Open Access

Systematic review and meta‑analysis of the efficacy and safety of Biqi capsule in rheumatoid arthritis patients

  • Authors:
    • Xiu‑Min Chen
    • Jia‑Qi Wu
    • Qing‑Chun Huang
    • Jian‑Yong Zhang
    • Jian‑Hong Pen
    • Zhi‑Sheng Huang
    • Yong‑Liang Chu
    • Xiao‑Hong He
    • Mao‑Jie Wang
    • Run‑Yue Huang
  • View Affiliations

  • Published online on: May 2, 2018     https://doi.org/10.3892/etm.2018.6121
  • Pages: 5221-5230
  • Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Biqi capsule is a Traditional Chinese Medicine preparation for treating rheumatoid arthritis (RA), and clinical studies have indicatedthat its effect may be more beneficial than that of Western medicine. The present study aimed to estimate the efficacy and safety of Biqi capsule alone or combined with methotrexate (MTX) compared with MTX alone for treating RA by performing a meta‑analysis of randomized controlled trials and controlled clinical trials. A systematic literature search of studies published until March 2017 was performed. References from relevant studies were screened to obtain additional articles. The results were independently evaluated for relevance, and full‑text studies were assessed for eligibility. The risk of bias was assessed using the Cochrane collaboration tool for assessing risk of bias. Out of 558 citations that were initially retrieved, a total of 5 studies comprising 522 patients met the inclusion criteria. The risk of bias of these trials was generally unclear or high. Meta‑analysis indicated that Biqi capsule had better effects on C‑reactive protein [standardized mean difference (SMD), ‑7.05; 95% CI ‑(10.77‑3.33)] and tender joint count [SMD, ‑3.02; 95% CI, ‑(3.81‑2.22)] and fewer adverse effects (AEs) than MTX [relative risk (RR), 0.19; 95% CI, 0.08‑0.43]. Biqi capsule plus MTX was superior to MTX in terms of the total effect (RR, 1.17; 95% CI, 1.06‑1.28), rheumatoid factor [SMD, ‑12.54; 95% CI, ‑(16.87‑8.20)], swollen joint count [SMD, ‑1.50; 95% CI, ‑(1.99‑1.01)], score of joint swelling [SMD ‑2.07; 95% CI, ‑(2.76‑1.38)], tender joint count [SMD, ‑2.16; 95% CI, ‑(2.86‑1.47)] and score of joint tenderness [SMD, ‑4.69; 95% CI, ‑(5.92‑3.47)]. There was no difference in AEs between Biqi capsule plus MTX and MTX (RR, 0.71; 95% CI, 0.34‑1.50). In conclusion, the present study indicated that compared with MTX, Biqi capsule plus MTX appeared to have more benefits but that Biqi capsule alone was not better for RA patients than MTX. In the other words, Biqi capsule plus MTX is more effective and has fewer AEs compared to MTX. However, the trials selected in the present meta‑analysis have various limitations, including the lack of blinding and the short duration of the treatment; therefore, the conclusions are not sufficiently definitive. More randomized controlled trials are necessary to evaluate the use of Biqi capsule for managing RA.

Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory disorder whose prevalence is estimated to be 0.3–1.0% worldwide (1,2). As a refractory disease, RA leads to not only a poor quality of life for patients, but also a heavy burden on society and the economy (3). In general, the drugs used for RA therapy include corticosteroids, non-steroidal anti-inflammatory drugs, conventional disease-modifying antirheumatic drugs (cDMARDs) and biological DMARDs. Of note, as a typical DMARD, methotrexate (MTX) is recommended as a first-line drug for the management of early and established RA (4).

