and relief in summer. Studies have shown that the pathogenesis of psoriasis is caused by the interaction of genetic, environmental and immune factors[1]. At present, there is no radical cure. Although the treatment strategy of western medicine is effective in controlling the condition of psoriasis, however, the potential side effects of drugs and the problem of repeated illness have become a major bottleneck in the treatment of psoriasis[2]. For a long time, traditional Chinese medicine(TCM) has accumulated rich clinical experience in the treatment of psoriasis, and its curative effect has been recognized by patients. Ancient and modern physicians also continue to supplement and improve the theoretical system of psoriasis while inheriting and carrying forward the TCM theoretical system of psoriasis, and have a rich understanding and systematic exposition of the mechanism of psoriasis caused by damp pathogen[3-4]. How to carry out the research of effective prescriptions of TCM and improve the curative effect is an urgent clinical demand, so the method of removing dampness has a key guiding significance for the clinical treatment of psoriasis. At present, the use of dampness-removing method in the treatment of psoriasis meta analysis has not been reported, so this study used meta analysis to explore the therapeutic effect and safety of TCM dampness-removing method on patients with PV.

1. Data and methods

1.1 Inclusion criteria

(1) Types of research: randomized controlled trials; (2) Subjects:patients diagnosed as PV according to the Guideline for the diagnosis and treatment of psoriasis in China(2018 complete edition)[1]; (3) Interventions: the experimental group adopted the measures of including or simply using the prescription for dispelling dampness,while the control group adopted Chinese medicine preparations and/or other treatments without dampness-removing Chinese herbal medicine. (4)Outcome: the total effective rate of treatment and the score of psoriasis area and severity index(PASI) were mainly used.Due to the differences in the definition of total effective rate in each study, in order to facilitate statistics, the curative effect criteria of each study are unified as follows: total effective rate=(number of cured cases + number of markedly effective cases + number of effective cases) / total number of cases × 100%.

1.2 Exclusion criteria

Non-randomized controlled trials, animal experiments; conferences,reviews, empirical literature; non-oral dampness-removing TCM preparations in the experimental group; the research data can not be extracted or the data are incomplete.

1.3 Retrieval strategy

The computer is used to search the four Chinese databases of CNKI, SinoMed, Wanfang and VIP and the three English databases of Medline, Cochrane Library and Embase. The time range of the search is from the establishment of the database to December 2020. With the combination of subject words and free words, the Chinese search words include "psoriasis", "dampness", "dampness syndrome", "removing dampness", "clinical trial", "random control"and so on, while the English search words include "psoriasis","dampness", "damp", "randomized controlled trial" and so on.

1.4 Literature screening, data extraction and quality evaluation

The two researchers independently screened the literature, extracted the data and checked and proofread each other according to the established criteria. If there is any objection, it will be discussed and decided by two researchers, and the third party will be consulted when it is critical. After the completion of literature retrieval, import Endnote X9 for preliminary weight check, and then read the title and abstract to remove the irrelevant literature, and the rest of the literature need to be screened out to meet the requirements after reading the full text. The Excel table was used to extract and sort out the required data, including the first author, year of publication,sample size of each group, interventions, course of treatment, TCM syndrome, outcome index, baseline comparability and so on.

The biased risk assessment tool recommended by Cochrane Handbook 5.1.0 was used to evaluate the literature quality from six aspects: random allocation method, allocation sequence hiding, blind method, data integrity, selective reporting bias and other biases."high risk", "low risk" or "unclear" were evaluated one by one.

1.5 Statistical methods

RevMan 5.3 software was used for Meta analysis, ratio ratio(OR) was used to describe the effect value of counting data, and mean difference (MD) was used to describe the effect value of measurement data, both of which were expressed by 95% confidence interval (CI). The heterogeneity between studies was qualitatively and quantitatively analyzed by X2test and I2test. When I2<50%,P>0.1, the homogeneity was considered to be better, and the fixed effect model was used directly. If I2>50% and P<0.1, it is considered that there is heterogeneity among studies, so it is necessary to analyze its source and subgroup analysis of the possible causes of heterogeneity. If the heterogeneity still exists, the random effect model is used for Meta analysis, and the sensitivity analysis is used to test the stability of the results. Finally, a funnel chart is made for publication bias analysis.

