Evaluating the Efficacy and Adverse Effects of Clearing Heat and Removing Dampness Method of Traditional Chinese Medicine by Comparison with Western Medicine in Patients with Gout

Objective. In China, the method of clearing heat and removing dampness medicine of Chinese traditional medicine has been widely used on gout. However, the clinical effects are various and not summarized systematically. Methods. In this study, a large number of randomized controlled clinical trials were reviewed and analyzed and the clinical efficacy and adverse reactions of traditional Chinese medicine with clearing heat and removing dampness effects for the treatment of gout were systematically evaluated. A comprehensive search of databases including pubMed, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database, Wanfang Data, and SinoMed was performed. Results. There are 69 randomized controlled trials with 5915 sample sizes meeting the criteria in the study. The results of the meta-analysis indicate that the effects of clearing heat and removing dampness medicine were slightly better than western medicine in the treatment of gout based on the following parameters: serum uric acid (standardized mean difference (SMD):-62.14, 95% confidence interval (CI): -78.12 to-46.15), C reactive protein (SMD: -4.21, 95% CI: -6.19 to -2.23), erythrocyte sedimentation rate (SMD: -6.23, 95% CI: -8.39 to-4.06), and overall clinical response (relative risk (RR): 1.11, 95% CI: 1.08 to 1.15) and, in the profile of adverse drug reactions, the clearing heat and removing dampness medicine showed less adverse reactions than traditional Western medicine (RR: 0.18, 95% CI: 0.10 to 0.32). Conclusions. Through a systemic evaluation of the clinical efficacy of the clearing heat and removing dampness medicine of traditional Chinese medicine and western medicine on gout, the clearing heat and removing dampness medicine and western medicine possessed similar clinical efficacy, but traditional Chinese medicine treatments are superior to western medicine in controlling adverse reactions.


Introduction
With the change of lifestyle and dietary factor, gout has been the global burden [1], mainly because of its high incidence in not only elderly people but also younger people [2]. Gout is a crystal deposition disease which results from local uric acid supersaturation as a consequence of systemic uric acid overload, leading to the formation of monosodium urate (MSU) crystals in the around joints, which caused severe pain and had a strong impact on quality of life. The most common clinical manifestation of gout is recurrent attacks of acute arthritis involving one joint at a time [3]; in some cases, joint injury and renal insufficiency will even occur in patient with gout.
In clinical, western medicines including corticosteroids, allopurinol, and NSAIDs are widely used in treating acute attack of gout [4]. But they all possessed various degrees of side-effect such as gastrointestinal tract reaction, tissue and organ damage, and other adverse reactions. In recent years, IL-1R antagonists appeared and was used for the patients who have contraindications to colchicine and nonsteroidal anti-inflammatory drugs and hormones (oral or injection) 2 Evidence-Based Complementary and Alternative Medicine [5]. However, the mechanism was unclear and the side effect was also not mentioned. Traditional Chinese medicine (TCM) has been used for preventing and treating gout with unique clinical effects since 200AD in China [6]. Clearing heat and removing dampness is a special medical method for treating patients with gout based on the theory of Chinese traditional medicine, which indicated that the pathogenesis of gout disease is closely related to the heat evil and wetness evil attacking [7]. Many randomized controlled trials (RCTs) in clinical published have selected heat and removing dampness method of Traditional Chinese Medicine to treat gout, and most have clearly shown that Traditional Chinese Medicine have achieved positive results in treating gout.
Meta-analysis, which is the statistical synthesis of relative literature to develop evidence-based conclusions, is able to systematically evaluate and summarize the consistency of multiple studies on the same topic [8]. To the best of our knowledge, there is no meta-analysis of the treatment of gout with heat and removing dampness method of Traditional Chinese Medicine. We need to have a clearer understanding of the application of heat and removing dampness method of Traditional Chinese Medicine in the treatment of gout and to evaluate its effectiveness of in the treatment of gout. The efficacy and side effect of clearing heat and removing dampness medicine and western medicine in the treatment of gout were compared using meta-analysis method in this study. The results will lay a foundation for the treatment of gout with clearing heat and removing dampness methods.