On occasion, cDMARDsdo notdecisively control the disease activity of RA (5). In addition, the long-term use of cDMARDs results in a reduction of drug efficacy and an accumulation of side effects (6). Biological agents, includingtumor necrosis factor (TNF)-α inhibitor, work faster in reducing disease activity than cDMARDs, but certain patients fail to maintain an initial response due to acquired drug resistance (7). Therefore, it is a concern for rheumatologists to optimize the current therapeutic strategies for RA management. Furthermore, in patients with MTX-refractory early RA, a treatment strategy commencing with the addition of the TNF inhibitor infliximab over 21 months has been associated with similar effects to those of salazosulfapyridine and hydroxychloroquine but higher costs (8). In fact, the use of biological agents imposes a heavy economic cost on the patients and on society in China (3,9).

Traditional Chinese Medicine (TCM) providesvarious useful and inexpensive methods for RA therapy, and TCM is frequently used as an add-on therapy in China. In addition, TCM is generally safer than cDMARDs (10). For instance, recently, in a 24-week, randomized, multicenter, single-blinded study, managing RA by using TCM appeared to be effective for treating RA and was associated with fewer side effects compared with cDMARDs (10). In the present study, clinical responses were defined by the American College of Rheumatology (ACR) core set of disease activity measures (11). An ACR20/50/70 response was defined as at least 20/50/70% improvement in the tender joint count and the swollen joint count and at least 20/50/70% improvement in 3 of the 5 core set measures, including the physician's assessment of disease activity, the patient's assessment of disease activity, the patient's assessment of pain, the patient's assessment of physical function and the levels of an acute-phase reactant [either the C-reactive protein (CRP) levels or the erythrocyte sedimentation rate (ESR)] (11). Although the ACR20 and ACR50 responses at 24 weeks were better in the group receiving cDMARD treatment, the ACR 70 response was not significantly different between the TCM and cDMARD groups, suggesting that the long-term use of TCM may have a similar clinical outcome to the long-term use of cDMARDs (10).

Biqi capsule is a TCM preparation for treating RA. It is composed of the followingnatural materials: The dried fruit of Strychnosnux-vomica (Maqianzi), the dried body of Pheretima aspergillum (Dilong), the root of Codonopsispilosula (Dangshen), the sclerotia of Poriacocos (Fuling), the rhizoma of Atractylodismacrocephalae (Baizhu), the root and rhizoma of Glycyrrhizauralensis (Gancao), the rhizoma of Ligusticumwallichii (Chuanxiong), the root and rhizoma of Salvia miltiorrhiza (Danshen), the root and rhizoma of Panaxnotoginseng (Sanqi) and the radix of Achyranthesbidentata (Niuxi). The dried fruit of Strychnosnux-vomicais the most important component of Biqi capsule. It has been proved that processing of semen strychnimay reduce the level of nitric oxide (NO) and NO synthase (NOS) in serum of rats, thereby possibly regulating immune disorders associated with RA (12). In addition, it has been demonstrated that cryptotanshinone, brucine and strychnine are the major anti-inflammatory components in the aqueous extract of Biqi capsule (13). Cryptotanshinone not only inhibits the secretion of NO but also suppresses the secretion of interleukin (IL)-6 in lipopolysaccharide (LPS)-induced RAW 264.7 cells (13).

Brucine, a major alkaloid monomer from the dried fruit of Strychnosnux-vomica, relieves pain, reduces inflammation, regulates cytokine expression and inhibits the proliferation of synovial fibroblasts; therefore, it has been frequently used to treat RA (14). Similar to numerous other TCM formulations, Biqi capsule has long been used to manage RA. It has been demonstrated that Biqi capsule effectively improves the clinical signs and symptoms of RA (15) and has the effect of relieving pain, eliminating inflammation in adjuvant arthritis (16) and regulating immune responses in RA (17). Pre-clinical studies have also demonstrated that Biqi capsule decreases lipid peroxidation and inflammatory responses induced by lipopolysaccharide in articular chondrocytes, enhances superoxide dismutase (SOD) activity of chondrocytes and oxyradical clearance, and protects the chondrocytes against LPS-induced inflammatory damage (18). However, the effect and safety of Biqi capsule in the treatment of RA and whether it is as effective as cDMARDsremain controversial. In the present study, a meta-analysis of randomized controlled trials (RCTs) and controlled clinical trials (CCTs) on RA patients was performed to assess the efficacy and safety of Biqi capsule alone or combined with MTX vs. MTX.

