reviewarticle - hindawi · 2019. 7. 30. · reviewarticle clinical efficacy of acupuncture on...

Review ArticleClinical Efficacy of Acupuncture on Rheumatoid Arthritis andAssociated Mechanisms: A Systemic Review

Pei-Chi Chou 1 and Heng-Yi Chu 2

1School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan2Department of Rehabilitation, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

Correspondence should be addressed to Pei-Chi Chou; [email protected] and Heng-Yi Chu; [email protected]

Received 25 January 2018; Accepted 7 March 2018; Published 12 April 2018

Academic Editor: Yuan Xu

Copyright © 2018 Pei-Chi Chou and Heng-Yi Chu. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Objective. The objective of this review is to investigate the detailed existing scientific information about the clinical efficacyof acupuncture on rheumatoid arthritis (RA) conditions and to reveal the proposed mechanisms. Methods. We searched thePubMed, EMBASE, Cochrane, AMED (Allied and ComplementaryMedicine), NCCAM (TheNational Center for Complementaryand Alternative Medicine), and CNKI (China National Knowledge Infrastructure) databases to identify relevant monographsand related references from 1974 to 2018. Chinese journals and theses/dissertations were hand searched. Results. 43 studieswere recruited. Each research was analyzed for study design, subject characteristics, intervention, selected acupoints, assessmentparameters, proposed mechanisms, and results/conclusions. Conclusions. In our review, we concluded that acupuncture alone orcombined with other treatment modalities is beneficial to the clinical conditions of RA without adverse effects reported and canimprove function and quality of life and is worth trying. Several important possible mechanisms were summarized including anti-inflammatory effect, antioxidative effect, and regulation of immune system function. However, there is still inconsistency regardingthe clinical efficacy and lack of well-designed human/animal double-blinded RCTs. Future discussion for further agreement ontaking traditional Chinese medicine (TCM) theory into consideration as much as possible is a top priority.

1. Introduction

Rheumatoid arthritis (RA) is the most common inflam-matory arthritis and has been known as a chronic andautoimmune disease involving inflammatory condition char-acterized with symmetrical and persistent synovitis anddestructive polyarthritis [1]. RA is also associated withmorbidity, chronic disability, and poor quality of life andthe cost of care is huge [2, 3]. The estimated prevalenceof RA is 0.2–1% [4]. As many factors like susceptibilitygenes, disease-causing immune cells, cytokine, and signaltransduction networks are involved in the pathogenesis ofRA [5], the treatment of RA has always been a challenge.The mainstream of the management regarding RA is the useof nonsteroid anti-inflammatory drugs, disease-modifyingantirheumatic drugs, analgesics, and biological agents [3].But the concerns may arise when taking accompanyingside effects and toxicity into consideration [6]. Given the

fact of the expanding awareness of unwanted side effectsof pharmaceutical treatment, there has been an increasedutilization of acupuncture as a contemporary healthcareoptionwhich has been reported as a kind of safemanagement[7, 8].

According to traditional Chinese medicine (TCM) the-ory, RA is categorized under the “Bi” or impediment disease,which means a group of diseases caused by the invasion ofwind, cold, dampness, or heat pathogen on the meridiansinvolving muscles, sinews, bones, and joints, manifestedby local pain, soreness, heaviness, or hotness, and evenarticular swelling, stiffness, and deformities, also referring toarthralgia.

Acupuncture has been regarded as an important partof TCM and has been used for thousands of years to treatvarious clinical disorders including “Bi” or RA like conditionsbased on TCM theory. There has been a trend to usecomplementary and alternative medicine (CAM) as 30–60%

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2018, Article ID 8596918, 21 pageshttps://doi.org/10.1155/2018/8596918

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https://doi.org/10.1155/2018/8596918

2 Evidence-Based Complementary and Alternative Medicine

of rheumatic patients used CAM [9]. In the United States, asmall but significant linear increase in the use of acupuncture(from 1.4% in 2007 to 1.5% in 2012 of the US adults) wasreported [10]. About 41% of patients with rheumatic diseasessought the help from acupuncture in Israel [11]. In Taiwan, arecent population-based study revealed the high prevalenceand specific usage patterns of TCM including acupuncture inthe RA patients [12]. 54.6% of the newly RA user of CAMselected acupuncture only in Korea [13].

However, discrepancy exists between previously con-ducted investigations and reviews regarding clinical efficacyof acupuncture for RA [14, 15]. As early as in 1985, a literatureanalysis of the efficacy using acupuncture for RA was doneby Bhatt-Sanders and no conclusion was drawn [16]. Ernstand Posadzki suggested that the evidence to support theeffectiveness of CAM as a treatment option for RA has alsobeen ambiguous [17]. On the other hand, Hughes concludedthat acupuncture elicited a range of effects which contributedto improvements in RA patients’ quality of life [18].

The actual mechanism by which acupuncture works alsoremains controversial. Among all the proposed mechanisms,anti-inflammatory effect has been the most often men-tioned which was supposed to provide nonanalgesic effectsvia suppression of inflammatory response, improvement ofblood flow, or relaxation of muscle tone, but they are stilllargely conjectural [19]. Others include regulating plasmaadrenocorticotropic hormone, serum cortisol levels, activityof synovial nuclear factor kappa B (NF-𝜅B), and the release ofendorphins [20–22].

In this article, we provide a descriptive and critical sys-temic review of the current researches available on the clinicalefficacy of acupuncture for RA conditions. We analyzed thedetails of each investigation in terms of study designs, sub-ject characteristics, interventions, outcome assessments, andresults/conclusions.Wewish to reveal the possible underlyingmechanisms as well.

2. Material and Methods

A comprehensive search of literatures which were publishedfrom 1974 to 2018 was undertaken using the followingkey words: rheumatoid arthritis, rheumatism, rheumaticdisease, acupuncture, electroacupuncture, laser acupunc-ture, traditional Chinese medicine (TCM), complementaryand alternative medicine (CAM), moxibustion, therapeu-tic effect/efficacy, and their synonyms. These terms wereused to search the following databases: PubMed, EMBASE,Cochrane, AME (Allied and Complementary Medicine),NCCAM (The National Center for Complementary andAlternative Medicine), and CNKI (China National Knowl-edge Infrastructure) databases. Additional articles were alsoidentified from the reference list of identified articles. Chinesejournals, theses, and dissertations that we thought might berelevant to our study were hand searched. In order to reviewas many investigations as possible, we reviewed any article inEnglish or Chinese with full-text available including animalstudies.There was no limitation regarding the study type. But

we did exclude some articles using the following exclusioncriteria:

(1) interventions not involving traditional acupunctureneedle insertion or electroacupuncture such as gold threadembedding or bee venomacupuncture butwe kept the studiesusing acupoints stimulation with transcutaneous electricnerve stimulation (TENS), laser, or other herbs;

(2) studies not aiming at the effect of acupuncture on RAsuch as reliability/validity tests for certain questionnaires;

(3) study protocols not involving human or animal sub-jects such as expert’s opinions or pure descriptive literaturereviews/systemic reviews.