Methods
. . Experimental Design. The clinical designs in all reports selected in this study were clinical randomized controlled trials (RCTs). Based on the intervention method, the trials were divided into experimental and control groups, oral administration of Chinese herbal decoction and disposition with other methods of traditional Chinese medicine were included in the experimental group, while oral administration of western medicine was regarded as the control group. The publication time was restricted to the period from January 2000 to May 2017, and the journals' languages were restricted in Chinese and English.
. . Subjects. According to the diagnostic criteria created by the 1977 American College of Rheumatology classification criteria and Guidelines for the diagnosis and treatment of primary gout established by the Chinese Rheumatology Association, etc., all subjects selected in the study were diagnosed with primary gout in the phase of acute arthritis. Subjects with other comorbidities were excluded.
. . Database Search Strategy. The titles of "Clearing heat and removing dampness" and "hyperuricemia" or "Clearing heat and removing dampness" and "gout" were searched from the databases including PubMed, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database, Wanfang Data, and China Biology Medicine disc during the period from January 2000 to May 2017.
. . Data Analysis. Three investigators who participated in the study extracted data from all publications selected in this study. The information of the first author, the year of publication, the number of cases in the experimental group and the control group, the intervention method, the end point evaluation index, and the Jadad score were included. One investigator did the first data extraction, the second investigator reviewed the literatures and confirmed the results afterwards, and the third investigator participated in the discussion when the disagreement occurred and reached a consensus with the other two finally.
. . Endpoint Indicators. The evaluations of effective and ineffective were reached artificially based on the indicators of measurement data, such as Serum uric acid (SUA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). And the evaluations of SUA, CRP, and ESR were collected after the period of gout attack. The reducing of blood uric acid, ESR, and CRP and the relieving of the clinical symptoms were regarded as effective. On the contrary, it was ineffective. The respective measurement data of blood uric acid, ESR, and CRP were also regarded as the primary indicators.
. . Assessment of Methodological Quality. Assessment of methodological quality is based on the validated Jadad scale by two reviewers (XN and CH) and the Jadad scale has three scoring points. The first is if the study was described as randomized, and with detailed descriptions. The second is if the blind method was adopted in the study and with detailed descriptions. And the third is if there was a description of withdrawals and dropouts. A paper reporting could therefore receive a Jadad score from 0 to 7, in which the scores with 1-3 and 4-7 were considered as low and high quality, respectively.
. . Statistical Methods. The measurement data were evaluated using the mean difference (MD) and 95% confidence interval (CI), or the relative risk (RR) and 95% confidence interval. If the heterogeneity of the study was within the acceptable range (I ≤ 50%), the fixed effect model was used. Otherwise, the random effects model was used. The collected data in clinical research were analyzed by RevMan 5.0 software.

Results
. . Selection of Studies. 971 articles about the treatment of gout using clearing heat and removing dampness medicine of Chinese traditional medicine were retrieved from five electronic databases, in which 442 duplicated publications articles were excluded. Then two reviewers independently screened the full texts of the remaining 529 articles. 109 non-RCT articles, 8 articles based on animal experiments, 88 articles had inconformity to inclusion standard but included the experimental group or the control group, 19 articles without diagnostic criteria, 143 articles about review and experience summary, and 93 articles about other directions. Finally, 69 articles were included in this study   (Figure 1). The characteristics of these studies were shown in Tables 1 and 2.  Evidence-Based Complementary and Alternative Medicine    Evidence-Based Complementary and Alternative Medicine      . . Risk of Bias. All of the selected trials adopted the method of randomization , which involved sealed envelopes11, randomized block [9, 10, 12, 13, 15, 17-33, 36-38, 40-51, 53-77], and random number table [14,16,34,35,39,52]. Therefore, those trials were considered low risks in terms of selection bias. Only one trial involved the method of blinding [36]. These parameters were considered low risk in terms of incomplete outcome data. Detection bias, reporting bias, and other potential biases were unclear in all studies (Figures 2  and 3).
. . Adverse Reactions. Adverse reactions data were provided from twenty-five RCTs, including 2217 patients (1147 cases in the experimental group and 1070 cases in the control group) [11, 20, 23, 24, 27, 30, 32, 34-36, 38-40, 42, 47, 48, 53-59]. The random model was applied finally because of its heterogenicity with I = 68% (Figure 4). The results indicated that the adverse reactions rate of patients taking Chinese herb and (or) receiving other traditional Chinese medicine treatment was lower than that of patients who take western medicine (0.18 times), and the difference was statistically significant (P < 0.00001).
. . Efficacy. The effective rate data were provided from sixty-six RCTs, including 5669 patients (2952 cases in the experimental group and 2717 cases in the control group) [9-13, 15-44, 46-69, 71-77]. The random model was used because of its heterogeneity with I = 75% ( Figure 5). The results indicated that the effective rate of patients who took Chinese herb and (or) treated with other traditional Chinese medicine methods were higher than that of those who used Western Medicine (1.11 times). The difference was statistically significant (P < 0.00001).
. . Serum Uric Acid Concentration ( mol/L). The serum uric acid concentration data were provided from forty-one RCTs, including 3549 patients (1834 cases in the experimental group and 1715 cases in the control group) . The random model was adopted according to I = 98% ( Figure 6). Compared with the patients in the control group who only took western medicine, the level of serum uric acid concentration was reduced by 62.14% in patients who took traditional Chinese herb and (or) treated with other traditional Chinese medicine methods. The results were statistically significant (P < 0.00001).  . . C-Reactive Protein (mg/L). The C-reactive protein data was provided from sixteen RCTs, including 1408 patients (704 cases in the experimental group and 704 cases in the control group) [12, 14, 21, 23, 24, 30, 37-42, 44, 50-52]. A random model was adopted according to I = 98% (Figure 7). Compared with the patients in the control group who only took western medicine, the level of C-reactive protein was reduced by 4.21% in patients who took traditional Chinese herb and (or) treated with other traditional Chinese medicine methods. They were statistically significant on the difference of two intervention methods to reduce C-reactive protein levels ( P <0.0001).