Materials and methods

Inclusion criteria

The present systematic review and meta-analysis wereprepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (19).

Patients in the studies involved were diagnosed with RA according to the criteria of the 1987 classification of the American College of Rheumatology (ACR) (20). All RCTs and CCTs including the comparison of Biqi capsule alone or combined with MTX and MTX in treating RA were considered. There were no restrictions for sex, age, disease course or administration doses of MTX. Multiple publications reporting the same groups of participants were excluded. Biqi capsule alone or combined with MTX was regarded as the experimental treatment and the cohort treated with MTX was regarded as a control.

Outcomes

The following outcomes were recorded: Clinical efficacy, adverse events (AEs), tender joint count (TJC), swollen joint count (SJC), score of joint tenderness (JTS), score of joint swelling (JSS), changes in rheumatoid factors (RF), CRP and ESR. The outcomes that were only sporadically reported were eliminated from the final analysis. The number of patients treated effectively in each group was counted based on the categories of ‘cured’, ‘markedly effective’ and ‘effective’. Patients who were cured were defined as those having four out of the five core set measures, including morning stiffness that lasted <15 min, no fatigue, no painful and tender joints, no SJC, and an ESR <20 mm/h (male) or 30 mm/h (female). Patients in which the treatment was markedly effective were defined as those having four of the six core set measures, including ≥50% decrease in the duration of morning stiffness, TJC, SJC, ESR or CRP, ≥50% increase ingrip strength, a >2-fold decrease in RF. Patients in which the treatment was markedly effective were defined as those havingthree of the aforementionedsix core set measures (15). The overall efficacy determined as the proportion of these patients compared with the total number of patients. Continuous data (RF, CRP, ESR, TJC, SJC, JTS and JSS) were expressed as the mean with standard deviation and dichotomous variables (the clinical efficacy and AEs) were expressed as absolute numbers for further statistical analysis.

Search methods

Associated studies from inception to March 2017 were retrieved from the following databases: Medline/PubMed, EmBase, the Cochrane Library, the China National Knowledge Infrastructure, the Chinese Medical Journal Database, Wang fang Data, VIP journal integration platform, the Chinese Biomedical Literature Database, the Chinese Scientific and Technological Journals Database, the Traditional Chinese Medicine Database and the China Doctorate Dissertation Full Text Database. The search terms included ‘Biqi capsule’ or ‘Biqi’ combined with ‘rheumatoid arthritis’, ‘arthritis, rheumatoid’ or ‘RA’. Furthermore, the references of selected articles were carefully screened, so that any studies fulfilling the inclusion criteria of the present study could be analyzed. Furthermore, recent data were manually retrieved by searching the periodicals, journals and symposium abstracts published until March 2017 that were available at the library of Guangzhou University of Chinese Medicine (Guangzhou, China). The language was limited to English or Chinese. The search was independently performed by three authors (XC, JW and RH).

Data extraction and handling of incomplete data

Trial selection and data extraction were performed by three authors (XC, JW and RH), and the relevant data were extracted andentered into an Excel spreadsheet. Two review authors (XC and JW) screened all selected articles and extracted the data independently. The relevant data included characteristics of trials, the first author, year of publication, baseline characteristics of patients, number of patients in the experimental group (EG) and control group (CG), duration of the study, intervention (treatment) methods, outcome measures and mainresults. Disagreements were resolved by discussion with the third review author (RH) and a group of rheumatologists (QH, MQ, YC and XH).