3. Results

149 studies from 1974 to 2018 were analyzed and 43 studieswere recruited into the review. As there are not manyresearches specific for acupuncture and RA, we tried toinclude as many articles as possible. The study designs,subjects’ characteristics and sample size, acupuncture andother intervention types, applied acupuncture points andtheir meridians, parameters used for comparison, proposedmechanisms, and the results/suggestions/conclusions of theresearches were summarized in Table 1 classified in an orderof the year when the study was done.

3.1. Study Design. Most of the studies (33 out of 43) arerandomized controlled trails (RCT) [22, 23, 25–27, 29, 30, 32–35, 37–45, 48–50, 52, 54–57, 59–62, 66]; 4 of them are double-blinded RCT [49, 54, 61, 62].There are two single case studies[31, 36]. The rest of the analyzed articles are clinical trialswithoutmentioned randomization or controls groups [24, 28,46, 47, 51, 53, 58, 63–65].

3.2. Subjects. There are studies with human RA patients [23,24, 28–30, 33–37, 42–66] and studies with animal subjects;most of them are rats [22, 26, 31, 32, 38–41] and rabbits [25, 27]with an established RA model group by in vivo injection ofadjuvant components.

Liu et al. included 180 human RA subjects with pepticulcer to investigate the efficacy of ginger-partitioned acupointstimulation which is known to be the research with mostsubjects included [37]. 5 studies contained human subjectsmore than 100 [23, 29, 37, 42, 60]. 2 researches focusedon elderly RA patients [24, 50], one focused on 6 femaleRA patients [46], and 3 researches recruited healthy humansubjects for control as well [33, 34, 66].

3.3. Language Used for the Studies. There are 18 researcheswritten in English [22, 24, 31, 34, 36–38, 43, 46, 47, 49, 51–54, 61, 62, 64] and the rest of the analyzed researches inChinese. English abstracts can be found for most of thestudies in Chinese.

3.4. Acupuncture Points Applied in the Studies. The selectionof acupoints has not been very unanimous according to theauthors’ clinical experience and TCM theory applied. Someinvestigations used single acupoint [27, 37, 62] while someused more than 10 acupoints [23, 24, 28, 36, 46, 49, 51, 53,56–58, 63]. ST36 is the most frequently used acupoint and

Evidence-Based Complementary and Alternative Medicine 3

Table1:Summaryof

researches

selected

andanalyzed.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Mengetal.2018

[23]

RCT

160RA

patie

nts

Acup

uncture(on

cedaily

for4

weeks)+

herbsv

ersus

medication

ST36,B

L18,BL

20,B

L23,

RN6,RN

4,ST

36,D

U14,

LI11,SJ4,ST5

,LI4,G

B34,

GB3

1,ST

34,K

I6,B

L60,

SP10,G

B33,EX

-LE4

,EX

-LE5

,SI11,SI9,LI15,

SJ14,B

L36,GB3

0,BL

54,

GB4

0,BL

62

RAsymptom

s,ES

R,RF

,CRP

,IL-1,IL-6,

TNF-𝛼,ICM

AM-1

Inhibitin

gthe

inflammatory

reactio

nand

improvingim

mun

efunctio

n

(1)A

cupu

ncture

+herbs

hadsig

nificantly

bette

reffecto

nRA

symptom

s(2)S

ignificantd

ifferences

inallp

aram

etersb

etween2

grou

ps

Adlyetal.2017

[24]

Clinicaltrial

30eld

erlyRA

patie

nts

Lasera

cupu

ncture

versus

reflexology

(12sessions

in4

weeks

forb

oth

grou

ps)

LR3,ST

25,ST3

6,SI3,

SI4,LI4,LI11,SP6

,SP9

,GB2

5,GB3

4,HT7

RAQoL

,HAQ

,IL-6,

MDA,A

TP,and

ROM

atwris

tand

ankle

joints

(1)A

nti-infl

ammatory

effect

(2)R

adiatio

nabsorptio

nby

the

respira

tory

chain

compo

nentsind

ucing

electro

nice

xcitatio

n(3)A

ntioxidativ

e

Sign

ificant

improvem

entin

each

grou

pbu

tacup

unctures

eemstobe

bette

r

Jieetal.2017

[25]

Animalstu

dy(RCT

)60

rabbits

Body

versus

buccal

acup

uncture

(needlingfor15s

then

needle

retainingfor3

0min

inbu

ccalgrou

p)

ST36,LE5

“Xi”in

buccal

region

Pain

threshold,

cholecystokinin-8

(CCK

-8),𝛼-EP

(𝛼-end

orph

in)

Upregulationof𝛼-EP

andCC

K-8contents

incerebrospinalfl

uid

(centralanalgesic

effect)

(1)Th

ecentralanalgesic

effecto

fbuccal

acup

unctureisb

etterthan

body-acupu

ncture

(2)B

othbu

ccal

acup

uncturea

ndbo

dy-acupu

ncture

can

effectiv

elyraise

thep

ain

thresholdin

acutea

rthritis

rabbits


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Caietal.2017

[26]

Animalstu

dy(RCT

)50

rats

Warm

needle

moxibustio

n(15m

in,onced

aily

for2

1days)

ST36,B

L23,GB39

Swellin

gvolumeo

fthea

ffected

knee-jo

int,IL-1𝛼,

IL-6,and

IL-8,

expressio

nof

SIRT

1(a

classIII

histo

ne/protein

deacetylase)and

NF-𝜅Bp65

proteins

inthes

ynovialtissue

(1)D

ownregulating

serum

inflammatory

cytokinesa

ndNF-𝜅B

p65

expressio

n(2)U

pregulatingSIR

T1expressio

n

Warm

needlemoxibustio

ncanrelieve

inflammatory

reactio

nsof

RArats

Duetal.2017

[27]

Animalstu

dy(RCT

)40

rabbits

Heat-r

einforcing

needlin

g(H

RN)

versus

reinforcing-redu

cing

needlin

g(RRN

),twirling-reinforcing

needlin

g(TRN

)(30m

in,oncea

day

for7

days)

ST36

Pain

threshold,local

skin

temperature,

endo

geno

usmetabolitesinthe

serum

(𝛼-ketoglutaric

acid,citricacid,

succinicacid,glucose,

inosito

l,d-rib

ose,and

D-m

anno

se)

