**2.1.1 Placebo-controlled trials**

352 Rheumatoid Arthritis – Treatment

Acupuncture, originating in China more than 3,000 years ago, is one of the most popular sensory stimulation therapies. It is an ancient technique of inserting and manipulating fine needles to stimulate specific anatomic points, also known as acupuncture points or meridian points. There have been extensive investigations into the biological mechanisms of acupuncture (Cho et al., 1998; Darras et al., 1992; Dhond et al., 2008; Gao et al., 1997; Han & Terenius, 1982; Han, 1997; Harris et al., 2009; Hui et al., 2000; Hui et al., 2005; Kaptchuk, 2002; Kovacs et al., 1992; Langevin et al., 2001a; Langevin et al., 2001b; Langevin et al., 2007; Li et al., 2007; Napadow et al., 2005; Napadow et al., 2007; Napadow et al., 2008; Pariente et al., 2005; Wu et al., 1999; Zhang et al., 2005). Some of the best evidence is in relation to treatment of pain. Three previous systematic reviews examined the efficacy of acupuncture in patients with rheumatoid arthritis and reported that acupuncture has conflicting evidence for treatment of RA in the placebo-controlled trials (Casimiro et al., 2005; Lee et al., 2008; Wang et al., 2008a). Another narrative review examined 63 Chinese studies with a variation of acupuncture therapies in patients with rheumatoid arthritis and concluded that acupuncture is helpful for rheumatoid arthritis (Suzuki et al., 2005). However, in addition to the complexities revealed by an evaluation of this sort of intervention, many of these prior studies have methodological concerns that limit their interpretation. Therefore, this section performs an updated review of all currently available data, including Chinese publications.

Explanatory mechanisms from eastern and western biological theory provide a supposed rationale for the effectiveness of acupuncture to treat the chronic inflammatory nature of rheumatoid arthritis (Han et al., 1986; Han, 2004; Wang et al., 1985; Zijlstra et al., 2003). Considerable evidence has shown that acupuncture analgesia may be imitated by stimulation of nerves, which, in turn, trigger endogenous opioid mechanisms. Recent functional magnetic resonance imaging studies also demonstrated that acupuncture has regionally specific, quantifiable effects on relevant structures of the human brain (Hsieh et al., 2001; Hui et al., 2000; Napadow et al., 2005; Pariente et al., 2005; Wu et al., 1999; Yoo et al., 2004). However, clinical research into the effects of acupuncture on chronic pain is challenged by methodological concerns, including finding appropriate inactive controls. For example, the larger literature on clinical trials of acupuncture on pain has failed to show a significant improvement over sham acupuncture (Brinkhaus et al., 2006; Linde et al., 2006; Melchart et al., 2005). Indeed, there are troublesome findings of non-superiority of

To update the current clinical evidence regarding the effects of acupuncture on rheumatoid arthritis, a comprehensive search of 10 western and Chinese databases and reference lists was performed based on our previous work (Wang et al., 2008a). The review included clinical trials with pain as an endpoint being measured by tender joint count or a pain scale. The effects of acupuncture on morning stiffness, erythrocyte sedimentation rate and Creactive protein were also reported. Nine studies met eligibility criteria with a total of 597 subjects. There were 4 placebo-controlled trials and 5 active-controlled trials (**Table 1**). The average study duration was 11 weeks. Mean (SD) numbers of acupuncture points and sessions were 11 (8) and 42 (62), respectively. The average duration of needle insertion was 24 minutes. Eight trials used traditional acupuncture (TA) (Cui et al., 2001; David et al.,

**2. Acupuncture for rheumatoid arthritis** 

**2.1 Acupuncture therapeutics** 

**2.2 Clinical evidence** 

acupuncture over shams.