Risk of bias in individual studies

The risk of bias of the trials included in the present review was assessed using the Cochrane collaboration's tool for assessing the risk of bias by two review authors (XC and JW) independently (21). Seven different risk of bias domains were assessed at the study level: Sequence generation, allocation concealment, study blinding, outcome assessor blinding, incomplete outcome data, selective outcome reporting and other bias. Each of the 7 specified risk of bias domains was evaluated in 3 groups: Low-risk, high-risk or unclear risk (22).

Statistical analysis

Review Manager software, version 5.3. (The Cochrane Collaboration, London, UK), was used to analyze the clinical data collected. The dichotomous outcomes, including treatment effects and AEs, were evaluated using the relative risk (RR) with the 95% confidence interval (CI). The standardized mean differences (SMDs) were calculated by dividing the difference between experimental groups and controls by the baseline variance. The SMD was used when different scales were used to measure the same concept. Sensitivity analyses were also used in this study. Heterogeneity was tested and was considered significant when I2 was >50%. A random-effects model was used for the meta-analysis if significant heterogeneity existed, and a fixed-effects model was used when the heterogeneity was not significant. If the data provided by the included studies were not appropriate for performing a meta-analysis, the study data were presented in narrative form.

Results

Search results and description of selected studies

From an initially retrieved 558 records, a total of 5 RCTs were identified (2327), including 522 patients that matched the inclusion criteria (Fig. 1). The details of these trials extracted in the present study are summarized in Table I. All 5 trials had been performed in China and published in Chinese from 2004 to 2016. The manufacturer of Biqi capsule in these 5 trials was identical (Tianjin DarentangJingwanhong Pharmaceutical Co. Ltd., Tianjin, China), so that the quality control of Biqi capsules was ensured and its composition was identical amongst all studies included. The 5 trials were non-blinded studies. The interventions included Biqi capsule or Biqi capsule plus MTX. The group treated with MTX only was considered to be the control group. Of the trials included, 3 compared Biqi capsule with MTX (2325), and 3 compared Biqi capsule plus MTX with MTX (2527). The duration of treatment in the 5 trials was 8–12 weeks, how ever the different durations of treatment were notcompared during the meta-analysis.

Table I.

Characteristics of individual studies.

Table I.

Characteristics of individual studies.

Sample sizeIntervention method


Author, yearEGCGEGCGDuration (weeks)Outcomes(Refs.)
Liu et al, 20056060BQC 1.2 g tidMTX 15 mg qw12TE, RF, ESR, AE, TJC, SJC,(23)
Bai and Li, 20095018BQC 1.2 g tidMTX 10 mg qw8TE, CRP, ESR, AE, JTS, JSS(24)
Jie et al, 20124446BQC 1.2 g tidMTX 10 mg qw12TE, RF, ESR, CRP, TJC, SJC, JTS, JSS(25)
Wan et al, 20122626BQC 1.2 g tid,MTX 7.5 mg qw12TE, RF, AE, TJC, SJC, JTS, JSS(26)
MTX 7.5 mg qw
Rao et al, 20167272BQC 1.2 g tid,MTX 10 mg qw12TE, AE, TJC, SJC, JTS, JSS(27)
MTX 10 mg qw
Jie et al, 20124846BQC 1.2 g tid,MTX 10 mg qw12TE, RF, ESR, CRP, TJC, SJC, JTS, JSS(25)
MTX 10 mg qw

[i] BQC, Biqi capsule; MTX, methotrexate; EG, experimental group; CG, control group; TE, total effect; RF, rheumatoid factor; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; AE, adverse effect; TJC, tender joint count; SJC, swollen joint count; JTS, score of joint tenderness; JSS, score of joint swelling; tid, three times per day; qw, once weekly.

Risk of bias in the included studies

Fig. 2 presents a summary of the risk of bias in the 5 trials included in the present review. The risk of bias was considered to be high in all trials. Two studies did not mention a random method (23,27). Allocation concealment and blinding were poorly reported. Regarding incomplete data, which is attrition bias, only one study was considered to have a low risk of bias (25), and the other 4 studies hadan unclear or high risk. In terms of selective reporting and other biases, all studies were considered to have an unclear risk.

