Tripterygium wilfordii also known as Thunder God Vine.
Human study regarding Rheumatoid arthritis (RA) an autoimmune disease.
The Effectiveness and Safety of Tripterygium wilfordii Hook. F Extracts in Rheumatoid Arthritis: A Systematic Review and Meta-AnalysisYing-Yan Zhou1,2, Xuan Xia1, Wen-Ke Peng3, Qin-He Wang4, Jian-Hong Peng5, Yan-lin Li6, Jian-Xiong Wu7, Jian-Yong Zhang8, Yue Zhao1, Xiu-Min Chen1, Run-Yue Huang1,9*, Per-Johan Jakobsson10,11, Ze-Huai Wen1 and Qing-Chun Huang1
Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane, Medline, CNKI, SinoMed and WanFang Library till 12 July 2017. All included studies were analyzed with the use of the Review Manager 5.2 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol.
Results: Fourteen randomized controlled trials (RCTs) were identified. TwHF extracts provided a statistically significant improvement in grip strength (GS), swelling joint count (SJC) and morning stiffness (MS) compared with placebo (P < 0.001). The meta-analysis showed significant differences between TwHF extract-treated group and the DMARDs group in GS, MS, C-reactive protein (CRP), and tender joint count (TJC) (P < 0.05), aside from ESR and SJC (P > 0.05). The pooled results also displayed significant differences between the combination of TwHF extracts with DMARDs and the DMARDs alone group in ESR, CRP, SJC, and TJC (P ≤ 0.05). For the safety analysis, two trials favored TwHF extract-treatment and one trial favored non-TWHF extract-treatment in AEs (P < 0.05). Eleven trials showed no statistically significant differences between TwHF extract-treated group and the DMARDs group (P > 0.05).
Conclusions: The findings of this systematic review with meta-analysis indicate that TwHF extracts provides statistically significant and clinically important improvement in RA symptoms and has an acceptable safety profile.
IntroductionRheumatoid arthritis (RA) is an autoimmune disease of still unknown etiology that is characterized by systemic, destructive, and progressive inflammatory polyarthritis (Smolen et al., 2016). RA could lead to joint deformity, disability, and increased mortality if inadequately treated (Picerno et al., 2015). According to the guidelines proposed by the American College of Rheumatology (ACR) for the management of RA (Singh et al., 2016), disease-modifying anti-rheumatic drugs (DMARDs) and specific targeted therapies (including inhibitors of tumor necrosis factor (TNF) and other novel biological compounds) are recommended to interfere with the disease process in RA. However, the discontinue rate after 2 years with TNF blocker is around 40–60% due to side effects, development of anti-drug antibodies and lack of efficacy (Iannone et al., 2015; Arends et al., 2017; Favalli et al., 2017). Furthermore, biologics are unlikely to be of general benefit in the developing world because of the financial constraints (Hodkinson et al., 2014) although costs are decreasing as several original drugs are subject for competition with recent biosimilars Tripterygium wilfordii Hook F (TwHF) is a member of the Celastraceae family and is abundant in south China (Tao and Lipsky, 2000). Anti-inflammatory and immunosuppressive compounds extracted from TwHF have been used for the treatment of a wide spectrum of autoimmune and inflammatory diseases, including RA (Fan and Li, 2006; Zeng et al., 2009), ankylosing spondylitis (AS) (Li et al., 2016), and systemic lupus erythematosus (SLE) (Du et al., 2000). Additionally, TwHF extracts have been demonstrated to exert beneficial effects on nephrotic syndrome (Jiang, 1994), Crohn's disease (Ren et al., 2007), and solid tumors (Yang et al., 2003). The potential molecular mechanisms underlying the anti-inflammatory and immunosuppressive effects of TwHF extracts includes the inhibition of platelet activation (Hu et al., 2009), nitric oxide induction (Wang et al., 2004), as well as prostaglandin E2 production (Geng et al., 2012). Based on studies both in vitro and in vivo, it is reasonable to speculate that TwHF extracts represent herbal DMARDs, which is different from synthetic DMARDs. Importantly, TwHF extracts have been listed in the Clinical Guidelines for diagnosis and treatment of RA in China since 2004.