2. Results

2.1 Search results

A total of 2309 articles were retrieved from the above 7 databases.After several screening, 24 articles were included, with a total of 2063 subjects, including 1055 in the experimental group and 1008 in the control group. The specific process is shown in figure 1.

2.2 Basic characteristics and quality evaluation of the included study

A total of 24 studies were included, and the baseline data of the subjects in each group were in good agreement. The basic characteristics of the literature are detailed in Table 1. The bias risk assessment results of each study are shown in figure 2. Although the specified outcome indicators are basically reported and the data integrity is good, only 6 studies use random number tables for grouping, and 5 studies do not achieve random assignment.The random allocation methods used in the remaining studies are unknown, and the bias risks of hidden and blind allocation methods are also high.

On the whole, the quality of the research included in the literature is low.

2.3 Meta analysis results

2.3.1 Total efficiencyAmong the 24 articles included, all the studies reported the outcome index of total efficiency. The results of the combination of fixed effect models showed that the homogeneity among the studies was good, and the results were P=0. 07 and I2=0%. There was significant difference in the total effective rate between the two groups (P<0.000 01), indicating that the method of removing dampness in traditional Chinese medicine was effective in improving the condition of patients with PV (OR=3.31, 95% CI[2.55,4.31]), as shown in figure 3.

In this study, the TCM syndrome differentiation of psoriasis mainlyincludes damp-heat syndrome, spleen deficiency and dampness syndrome, blood-heat syndrome, spleen deficiency and damp-heat syndrome, cold-dampness syndrome and yin deficiency and blood dryness with dampness-heat syndrome. The results showed that except spleen deficiency and damp-heat syndrome and yin deficiency and blood dryness with dampness-heat syndrome, the curative effect of removing dampness method in the treatment of psoriasis of other syndrome types was significantly different from that of the control group(P＜0.05). And in terms of curative effect, bloodheat syndrome(OR=5.67) > cold-dampness syndrome(OR=4.11)> dampness-heat syndrome(OR=3.75) > spleen deficiency and dampness syndrome(OR=2.01). However, since there is little or only one included literature in some subgroups, the above results need to be treated with caution.

Tab 1 Basic characteristics of the included studies

2.3.2 PASI scoreA total of 15 literatures reported the outcome index of PASI, and the heterogeneity test showed that there was heterogeneity among the studies. Compared with the control group, the results of random effect model showed that the dampness-dispelling herbs showed a better effect in reducing PASI score and alleviating the severity of skin lesions (MD=-2.57, 95%CI[-3.08,-2.06]), as shown in figure 4.At the same time, it is speculated that the source of heterogeneity may be related to TCM syndrome types and complex intervention measures. Subgroup analysis is carried out from these two aspects,and random effect model is used to merge. It can be seen from figure 5 that there are significant differences in PASI scores of the other three TCM syndrome types except cold-dampness syndrome (MD=-2.35,95% CI of dampness-heat syndrome[-2.89,-1.81]; MD=-3.25, 95%CI of spleen deficiency and dampness syndrome[-4.57,-1.94]; MD=-4.16, 95% CI of spleen deficiency and dampness-heat syndrome[-5.51,-2.81]). From figure 6, we can see that there are statistically significant differences in PASI scores among the 6 subgroups divided according to the intervention measures. The comparison of the curative effect of each group: dampness dispelling traditional Chinese medicine vs.Acitretin/Tripterygium wilfordii polyglycosides+loratadine(MD=-4.61, 95%CI[-6.64,-2.57]) > dampness dispelling herbs+external washing vs.Acitretin+carpotriol ointment(MD=-3.90, 95%CI[-4.65,-3.15]) > dampness dispelling herbs + topical ointment vs.Topical ointment(MD=-2.88, 95%CI[-3.70,-2.07]) > dampness dispelling herbs+acitretin vs.Acitretin(MD=-2.53, 95%CI[-4.11,-0.95]) >dampness dispelling Chinese herbal medicine+NB-UVB vs.NBUVB(MD=-2.41, 95%CI[-2.90,-1.91]) > dampness dispelling Chinese herbal medicine vs.Compound Qingdai capsule/Danqing capsule(MD=-1.57, 95% CI[-2.29,-0.86]). Due to the small number of included studies in some subgroups, the credibility of the above results remains to be further confirmed.

