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European Journal of Integrative Medicine 3 (2011) e219–e231

Review article

Chinese herbal medicines versus disease modifying antirheumatic drugs formanagement of rheumatoid arthritis: A systematic review

Chi Zhang a, Miao Jiang a, Aiping Lu a,b,∗a Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China

b E-Institute of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Received 8 April 2011; received in revised form 23 June 2011; accepted 24 June 2011

bstract

ackground: Chinese herbal medicines (CHMs) have been used for a long time to treat rheumatoid arthritis (RA), and many controlled trials haveeen done. This review aims to assess the beneficial and harmful effects of CHMs versus disease-modifying antirheumatic drugs (DMARDs) inatients with RA.ethods: Databases including The Cochrane Library, MEDLINE, EMBASE, The Chinese Biomedical Database, CNKI and Wanfang Data were

earched to identify randomized controlled trials published before May 2011 that compared CHMs with DMARDs. The Cochrane Collaboration’sool for assessing risk of bias was employed to address the quality of the included trials.esults: Twenty trials involving 1849 participants met the inclusion criteria. The trials had high risk of bias. Methodological quality was generally

ow. Seventeen different herbal medicines were tested. Most of the included trials had positive results on the response rate and demonstrated CHMpecificity. The trials report adverse events related both to CHM and DMARD treatment, 115 in the CHM groups versus 258 in the DMARD

roups.onclusion: Despite some favorable results in clinical trials, these findings should be carefully interpreted due to the low methodological quality.urther clinical trials with optimal CHM treatment protocols, rigorous and well-controlled randomized design are warranted.2011 Elsevier GmbH. All rights reserved.

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eywords: Rheumatoid arthritis; Chinese herbal medicine; Disease modifying

ntroduction

Rheumatoid arthritis (RA) is a systemic, chronic inflamma-ory disease, which is associated with disability and a decreasen a patient’s quality of life. The aetiology of RA is unknown andhere is currently no cure for the disease, and a dependence on

edications that are not always fully able to provide symptomelief [1–3].

Disease modifying anti-rheumatic drugs (DMARDs) are aroup of medications commonly used in patients with rheuma-

oid arthritis. They work to decrease pain and inflammation,educe or prevent joint damage, preserve the structure and func-ion of the joints, and improve the person’s sense of well-being

∗ Corresponding author at: Institute of Basic Research in Clinical Medicine,hina Academy of Chinese Medical Sciences, Beijing, China.el.: +86 10 64067611; fax: +86 10 84032881.

E-mail address: lap64067611@126.com (A. Lu).

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876-3820/$ – see front matter © 2011 Elsevier GmbH. All rights reserved.oi:10.1016/j.eujim.2011.06.003

heumatic drugs; Systematic review

2–4]. However, treatments are limited in their efficacy and thereere withdrawals from conventional DMARD therapy due to

ong term use, unfavorable toxicity profiles and requires frequentonitoring [5–9].Hence there appears to be a need for drugs with good efficacy

nd low toxicity in the treatment of RA. In recent years it hasecome acceptable to widen the range of medical solutions andeek symptom relief “outside of the prevailing scientific main-tream” [10]. More individuals are turning increasingly to herbaledicines [11–13].Chinese herbal medicines (CHMs) have been used for a long

ime to treat rheumatic diseases. RA is mainly categorized asi Zheng, impediment condition, in Chinese medicine. Bi or

mpediment means a blockage or obstruction resulting in pain.he Chinese had developed numerous formulas for RA treat-

ent. And now CHMs are still widely used and have been felt

o be effective in the treatment of RA. For example, Tripterygiumilfordii Hook. f. (TWHF), one of the commonly used CHM,as been successfully used for the treatment of human and exper-

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mental autoimmune and inflammatory diseases, including RA14].

Despite the results of numerous trials suggesting that treat-ent with CHMs may have potential for relieving pain, reducing

welling, and improving the damage to joints. However, therere reports of adverse events with using CHMs [14]. Therere systematic reviews (SRs) summarizing the positive effectf complementary and alternative medicine (CAM) for patientsith RA. These include herbal medicines [15–18], acupuncture

19], and Tai Ji [20]. However there are limitations in collectinghe related Chinese papers and several questions remain unclear.

hat is the relative benefit and toxicity of CHMs versus theainstay of treatment (such as DMARDs)? When should the

ombination of CHMs and DMARDs be used? These ques-ions are particularly salient in many countries or regions inhich herbal therapies are popularly used. The objective of thisaper is to systematically review randomized controlled trialshat compared CHMs with DMARDs.

aterials and methods

earch strategy

We performed a comprehensive search, and the follow-ng electronic databases were searched regardless of languagend publication status: The Cochrane Library, including theochrane Controlled Trials Register (CENTRAL, Issue 10,010); MEDLINE (from 1966 to May 2011); EMBASE (from974 to May 2011); Chinese Biomedical Literature Databasefrom 1979 to 2011); CNKI (from 1994 to May 2011); Wanfangata (from 1998 to May 2011); Database of the grey literature

China Doctor Dissertations Full-text Database, China Mas-er’s Theses Full-text Database). And we searched databasesf ongoing trials: “Chinese Clinical Trial Register (ChiCTR)”http://www.chictr.org/).