Only a few multicenter clinical trials have been performed to confirm the effects of TwHF extracts in the treatment of RA, except for the trial conducted by Peking Union Medical College Hospital in 2015 (Lv et al., 2015). The symbolic trial proved that TwHF monotherapy was not inferior to methotrexate (MTX) monotherapy, while the combination of MTX and TwHF was better than MTX monotherapy, with respect to effects in controlling disease activity in patients with active RA. Although several systematic reviews and meta-analyses regarding the efficacy and safety of TwHF extracts in the treatment of RA have been reported, these systematic reviews are dated and achieved, to some extent, the contradictory conclusions (Canter et al., 2006; Jiang et al., 2009; Cameron et al., 2011; Little and Parsons, 2011; Liu et al., 2013). This study intends to re-systematically review the potential effects and safety of the TwHF extracts in the treatment of RA with regard to the published articles recently.
MethodsWe conducted and reported this review according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).
Search Strategy for Identification of StudiesWe searched the following digital databases to identify trials: PubMed, Embase, Medline and Cochrane. In addition, we searched the Chinese databases: CNKI Database, VIP Database, CBM Database and WanFang Database. All of the databases were searched to identify all relevant human clinical studies published until 12 July 2017. For the English databases, the search strategy used was as follows: ([“Tripterygium wilfordii Hook F”] OR [“Tripterygium wilfordii”] OR [“Tripterygium” or “thunder god vine”] OR [“lei gong teng”]) AND ([“rheumatoid arthritis”] OR [“RA”]) AND ([“random control trials”] OR [“RCT”]). For the Chinese databases, free text terms were used, such as “lei gong teng” (which means Tripterygium wilfordii Hook F in Chinese) and “lei feng shi guan jie yan” (which means rheumatoid arthritis in Chinese) and “sui ji dui zhao shi yan” (which means RCT in Chinese). To collect an adequate number of trials, the reference lists of relevant publications were also searched to identify additional studies.
Selection CriteriaStudies were selected for subsequent analyses if they satisfied the following criteria: (1) the study was a RCT with a parallel or crossover design regardless of blinding; (2) people enrolled were diagnosed with RA, according to the 1987 guidelines of the American Rheumatology Association (Arnett et al., 1988), and were excluded with any other autoimmune diseases; (3) TwHF extracts were used as an active treatment intervention whether the subjects took extracts of TwHF alone or with other DMARDs for at least 4 weeks; (4) the outcomes included tender joint count (TJC), swelling joint count (SJC), grip strength (GS), morning stiffness (MS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and AEs.
Data Extraction and ManagementTwo examiners selected the articles and extracted the relevant data independently. Divergences were resolved by consensus. Based on the PRISMA requirements, a flow diagram of the study selection has been generated. Essential information from each trial was collected: study design, characteristics of participants, intervention and dosing regimen, concomitant therapy, duration of treatment, and clinical outcomes. All studies were also scored by two independent reviewers in accordance to the Cochrane Collaboration's Risk of Bias tool (Higgins and Green, 2014).
Statistical AnalysisAll included studies were analyzed with the use of the Review Manager 5.2 software.
For continuous outcomes, results were summarized using a mean difference and a 95% confidence interval (CI). Heterogeneity was evaluated statistically using the I2 statistic. The meta-analyses were carried out using a random effects model if I2 > 50% but a fixed effects model if I2 ≤ 50%. A significance level of 5% was used for all statistical tests.
ResultsLiterature Search ResultsThe process of study selection is shown in Figure 1. According to the selection criteria defined in the Methods section, 14 RCTs were included for systematic review and 14 RCTs were included in the meta-analysis. The characteristics of the included trials are shown in Table 1.
