Si Miao is the herbal combination of Cortex Phellodendri Chinensis, Rhizoma Atractylodis Lanceae, Radix Achyranthis Bidentatae, and Semen Coicis Lachryma-Jobi. It is also well known as the Four-Marvels Pill ⁸ . It is also available in a modified form with some additional herbs in actual formulation and has been used in the treatment of gout and arthritis. Acupuncture has been used to treat health conditions, including pain, for over 3,000 years, yet it has only been in the last half a century that biochemistry and neural imaging advances have allowed for the scientific understanding of its physiological mechanisms ⁹ . A number of studies have found the effectiveness of acupuncture in the treatment of gouty arthritis ^{10, 11} . Lee, et al. have performed a systematic review on acupuncture for gouty arthritis and found it to be an effective complementary medicine ¹² . Cupping therapy, commonly known as Al-hijamah in Islamic medicine, is also well-known amongst traditional practitioners in treating arthritis ^{12– 14} .

Modified Si Miao San extract inhibits an inflammatory response and modulates insulin sensitivity in hepatocytes through an IKKβ/IRS-1/Akt-dependent pathway ¹⁵ . Acupuncture helps in reducing the pain and inflammation through an increase in IL-10 concentrations in the muscle ¹⁶ . Wet cupping helps to remove oxidants and reduce the oxidative stress through oxidative balance ¹⁷ . The imbalance of oxidative stress will result in an increase in the inflammatory response ¹⁸ .

A total number of 238 (n=238) articles were identified from different databases (PubMed, PubMed Central, and CNKI). The records were screened in two stages on the basis of number of duplications followed by some initial criteria where irrelevant articles, review articles, and animal and chemical studies had been excluded. After the initial screening, 132 (n=132) articles were identified. Microsoft Excel 2016 ²⁰ and Mendeley version 1.19.2 ²¹ were used for data deduplication and citation management.

The included studies were based upon the use of the modified Si Miao (M-Si-M) combined with acupuncture and cupping for the treatment of gout and arthritis. The selected studies included both the Chinese and English languages but most of the studies available were in the Chinese language. The articles that focussed on the Si Miao formulation, modified Si Miao (M-Si-M) or combination of modified Si Miao (M-Si-M) with western medicine were excluded. After the application of the eligibility criteria, the number of articles had been reduced to six (n=6) articles and 126 articles (n=126) had been excluded. One article (n=1) had been removed further for qualitative synthesis and data extraction because of the absence of a randomised clinical trial (RCT). Clinical effectiveness, uric acid (UA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were accessed as the main outcome whereas the visual analogue Scale (VAS) and symptom scale had been excluded. Two articles (n=2) had been excluded because of unavailable outcome indicators which restrict the use to only three studies (n=3) for the meta-analysis. The flow chart of the study’s selection process according to the PRISMA flow diagram has been mentioned in Figure 1.

The Cochrane Handbook for Systematic Reviews of Interventions ²² and JBI Systematic Reviews were used as reporting channels to assess the quality of the manuscript ²³ . Two researchers independently evaluated the quality of the included studies, and a third party was consulted for resolution of any disagreement. The study design, participants, intervention, and outcome (SPIO) criteria have been mentioned in Table 2. The authors evaluated the methodological assessment under: aim/hypothesis clearly defined, adequate sample representation, patient care quality assurance, ethical approval protocol number, outcome clearly described, validity and reliability of outcome measure, attempt to blind researcher, follow-up, appropriate statistical analysis, and missing data reported ( Figure 2). The bias assessment of the studies included in the qualitative synthesis included random sequence, allocation concealment, selective reporting, blinding of participants and personnel, blinding of outcome assessment, and incomplete outcome data according to the Cochrane guidelines ( Table 3) ²² . The study characteristics of the selected studies were assessed according to the study design, treatment, control, statistical tool used, software to assess the outcome, and final outcome of the findings ( Table 4). Uric acid, erythrocyte sedimentation rate, and C-reactive protein were the clinical parameters used after the treatment and further evaluation for the meta-analysis ( Table 5). Microsoft Excel 2016 ²⁰ (Microsoft Corporation, Redmond, WA) was used to extract the data, removing study duplications, and Mendeley desktop 1.19.2 ²¹ was used for importing the references.