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Fig. 1. Flow chart showing the retrieval process of R

rative Medicine 3 (2011) e219–e231

Appropriate studies were randomized controlled trials involv-ng human subjects. A search strategy was used to combine freeext, Medical subject headings (MeSH), keywords and abstract.hesaurus and free text searches were performed across eachatabase to combine the terms ‘arthritis’ and ‘herbal medicine’nd ‘DMARDs’. The general structure of the search strat-gy was ‘arthritis (or synonyms) and herbal (or synonym)’nd DMARDs (related drug terms of DMARDs). The searchtrategy for the English language databases was an “OR”f the terms “Methotrexate”; “Leflunomide”; “Sulfasalazine”;hydroxychloroquine”; “penicillamine”; “Disease modifyingnti-rheumatic drugs” and related drug terms of DMARDs;OR” of the terms “Chinese medicine”; “herbal medicine”; andAND” of the terms “rheumatoid arthritis”. The search resultsere then limited to the reports of randomized controlled trials

RCTs) and human. Slight syntax modifications to the searchtrategy were made to suit various English language databases.n the Chinese language; the search strategy used an “OR” andAND” combination of Chinese terms “Zhong Yao” (Chineseerbal medicine); “Zhong Yi” (Chinese medicine) and “Jia Anie Ling” (Methotrexate); “Liu Dan Huang An Pi Ding” (Sul-

asalazine); “Qiang Lv Kui” (hydroxychloroquine); “Qing Mein” (penicillamine); “Lai Fu Mi Te” (Leflunomide); “Jin Zhi Ji”

Gold compound); Jin Nuo Fen (Auranofin); “Gai Shan Binging Kang Feng Shi Yao” (disease modifying anti-rheumaticrugs); other related terms and the search result was limited tohe reports of human studies and RCTs.

We hand searched three medical journals (Chinese Journalf Rheumatology, Chinese Journal of Integrative Medicine, andournal of traditional Chinese medicine from the first publicationate onwards) with the expectation that high quality research

ould be published in highly ranked medical journals. We tried

o identify potentially eligible studies by searching the referenceists of relevant trials and reviews articles identified. Fig. 1 flow

CT reports included in the systematic review.

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hart shows the retrieval process of RCT reports included in theR.

nclusion criteria

Two reviewers (CZ and MJ) independently screened the titlesnd abstracts of the citations and retrieved relevant articles. Alluthors evaluated the eligibility of the trials, resolving disagree-ents by discussion. The following selection criteria were used:

. RCTs of CHMs versus DMARDs: The CHM interventionsinclude extract from herbs, single herbs, Chinese proprietarymedicines, or a compound of herbs that is prescribed (indi-vidualized treatment) by Chinese medicine practitioner. Thecontrol intervention includes DMARD intervention. Herbalmedicines plus other therapies such as a Chinese holis-tic treatment, for example, herbs plus acupuncture, wereexcluded.

. Participants met the American College of Rheumatology(ACR; formerly, the American Rheumatism Association)1987 revised criteria for RA with age equal to or older than18 years.

. Data available on one or more of the following pre-specifiedoutcomes measurements: Number of tender joints; number ofswollen joints; pain (visual analogue scale or VAS); patientglobal assessment; physician global assessment; functionalstatus (Health Assessment Questionnaire or HAQ, Arthri-tis Impact Measurement Scales or AIMS, and ProblemElicitation Technique or PET), and acute phase reactant –erythrocyte sedimentation rate (ESR) and C-reactive protein(CRP); American College of Rheumatology (ACR) core set;Disease activity score 28 (DAS28); European League againstRheumatism (EULAR) response; Guiding principles for clin-ical research on new drugs of traditional Chinese medicineresponse (This is a national criteria from Ministry of PublicHealth P.R. China, and it is widely used in Chinese medicineresearch. This is similar to the utility of the ACR in eval-uating the effect in RA patients); Number of patients whoexperienced adverse events.

ata extraction

Data were extracted independently by two authors (CZ andJ). We noted study design, number of patients, duration of

reatment, interventions, outcomes, adverse events and quality.e described in detail the type of interventions in each trial.

ssessment of risk of bias

One author (CZ) assessed risk of bias in the trials, and anotheruthor (MJ) checked it. We noted the generation of the alloca-ion sequence, allocation concealment, blinding, and follow-up.

rials with adequate generation of the allocation sequence, ade-uate allocation concealment, adequate blinding, and adequateollow-up were considered low-bias risk trials (high method-logical quality). Trials with one or more unclear or inadequate

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rative Medicine 3 (2011) e219–e231 e221

uality components were classified as high-bias risk trials (lowethodological quality).

ata collection and analysis

Data were analyzed independently by two authors (CZ andJ). The trial data were tabulated and then qualitatively ana-

yzed to determine the risk of bias, trial characteristics and properHM treatments. Quantitative synthesis was not conducted. Theethodological quality was assessed using the five-point Jadad

cale [21]. After our initial data extraction, meta-analysis was noterformed because there was not enough available informationor formal quantitative analysis.