Overall efficacy

All 5 trials included in the present review provided the overall efficacy of Biqialone or plus MTX compared with MTX. Fig. 3A demonstrated that I2=73% (P=0.02), therefore the analysis used a random effects model. The results indicated that no difference was identified between Biqi capsule and MTX (RR, 1.35; 95% CI, 1.00–1.82; P=0.05). Biqi capsule and MTXhad similar overall efficacy. Furthermore, Fig. 3B revealed that I2=0% (P=0.55), so the analysis used a fixed effects model. A significant difference was observed in the number of patients who were treated effectively by Biqi capsule plus MTX vs. MTX, (RR, 1.17; 95% CI, 1.06–1.28; Fig. 3).

Laboratory indexes

Of the 5 trials, 3 included data on the serum concentration of RF. Fig. 4 demonstrated that there was no heterogeneity, therefore the analysis was performed using a fixed effects model. Meta-analysis indicated no significant difference between Biqi capsule and MTX (SMD, −3.42; 95% CI, −16.57–9.74) but a significant difference between Biqi capsule plus MTX and MTX [SMD, −12.54; 95% CI, -(16.87–8.20); Fig. 4]. Three trials were included in the meta-analysis on the ESR. Fig. 5 revealed that I2=0%, therefore afixed effect model was adopted. A statistically significant difference in the reduction of the ESR was identified between Biqi capsule and MTX [SMD, −4.74; 95% CI, -(9.10–0.38); Fig. 5]. Among the trials selected, 2 studies provided data on CRP. As illustrated in Fig. 6, I2=0%, and a fixed effects model was adopted for the analysis. The combined SMD was −7.05, and the 95% CI ranged from −10.77 to −3.33 (P=0.0002), which indicated a significant difference between Biqi capsule and MTX (Fig. 6). However, it was not possible to perform any meta-analysis for the comparison between Biqi capsule plus MTX and MTX in reducing ESR or CRP, as only one or none of the studiesreported on them. Overall, it may be concluded thatregarding the capacity to reduce the serum RF concentration in RA patients, no difference was identified between Biqi capsule alone and MTX, but a significant difference was determined between Biqi capsule plus MTX and MTX. Biqi capsule plus MTX was more efficacious on reducing the serum RF concentration compared with MTX. Regarding the capacity to reduce the serum ESR and CRP levels, Biqi capsule was more efficacious compared with MTX.

Improvement of clinical signs and symptoms

A total of 4 trials compared TJC and SJC between different treatment arms. As illustrated in Fig. 7, I2=0% or 43%, there fore a fixed effects model was adopted for the analysis. The meta-analysis indicated a significant difference between Biqi capsule and MTX [SMD, −3.02; 95% CI, -(3.81–2.22)] or Biqi capsule plus MTX and MTX [SMD, −2.16; 95% CI, -(2.86–1.47)] in terms of TJC. Fig. 8A demonstrated that I2=95%, therefore the analysis used a random effects model. Fig. 8B revealed that there was no heterogeneity, therefore a fixed effects model was used. Regarding the effect on the SJC, the meta-analysis indicated no significant difference between Biqi capsule and MTX (SMD, −0.90; 95% CI, −5.02–3.22) but a significant difference between Biqi capsule plus MTX and MTX [SMD, −1.50; 95% CI, -(1.99–1.01); Fig. 8]. The JTS and JSS after treatment were provided by 4 trials. As illustrated in Figs. 9 and 10, when I2<50%, a fixed effects model was adopted, while if I2>50%, a random effects model was used. The results indicated no difference between Biqi capsule and MTX (JTS: SMD, −4.31; 95% CI, −9.47–0.85; JSS: SMD, −0.39; 95% CI, −3.52–2.74) but a significant difference between Biqi capsule plus MTX and MTX [JTS: SMD, −4.69; 95% CI, -(5.92–3.47); JSS: SMD, −2.07, 95% CI, -(2.76–1.38); Figs. 9 and 10]. In summary, the results indicated that Biqi capsule alone or plus MTX may decrease TJC better compared withMTX. At the same time, on amelioration of SJC, JTS and JSS, Biqi capsule plus MTX was more efficacious compared with MTX.