Comprehensive Meta-Analysis (CMA) V2 software (Biostat, NJ) was used for data synthesis. Heterogeneity was quantitatively assessed using the I ² index. An I ² greater than 50% indicated significant heterogeneity amongst the studies. The results were expressed as mixed methods using both random and fixed effects. Effect sizes were expressed as odds ratio (OR), standard mean difference (SMD), Hedge’s g (HG), Standard paired difference (SPD), Correlation (C), and 95% confidence interval (CI). A Z score was calculated to determine the overall effect. Funnel plot analysis was used to evaluate the presence of publication bias. The extent of variation amongst the effects observed in different studies (between-study variance) is referred to as tau-squared, τ2, or Tau2 ²⁹ .

Meta-analysis was conducted using the trial version of Comprehensive Meta-analysis (CMA) version 2.0 software ³⁰ . A forest plot displaying the standard difference in mean, Hedge’s g, odds ratio, Standard paired difference, and Correlation 95% CIs for the impact of the observed therapy versus the control on different parameters were observed. True heterogeneity amongst the trials was assessed using the tau, T ^{2 31} , and the extent of the inconsistency was measured by the I ² index ³² .

All the included studies employed clinical effect as the outcome assessment. The clinical parameters included CRP, ESR, and uric acid concentration after treatment with the modified Si Miao decoction combined with acupuncture and cupping therapy. The cumulative effect was observed by the meta-analysis of three randomised clinical treatment arms that suggested a significant reduction in the clinical parameters using the modified Si Miao decoction combined with acupuncture and cupping therapy (SMD: −0.91,95% CI: −1.081, −0.741, p = 0.000) (OR: −1.652, 95% CI: −1.960, −1.344, p = 0.000). The forest plot, funnel plot of Cumulative std difference in means, and Log odds ratio of the Si Miao decoction combined with acupuncture and cupping therapy versus the Control have been expressed in the Extended data (Figures 3 and Figure 4), respectively. A high heterogeneity test was indicated (Q=146.548, P = 0.00, I ² = 94.54%) ( Extended data: Figure 5). The estimated between-study variances of the cumulative Log odds ratio of the Si Miao decoction combined with acupuncture and cupping therapy versus the Control were tau= 1.974, Tau-squared = 3.897 with a standard error= 2.129, and variance= 4.533 ( Extended data: Figure 5). The estimated between-study variances of the cumulative standard difference in means of the Si Miao decoction combined with acupuncture and cupping therapy versus the Control were tau= 1.088, Tau-squared = 1.184 with a standard error= 0.647, and variance= 0.419 ( Extended data: Figure 6).

Three studies measured blood uric acid as the outcome; a comparison between the observed versus the Control post-treatment was calculated. Data extracted from the three individual studies showed that heterogeneity existed (Q=34.154, P = 0.000, I ² = 94.144%; Extended data: Figure 7). The fixed and random effects model was utilised for the statistical analysis. The estimated between-study variances of the std difference in the mean of the Si Miao decoction combined with acupuncture and cupping therapy versus the Control were tau= 1.042, Tau-squared = 1.085 with a standard error= 1.163, and variance= 1.353 ( Extended data: Figure 7). The data suggested that the Si Miao decoction combined with acupuncture and cupping therapy could further decrease uric acid as compared to the control (SDM -0.960; 95% CI -1.240, -0.660; P < 0.000) (Hg -0.940; 95% CI -1.227, -0.652; P < 0.000) (OR 0.179; 95% CI 0.105, 0.302; P < 0.000) (SPDM -0.950; 95% CI -1.240, -0.660; P < 0.000) (CORR -0.513; 95% CI -0.597, -0.417; P < 0.000) ( Extended data: Figure 8). The funnel plot displaying the (A) standard difference in mean, (B) Hedge’s g, (C) odds ratio, (D) Standard paired difference, and (E) Correlation 95% CIs for the impact of the observed therapy versus the Control on the uric acid concentrations have been represented in Extended data (Figure 9).