Concerned the important role of CM pattern classification inM, we also calculated and noted the details of studies described

n the trial.

esults

he characteristics of the included studies

Twenty randomized trials, involving 1849 participants, methe inclusion criteria. Seventeen different herbal medicines wereested in the included trials [22–41]. The characteristics of alltudies are summarized in Table 1. Table 2 provides detailselated to treatments in the included studies. All were publishedn Chinese. All studies were published between 2000 and 2010.

ost studies reported the mean (or median) age and genderf participants. Reporting of other potentially relevant baselineharacteristics was less widespread. The intervention durationanged between 30 days and 35 weeks. The longest term ofollow-up was 2 years. Sample sizes ranged from 40 to 203 withn average of 92. In total, 3 studies reported ACR20 responseates [33,37,38], none reported EULAR response rates and DAS-8 improvement and none HAQ improvement was reported. Theuality of all included studies is presented in Table 1. Of the0 trials, no trial reported the methods to generate the allo-ation sequence. Three trials applied blinding [22,29,39]. Onerial reported information on withdrawal [25], but no trial men-ioned intention-to-treat analysis. The methodological quality,sing the Jadad scale [21], ranged in quality from 1 to 2 (maxi-um score of 5) with an average quality of 1.2. Accordingly, the

ncluded trials had generally low methodological quality. Fur-hermore, in general, most trials were assessed as high risk ofias and the remaining as inadequate and to be associated withisk of bias (Fig. 2).

ffects of interventions

CHM therapies were demonstrated to be significantly supe-ior to DMARD in relation to the different efficacy outcomeeasures of RA in 18 RCTs. CHMs combined treatments (com-

ination of CHMs and DMARDs) are more effective in the

reatment of RA in outcome measures compared with DMARDherapy. None study reported the relapse rate. Furthermore,

cGill Pain Questionnaire and Self-rated Health Measurementcale were conducted in one trial [26]. Significant change

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Table 1Summary of the characteristics of included studies.

Authors Jadad score Trial size(treatment,control)

Treatment Control Outcomes reported Results Foundationsupport (Y/N)

Yin and Qie [22] 2 60 (30, 30) Total glucosides of paeonycapsule

MTXa Swollen joint count, tender jointcount, duration of morningstiffness, RF, ESR and CRP

Significant improvement intreatment group in swollen jointscore, morning stiffness, ESRand CRP compared with MTX

N

Wu et al. [23] 1 60 (30, 30) Total glucosides of paeonycapsule

MTX Rest pain, swollen joint count,tender joint count, duration ofmorning stiffness, RF, ESR, CRPand X-ray

No significant difference inimprovement between groups

N

He et al. [24] 1 60 (30, 30) Bi Tong Decoction + WutengPowder

LEFa Grip strength, 20 m walking time,swollen joint count, tender jointcount, duration of morningstiffness, RF, ESR, CRP andX-ray

Significant improvement in gripstrength, 20 m walking time,swollen joint count, tender jointcount duration of morningstiffness, and morning stiffnessfor treatment group comparedwith LEF

N

Liang et al. [25] 2 96 (50, 46) Bi Zhong Xiao Decoction MTX Swollen joint count, tender jointcount, duration of morningstiffness, functional class, ESR,CRP, RF, IgG, IgA and IgM

After one month treatment,swollen joint count, tender jointcount, and arthralgia of patientsin BZXT improved notably,while those of patients in MTXgroup did not improve. After 3months treatment, significantimprovement in ESR, CRP, RF,IgG, IgA and IgM for treatmentgroup compared with MTX

Y

Chen et al. [26] 1 164 (82, 82) Triterygium Hypoglaueum(Level) Hutch

MTX Swollen joint count, tender jointcount, duration of morningstiffness, RF, ESR and CRP,McGill Pain Questionnaire,Self-rated Health MeasurementScale

Significant improvement inswollen joint count, tender jointcount, duration of morningstiffness, RF, ESR and CRP fortreatment group compared withMTX

Y

Liu [27] 1 63 (32, 31) Gui Zhi Shao Yao Zhi MuDecoction + Si MiaoPowder + LEF

LEF Grip strength, 20 m walking time,swollen joint count, tender jointcount, duration of morningstiffness, functional class, ESR,and CRP

Significant improvement in“Guiding principles for clinicalresearch on new drugs oftraditional Chinese medicine” forcombination therapy comparedwith LEF monotherapy

N

Ouyang [28] 1 112 (56, 56) Gui Zhi Shao Yao Zhi MuDecoction + Insect drugs

MTX Grip strength, swollen jointcount, tender joint count,duration of morning stiffness

Significant improvement in gripstrength, swollen joint count,tender joint count duration ofmorning stiffness for treatmentgroup compared with MTX

N

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e219–e231e223

Cui and Pang [29] 2 67 (35, 32) Gui Zhi Shao Yao Zhi MuDecoction

MTX Duration of morning stiffness,swollen joint count, grip strength,ESR and RF

Significant improvement induration of morning stiffness andswollen joint count for treatmentgroup compared with MTX

N

Zhang et al. [30] 1 203 (115, 88) Huang Hu Bi Ke Granule MTX Swollen joint count, functionalclass, ESR and RF