AEs

AEs were described in 4 of the trials included. The most common AEs in the Biqi capsule groups were elevated blood pressure, gastrointestinal discomfort, skin discomfort and dizziness, and in the control groups, they were gastrointestinal discomfort, abnormal liver function and blood cell reduction. None of these AEs affected the treatment of RA whether or not AEs occurred. The meta-analysis demonstrated that there was no heterogeneity, and the analysiswas performed using a fixed effects model. According to the meta-analysis, a statistically significant difference was presentbetween the AEs in the groups treated with Biqi capsule and those with MTX (RR, 0.19; 95% CI, 0.08–0.43), but no significant difference was observed between Biqi capsule plus MTX and MTX (RR, 0.71; 95% CI, 0.34–1.50; Fig. 11). There were fewer AEs when using Biqi capsule to treat RA compared with the use of MTX.

Discussion

Biqi capsule, which is a typical TCM preparation for the treatment of RA, has been demonstrated to be effective and safe in the treatment of RA. Studies have indicated that Biqi capsule improves clinical symptoms and reduces inflammatory markers in RA patients (28,29). Indeed, as supported by the effects of the major components, numerous in vivo studies have indicated that Biqi capsule significantly reduces the swelling degree of ankles, synovial hyperplasia, pannus formation, and the destruction of articular cartilage and bone (18,30,31). The possible mechanisms have also been demonstrated in animal models of RA, and Biqi capsule is thought to exert its effects by reducing the expression of Janus kinase 3 and signal transducer and activator of transcription 3, and by suppressing the expression of interleukin (IL)-4, interferon-γ, IL-1 and other inflammatory cytokines (30), as confirmed by several clinical studies reporting that Biqi capsule markedly decreases the levels of IL-17, IL-1 and TNF-α in patients with RA (23,26). Of note, it was reported that the decreases in IL-1 and TNF-α were accompanied by an improvement in the clinical symptoms and physical signs of patients with RA (23). Taken together, these observations strongly suggest that Biqi capsule improvesaffected joints and systemic pathological changes in RA and inhibits joint damage in patients with RA, which is in agreement with the results of the present study.

The meta-analysis performed in the present study indicated that, compared with MTX, Biqi capsule may be more favourable with regard to reducing serum of CRP and decreasing the TJC, and may possess an efficacy comparable to that of MTX for ameliorating the serum levels of ESR. In addition, Biqi capsule plus MTX appeared to have a higher clinical efficacy than MTX, and in a significantly higher proportion of RA patients treated with Biqi capsule plus MTX, the clinical condition wasmarkedly improved after treatment. Furthermore, combination treatment may be better than MTX alone for the amelioration of RF, TJC, SJC, JTS and JSS

No severe side effects were reported in any of the included trials. MTX, as a first-line drug for treating RA, may cause a variety of AEs, specifically abnormal liver function and white blood cell reduction. These AEs may affect patient compliance to a certain extent. By contrast, AEs did not occur with Biqi capsule treatment. However, MTX and Biqi capsule may also cause gastrointestinal discomfort, but the severity of that induced by Biqi capsule is lower than that of MTX. A significant difference in AEs was observed between Biqi capsule and MTX, but no difference was present between Biqi capsule plus MTX and MTX. Thus, Biqi capsule had fewer AEs than MTX, and combined therapy did not increasethe frequency and severity of the AEs.