The four placebo-controlled trials involved 160 participants. Of those, two had optimal quality and two had moderate quality (David et al., 1999; Man & Baragar, 1974; Tam et al., 2007; Zanette Sde et al., 2008). Two high quality double-blind randomized, placebocontrolled trials and two moderate quality trials evaluated the effects of either traditional or electroacupuncture versus sham acupuncture. Tam et al (2007) conducted a trial in Hong Kong among 36 patients with RA and a disease duration of 9.3 years. Patients were randomly assigned to three groups: traditional acupuncture (TA), electroacupuncture (EA), and sham acupuncture (placebo needles). Patients received a total of 20 sessions for 10 weeks using six acupuncture points. The authors found that tender joint count improved for both EA and TA groups compared with the control group (tender joint count 5.5 vs. 0.5, p<0.05 and tender joint count 4 vs. 0.5, p<0.05, respectively). Physician's global score significantly improved for the EA group while patient's global score significantly improved for the TA group. Of note, the pain score remained unchanged in all three groups. The ACR core disease measures and DAS 28 score were not achieved at week 10.

In a contemporaneous high quality study conducted by Zanette Sde et al (2008), 40 patients with long-standing RA were randomized to traditional acupuncture or a control group using superficial acupuncture at non-acupuncture points. All participants received a total of 10 sessions, twice a week for five consecutive weeks. Tender joint count improved for the TA group compared with the control group (tender joint count 8.35 vs. 2.45, p=0.145). There was no significant difference between groups regarding ACR 20 improvement criteria (primary outcome) after the 5th and 10th sessions. At the last visit, there was a trend in favor of the acupuncture intervention compared with the control group (40% vs. 10% of each group achieved ACR20 criteria, p=0.07, respectively). In addition, there was a significant difference favoring the TA group on physician's global assessment of the treatment (p=0.012), and patient's (p=0.003) and physician's global assessment of disease activity (p=0.011), but there was no difference for other endpoints. The authors concluded that the negative result could be related to the small sample size, selection of patients, type of acupuncture protocol applied, and difficulties in establishing an appropriate control group.

A double-blind randomized placebo-controlled trial conducted by David et al (1999) used a six-week crossover design comparing traditional acupuncture with sham acupuncture in 64 patients. There was a total of five weekly sessions. After a washout period of six weeks, participants were crossed-over into the other intervention arm (acupuncture or control) for an additional five weeks. The tender joint count, swollen joints count, pain scale, patient's and physician's global assessments, modified DAS, ESR, and C-reactive protein were assessed at baseline and at the end of both intervention periods. The authors found no

Complementary and Alternative Medicine in the Treatment of Rheumatoid Arthritis 355

2003; Zanette Sde et al., 2008; Zhou & Zhu, 2000); but only 1 study showed a significant difference for both erythrocyte sedimentation rate and C-reactive protein (Jiang & Fan,

Three decades worth of cumulative literature on acupuncture for the treatment of RA have been evaluated in both Chinese and western populations. Despite some favorable results in one placebo-controlled and 5 active-controlled trials, conflicting evidence remains regarding the efficacy of acupuncture for RA in the placebo-controlled trials. While an early RCT reported that compared to sham, 1 EA session significantly improved knee pain in 20 patients with seropositive RA (Man & Baragar, 1974), a later randomized crossover study with 56 patients with RA reported no significant differences between traditional and sham acupuncture in pain relief or inflammation (David et al., 1999). A recent systematic review which utilized these two trials in their analysis concluded that the evidence was limited due to methodological considerations, such as the type of acupuncture (acupuncture vs. electroacupuncture), the site of intervention and the small sample size of the studies

All five active comparator trials published in China concluded that acupuncture treatment was associated with a significant decrease in tender joint count and was effective in relieving other symptoms of RA compared with controls. However, the methodological limitations of the Chinese studies included inappropriate control interventions (non-comparable), no doubleblind interventions, inadequate description of the randomization process, and scarce use of validated outcome measures. The Chinese studies also used active drugs in place of placebo

Accurate quantitative estimates of treatment effects were not obtained due to the heterogeneity of the studies, as well as differences in acupuncture interventions, including dose/intensity and treatment duration. For instance, the number of acupuncture points ranged from 1 to 24, the duration of needle insertion ranged from 4 to 40 minutes, and the number of sessions varied from 1 to 180**.** The time elapsed between sessions also