Thes

pecific

regu

latio

nforthe

Krebsc

ycleand

glycom

etabolism

(1)Th

eeffectof

HRN

grou

pwas

significantly

bette

rthan

RRNandTR

Ngrou

p(2)H

RNforR

Awith

cold

synd

romeise

ffective

Chiand

Hsu

2016

[28]

Clinicaltrial

42RA

patie

nts

Acup

uncture(on

cedaily

for10days,8

sessions)+

warm

needleacup

uncture

ST36,SP6

,LI4,LR3

,GB3

4,LI11,SJ5,SJ4,

EX-U

E9,E

X-UE4

,EX

-LE5

,EX-

LE2

,SP9

,ST

34,B

L62,BL

60,K

I6,

KI3,As

hipo

ints

RAsymptom

s,RF

,ES

RTC

Mtheory

Totaleffectiver

atew

as95.2%

Fong

andCh

ao2016

[29]

RCT

120RA

patie

nts

Acup

uncture(on

cedaily

for15days,2

sessions)w

ithherb

steam

ingversus

herb

steam

ingon

ly

LI11,LI5,SJ5,LI4,SP10,

ST36,G

B34,SP

9,ST

41RA

symptom

sTC

Mtheory

Acup

uncturec

ombined

with

herb

steam

inghada

bette

reffecton

RAsymptom

sthanherb

steam

ingalon

e


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Zhou

etal.2016

[30]

RCT

68RA

patie

nts

Electro

acup

uncture

(3tim

esaw

eekfor

12weeks)+

oral

medicationversus

oralmedication

BL18,B

L23,G

B39,

ST36,LR3,LI

4

VAS,clinical

symptom

s,DAS28,

ACR20,H

AQ,T

CMsymptom

sscore,E

SR,

CRP

(1)Th

eeffectso

fthe

EA+

medicationgrou

pwas

bette

rthanmedication

grou

pin

term

sof

symptom

sand

functio

n(2)A

dverse

reactio

nscan

beredu

cedby

EAtherapy

coordinatedwith

western

medicine

Don

getal.2016

[31]

Animalstu

dy(singlec

ase

study)

1rat

Electro

acup

uncture

(30m

indaily

for2

8days)

ST36,B

L60

Arthritisind

ex,paw

swellin

g,TL

R4,

MYD

88,N

F-𝜅B

Anti-infl

ammatoryby

redu

cing

the

expressio

nof

TLR4

,MYD

88,and

NF-𝜅B

Acup

uncturem

ayplay

anim

portantroleintre

atment

ofadjuvant

arthritisrat

Zhangetal.2016

[32]

Animalstu

dy(RCT

)32

rats

Electro

acup

uncture

(30m

in,onced

aily

for10days)v

ersus

medication

(predn

isolone)

ST36,B

L60

Rats’

leftankle

diam

eter,serum

TNF-𝛼,IL-1𝛼,and

ICAM-1

Dow

nregulatingthe

levelsof

serum

TNF-𝛼,IL-1𝛼,and

ICAM-1

(1)E

Ainterventio

nis

effectiv

einrelieving

RArats’

inflammatoryreactio

n(2)N

osig

nificant

differences

betweenthe

medicationandEA

grou

ps

Duetal.2016

[33]

RCT

60RA

patie

nts+

30healthysubjects

ascontrol

Heat-r

einforcing

needlin

g(H

RN)

versus

unifo

rmreinforcing-redu

cing

needlin

g(U

RN)

(onced

aily,

5days

aweek,twoweeks)

CV4,CV

6,ST

36

TCM

symptom

scoringsyste

m,the

expressio

nof

plasma

ATPsynthase

subu

nit

O(Atp5O)m

RNA

andlysosomalV1

subu

nitB

2(Atp

6V

1B2)

mRN

A

Upregulating

expressio

nsof

plasma

Atp5OmRN

Aand

Atp6V1B

2mRN

A

Both

HRN

andURN

can

improveR

Apatie

nts’

clinicalsym

ptom

swhile

HRN

was

bette

r


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Attia

etal.2016

[34]

RCT

30RA

patie

ntsa

nd20

healthysubjects

Lasera

cupu

ncture

(3days/w

eekfor4

weeks)

LI4,TE

5,LI

11,D

U14,

LIV3,SP

6,GB3

4,and

ST36

SOD,G

R,catalase,

GSH

,plasm

aATP

concentration,

plasma

MDA,serum

nitrate

andnitrite,serum

CRP,plasmaI

L-6,

GPx

activ

ity,E

SR,

DAS28score

Alleviatingoxidative

stressa

ndinflammation,

improving

antio

xidant

and

energy

metabolic

status

(1)Th

estudy

grou

prevealed

significantly

increasedplasmaS

OD,G

R,GSH

,and

plasmaA

TPconcentrations

(2)S

ignificantly

redu

ced

plasmaM

DA,serum

nitratea

ndnitrite,C

RP,

IL-6

GPx

activ

ityES

R

Chen

2015

[35]

RCT

78RA

patie

nts

Group

A=western

medication;

B=A+herb;

C=A

+B+

acup

uncture(on

cedaily

for7

days,24

sessions)

ST35,E

X-LE

2,ST

36,

SP10,A

hipo

ints

RAsymptom

sNot

mentio

ned

Totaleffectin

grou

pCwas

significantly

bette

rthan

grou

psAandB

Shettyetal.2015

[36]

Sing

lecase

study

1RAsubject

EMMS

(electroacup

uncture,

massage,m

ud,and

saun

atherapies)

(15–45

min

for3

weeks)

GV20,LI4,LI11,BL

11,

GB4

,SP6

,KI3,ST4

4,EX

28,and

EX36

VAS,10-m

eter

walk

test,

isometric

hand

-grip

test,

The

Pittsbu

rghSleep

QualityIndex,

DepressionAnx

iety

andStressScales,

SF-36,health

survey,

bloo

dandurine

analysis

Not

mentio

ned

TheE

MMStherapymight

beconsidered

asan

effectiv

etreatmentsin

redu

cing

pain,depression,

anxiety,andstr

essw

ithim

provem

entinph

ysical

functio

ns,qualityof

sleep,

andQOLin

patie

ntwith

RA


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Liuetal.2015

[37]

RCT

180RA

subjects

with

pepticulcer

Ginger-partition

edacup

oint

stim

ulation

(15m

in,twiced

aily

for2

mon

ths)versus

antirheum

aticdrugs

(ARD

)versus

combinatio

ntre

atment

ST36

RAsymptom

s,gripping

strength,

self-repo

rted

pain

score,DAS-28

RAdiseasea

ctivity

score,

HAQ

,RF,antic

yclic

citrullin

ated

peptide

(anti-C

CP),ES

R,and

CRP

TCM

theory/anti-

inflammatory

effect

Com

binatio

ntre

atment

with

ginger-partitioned

acup

oint

stim

ulation,

oral

sanh

uang

wujip

owder,and

ARD

shad

abetterc

linical

effectfor

RAwith

complicated

pepticulcer

Lietal.2015[

38]