2.3.3 sensitivity analysis and publication bias analysisFrom the two aspects of total effective rate and PASI score, Meta analysis was carried out on other studies after single study was excluded item by item. The results show that the combined effect value before and after excluding any one study is relatively close,indicating that the results of this study are relatively stable. The funnel chart was drawn with the total effective rate as the observation index for the 24 articles included. It can be seen from figure 7 that the symmetry of the funnel chart is poor, and the Egger linear regression method is used to test the asymmetry of the funnel chart,and the result shows that there is no obvious publication bias.

2.3.4 Quality of life assessment

A total of 6 literatures evaluated the quality of life of patients with psoriasis before and after treatment. Because individual studies did not clearly mention which scoring scale was used and the data were incomplete, they were finally included in 4 studies for analysis. The results showed that the effective dose MD=-3.23,95% CI[-3.70,-2.76]and the method of removing dampness played a positive role in improving the quality of life of patients with psoriasis, as shown in figure 8.

2.3.5 Safety evaluationA total of 12 articles reported adverse reactions during the trial, of which 7 articles mentioned blood routine examination and liver and renal function examination before and after treatment, and the results were not significantly abnormal. In addition, the safety of dispelling dampness method in the treatment of PV was evaluated from four aspects: gastrointestinal discomfort, dry skin and mucous membrane reaction, light side effect and increased ALT. The overall adverse reactions in the dispelling dampness prescription group were slighter than those in the control group (OR=0.42,95%CI[0.29,0.61]), see figure 9. The use of anti-dampness herbs can reduce the symptoms of gastrointestinal discomfort (Z=2.37,P=0.02) and the side effects of light caused by the use of UB-NVB (Z=3.37,P=0.000 7). However,there was no significant difference in the dry reaction of skin and mucosa and the increase of ALT between the two groups.

3. Discuss

At present, the mainstream of TCM syndrome differentiation and treatment of psoriasis is still "treatment based on blood differentiation". This theory has also been confirmed from more clinical practice and basic research[29-32], but it still can not fully reflect the full connotation of the disease. For this reason, some modern doctors have made a new exploration on the pathogenesis of psoriasis, paying attention to the influencing factors such as regional natural environment and residents' living habits, and have a deeper understanding of the etiology and pathogenesis of wet psoriasis[33]. In addition, through the investigation of TCM physique and syndrome elements distribution of psoriasis patients through epidemiological methods, it is found that many psoriasis patients show the physical characteristics of deficiency and dampness and the syndrome characteristics of "dampness"[34-36]. Many doctors also verify the theoretical reliability of the disease caused by damp pathogen through clinical research, which makes the connotation of treating psoriasis from dampness more perfect.

Under this trend, this study attempts to scientifically and systematically evaluate the efficacy and safety of dampnessremoving therapy in the treatment of PV with the help of modern evidence-based medicine. A total of 24 studies were included in this study for Meta analysis. Compared with the control group,the results showed that the Qushi prescription group showed a better effect in the total effective rate, reducing the PASI score and improving the quality of life, and there were fewer adverse reactions.The asymmetry test of the published bias funnel chart also indicates that the conclusion of this study is reliable, which reflects that the method of removing dampness in traditional Chinese medicine can treat PV accurately and effectively, and provide guidance for clinical application and promotion.