FIGURE 1
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- 1Key Unit of Methodology in Clinical Research, Department of Rheumatology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- 2Postdoctoral Mobile Research Station, Guangzhou University of Chinese Medicine, Guangzhou, China
- 3Guangzhou Panyu Sanatorium, Guangzhou, China
- 4Department of Rheumatology, Chinese Medicine Hospital, Jieyang, China
- 5Department of Rheumatology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, China
- 6Department of Rheumatology, Zhongshan Hospital of Chinese Medicine, Zhongshan, China
- 7Department of Rheumatology, Guangzhou Orthopedic Hospital, Guangzhou, China
- 8Department of Rheumatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
- 9Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- 10Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- 11Rheumatology Clinic, Karolinska University Hospital in Solna, Stockholm, Sweden
Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane, Medline, CNKI, SinoMed and WanFang Library till 12 July 2017. All included studies were analyzed with the use of the Review Manager 5.2 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol.
Results: Fourteen randomized controlled trials (RCTs) were identified. TwHF extracts provided a statistically significant improvement in grip strength (GS), swelling joint count (SJC) and morning stiffness (MS) compared with placebo (P < 0.001). The meta-analysis showed significant differences between TwHF extract-treated group and the DMARDs group in GS, MS, C-reactive protein (CRP), and tender joint count (TJC) (P < 0.05), aside from ESR and SJC (P > 0.05). The pooled results also displayed significant differences between the combination of TwHF extracts with DMARDs and the DMARDs alone group in ESR, CRP, SJC, and TJC (P ≤ 0.05). For the safety analysis, two trials favored TwHF extract-treatment and one trial favored non-TWHF extract-treatment in AEs (P < 0.05). Eleven trials showed no statistically significant differences between TwHF extract-treated group and the DMARDs group (P > 0.05).
Conclusions: The findings of this systematic review with meta-analysis indicate that TwHF extracts provides statistically significant and clinically important improvement in RA symptoms and has an acceptable safety profile.
IntroductionRheumatoid arthritis (RA) is an autoimmune disease of still unknown etiology that is characterized by systemic, destructive, and progressive inflammatory polyarthritis (Smolen et al., 2016). RA could lead to joint deformity, disability, and increased mortality if inadequately treated (Picerno et al., 2015). According to the guidelines proposed by the American College of Rheumatology (ACR) for the management of RA (Singh et al., 2016), disease-modifying anti-rheumatic drugs (DMARDs) and specific targeted therapies (including inhibitors of tumor necrosis factor (TNF) and other novel biological compounds) are recommended to interfere with the disease process in RA. However, the discontinue rate after 2 years with TNF blocker is around 40–60% due to side effects, development of anti-drug antibodies and lack of efficacy (Iannone et al., 2015; Arends et al., 2017; Favalli et al., 2017). Furthermore, biologics are unlikely to be of general benefit in the developing world because of the financial constraints (Hodkinson et al., 2014) although costs are decreasing as several original drugs are subject for competition with recent biosimilars Tripterygium wilfordii Hook F (TwHF) is a member of the Celastraceae family and is abundant in south China (Tao and Lipsky, 2000). Anti-inflammatory and immunosuppressive compounds extracted from TwHF have been used for the treatment of a wide spectrum of autoimmune and inflammatory diseases, including RA (Fan and Li, 2006; Zeng et al., 2009), ankylosing spondylitis (AS) (Li et al., 2016), and systemic lupus erythematosus (SLE) (Du et al., 2000). Additionally, TwHF extracts have been demonstrated to exert beneficial effects on nephrotic syndrome (Jiang, 1994), Crohn's disease (Ren et al., 2007), and solid tumors (Yang et al., 2003). The potential molecular mechanisms underlying the anti-inflammatory and immunosuppressive effects of TwHF extracts includes the inhibition of platelet activation (Hu et al., 2009), nitric oxide induction (Wang et al., 2004), as well as prostaglandin E2 production (Geng et al., 2012). Based on studies both in vitro and in vivo, it is reasonable to speculate that TwHF extracts represent herbal DMARDs, which is different from synthetic DMARDs. Importantly, TwHF extracts have been listed in the Clinical Guidelines for diagnosis and treatment of RA in China since 2004.