Animalstu

dy(RCT

)60

rats

Acup

uncture

(15m

indaily

for3

weeks)v

ersussham

acup

uncture

ST36,G

B39,BL

23

Arthritisind

ex,the

expressio

nlevelsof

TNF-𝛼andNF-𝜅B

(p65)insyno

vialcells,

andthec

ontent

ofserum

inflammatory

cytokines

Acup

uncture

mediatesthe

anti-inflammatory

NF-kB

pathway

(1)P

aram

etersw

erelow

erforthe

acup

unctureg

roup

than

forthe

mod

elgrou

p(2)N

osta

tistic

ally

significantd

ifference

betweenthem

odeland

sham

acup

unctureg

roup

Guo

etal.2015

[39]

Animalstu

dy(RCT

)32

rats

Electro

acup

uncture

(EA;onced

ailyfor5

days

andrestfor2

days,3

sessions)

versus

prednisolone

ST36,B

L60

Rats’

ankled

iameter,

IL-17,andIL-23

Dow

nregulating

serum

andkn

ee-jo

int

IL-17andIL-23levels

(1)E

Acanredu

ceinflammatoryreactio

nof

thea

nkle-jo

intinRA

rats

(2)N

oobviou

sdifferences

werefou

ndbetweentheE

Aandprednisolone

grou

psexcept

IL-17protein

expressio

nlevel


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Zhangetal.2013

[40]

Animalstu

dy(RCT

)40

rats

Fire

needlin

g(once

every3days,8

times)v

ersus

medication(M

TX)

ST36,E

XB2

Weight,sw

ellingrate

offoot,joint

pain

scorea

ndpo

lyarthritisindexof

rats,

pathological

change

ofliver

tissue

Not

mentio

ned

Thefi

reneedlin

ghas

significantefficacy

forrats

with

adjuvant

arthritis

with

outany

damagetothe

liver

andseem

stobe

bette

rthan

MTX

treatment

Han

etal.2012

[41]

Animalstu

dy(RCT

)40

rats

Fire-needle

acup

uncture(on

ceevery3days,8

times)v

ersusM

TX

ST36,E

XB2

Rat’srig

hthind

paw

swellin

gvolume,

serum

IL-1and

TNF-alph

a,pathologicalchanges

ofsyno

vium

tissueo

fther

ight

knee-jo

int

Dow

nregulating

serum

IL-1and

TNF-alph

acon

tents

(1)N

osig

nificant

differences

werefou

ndin

thes

wollenpawvolumes

onday12

(2)B

othgrou

psshow

edbette

rpatho

logical

observation

Hee

tal.2011

[22]

Animalstu

dy(RCT

)75

rats

Electro

acup

uncture

(15m

in,oncee

very

otherd

ayfor15

days)v

ersussham

ST36,G

B39,BL

23

Body

weight,paw

volume,histo

logic

inflammationscoring,

VIP

Partially

throug

hthe

indu

ctionof

VIP

expressio

n

EAmarkedlydecreasedthe

pawsw

ellin

gandthe

histo

logics

coreso

finflammationin

the

syno

vialtissuea

ndredu

ced

theb

odyweightloss


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Gao

2011[42]

RCT

114RA

patie

nts

Group

A=Western

medication,

B=A+

acup

uncture(on

cedaily,5

times

aweek

for3

mon

ths)

RN6,RN

4,ST

36,B

L18,

BL20,B

L23

RAsymptom

sTC

Mtheory

Group

Bhadmuchbette

rclinicaleffectthan

grou

pA

Ouyangetal.

2011[43]

RCT

63RA

patie

nts

Electro

acup

uncture

(EA)v

ersussim

ple

needlin

g(SN)o

nce

everyotherd

ayfor

10tim

es,3

sessions

Acup

ointsw

eres

elected

mainlyfro

myang

-meridianandlocal

Ashi

points(pain-po

int)

TNF-𝛼,V

EGFin

perip

heralblood

and

jointsyn

ovia

LoweringTN

F-𝛼and

VEG

Fin

perip

heral

bloo

dandjoint

syno

via

(1)E

AandSN

couldbo

thredu

cetheT

NF-𝛼and

VEG

F(2)Th

elow

eringof

VEG

Fwas

mores

ignificantinthe

EAgrou

p

Ouyangetal.

2010

[44]

RCT

63RA

subjects

Electro

acup

uncture

(EA)v

ersussim

ple

needlin

g(SN)(on

ceeveryotherd

ayfor

20tim

es,3

sessions)

GV20,G

B20,LI11,T

E5,

CV4,ST

36

IL-1,IL-4,IL-6,and

IL-10in

perip

heral

bloo

dandjointfl

uid

Decreasingthe

proinfl

ammatory

cytokine

ofIL-1and

IL-6

andincreasin

gtheinh

ibition

cytokine

ofIL-4

and

IL-10

(1)B

othgrou

psredu

cedthe

interle

ukins

(2)E

Agrou

phadag

reater

effectthanSN

grou

p

Liu2009

[45]

RCT

57RA

patie

nts

Acup

uncture(on

cedaily

for15days,2

sessions

for

consecutive2

-3years)versus

medication

SP6,SP

9,ST

36Fu

nctio

nal

assessment

TCM

theory

Acup

unctureg

roup

had

significantly

bette

rADL

functio

n(81.5

%compared

with

50.0%)


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Sato

etal.200

9[46]

Clinicaltrial

6femaleR

Apatie

nts

Acup

uncture(10

acup

uncture

treatmentsin

2mon

ths)

ST34,ST3

5,ST

36,SP9

,SP

10,B

L39,BL

40,B

L56,

KI10,G

B31,andGB3

4

VAS,RO

M,faces

cale

(moo

d),M

HAQ

,FD

G-PET

images,

ESR,

CRP

Not

throug

hredu

ctionof

region

alinflammation

VAS,RO

M,faces

caleand

MHAQ

improved

inall

patie

ntsa

ndsig

nificantly

after

acup

uncture,bu

tno

significantchangeinES

R,CR

P,andPE

Tim

ages

Kim

etal.200

9[47]

Clinicaltrial

21RA

patie

nts:

respon

ders(atleast

50%redu

ctionin

swollenjoint

coun

ts)or

nonrespo

nders

(lessthan

50%

redu

ctionin

swollenjoint

coun

ts)