For all these reasons, the evidence for the efficacy of acupuncture for pain relief in RA is modest and uncertain. Furthermore, the long-term benefits remain unknown. Because it is difficult to compare such divergent trials and there is a lack of standardized treatment protocols, future studies should focus on the optimum dose for acupuncture therapy in persons with RA, such as effective evidence-based dose/intensity , and number of acupuncture points, duration of needle insertion, frequency of acupuncture sessions, and intervention duration. It is possible that some studies, while designed correctly from a western scientific approach, do not have the correct Chinese medical approach (i.e. inappropriate dose/intensity and duration of acupuncture, insufficient expertise of acupuncturist leading to inappropriate needle insertion and manipulation techniques, or inappropriate acupuncture point selection by a standardized protocol that may neglect the individualized Chinese medical diagnosis). These reasons might explain why no specific

This comprehensive review of acupuncture for rheumatoid arthritis illustrates the need for methodologically rigorous acupuncture study designs that adhere to both the high standards of western scientific randomized controlled trials and accommodate the correct Chinese medical approach. Further research is needed to understand the effects of acupuncture on RA and how patients may or may not benefit from its inclusion in their

acupuncture, which makes comparisons across studies difficult.

2003).

fluctuated.

treatment.

included (Casimiro et al., 2005).

effects were observed in western studies.

significant differences between the intervention and control groups for any of the endpoints at the end of both intervention periods and at the follow-up assessment.

An early RCT conducted by Man & Baragar (1974) used a parallel design among 20 participants with seropositive RA. Patients were randomly assigned to either electroacupuncture or control groups. The pain was assessed with a pain scale ranging from 0 to 4 at 24 hours after treatment. The authors reported that EA had a significant moderate and marked decrease in knee pain for 80% of the participants (60% and 20%, respectively) compared with no pain reduction in the control group. At three months, 70% of the participants in the EA group reported a significant minimal or moderate decrease in pain compared with no pain reduction in the control group. However, as no baseline data was reported, we estimated the following percentage improvements on the pain scale from the published figure (51% and 23%, at 24 hours and 3 months, respectively) for the EA group compared with no change in the control group (Man & Baragar, 1974).

#### **2.1.2 Active-controlled trials**

Since 2000, five active drug-controlled Chinese studies of modest quality have been conducted in China and include 468 subjects (Cui et al., 2001; Jiang & Fan, 2003; Liu et al., 2003; Wang, 2002; Zhou & Zhu, 2000). The mean study duration was 7 weeks, with 14 to 180 sessions. The number of acupuncture points varied from 8 to 24. In the control groups, two studies used indomethacin (25 mg tid for 4 weeks) (Jiang & Fan, 2003; Zhou & Zhu, 2000), one study used indomethacin (50 mg tid) plus triptolide (20 mg tid) for three weeks (Wang, 2002), one study used methotrexate (5 mg/week 1, 10 mg/week 2, 15 mg/week 3) and diclofenac (20 mg bid for 3 months) (Liu et al., 2003), and one study compared acupuncture with topical Votalin ointment (bid) (Cui et al., 2001), which may be considered as an NSAID. All five Chinese publications consistently reported that acupuncture treatment was associated with a significant decrease in pain (tender joint count mean change: -3.9) compared with controls. Three studies reported a significant reduction in morning stiffness (mean change: - 29 minutes) compared with controls (Jiang & Fan, 2003; Liu et al., 2003; Zhou & Zhu, 2000). In addition, three studies observed a reduction in ESR (mean change: - 5.5 mm/hour) (Jiang & Fan, 2003; Liu et al., 2003; Zhou & Zhu, 2000) and 2 noted a Creactive protein reduction (mean change: -3.0 mg/dl) (Jiang & Fan, 2003; Zhou & Zhu, 2000), but only one showed a significant difference for ESR and C-reactive protein (Jiang & Fan, 2003). No dropouts were reported**.** Although these trials concluded that acupuncture was effective in relieving symptoms of RA, the long-term benefits remain unknown.