Significant improvement inswollen joint count, functionalclass, ESR and RF for Huang HuBi Ke Granule compared withMTX

N

Meng and Yang [31] 1 60 (30, 30) Wu Bang Pill + LEF LEF Swollen joint count, tender jointcount, duration of morningstiffness, functional class, ESR,RF

Significant improvement inswollen joint count, tender jointcount duration of morningstiffness, functional class, ESR,and RF for combination therapycompared with LEF monotherapy

N

Zhao and Liu [32] 1 80 (40, 40) Total glucosides of paeonycapsule + LEF

LEF Grip strength, 20 m walking time,swollen joint count, tender jointcount, duration of morningstiffness, functional class, ESR,CRP, C3, IgG, IgA and IgM

Each group improvedsignificantly in morning stiffness,tender joint count, swollen jointcount, GPI, ESR, CRP, RF, andC3Significant improvement in gripstrength, 20 m walking time,swollen joint count, tender jointcount duration of morningstiffness, functional class, ESR,CRP, C3, IgG, IgA and IgM forcombination therapy comparedwith LEF monotherapy

N

Piao and Wang [33] 1 80 (40, 40) Qing Re Huo Xue Juan BiDecoction

MTX ACR20,50,70, joint erosionscore, joint space narrowing score

Significant improvement inACR20,50,70, joint erosionscore, joint space narrowingscore for treatment groupcompared with MTX

Y

Ji and Zhu [34] 1 60 (30, 30) Zheng Qing Feng Tong NingTablet + MTX

MTX Grip strength, swollen jointcount, tender joint count,duration of morning stiffness,ESR, CRP, and RF

No significant difference on ESR,CRP and RF between groupsSignificant improvement in gripstrength, swollen joint count,tender joint count and duration ofmorning stiffness for treatmentgroup compared with MXT

N

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Table 1 (Continued)

Authors Jadad score Trial size(treatment,control)

Treatment Control Outcomes reported Results Foundationsupport (Y/N)

Zhang and Sun [35] 1 180 (60, 60, 60) Zheng Qing Feng Tong NingRetard Tablet

1. MTX2.Triptery-giumGlyco-sides

Grip strength, 20 m walking time,swollen joint count, tender jointcount, duration of morningstiffness, functional class, ESR,CRP, IgG, IgA and IgM

No significant difference betweenZheng Qing Feng Tong NingRetard Tablet group and MTXgroupEach group improvedsignificantly in duration of gripstrength, 20 m walking time,swollen joint count, tender jointcount duration of morningstiffness, functional class, ESR,CRP, IgG, IgA and IgM

N

Sun [36] 1 40 (20, 20) Zheng Qing Feng Tong NingRetard Tablet

MTX Swollen joint count, tender jointcount, duration of morningstiffness

Each group improvedsignificantly in swollen jointcount, tender joint count andduration of morning stiffnessSignificant improvement inswollen joint count, tender jointcount, duration of morningstiffness for treatment groupcompared with MTX

N

Liu et al. [37] 1 120 (60, 60) Zheng Qing Feng Tong NingRetard Tablet

MTX Grip strength, swollen jointcount, tender joint count,duration of morning stiffness,ESR, and RFACR20,50,70

Each group improvedsignificantly in grip strength,swollen joint count, tender jointcount, duration of morningstiffness, ESR, and RFSignificant improvement inACR20,50,70 for treatment groupcompared with MTX

N

Zheng et al. [38] 1 102 (53, 49) Feng Shi Kang Granule + MTX LEF + MTX Grip strength, pain scores,functional class, swollen jointcount, tender joint count,duration of morning stiffness,VAS, ESR, RF, ACR20,50,70

Significant improvement infunctional class, swollen jointcount, tender joint count,duration of morning stiffness andACR70 for treatment groupcompared with controlled groupNo significant difference inACR20,50 between groups

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P < 0.05) was observed for in improve pain management,atient’s self-evaluation and quality of life in the treated groupere better than those in the control group.The rheumatoid factor (RF) test was reported in fourteen stud-

es, four of these reported that CHM was superior to DMARD.ine different herbal medicines were reported to be more

ffective in reducing the erythrocyte sedimentation rate (ESR)ompared with DMARD. “Morning stiffness” was reported ineventeen trials. Three RCTs assessed pain outcomes and did notemonstrate effectiveness on pain reduction. Joint swelling andoint tenderness were detailed reported in nineteen and eighteenrials respectively. Four studies describe the trial design based onM pattern classification. Three of four took one pattern of RAccording Chinese theory as additional include criteria and onetudy with “additions” in intervention as individually prescribedherapies of decoctions.