Acup

uncture(14

sessions

in6weeks)

Not

mentio

ned

TASin

thes

erum

,the

SOD,catalase

Theincreased

activ

ities

ofSO

Dand

catalase

inthes

erum

(1)Th

erespo

nderssho

wed

significantly

greater

changesinthea

ctivity

ofSO

D(2)N

osig

nificant

differences

inthec

hanges

ofthec

atalasea

ctivity

and

TASbetweentheg

roup

s

Chen

etal.200

9[48]

RCT

60RA

patie

nts

Muscular

acup

uncture(on

cedaily

for3

mon

ths)

versus

medication

L11,SP

6,andscarrin

gmoxibustio

non

GV14,

ST36

RAsymptom

s,ES

R,RF

Not

mentio

ned,

possible

anti-inflammatory

effect

(1)B

othgrou

pswere

effectiv

ebut

with

nosig

nificantd

ifferences

(2)A

cupu

ncture

caused

lessa

dverse

effects


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Zanette

etal.

2008

[49]

Pilotd

ouble-

blinded

RCT

40RA

patie

nts

Acup

uncture(AC

)versus

sham

(con

trol

AC)(5–10

treatment

sessions,followed

upat1m

onth)

EX1,PC

6,IG

4,EX

28,

CV12,C

V6,ST

36,SP

6,LV

3,UB20,U

B22,

UB23,G

V4,GV14,U

B11,U

B60

ACR2

0,DAS,VA

S,HAQ

,ESR

,CRP

Not

throug

hanti-inflammatory

effect

(1)A

trend

forb

etter

efficacy

intheA

Cgrou

p(A

CR20)

(2)O

ther

varia

bles

didno

tdifferinbo

thgrou

ps

Pang

etal.2008

[50]

RCT

86RA

patie

nts

Acup

uncture(on

cedaily

for2

0days,2

sessions)+

medicationversus

medication

DU14,LI11,LI4,SP

6,DU3,BL

20,R

N4,As

hipo

ints

RAsymptom

s,ES

R,CR

P,RF

,IgG

,IgA

,IgM

Anti-infl

ammatory

effect

Medicationcombinedwith

acup

unctureg

roup

with

bette

rclin

icaleffectsin

term

sofeachparameter

Leee

tal.2008

[51]

Pilotclin

ical

trial

25RA

patie

nts

Acup

uncture(14

sessions

for6

weeks)

HT8

,KI10,ST

36,SP3

,LR

8,LR

2,SP

2,LR

1,SP

1,SI5,ST

41,G

B41,ST

43,

SI3,BL

66,SI2,LU8,KI

7,SP

3,KI

3

ACR20,50,and70,

DAS28,sw

ollenjoint

coun

t,SF-36,ES

R

Anti-infl

ammatory

effects

(1)A

t6weeks,44%

,20%

,and12%of

patie

nts

achieved

ACR20,50,and

70respon

ses,respectiv

ely(2)A

cupu

ncture

also

prod

uced

statistically

significantimprovem

ents

inDAS28,pain

andglob

alactiv

ity,swollenjoint

coun

t,SF-36,andES

R

Bernatecketal.

2008

[52]

RCT

44RA

patie

nts

Auric

ular

electroacup

uncture

(EA)v

ersus

autogenictraining

(AT)

(oncew

eekly

for6

weeks,

follo

w-upat3

mon

ths)

NA

VAS,DAS28,theu

seof

pain

medication,

thep

aindisability

index(PDI),the

clinicalglobal

impressio

n(C

GI),

andproinfl

ammatory

cytokine

levels

Anti-infl

ammatory

effect

(1)B

othEA

andAT

resultedin

significant

short-andlong

-term

effects

(2)Th

etreatmenteffectso

fauric

ular

EAwerem

ore

pron

ounced


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Wangetal.2007

[53]

Clinicaltrial

47RA

patie

nts

Acup

uncture:3

coursesv

ersus6

courses

ST36,C

V8,EX

UE9

,EX

LE5,SI3,SI8,LI3,

LI4,LI5,LI10,LI11,TE

4,TE

5,PC

7,LU

5,LR

2,BL

62,K

I3,K

I6.ST4

1,GB3

4,SP

10

Morning

rigidity,

swellin

g,andpain

ofjointsas

wellasR

F,ES

R,CR

P

Not

mentio

ned,

possible

anti-inflammatory

effect

6coursesh

adgreatere

ffect

onparametersthan2

courseso

facupu

ncture

treatment

Tam

etal.2007

[54]

Pilotd

ouble-

blinded

RCT

36RA

patie

nts

Electro

acup

uncture

(EA)v

ersus

tradition

alCh

inese

acup

uncture(TC

A)

andsham

acup

uncture(Sham

)(20sessions

for10

weeks)

LI11,T

E5,LI4,ST3

6,GB3

4,GB3

9

Pain

score,changesin

theA

CRcore

disease

measures,DAS28

score,andthe

numbero

fpatients

who

achieved

ACR20

atweek10,E

SR,C

RP

Not

mentio

ned,

possible

anti-inflammatory

effect

(1)Th

enum

bero

ftender

jointswas

significantly

redu

cedforthe

EAand

TCAgrou

ps(2)P

hysic

ian’s

glob

alscore

was

significantly

redu

ced

forthe

EAgrou

pand

patie

nt’sglob

alscorew

assig

nificantly

redu

cedfor

theT

CAgrou

p

FanandXia

2007

[55]

RCT

96RA

patie

nts

Acup

uncture(heat

electroacup

uncture

instrumentw

ithCh

ineseh

erb

iontop

horesis

plus

medicine)versus

control(medicine

only)(follo

wed

upat

onem

onth)

LI11,G

B33,GB3

4,ST

34RA

symptom

s,CR

P,RF

,ESR

,WBC

,platele

t

Anti-infl

ammatory

effect

(1)Th

eeffectiver

atew

as79.2%in

thetreatment

grou

pand52.1%

inthe

controlgroup

(2)Th

edecreases

ofbloo

dCR

P,ES

R,PL

Tin

the

treatmentg

roup

were

more

significantly

ascompared

with

thec

ontro

lgroup


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Chen

andGuo

2006

[56]

RCT

137patie

nts

Acup

uncture(on

cead

ayfor10days,3

sessions)+

moxibustio

nversus

acup

uncture

SI4,LI5,LI11,SJ5,LI4,

ST36,G

B34,Sp6,LR

3,GB4

1,EX

-UE9

,ST4

1RA

symptom

sTC

Mtheory

Totaleffectiver

atew

asbette

ringrou

pwith

acup

uncturea

ndmoxibustio

n(88.51%versus

64.0%)

