| BackgroundGout is a type of potentially progressive and debilitating inflammatory arthritis, the most common condition in adult men, characterized by joint pain, functional disability, inflammation, acute and recurrent gout flares. Hpidemiological data are consistent with a rise in prevalence of gout, with greatly impact on disease burden, change of lifestyle of humans and its influence on health care services, and the fact that gout reduces productivity and increases annual total healthcare cost. Due to limitations of modern treatment of gout, there is a rise in gout patients seeking for Chinese herbal therapies, and a recent resurgence of interest in clinical and research attention to Chinese herbal medicine for gout. A great amount of evidence has been accumulated.ObjectivesTo systematically review randomized controlled trials on Chinese herbal medicine for treatment of gout, and summarize the current evidence from clinical research, in the purpose of evaluating effectiveness and safety of Chinese herbal medicine for gout, compared to no treatment, placebo, conventional medications, or in combined remedies compared to the same conventional therapies. And provide evidence-based suggestions for clinical practice. Meanwhile, in the methodological section, by exploring the current situation of outcomes selection and measurement in randomized controlled trials of Chinese herbal medicine for gout, the searcher intends to put forward some suggestions for clinical research design and results report from the perspective of evidence-based medicine, in order to improve the quality of clinical research of traditional Chinese medicine.Materials and MethodsMethodology derived from Cochrane systematic reviews was used in this study. Data extraction of included randomized controlled trials, risk of bias evaluation, qualitative and quantitative data analysis were performed and reported in the results part. By discussing the results, methodological quality of included trials and limitations of this systematic review, suggestions on improving the design and report of clinical studies were given in the discussion part of the systematic review and in the methodology section of this study.Literature search:we searched randomized controlled trials on Chinese herbal medicine for treatment of gout in Medline via Pubmed, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, China Biology Medicine Database, Wanfang Database on Academic Institutions in China. The search ended in December2012.Inclusion criteria:randomized controlled trials of Chinese herbal medicine for gout. Adult patients, with diagnose criteria met American College of Rheumatology preliminary criteria for the classification of gout, or monosodium urate crystal diagnosis, or both diagnostic criteria. Experimental interventions consist of Chinese herbal medicine or integrative traditional Chinese herbal and conventional drugs, compared to no treatment, placebo, and/or conventional medications, such as colchicines, allopurinol, uricosuric agents and non-steroidal anti-inflammatory drugs. No limitation on treatment course and follow-up duration. At least one of the following outcomes that directly relate to patient or reflect the change of primary outcomes was reported in the trial:pain relief, joint function recovery, recurrent attacks during the follow-up, quality of life, serum uric acid level, C-reactive protein, relief of joint swelling or tenderness, and side reactions.Data extraction and analysis:two reviewers extracted the data independently and evaluated the risk of bias of included randomized controlled trials according to Cochrane Handbook for Systematic Reviews of Interventions. We used Review Manager5.2.3version for quantitative data analysis on primary and secondary outcomes. Continuous data was expressed as mean difference. Dichotomous data were expressed as risk ratio.95%confidence intervals were provided. In the case of more than two trials that reported the. same outcomes and interventions, meta-analysis would be performed, with heterogeneity tested and corresponding effect model chosen.ResultsA total of57randomized controlled trials involving4527patients were included. The methodological quality was generally poor.41randommized controlled tirlas compared Chinese herbal medicine to conventional medications, and the other16compared integrated Chinese herbal and conventional medications to the latter. No trial reported health-related quality of life in patients. For pain control,17trials reported pain relief by using visual analog scale or numeric rating scale, including five reported average time to pain relief (day). Thirteen trials reported patients’targeting joint function limitation relief after treatment. Only eight trials reported follow-up after the treatment, lasting from one month to more than two years, four of which reported patients’relapse information in the follow-up. All57trials reported the blood uric acid level of patients immediately after treatment (μmol/L), including two reported the patients’uric acid change value. Sixteen trials reported patients’C-reactive protein level after treatment (mg/L), and13trials reported patients’inflammation control by scoring swelling or tenderness severity after treatment. Thirty-seven trials reported safety in the results part and four observed no side reaction neither in experimental groups nor control groups.Pain relief, only two studies found Chinese herbal medicine statistically effective compared to conventional drugs (2/12trials,16.7%), one tested Lexing Tongfengke perscription (n=68, p=0.02) and the other Simiao pill modified (n=53, p<0.01). Meta-analysis found no statistical difference between Tongfeng granule group and colchicines, allopurinol group on average time to pain relief (n=120, MD-0.34,95%CI-2.01to1.32, p=0.69). One trial found that the average pain relief time in the control group was statistically shorter than that in experimental group (MD2.3,95%CI0.41to4.19). Three trials’ results showed that inlegrative Chinese herbal and conventional medications were effective in pain relief, with statistical differences between groups.Joint function limitation relief: only two studies found Chinese herbal medicine effective in relieving joint functional limitation when comparing Chinese herbal medicine to conventional therapies (2/8trials,25.0%), and the herbal medicine were Simiao pill modified (MD-0.51,95%CI-0.83to-0.19) and Simiao powder (MD-0.46,95%CI-0.6to-0.32). The other six trials did not found statistical difference between groups. Another three trials comparing herbal medicine in combined remedies to conventional medieations found that experimental interventions superior to conventional therapies in control groups.Recurrence in follow-up: four randomized controlled trials have observed this outcome. In the trial that compared Huzhang Tongfeng granule to Daifen, the follow-up lasted for ten weeks, identifying recurrence of gout attacks in23patients, and found no statistical difference between groups (RR0.45,95%CI0.20to1.02, p=0.06). One trial found that Tongfeng granule was superior to allopurinol in preventing relapse in a three-month follow-up (RR0.25,95%CI0.09to0.70, p<0.01). In the trial that tested Simiao Tongfeng decoction combined with Diclofenac, the follow-up lasted for three months, and found the recurrence rate in the experimental group statistically lower than that in the control group (MD-0.41,95%C1-0.73to-0.08, p=0.02). Another trial that compared Situ Simiao decoction combined with Ibuprofen, Benzbromacrone and allopurinol found statistical difference between group with11relapse in the three-month follow-up (RR0.29,95%C10.09to0.90, p=0.03).Serum uric acid level: in15randomized controlled trials that compared herbal medicine to colchicines and/or allopurinol, meta-analysis found that Simiao powder showed effectiveness in control of uric acid level compared to colchicines (n=164, MD-142.31,95%CI-156.56to-128.05,I2=0%), Rebixiao granule superior to Diclofenac Sodium Enteric (n=150, MD-35.94,95%Cl-60.79to-11.09, I2=O%), and Tongfeng granule superior to colchicines and allopurinol (n=278, MD-41.12,95%CI-62.36to-19.88, I2=18%). In the other33randomized controlled trials,19found Chinese herbal medicine effective in management of serum uric acid level in gout patients, and another16trials that compared herbal medicine in combined remedies superior to conventional medicines.Inflammation relief: in the effectiveness of relieving joint swelling and tenderness, two randomized controlled trials found that Lexing Tongfengke prescription, Simiao pill modified were superior to conventional medications, and another four trials found that Tongfengtai granule. Simiao Tongfeng decoction, Qingre Jiedu Qushi Huazhuo decoction and Situ Simiao decoction in combined remedies were superior to conventional medications. In the effectiveness of lowering patients’ C reaction protein level, seven trials found that Chinese herbal medicine superior to conventional therapies, and three trials found that integrative Chinese herbal and western medicine better than control group. In the formulation of Chinese herbal prescriptions, herbs with function of clearing the heat, removing toxin and stasis, relieving pain were used for inflammation relief. Safety:in sum,44patients had side reactions to experimental interventions, and324patients reacted to control medications (RR0.11,95%CI0.08to0.15, Z=13.87, p<0.01). Side reactions include:gastrointestinal reactions, headache or dizziness, allergic skin rash, decreased white blood cells, increased creatinine, increased liver enzyme, renal dysfunction and liver function damage.There are some limitations in the randomized controlled trials of Chinese herbal medicine or integrative Chinese herbal and conventional medicine for treatment of gout, including insufficient baseline data of participants, obscure discrimination between primary outcomes and secondary outcomes, improper selection of effectiveness outcomes, shortness of standard criteria of outcome measurements and unsatisfactory report of safety related outcomes.ConclusionsChinese herbal medicine has potential effectiveness and promising safety for treatment of gout. More than half of included randomized controlled trials found Chinese herbal medicine effective in control of serum uric acid level, indicating that Chinese herbal medicine has potential efficacy in preventing recurrence of gout and in treating hyperuricaemia. Current data showed that the methodological quality from randomized controlled trials of Chinese herbal medicine in not promising, and the selection of outcome measurements in randomized controlled trials of Chinese herbal medicine for gout is not consistent with the international and independent initiative of outcome measures in gout, which leads to limitations on power in evaluating the effectiveness and safety. Therefore, we need to concentrate on randomization, selection of outcomes and measurements, follow-up design and results report, in order to improve the quality of clinical research, and make effort in access to high-quality clinical evidence of Chinese herbal medicine for treatment of gout. |
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