Only a few multicenter clinical trials have been performed to confirm the effects of TwHF extracts in the treatment of RA, except for the trial conducted by Peking Union Medical College Hospital in 2015 (Lv et al., 2015). The symbolic trial proved that TwHF monotherapy was not inferior to methotrexate (MTX) monotherapy, while the combination of MTX and TwHF was better than MTX monotherapy, with respect to effects in controlling disease activity in patients with active RA. Although several systematic reviews and meta-analyses regarding the efficacy and safety of TwHF extracts in the treatment of RA have been reported, these systematic reviews are dated and achieved, to some extent, the contradictory conclusions (Canter et al., 2006; Jiang et al., 2009; Cameron et al., 2011; Little and Parsons, 2011; Liu et al., 2013). This study intends to re-systematically review the potential effects and safety of the TwHF extracts in the treatment of RA with regard to the published articles recently.
MethodsWe conducted and reported this review according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).
Search Strategy for Identification of StudiesWe searched the following digital databases to identify trials: PubMed, Embase, Medline and Cochrane. In addition, we searched the Chinese databases: CNKI Database, VIP Database, CBM Database and WanFang Database. All of the databases were searched to identify all relevant human clinical studies published until 12 July 2017. For the English databases, the search strategy used was as follows: ([“Tripterygium wilfordii Hook F”] OR [“Tripterygium wilfordii”] OR [“Tripterygium” or “thunder god vine”] OR [“lei gong teng”]) AND ([“rheumatoid arthritis”] OR [“RA”]) AND ([“random control trials”] OR [“RCT”]). For the Chinese databases, free text terms were used, such as “lei gong teng” (which means Tripterygium wilfordii Hook F in Chinese) and “lei feng shi guan jie yan” (which means rheumatoid arthritis in Chinese) and “sui ji dui zhao shi yan” (which means RCT in Chinese). To collect an adequate number of trials, the reference lists of relevant publications were also searched to identify additional studies.
Selection CriteriaStudies were selected for subsequent analyses if they satisfied the following criteria: (1) the study was a RCT with a parallel or crossover design regardless of blinding; (2) people enrolled were diagnosed with RA, according to the 1987 guidelines of the American Rheumatology Association (Arnett et al., 1988), and were excluded with any other autoimmune diseases; (3) TwHF extracts were used as an active treatment intervention whether the subjects took extracts of TwHF alone or with other DMARDs for at least 4 weeks; (4) the outcomes included tender joint count (TJC), swelling joint count (SJC), grip strength (GS), morning stiffness (MS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and AEs.
Data Extraction and ManagementTwo examiners selected the articles and extracted the relevant data independently. Divergences were resolved by consensus. Based on the PRISMA requirements, a flow diagram of the study selection has been generated. Essential information from each trial was collected: study design, characteristics of participants, intervention and dosing regimen, concomitant therapy, duration of treatment, and clinical outcomes. All studies were also scored by two independent reviewers in accordance to the Cochrane Collaboration's Risk of Bias tool (Higgins and Green, 2014).
Statistical AnalysisAll included studies were analyzed with the use of the Review Manager 5.2 software.
For continuous outcomes, results were summarized using a mean difference and a 95% confidence interval (CI). Heterogeneity was evaluated statistically using the I2 statistic. The meta-analyses were carried out using a random effects model if I2 > 50% but a fixed effects model if I2 ≤ 50%. A significance level of 5% was used for all statistical tests.
ResultsLiterature Search ResultsThe process of study selection is shown in Figure 1. According to the selection criteria defined in the Methods section, 14 RCTs were included for systematic review and 14 RCTs were included in the meta-analysis. The characteristics of the included trials are shown in Table 1.
FIGURE 1
click here for the full article https://www.frontiersin.org/articles/10.3389/fphar.2018.00356/full