We did not perform meta-analysis due to the variability ofhe interventions and some herbal remedies were tested onlynce. Two formulas were further analyzed because their widese: Gui Zhi Shao Yao Zhi Mu Decoction and Zheng Qing Fengong Ning Tablet. Two studies reported information on Gui Zhihao Yao Zhi Mu Decoction [28,29]. Gui Zhi Shao Yao Zhi Muecoction was better than MTX on reducing morning stiffness

ime and improving swollen joint count. And MTX was moreffective in improving grip strength than Gui Zhi Shao Yao Zhiu Decoction. Three studies reported data comparing outcomes

f patients receiving Zheng Qing Feng Tong Ning Tablet withhose receiving the treatment of MTX [35–37]. Zheng Qing Fengong Ning Tablet was more effective in lowering morning stiff-ess time than MTX and better than MTX on improving swollenoint count, tender joint count and RF. Zheng Qing Feng Tonging Table was less effective than MTX in ESR and did notppear superior to MTX for grip strength.

otal adverse reactions

Adverse reactions were reported in sixteen of the twenty trialsTable 3, 373 patients: 115 in the CHM groups versus 258 in theMARD groups). The trials report adverse events related to bothHMs and DMARDs. The information of some included studies

s unsatisfactory. The missing values are located in Table 3 andrevented meta-analyses. Although CHM therapy has relativelyittle side-effects than DMARDs were mentioned in most stud-es, the evidence is insufficient to draw firm conclusions abouthether CHM is better than DMARD.No study report withdrawal due to lack of efficacy (LOE) and

ne study report withdrawal due to adverse events (AE) [25].

iscussion

The aim of this SR was to determine the effect of CHMsompared with DMARDs. Additionally, the safety of CHMsas evaluated. Evidence for the specificity of CHM treatments

s heterogeneous, and no definitive conclusion could be drawn.n recent years, there were some SRs of CHMs for RA publishednline. The main results include: three SRs [14,42,43] evaluatehe effect and safety of Lei Gong Teng (Herba Tripterygii Wil-

e226 C. Zhang et al. / European Journal of Integrative Medicine 3 (2011) e219–e231

Table 2Summary of the Chinese herbal medicine interventions of included studies.

Intervention Ingredients CM treatment principles

Agkistrodon Powder Bai Hua She (Agkistrodon/Bungarus), powdered andtaken with the decoction

Inhibit bending and stretching. Strengthen and reinforcethe sinews and bones.

Bi Tong Decoction Dang Gui (Radix Angelicae Sinensis); Qiang Huo(Radix Et Rhizoma Notopterygii); Jiang Huang(Rhizoma Curcumae Longae); Huang Qi (RadixAstragali); Bai Shao (Radix Paeoniae Albae); FangFeng (Radix Saposhnikoviae); Gan Cao (RadixGlycyrrhizae); Chuan Xiong (Rhizoma Chuanxiong);Tao Ren (Semen Persicae); Hong Hua (Flos Carthami);Sang Zhi (Ramulus Mori)

Supplement and boost the liver and kidneys, foster yinand clear heat, boost the qi and nourish the blood, dispelphlegm, free the flow of the network vessels andimprove marked joint aching and pain.

Bi Zhong Xiao Decoction Bai Hua She She Cao (Herba Hedyotis Diffusae); ZhongJie Feng (Ramulus Et Folium Sarcandrae); Dan Shen(Radix Salviae Miltiorrhizae); Yi Yi Ren (Semen Coicis)

Clear heat and resolve toxins, boost the qi and quickenthe blood assisted by clearing heat, moistening dryness,and freeing the flow of the network vessels.

Bu Pi Chu Bi Decoction Huang Qi (Radix Astragali); Dang Shen (RadixCodonopsitis); Bai Zhu (Radix AtractylodisMacrocephalae); Chi Shao (Radix Paeoniae Rubrae);Shu Di (cooked Radix Rehmanniae); Lei Gong Teng(Herba Tripterygii Wilfordii); Chuan Xiong (RhizomaChuanxiong); Dang Gui (Radix Angelicae Sinensis);Qing Shi Teng (Ajuga decumbens Thunb);Luo Shi Teng(Caulis Trachelospermi); Ji Xue Teng (CaulisSpatholobi); Ye Jiao Teng (Caulis Polygoni Multiflori);Ma Yi (Formica fusca Linnaeus); Di Long (Pheretima);Di Bie Chong (Eupolyphaga/Steleophaga); Wu Shao She(Zaocys)Additions: processed Cao Wu Tou (Radix AconitiKusnezofii); Zhi Fu Zi (Radix Lateralis PraeparatusAconiti Carmichaeli); Zhi Mu (RhizomaAnemarrhenae); Ren Dong Teng (Caulis Lonicerae); NuZhen Zi (Fructus Ligustri Lucidi); Gou Qi (FructusLycii); Tian Xian Teng (Fibraurea recisa Pierre); QuanXie (Scorpio); Bie Jia (Carapax Trionycis); Fu Ling(Poria); Sha Ren (Fructus Amomi)

Course the liver and fortify the spleen, disinhibit the qimechanism and harmonize upbearing and downbearing.Quicken the blood and transform stasis, free the flow ofthe network vessels and stop pain. The Chinesemedicine theory “transforming blood before expellingwind, self-eliminating of wind after blood circulating”is basic theory of this decoction. Decoctions with“Additions” are individually prescribed therapies.

Feng Shi Kang Granule Huang Bai (Cortex Phellodendri); Niu Xi (RadixAchyranthis Bidentatae); Qin Jiao (Radix GentianaeMacrophyllae); Zhi Mu (Rhizoma Anemarrhenae); XuChang Qing (Radix Seu Rhizoma Cynanchi); Bai Shao(Radix Paeoniae Albae); Gui Zhi (RamulusCinnamomi); Xi Xian Cao (Herba Siegesbeckiae)

Clear heat and eliminate dampness, dispel wind, free theflow of impediment and stop pain.