Gao

etal.200

6[57]

RCT

98RA

patie

nts

Acup

uncture(on

cedaily

for10days)

andmoxibustio

nversus

herbs

LI11,SJ5,E

X-UE9

,EX

-LE4

,EX-

LE5,BL

40,

GB3

4,ST

36,SP6

,GB4

0,EX

-LE10

RAsymptom

sTC

Mtheory

Totaleffectiver

atew

asbette

ringrou

pwith

acup

uncturea

ndmoxibustio

n(94.3%

versus

80.0%)

Shuain

andHsu

2006

[58]

Clinicaltrial

20RA

patie

nts

Acup

uncturea

ndherbs

LI11,ST3

6,ST

40,A

P6,

GB3

9,GB3

0,PC

7,LU

5,LI4,SJ5,ST

34,G

B33,

BL60

RAsymptom

sand

ESR

TCM

theory

and

anti-inflammatory

effect

Totaleffectiver

atew

as95%

Hee

tal.2006

[59]

RCT

50RA

patie

nts

Needle-sticking

metho

dversus

routinefi

liform

needletherapy(2

sessions)

Not

mentio

ned

RAsymptom

s(painful

andsw

ollen

joints)

,RF,CR

P,ES

R

Possible

anti-inflammatory

effect

Both

grou

pshadan

apparent

therapeutic

effect

onRA

,but

needle-sticking

metho

dwas

bette

rinterm

sof

RFandsymptom

s


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Aietal.2005

[60]

RCT

146RA

patie

ntsa

tactiv

estage

Electro

acup

uncture

versus

medication

LI4,LI11,G

B34

RAsymptom

sNot

mentio

ned

Effectiv

eratew

as79.73%

inthetreatmentg

roup

and

51.39

%in

thec

ontro

lgroup

with

asignificantd

ifference

Usic

henk

oetal.

2003

[61]

Dou

ble-

blinded

RCT

12RA

patie

nts

Electro

magnetic

millim

eter

waves

(MW)app

liedto

acup

uncturep

oints

versus

sham

versus

MW

expo

sure

40min

Not

mentio

ned

RAsymptom

sNot

mentio

ned

Patie

ntsfrom

MW

grou

prepo

rted

significantp

ain

reliefand

redu

cedjoint

stiffn

essd

uringandaft

erthec

ourseo

ftherapy.M

Vmay

bean

adjuvant

therapy

forR

A

David

etal.1999

[62]

Dou

ble-

blinded

RCT

56RA

patie

nts

Acup

uncturev

ersus

sham

(5tre

atmentsat

weeklyintervalfor5

weeks/2

sessions

and

one6

-weekwasho

utperio

din

between)

LI3

ESR,

CRP,VA

S,glob

alpatie

ntassessment,

DAS28,GHQ

Not

throug

hanti-inflammatory

effect

Nosig

nificanteffectof

treatmento

rperiodandno

significantinteractio

nbetweentre

atmentand

perio

dfora

nyou

tcom

evaria

ble

Lietal.1999

[63]

Clinicaltrial

55RA

patie

nts

Acup

uncture+

needlewarmingby

moxibustio

n(once

daily

for2

mon

ths)

LU9,P7,H

7,SP

3,LI3,

K3,L3,SI3,SJ3,ST

43,

GB4

1,UB6

5,ST

36,

GB3

4.GB3

9,RN

4

RAsymptom

s,ES

R,RF

,X-rayso

fhands

TCM

theory

(1)Th

etotaleffectiv

erate

was

90.9%

(2)N

ochangesfou

ndin

X-rays


Table1:Con

tinued.

Authorsa

ndyear

Stud

ydesig

nSubject

characteris

tics

Interventio

nsAc

upun

cturep

oints

applied

Outcomea

ssessm

ent

Possiblemechanism

sprop

osed

Results

andconclusio

ns

Guanand

Zhang1995

[64]

Clinicaltrial

12RA

patie

nts

Acup

uncture(on

cedaily

for10days,1–3

sessions)

Ex17,U

B12,UB13,LI4,

LU7,RE

N22,LU6,ST

36,

ST40

,LU5,LU

9,RE

N4,

REN17

Serum

IgG,IgM

,IgA

Ther

einforcemento

ftheimmun

ological

functio

n

IgG,IgA

,and

IgM

decreased,whileIgEdid

notchangee

vidently

Liuetal.1993

[65]

Clinicaltrial

54RA

patie

nts

Warm

needlin

gversus

point

injection

NKactiv

ityandIL-2

Regu

latory

effecto

nthec

ellular

immun

ological

functio

n

TheN

Kactiv

ityandIL-2

valueinRA

patie

ntsw

ere

foun

dto

belower

than

thoseo

fnormal

individu

als;bo

thincreased

after

treatment

Xiao

etal.1992

[66]

RCT

41RA

patie

ntsa

nd16

healthysubjects

ascontrol

Acup

uncturew

ithmoxibustio

nversus

pointinjectio

nNot

mentio

ned

IL-2

levels

Aninflu

ence

onthe

immun

itysyste

mthroug

hneuroend

ocrin

esyste

mto

improvethe

IL-2

prod

uctio

n

TheIL-2levelincontrol

grou

pwas

unchangedbu

tincreasedconsiderablyin

twoRA

grou

ps


was selected in almost every research, followed by GB34, LI4,BL60, GB39, and so forth. Please refer to Table 1 for extensivedetails.

3.5. If with TCM Syndrome Differentiation of RA. Severalstudies mentioned the specific inclusion criteria regardingTCM syndrome differentiation [23, 24, 30, 33, 37, 59] includ-ing one animal study [27].

3.6. Details of Acupuncture Protocols. The details of theacupuncture protocol are summarized in Table 1. The follow-ing describes the detailed items summarized in the table:

(1) Intervention type: traditional acupuncture with dif-ferent manual techniques, laser acupuncture, electroacu-puncture, buccal acupuncture, auricular electroacupuncture,warm needling with or without moxibustion, and acupointstimulation with herbs.

(2) Modalities used for control or combined therapy: oralor injected form of Western medication, reflexology, mox-ibustion, herb steaming, massage, mud and sauna therapy,sham acupuncture, autogenic training, herb iontophoresis,oral use of herbs, and electromagnetic millimeter wave.

(3) Treatment frequency/duration and follow-up periodof each research summarized in detail as shown in Table 1.

Wang et al. used the same acupuncture protocol butcompared the treatment efficacy for 3 and 6 courses [53].