Three studies measured blood Erythrocyte Sedimentation Rate (ESR) as the outcome; a comparison between the observed versus the Control post-treatment was calculated. The data extracted from the three individual studies showed that heterogeneity existed (Q=12.092, P = 0.002, I ² = 83.460%; Extended data: Figure 7). Fixed and random effects models were utilised for the statistical analysis. The estimated between-study variances of the std difference in the mean of the Si Miao decoction combined with acupuncture and cupping therapy versus the Control were tau= 0.556, Tau-squared = 0.310 with a standard error= 0.372, and variance= 0.139 ( Extended data: Figure 7). The data suggested that the Si Miao decoction combined with acupuncture and cupping therapy could further decrease the ESR as compared to the Control (SDM -0.808; 95% CI -1.087, 0.530; P < 0.000) (Hg -0800; 95% CI -1.076, -0.524; P < 0.000) (OR 0.231; 95% CI 0.139, 0.383; P < 0.000) (SPDM -0.808; 95% CI -1.087, 0.530; P < 0.000) (CORR -0.400; 95% CI -0.500, -0.289; P < 0.000) ( Extended data: Figure 10). The funnel plot displaying the (A) standard difference in mean, (B) Hedge’s g, (C) odds ratio, (D) Standard paired difference, and (E) Correlation 95% CIs for the impact of the observed therapy versus the Control on the uric acid concentrations have been represented in the Extended data (Figure 11).

Three studies measured blood C-Reactive Protein (CRP) as the outcome; a comparison between the observed versus the Control post-treatment was calculated. The data extracted from the three individual studies showed that heterogeneity existed (Q=99.391, P = 0.000, I ² = 97.988%; Extended data: Figure 7). Fixed and random effects models were utilised for the statistical analysis. The estimated between-study variances of the std difference in the mean of the Si Miao decoction combined with acupuncture and cupping therapy versus the Control were tau= 2.056, Tau-squared = 4.228 with a standard error= 4.483, and variance= 20.099 ( Extended data: Figure 7). The data suggested that the Si Miao decoction combined with acupuncture and cupping therapy could further decrease the CRP as compared to the Control (SDM -3.892; 95% CI -4.637, -3.146; P < 0.000) (Hg -0.940; 95% CI -1.227, -0.652; P < 0.000) (OR 0.179; 95% CI 0.105, 0.302; P < 0.000) (SPDM -0.950; 95% CI -1.240, -0.660; P < 0.000) (CORR -0.513; 95% CI -0.597, -0.417; P < 0.000) ( Extended data: Figure 12). The funnel plot displaying the (A) standard difference in mean, (B) Hedge’s g, (C) odds ratio, (D) Standard paired difference, and (E) Correlation 95% CIs for the impact of the observed therapy versus the Control on theuric acid concentrations have been represented in Extended data (Figure 13).

All data underlying the results are available as part of the article and no additional source data are required.

Open Science Framework: Analysis of Clinical efficacy of Si Miao decoction combine with Acupuncture and Cupping treatment for Gout: A systematic review and meta-analysis, https://doi.org/10.17605/OSF.IO/PUCX6 ⁴² .

This project contains the following extended data:

Open Science Framework: PRISMA checklist for ‘Analysis of clinical efficacy of Si Miao decoction combine with acupuncture and cupping treatment for gout: a systematic review and meta-analysis’, https://doi.org/10.17605/OSF.IO/PUCX6 ⁴² .

Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).