. . Erythrocyte Sedimentation Rate (ESR) (mm/h).
The Erythrocyte sedimentation rate data was provided from twentytwo RCTs, including 1951 patients (988 cases in the experimental group and 963 cases in the control group) [10-12, 14, 17, 19, 20, 23, 24, 26, 27, 30, 37-41, 44, 50-52]. A random model was adopted according to I = 95% (Figure 8). Compared with the patients in the control group who only took western medicine, the level of Erythrocyte sedimentation rate was reduced by 6.23% in patients who took traditional Chinese herb and (or) treated with other traditional Chinese medicine methods. There was significant difference between the experimental group and the control group on ESR (P < 0.00001).

Discussion
With the continuous improvement of people's living standard, the change of dietary structure and the influence of environmental factors, the incidence of gout has been gradually increased every year all over the world. Nowadays, the patient with gout could only be alleviated but not cured with existing clinical treatments; thus searching for a better therapeutic method has been appeared to be very important. Our current study analyzed data from 69 RCTs that aimed to assess the therapeutic effect and safety of heat and removing dampness method of Traditional Chinese Medicine for gouty arthritis.
In respect of adverse reaction rate, clearing heat and removing dampness method with or without other traditional Chinese medicine therapy are better than western medicine treatment (RR = 0.18). The adverse reactions often occurred during the process of using drugs, such as abdominal pain, diarrhea, vomiting, and inappetence, and even causing damage of liver and kidney in severe cases. Compared with western medicine, clearing heat and removing dampness method was shown to be more effective to the patients with gout, with less adverse reactions mentioned above at the same time, probably due to the synergistic action of multicomponents and multitargets in the traditional Chinese medicine and the integrity of human body. The clearing heat and removing dampness method which is the unique medical method based on Chinese traditional medicine has Evidence-Based Complementary and Alternative Medicine    a good effect to treat patients with gout, mainly because of the pathogenesis of gout disease which is that the meridian is blocked by a pathogenic factor formed by blending of heat and wetness evils [7].
According to our results, the clearing heat and removing dampness method of Chinese traditional medicine adjuvant treatment of Chinese medicine such as acupuncture and cupping could effectively reduce uric acid, C-reactive protein, and ESR in patients with gout. Different researchers have chosen different modalities of the clearing heat and removing dampness method of Chinese traditional medicine, such as Si Miao San [29][30][31], Xuan Bi Fang [38,39], acupuncture and Chinese medicine combination [41,59,76], etc. Among them, the types of Chinese medicine, the dose, and the acupoint selection of acupuncture and acupuncture techniques are inconsistent. Therefore, our results cannot get a clear conclusion, we do not know which treatment method has the best effect on gout and the least adverse reactions.
In this study, there are many shortcomings: a lot of randomized controlled trials are not amply descripted in grouping; it is not sufficient to prove that the randomization program is executed correctly. The overall methodological quality is poor, which limits the value of the effect of the clearing heat and removing dampness method of Chinese traditional medicine in the treatment of gout. Therefore, an indepth investigation and further extensive study were need in the future.

Disclosure
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.