#### **2.1.3 Summary of clinical evidence**

Collectively, seven studies reported a decrease in pain for acupuncture compared with controls, and five showed a statistically significant improvement (Cui et al., 2001; Jiang & Fan, 2003; Liu et al., 2003; Tam et al., 2007; Zhou & Zhu, 2000). Compared with controls, the mean or median changes of acupuncture-decreased tender joint count pain ranged from 1.5 to 6.5. In addition, four studies reported a significant reduction in morning stiffness (mean change -29 minutes) but the difference was non-significant compared with controls (Jiang & Fan, 2003; Liu et al., 2003; Zanette Sde et al., 2008; Zhou & Zhu, 2000). With regards to inflammatory markers, five studies observed a reduction in ESR (mean –3.9 mm/hour) (Jiang & Fan, 2003; Liu et al., 2003; Tam et al., 2007; Zanette Sde et al., 2008; Zhou & Zhu, 2000) and three noted a reduction in C-reactive protein (mean -2.9 mg/dl**)** (Jiang & Fan,

significant differences between the intervention and control groups for any of the endpoints

An early RCT conducted by Man & Baragar (1974) used a parallel design among 20 participants with seropositive RA. Patients were randomly assigned to either electroacupuncture or control groups. The pain was assessed with a pain scale ranging from 0 to 4 at 24 hours after treatment. The authors reported that EA had a significant moderate and marked decrease in knee pain for 80% of the participants (60% and 20%, respectively) compared with no pain reduction in the control group. At three months, 70% of the participants in the EA group reported a significant minimal or moderate decrease in pain compared with no pain reduction in the control group. However, as no baseline data was reported, we estimated the following percentage improvements on the pain scale from the published figure (51% and 23%, at 24 hours and 3 months, respectively) for the EA group

Since 2000, five active drug-controlled Chinese studies of modest quality have been conducted in China and include 468 subjects (Cui et al., 2001; Jiang & Fan, 2003; Liu et al., 2003; Wang, 2002; Zhou & Zhu, 2000). The mean study duration was 7 weeks, with 14 to 180 sessions. The number of acupuncture points varied from 8 to 24. In the control groups, two studies used indomethacin (25 mg tid for 4 weeks) (Jiang & Fan, 2003; Zhou & Zhu, 2000), one study used indomethacin (50 mg tid) plus triptolide (20 mg tid) for three weeks (Wang, 2002), one study used methotrexate (5 mg/week 1, 10 mg/week 2, 15 mg/week 3) and diclofenac (20 mg bid for 3 months) (Liu et al., 2003), and one study compared acupuncture with topical Votalin ointment (bid) (Cui et al., 2001), which may be considered as an NSAID. All five Chinese publications consistently reported that acupuncture treatment was associated with a significant decrease in pain (tender joint count mean change: -3.9) compared with controls. Three studies reported a significant reduction in morning stiffness (mean change: - 29 minutes) compared with controls (Jiang & Fan, 2003; Liu et al., 2003; Zhou & Zhu, 2000). In addition, three studies observed a reduction in ESR (mean change: - 5.5 mm/hour) (Jiang & Fan, 2003; Liu et al., 2003; Zhou & Zhu, 2000) and 2 noted a Creactive protein reduction (mean change: -3.0 mg/dl) (Jiang & Fan, 2003; Zhou & Zhu, 2000), but only one showed a significant difference for ESR and C-reactive protein (Jiang & Fan, 2003). No dropouts were reported**.** Although these trials concluded that acupuncture was

at the end of both intervention periods and at the follow-up assessment.

compared with no change in the control group (Man & Baragar, 1974).

effective in relieving symptoms of RA, the long-term benefits remain unknown.