Of note, all of the trials selected for inclusion in the present meta-analysis were highly bias. The biases of random sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment were high, which led to conflicting results in the analysis, and thus lowered the validity and reliability of each individual study and the results of the meta-analysis. In addition, various trials included only had a small number of patients. Compared with other DMARDs, MTX is considered to be the first-line drug for treating inflammatory arthritis. Although the best duration of MTX treatment for RA is 6 months, the time until the drug takes effect is only 4–12 weeks (32). Therefore, the duration of the trials included in the presentstudy was sufficient to observe efficiency, but a longer duration may be better for observing long-term efficiency and AEs. In addition, the most important criteria, including ACR20, ACR50 and ACR70, were not reported in any of the studies. For these reasons, the conclusionsare not sufficiently convincing. Thus, prospective, large-sample and long-term studies are required in the future. As MTX is considered to be the cornerstone of treatment for RA and the anchor drug in combination with other DMARDs or biological agents (4), clinical studies on Biqi capsule plus MTX compared with MTX plus leflunomidemay be performed in the future.

In conclusion, treatment with Biqi capsule plus MTX appears to have more benefits for RA patients than MTX alone. In addition, administration of Biqi capsule had fewer AEs than that of MTX, and Biqi capsule plus MTX does not increase the number of AEs. Therefore, Biqi capsule may be suitable for use. However, the trials selected for inclusion in the present meta-analysis have numerous methodological flaws and a high risk of bias, which makes the conclusions insufficiently reliable. As the results of the present study suggest beneficial effects of Biqi capsule, high-quality RCTs are recommended in the future.

Acknowledgements

Not applicable.

Funding

This study was supported by the Science and Technology project of Guangdong Province (grant no. 2016KT1269), the Natural Science Foundation of Guangdong Province (grant nos. 2015KT1753 and 2017KT1805) as well as the Science and Technology Project of Tianjin (grant no. 15YDLJSY00090).

Availability of data and materials

The analysed data sets generated during the study are available from the corresponding author on reasonable request.

Authors' contributions

XMC and JQW wrote the manuscript, researched the literature, selected the trials, extracted the data and assessed the risk of bias. QCH designed the study and modified the manuscript. JYZ performed the meta-analysis. JHP and MJW were major contributors in performing the meta-analysis. ZSH analysed the data. YLC analysed the data and was a major contributor in writing the manuscript. XHH was a major contributor in analysing the data. MJW was a major contributor in writing the manuscript. RYH modified the manuscript, searched literatures, selected trials and extracted data. All authors read and approved the final manuscript.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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June-2018
Volume 15 Issue 6

Print ISSN: 1792-0981
Online ISSN:1792-1015

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Copy and paste a formatted citation
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Spandidos Publications style
Chen XM, Wu JQ, Huang QC, Zhang JY, Pen JH, Huang ZS, Chu YL, He XH, Wang MJ, Huang RY, Huang RY, et al: Systematic review and meta‑analysis of the efficacy and safety of Biqi capsule in rheumatoid arthritis patients. Exp Ther Med 15: 5221-5230, 2018
APA
Chen, X., Wu, J., Huang, Q., Zhang, J., Pen, J., Huang, Z. ... Huang, R. (2018). Systematic review and meta‑analysis of the efficacy and safety of Biqi capsule in rheumatoid arthritis patients. Experimental and Therapeutic Medicine, 15, 5221-5230. https://doi.org/10.3892/etm.2018.6121
MLA
Chen, X., Wu, J., Huang, Q., Zhang, J., Pen, J., Huang, Z., Chu, Y., He, X., Wang, M., Huang, R."Systematic review and meta‑analysis of the efficacy and safety of Biqi capsule in rheumatoid arthritis patients". Experimental and Therapeutic Medicine 15.6 (2018): 5221-5230.
Chicago
Chen, X., Wu, J., Huang, Q., Zhang, J., Pen, J., Huang, Z., Chu, Y., He, X., Wang, M., Huang, R."Systematic review and meta‑analysis of the efficacy and safety of Biqi capsule in rheumatoid arthritis patients". Experimental and Therapeutic Medicine 15, no. 6 (2018): 5221-5230. https://doi.org/10.3892/etm.2018.6121