Gui Zhi Shao Yao Zhi Mu Decoction Bai Shao (Radix Paeoniae Albae); Zhi Mu (RhizomaAnemarrhenae); Gui Zhi (Rhizoma Cinnamomi); BaiZhu (Rhizoma Atractylodis Macrocephalae); Cang Zhu(Rhizoma Atractylodis); Fang Feng (RadixSaposhinikoviae); Ma Huang (Herba Ephedrae); GanCao (Radix Glycyrrhizae)

Free the flow of yang, dispel wind, and eliminatedampness, clear heat and stop pain. Free the flow ofyang and clears heat. Nourish the sinews and relaxspasm.

Huang Hu Bi Ke Granule Huang Bai (Cortex Phellodendri); Hu Zhang (RhizomaPolygoni Cuspidati); Sheng Di (uncooked RadixRehmanniae); Zhi Mu (Rhizoma Anemarrhenae); DanShen (Radix Salviae Miltiorrhizae); Gui Zhi (RhizomaCinnamomi); Bai Shao (Radix Paeoniae Albae); BaiJiang Can (Bombyx Batryticatus); Ren Dong Teng(Caulis Lonicerae)

Clear heat and disinhibit dampness, dispel wind and freethe flow of the network vessels, eliminate dampness,clear heat and free the flow of the network vessels.

Qu Bi Capsule Huang Qi (Radix Astragali); Gui Zhi (RamulusCinnamomi); Gan Cao (Radix Glycyrrhizae); Quan Xie(Scorpio); Di Long (Pheretima); Di Bie Chong(Eupolyphaga/Steleophaga)

Boost the qi and course wind, resolve toxins anddisperse swelling. Improve severe pain and obstinateimpediment.

Si Miao Powder Yi Yi Ren (Semen Coicis); Cang Zhu (RhizomaAtractylodis); Niu Xi (Radix Achyranthis Bidentatae);Huang Bai (Cortex Phellodendri)

Clear heat and disinhibit dampness, diffuse impedimentand stop pain.

Strychnos Powder Ma Qian Zi (Semen Strychnotis), powdered and takenwith the decoction

Disinhibit the channels and stop pain.

C. Zhang et al. / European Journal of Integrative Medicine 3 (2011) e219–e231 e227

Table 2 (Continued)

Intervention Ingredients CM treatment principles

Tong Luo Juan Bi Decoction Wei Ling Xian (Radix Clematidis); Qin Jiao (RadixGentianae Macrophyllae); Gui Zhi (RamulusCinnamomi); Qiang Huo (Radix Et RhizomaNotopterygii); Du Huo (Radix Angelicae Pubescentis);Qing Feng Teng (Rhizoma Sinomenii Acuti); Ren DongTeng (Caulis Lonicerae); Quan Xie (Scorpio); Di Long(Pheretima); Chuan Shan Jia (Squama Manitis); LuFeng Fang (Nidus Vespae); Huai Niu Xi (RadixAchyranthis Bidentatae); Sang Ji Sheng (Herba Taxilli);Shu Di (cooked Radix Rehmanniae); Xi Xin (HerbaAsari); Bai Jie Zi (Semen Sinapis); Chuan Xiong(Rhizoma Chuanxiong); Huang Qi (Radix Astragali)

Eliminate wind, overcome dampness, and scatter cold,quicken the blood, supplement vacuity, and free the flowof the network vessels.

Total glucosides of paeony capsule Bai Shao (Radix Albus Paeoniae Lactiflorae) activeglucoside in Shaoyao (peony root)

Nourish liver blood and the sinews and relax spasm.

Tripterygium Lei Gong Teng (Herba Tripterygii Wilfordii) Dispels dampness and disperses swelling, soothes thesinews, quickens the network vessels, and stops pain.

Worm and Insect Medicinals Di Long (Pheretima); Jiang Can (Bombyx Batryticatus);Wu Shao She (Zaocys); Lu Feng Fang (Nidus Vespae)

Transform stasis and free the flow of the networkvessels, expel wind and dispel dampness, warm thechannels and scatter cold.

Wu Bang Pill Dao Yang Hua (Flos Rhododendri Mollis); Qing FengTeng (Rhizoma Sinomenii Acuti); processed Chuan WuTou (Radix Aconiti Carmichaeli); processed Cao WuTou (Radix Aconiti Kusnezofii); Ge Gen (RadixPuerariae); Ma Huang (Herba Ephedrae); Gui Zhi(Rhizoma Cinnamomi); Du Zhong (CortexEucommiae); Niu Xi (Radix Achyranthis Bidentatae);Sang Ji Sheng (Herba Taxilli); Ji Xue Teng (CaulisSpatholobi); Huang Qi (Radix Astragali); Dang Gui(Radix Angelicae Sinensis); Shui Zhi (Hirudo); WuShao She (Zaocys); Bai Shao (Radix Paeoniae Albae);mix-fried Gan Cao (Radix Glycyrrhizae)

Expel wind and dispel dampness, warm the channelsand scatter cold, warms the channels, and scatters cold.Supplements the kidneys. Free the flow of the networkvessels, and stops pain. Gan Cao harmonizes the othermedicinal in this formula and checks the toxicity of CaoWu and Chuan Wu.