3.7. Parameters Used for Efficacy Comparison3.7.1. PrimaryOutcomes. Most primary outcome assessmentsare associated with clinical RA symptoms (pain, morningstiffness, and so forth) and RA symptoms related scales suchas pain threshold, visual analogue scale (VAS), pain disabilityindex (PDI), TCM symptom scoring, 28 joints activity index(disease activity score, DAS 28), range of motion of the joint(ROM), 10-meter walk test, grip power, American College ofRheumatology 20 (ACR 20, i.e., 20% of clinical improvingrate), ACR 50, and ACR 70.

Parameters specifically used for animals include swellingvolume of the joints, limb diameter, and number of swollenjoints, arthritis index, skin temperature, and weight.

There are many questionnaires applied in each domainspecifically for human RA subjects including quality of lifesuch as the rheumatoid arthritis quality of life questionnaire(RAQoL), health assessment questionnaire (HAQ), shortform-36 health survey (SF36), the Pittsburgh sleep qualityindex, depression, anxiety, and stress scale and face scalefor mood, and modified health assessment questionnaire(MHAQ).

Table 1 has the details of each assessment tool used in eachstudy.

3.7.2. Secondary Outcomes. Most of the secondary outcomeassessment samples are from the blood and tissues likesynovium including two major categories:

(1) Regarding Anti-Inflammation. There are serum levels oferythrocyte sedimentation rate (ESR), C-reactive protein(CRP), rheumatoid factor (RF), interleukins (IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, and IL-23), vascular endothelial

growth factor (VEGF), immunoglobulins (IgE, IgA, andIgM),white blood cell (WBC), platelet, nuclear factor kappaB(NF-𝜅B), tumor necrosis factor alpha (TNF-𝛼), intercellularadhesion molecule 1 (ICAM-1), cholecystokinin-8 (CCK-8),endorphin, protein deacetylase (SIRT-1), myeloid differentia-tion factor 88 (MYD88), toll-like receptor (TLR4), anti-cycliccitrullinated peptide (anti-CCP), and vasoactive intestinalpeptide (VIP).

(2) Regarding Antioxidation. There are superoxide dismutase(SOD), catalase, total antioxidant status (TAS), malondialde-hyde (MDA), adenosine triphosphate (ATP), ATP synthasesubunit, glutathione reductase (GR), and glutathione peroxi-dase (GPx).

However, pathological changes of animal tissues (syn-ovium, liver) were also collected [22, 26, 38, 40, 41, 43].

3.7.3. Special Imaging Tools. One study employed positron-emission tomography (PET) scan to detect the regionalimprovement of inflammation [46] and another study usedX-ray of hands for before-after treatment comparison [63].

Please refer to Table 1 for more details.

3.8. Proposed Mechanisms. Not every investigation proposedthe possible mechanisms of how acupuncture works on theRA condition. Proposed mechanisms could be summarizedas the following categories.

3.8.1. Anti-Inflammatory Effect. Among all the mechanismsproposed, this is the single theory suggested by most authors[22, 23, 26, 34, 37–39, 41, 43, 44, 46, 50–52, 55, 58, 59].

3.8.2. Regulating Immune Function. Several studies also indi-cated the mechanisms to result from regulating immuneactivities [23, 25, 31, 32, 64–66].

3.8.3. Antioxidative Effect. Some authors believed it to berelated to the antioxidation [24, 34, 47].

3.8.4. Miscellaneous. Jie et al. have indicated the fact thatthere is central analgesic effect by increasing 𝛼-endorphinlevel in the cerebrospinal fluid [25], while Adly et al. thoughtthe effects to be via inducing electronic excitation [24].Specific regulation of the Krebs cycle (also known as thetricarboxylic acid cycle) and glycometabolism were alsomentioned in the work of Du et al. [27]. Du et al. suggestedthe role of biological heat production by acupuncture [33].For most researches in Chinese, the authors selected thetreatment protocol and acupoints according to the TCMtheory.

3.9. Clinical Efficacy. Almost every investigation found thatany kind of acupuncture as the main treatment or adjuvanttreatment tool could benefit clinical conditions of RA inhuman or animal subjects except one [62].

There were no adverse effects of acupuncture reported.

4. Discussion

RA has been regarded as a chronic inflammatory condi-tion with various clinical manifestations and some of them


could cause serious disabilities and handicaps. Clinicianshave been working very hard to suspend the devastatingdisease progression and deal with the symptoms as well asthe impaired function and accompanying stress and cost.However, the actual pathogenesis of rheumatoid arthritisremains incompletely understood. Previous researches haveshed light into the cellular and molecular mechanisms andfrom that base modern Western medications have derived[3]. Contemporary use of medication is linked with theconcern of adverse effect and may limit the compliance suchas the case of methotrexate (MTX) [67].

An estimated 60–90% of arthritis patients are reportedto use CAM including acupuncture [68]. There have beenseveral reviews concerning the clinical efficacy of CAM onrheumatic diseases [8, 9, 17, 69–72] but the latest reviewspecifically focused on the efficacy of acupuncture for RAconditions was conducted in 2008 [14, 15].

Seca et al. suggested a protocol for systemic reviewfocused on pain, physical function, and quality of life but willexclude animal studies and has not been completed [73]. Toour knowledge, the present review is themost comprehensiveone covering studies from 1974–2018 including human andanimal studies and with discussion of the details of studydesigns, interventions, parameters used for comparison, andthe possible proposed mechanisms as well as results andconclusions.

When taking study design into consideration, TCMtheory was adapted substantially in most of the investiga-tions. TCM represents the most significant component ofcomplementary and alternative medicine [74]. Accordingto the TCM theory, patients who suffer from the samedisease may present different TCM syndrome patterns thatalso correspond to different biological processes and areassociated with different related biomarkers [75]. Lu et al.indicated that RA patients may be divided into cold andheat pattern and they have different molecular signatureprocesses and react differently to certain treatment [76], sotheoretically RA patients may be treated by acupuncturewithout unanimous acupoints according to their TCM syn-drome differentiation. These facts have led to obstacles whentrying to conduct contemporary researches which criticsmay face in terms of methodology. Double-blinded RCT isthought to be the most optimal study design to establishscientific evidence, but acupoints selection by TCM theorywould experience difficulties which may be the reason of theexisting discrepancies between studies of human subjects. Inaddition, it is also difficult to classify animals into appropriateTCM syndrome categories like human. Another question isthe standard localization of acupoints in animals and thecorrelation and difference between different species.

A RA animal model is often established in animal studiesby injection of substance such as bovine collagen [26],Freund’s adjuvant [32], or ovalbumin and extra freezingprocess to imitate the cold syndrome as classified in TCM[27], the disease progression may not be the same in realRA patients, and most of the investigations did not haveadequate follow-up period till the chronic stage was achieved(e.g., 10 days [32]). As compared to most human studies,there were at least 3–12 weeks of treatment and follow-up

with the longest follow-up period of 3 years [45]. This madethe conclusions drawn less practical and applicable for RApatients. But Jie et al. used buccal acupuncture and found thatcentral analgesic effect with upregulation of endorphin andCCK-8 in cerebrospinal fluid could be observed with needleretaining for 30 minutes in RA rabbits; this is the shortestobservation but with good results [25].