Wu Teng Powder Hong Teng (Caulis Sargentodoxae); Ji Xue Teng (CaulisSpatholobi); Qing Feng Teng (Rhizoma SinomeniiAcuti); Lei Gong Teng (Herba Tripterygii Wilfordii);Hei Gu Teng (Periploca forrestii Schltr); Ma Huang(Herba Ephedrae); Chuan Xiong (RhizomaChuanxiong); Gui Zhi (Ramulus Cinnamomi); Tao Ren(Semen Persicae); Ru Xiang (Olibanum); Jiang Can(Bombyx Batryticatus)

Clear heat and eliminate dampness, quicken the bloodand transform stasis, transform stasis, and stop pain.

Z i Acu

feamgP

Tto

F

heng Qing Feng Tong Ning Qing Feng Teng (Rhizoma SinomeniSinomenone Hydrochloride

ordii) and its extracts. Authors gave conclusions that limitedvidence suggested that some favorable results in clinical tri-ls, these findings should be carefully interpreted due to the low

ethodological quality and limited number of trials. The total

lucosides of peony (TGP), a powdery substance extracted fromaeonia lactiflora pall root, is a main effective component of

wbH

Adequate sequence generation?

Allocation concealment?

Blinding?

Incomplete outcome data addressed?

0%

Yes (low risk of bias) Unclear

ig. 2. Methodological quality graph: review authors’ judgments about each method

ti) Boost the qi, blood, and yang vacuity with winddampness, transform cold impediment and blood stasis.

GP. TGP has been recognized as the valuable CHM used in thereatment of RA. A systematic review [44] evaluates the efficacyf TGP combined with Methotrexate (MTX), another combined

ith immunosuppressant for RA [45], the results show the com-ination therapies are better than biomedicine monotherapy.igh-quality and large-scale RCTs are needed to further prove

25% 50% 75% 100%

No (high risk of bias)

ological quality item presented as percentages across all included studies.

e228 C. Zhang et al. / European Journal of Integrative Medicine 3 (2011) e219–e231

Table 3Summary of the adverse events of included studies.

Trial ID Treatment group Controlled group

Total glucosides of paeony capsule/MTXa Nausea, vomiting and anorexia:16Liver function test abnormal andkidney test abnormal: 8Soft stool and increase number ofstools per day: 7

Nausea, vomiting and anorexia:18Liver function test abnormal andkidney test abnormal: 6Soft stool and increase number ofstools per day: 1

Total glucosides of paeony capsules/MTX No adverse events Nausea, vomiting and anorexia: 4Bi Tong Decoction + Wu Teng Powder/LEFa Diarrhea: 2; exanthema: 1 Stomach pain: 2; exanthema: 1;

leukocyte reduction: 1; liver testabnormal: 1

Bi Zhong Xiao Decoction/MTX Nausea: 2 Fatigue: 6; dizziness: 5; nausea:6; hair loss: 4; epigastricdiscomfort: 7; aphthousulceration: 4; leukocytereduction: 5; liver test abnormal:34 cases: withdrawal due toadverse events

Triterygium Hypoglaueum (Level) Hutch/MTX Not indicated Not indicatedGui Zhi Shao Yao Zhi Mu Decoction + Si Miao Powder + LEF/LEF Not indicated Not indicatedGui Zhi Shao Yao Zhi Mu Decoction + Insect drugs/MTX Not indicated Not indicatedGui Zhi Shao Yao Zhi Mu Decoction/MTX Headache: 1; nausea: 1; anorexia:

1Leukocyte reduction: 3; liver testabnormal: 3; respiratoryinfections: 3

Huang Hu Bi Ke Granule/MTX None reported Not indicatedWu Bang Pill + LEF/LEF Slight dizziness and exanthema: 1 Leukocyte reduction and alanine

aminotransferase elevations: 6Total glucosides of paeony Capsules + LEF/LEF Nausea and anorexia: 5;

palpitations: 3; dizziness: 2;exanthema: 2; leukocytereduction: 2

Flatulence and diarrhea: 4;stomach burning: 2; headache: 2

Qing Re Huo Xue Juan Bi Decoction/MTX 2 cases but not indicated concreteevents

14 cases but not indicatedconcrete events

Zheng Qing Feng Tong Ning Tablet/MTX Leukocyte reduction: 5;exanthema: 1

Not indicated

Zheng Qing Feng Tong Ning Retard Tablet/MTX/Tripterygium Glycosides Leukocyte reduction: 1Gastrointestinal discomfort: 2Exanthema: 1

MTXLeukocyte reduction: 2;gastrointestinal discomfort: 6;liver test abnormal: 5; angularcheilitis and exanthema: 2Tripterygium GlycosidesGastrointestinal discomfort: 5;liver test abnormal: 2; angularcheilitis and exanthema: 2;leukocyte reduction: 3

Zheng Qing Feng Tong Ning Retard Tablet/MTX Not indicated Not indicatedZheng Qing Feng Tong Ning Retard Tablet/MTX Slight dizziness: 2 Gastrointestinal discomfort: 6;

leukocyte reduction: 2;transaminase elevations: 2

Feng Shi Kang Granule + MTX/LEF + MTX Nausea and vomiting: 4;anorexia: 6; diarrhea: 7; ALTelevations: 3; AST elevations: 2;leukocyte reduction: 1

Nausea and vomiting: 11;anorexia: 13; diarrhea: 19; ALTelevations: 9; AST elevations: 8;leukocyte reduction: 7

Bu Pi Chu Bi Decoction + MTX/SASPa + MTX Gastrointestinal discomfort: 8 Gastrointestinal discomfort: 10;liver test abnormal: 4; leukocytereduction: 4

Tong Luo Juan Bi Decoction + Agkistrodon Powder + Strychnos Powder/MTX Epigastric discomfort: 7; slightlimbs tremble: 3

Flatulence and anorexia: 12;leukocyte reduction: 2; ALTelevations: 4

Qu Bi Capsule + MTX/MTX 6 cases but not indicated concreteevents

5 cases but not indicated concreteevents

a MTX: Methotrexate; LEF: Leflunomide; SASP: Sulfasalazine.

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he results because of the limited quality of the included stud-es. Chinese herbal medicine, as a whole intervention in SR,as tested. Two authors gave detailed describe in their master’s

hesis [46,47], but still limited for the poor quality of includedrials. Furthermore, Compositae, a species of snow lotus fromhina for treating RA was tested. This poor quality report didot appear valid and convincing [48]. A Cochrane review showsripterygium wilfordii products may reduce some RA symp-oms, however, oral use may be associated with several sideffects. Many trials of herbal therapies are hampered by researchesign flaws and inadequate reporting. Further investigation ofach herbal therapy is warranted, particularly via well designed,ully powered, confirmatory clinical trials that use Americanollege of Rheumatology improvement criteria to measure out-omes and report results according to CONSORT guidelines49]. All included RCTs are in the English language journals.lthough no definitive conclusions can be drawn from theseuantitative analyses, caution should be used when consideringhe effect of CHMs treatment for RA patients, as we will discussn detail below.

linical heterogeneity

The evidence from 20 articles is insufficient to draw conclu-ions about differences in effect. The extent of heterogeneityn many of these RCTs prevented meaningful meta-analysis.HM treatments and control interventions to be tested shoulde selected carefully, and the potentially important treatmentsre priority treatments for efficacy evaluation.

imitations of CM pattern classification

Large CM clinical practices have shown that CHMs hadome advances in treatment of RA. Though the efficacy in somevaluated CHMs interventions remains uncertain with RCTs, ithould be carefully interpreted due to issues of methodology.M is holistic and conceptual, and it identifies and treats pat-

erns rather than diseases. Because of the unique characteristicsf CM pattern classification, more quality clinical trials with pat-ern classification theory design are needed for collecting morevidence to support CHM clinical application.

HM economics

RA carries “social costs” as well as economic burden [50].M is characterized by its simple, convenient, cheap and effec-

ive method of treatment [51]. But there is little evidence on CMconomics.

anguage gap

A complete system and “obscure” language are all these form

veil over its therapeutic philosophy. Also most CHM clinical

rials have been published in Chinese, and they are inaccessibleo western researchers for further analysis, as we mentionedbove. We expect that improvement on reporting more CHM

rative Medicine 3 (2011) e219–e231 e229

linical studies in high level international journals in the nearuture.

imitations of our review

Several limitations of our review should be considered. First,ost of our findings stem from short-term efficacy trials. Given

he chronic nature of RA, it is important to obtain the evidencen long-term therapy of RA with CHMs. Future studies, long-erm adverse event studies will help clinicians and patients bettereigh the benefits of these treatments. Secondly, publicationias is a concern in all reviews or SRs, selective availabilityf studies with positive results can seriously bias conclusions.urthermore, for ethical reasons, there are a numerous of com-ination therapy with non steroidal anti-inflammatory drugsNSAIDs) or steroids in controlled group. It did influence eval-ation of CHMs for inclusion criteria excluded NSAIDs andteroids interventions.

onclusions

In this review, the efficacy of several CHMs interventions forA was explored. Based on this study, some herbal medicinesave beneficial effects on pain management and swollen jointelief in people with RA. However, at the moment we cannotecommend any of the examined herbs for clinical routine use,ince the majority of the trials had low methodological qual-ty and the benefit has not been confirmed by large trials ofigh-quality. On the basis of this review, we suggest that specialttention should be given to the design of CHM trials, CM patternlassification, the use of responsive, reliable, and valid outcomeeasures, inclusion of a sufficient number of patients to create

tatistical power, and presentation of trial results according tonternational standards.

ompeting interest

The authors declare that they have no competing interests inelation to this article.

cknowledgements

This study was supported jointly by MOST Innovationroject (No. 2008IM020400), China Academy of Chinese Medi-al Sciences Project (No. Z0148) and by E-institutes of Shanghaiunicipal Education Commission (No. E03008).

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