Some authors provided better clinical efficacy usingdifferent needling techniques including warm needling[26–28, 33, 41, 55, 63, 65], plus herb steaming [29],needle-sticking method [59], reinforcing-reducing/twirling-reinforcing needling [27], and moxibustion [57, 66]. EA wasused in several studies [22, 30–32, 36, 43, 44, 52, 54, 60],and some authors suggested a better effect than traditionalacupuncture [43, 44, 52, 54]. Several studies employed shamacupuncture or EA as the control group [22, 38, 49, 54, 61, 62].Special forms of acupoints stimulation included laser [24, 34],ginger-partitioned therapy [37], and millimeter waves [61].

We found an interesting fact that acupoint ST36 wasused in almost every research and followed by GB34 andLI4. According to TCM theory, RA should fit the diseasecondition called “Bi” or impediment disease, which meansany disease pattern that results from blockage of the merid-ians occurring when wind, cold, and dampness invade thefleshy exterior and the joints, and that manifests in symptomssuch as joint pain, sinew and bone pain, and heaviness ornumbness of the limbs as stated in Elementary Questions(Su Wen, bi lun). Distinction is made between three patterntypes, each of which corresponds to a prevalence of one ofthose three evils: wind impediment (or moving impediment)characterized by wandering pain and attributed to a preva-lence of wind; cold impediment (or painful impediment)characterized by acute pain and attributed to a prevalence ofcold; damp impediment (or fixed impediment) characterizedby heaviness and attributed to a prevalence of dampness. Afourth type, heat impediment, arises when the three evilstransform into heat. The basic philosophy of how all theacupoints were selected derived from the above theory. As aresult, the number of acupoints used seems not to affect theclinical efficacy.

Measurements of quality of life domain have gainedmore interest among RA patients than other disease-relatedparameters such as inflammatory biomarkers or joint counts[77]. In this review, some studies have adopted relatedquestionnaires [24, 30, 36, 37, 46, 62] and acupuncturewas able to improve the quality of life except in one study[62].

Anti-inflammatory effect has been the most well-knownmechanism of how acupuncture works for RA as manystudies in this review used inflammatory biomarkers forcomparison such as ESR, CRP, RF, IL, NF-𝜅B, and TNF-𝛼.Most of the studies comparing these biomarkers indicatedthe anti-inflammatory effect of acupuncture [22–24, 26, 31,32, 37–39, 41, 43, 44, 50–55, 58, 59, 66]. Wang et al. indicatedthe reduction of ESR and CRP after acupuncture in RAsubjects in their review as well [15]. Han et al. thought thatacupuncture can lower TNF-𝛼 andVEGF in peripheral bloodand joint synovia to improve the internal environment whichis beneficial for RA [41].


Dong et al. indicated that toll-like receptor (TLR) signal-ing pathway contributed to the development and progressionof RA and acupuncture could reduce the expression ofTLR4, thus leading to anti-inflammation [31]. However, someauthors did find clinical effect but not via anti-inflammation[46, 49]. Efthimiou and Kukar indicated that even thoughno clear anti-inflammatory effect has been demonstrated,acupuncture may still be a useful adjuvant for pain [70]. Inour review, we think anti-inflammatory effect acts in certainoccasion to improve the RA conditions.

Another possible mechanisms could be attributed to theantioxidative effect (such as inducing the increased activitiesof SOD and catalase in the serum of RA, alleviating oxidativestress and inflammation, and improving antioxidant andenergy metabolic status) [33, 34, 47] and triggered release ofendorphins [25] and regulation of immune function as IgG,IgA, and IgM decreased, while IgE did not change evidentlyafter acupuncture in 12 RA patients [23, 32, 64–66].

Forestier et al. concluded in 2009 the evidence level ofacupuncture for RA is limited to professional agreement withno scientific evidence [78]. Along with other inconclusiveinformation regarding the clinical efficacy [54, 72], well-designed RCTs are warranted [79]. Most animal studies lackthe consistency in establishing the RA model such as thestandard injected substance, the dosage, the injected site,the duration of observation after injection, the treatmentprotocol including acupoints selection, animal acupuncturelocalization standard, TCM syndrome differentiation, theperiod of follow-up, and assessment parameters. As forhuman study, the most important thing is to decide if treat-ment protocol should vary according to TCM differentiation.Although different mechanism leads to different study designin terms of the parameters that will be assessed, efforts shouldbe put on the standardization and it should be thoughtwhether other methods like functional imaging test would beappropriate.

Acupuncture has its root in TCM and traditionally TCMhas one distinguished character; that is, it does not completelyseek the specific pathogen and pathological changes in a spe-cific organ or individual, but it seeks the disturbances amongthe self-controlled systems by analyzing all symptoms andsigns. The TCM intervention is based on the differentiationof symptoms to clarify what is wrong in the self-controlledsystem. TCM seeks the therapeutic mechanism from theintegrity and balance, in each individual and between theindividual and the environment. The therapeutics work byactivating and improving system connection and enhancinghuman resistance. The mechanism in TCM is not likemodern medicine that seeks the mechanism from cellularor molecular perspectives [80]. In light of this, to attendsimultaneously to a well-designed RCT with every possiblevariable controlled and TCM theory is extremely difficult.Future agreement on this issue warrants extensive discussion.

Although we have tried our best searching and analyzingall the eligible articles, some earlier works are not availabledue to language barriers. We were not able to level the qualityof each article as there are not many of them.We also excludesome investigations such as ones using venom acupunctureor gold thread embedding asmore information about efficacy

and mechanism may not be revealed. Some Chinese articlesdid bring about the treatment philosophy according to TCM,but it was very hard to organize and summarize well.

5. Conclusions

In our review, we concluded that acupuncture alone orcombined with other treatment modalities is beneficial to theclinical conditions of RAwithout adverse effects reported andcan improve function and quality of life and is worth trying.Several important possible mechanisms were summarizedincluding anti-inflammatory effect, antioxidative effect, andregulation of immune system function. However, there isstill inconsistency regarding the clinical efficacy and lack ofwell-designed human/animal double-blinded RCTs. Futurediscussion for further agreement on taking TCM theory intoconsideration as much as possible is a top priority.

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper.

Acknowledgments

This work is supported by research grants from ChinaMedical University, Taiwan (CMU103-S-48).

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