Collectively, seven studies reported a decrease in pain for acupuncture compared with controls, and five showed a statistically significant improvement (Cui et al., 2001; Jiang & Fan, 2003; Liu et al., 2003; Tam et al., 2007; Zhou & Zhu, 2000). Compared with controls, the mean or median changes of acupuncture-decreased tender joint count pain ranged from 1.5 to 6.5. In addition, four studies reported a significant reduction in morning stiffness (mean change -29 minutes) but the difference was non-significant compared with controls (Jiang & Fan, 2003; Liu et al., 2003; Zanette Sde et al., 2008; Zhou & Zhu, 2000). With regards to inflammatory markers, five studies observed a reduction in ESR (mean –3.9 mm/hour) (Jiang & Fan, 2003; Liu et al., 2003; Tam et al., 2007; Zanette Sde et al., 2008; Zhou & Zhu, 2000) and three noted a reduction in C-reactive protein (mean -2.9 mg/dl**)** (Jiang & Fan,

**2.1.2 Active-controlled trials** 

**2.1.3 Summary of clinical evidence** 

2003; Zanette Sde et al., 2008; Zhou & Zhu, 2000); but only 1 study showed a significant difference for both erythrocyte sedimentation rate and C-reactive protein (Jiang & Fan, 2003).

Three decades worth of cumulative literature on acupuncture for the treatment of RA have been evaluated in both Chinese and western populations. Despite some favorable results in one placebo-controlled and 5 active-controlled trials, conflicting evidence remains regarding the efficacy of acupuncture for RA in the placebo-controlled trials. While an early RCT reported that compared to sham, 1 EA session significantly improved knee pain in 20 patients with seropositive RA (Man & Baragar, 1974), a later randomized crossover study with 56 patients with RA reported no significant differences between traditional and sham acupuncture in pain relief or inflammation (David et al., 1999). A recent systematic review which utilized these two trials in their analysis concluded that the evidence was limited due to methodological considerations, such as the type of acupuncture (acupuncture vs. electroacupuncture), the site of intervention and the small sample size of the studies included (Casimiro et al., 2005).

All five active comparator trials published in China concluded that acupuncture treatment was associated with a significant decrease in tender joint count and was effective in relieving other symptoms of RA compared with controls. However, the methodological limitations of the Chinese studies included inappropriate control interventions (non-comparable), no doubleblind interventions, inadequate description of the randomization process, and scarce use of validated outcome measures. The Chinese studies also used active drugs in place of placebo acupuncture, which makes comparisons across studies difficult.

Accurate quantitative estimates of treatment effects were not obtained due to the heterogeneity of the studies, as well as differences in acupuncture interventions, including dose/intensity and treatment duration. For instance, the number of acupuncture points ranged from 1 to 24, the duration of needle insertion ranged from 4 to 40 minutes, and the number of sessions varied from 1 to 180**.** The time elapsed between sessions also fluctuated.

For all these reasons, the evidence for the efficacy of acupuncture for pain relief in RA is modest and uncertain. Furthermore, the long-term benefits remain unknown. Because it is difficult to compare such divergent trials and there is a lack of standardized treatment protocols, future studies should focus on the optimum dose for acupuncture therapy in persons with RA, such as effective evidence-based dose/intensity , and number of acupuncture points, duration of needle insertion, frequency of acupuncture sessions, and intervention duration. It is possible that some studies, while designed correctly from a western scientific approach, do not have the correct Chinese medical approach (i.e. inappropriate dose/intensity and duration of acupuncture, insufficient expertise of acupuncturist leading to inappropriate needle insertion and manipulation techniques, or inappropriate acupuncture point selection by a standardized protocol that may neglect the individualized Chinese medical diagnosis). These reasons might explain why no specific effects were observed in western studies.

This comprehensive review of acupuncture for rheumatoid arthritis illustrates the need for methodologically rigorous acupuncture study designs that adhere to both the high standards of western scientific randomized controlled trials and accommodate the correct Chinese medical approach. Further research is needed to understand the effects of acupuncture on RA and how patients may or may not benefit from its inclusion in their treatment.

Complementary and Alternative Medicine in the Treatment of Rheumatoid Arthritis 357

Needle insertion time: 30 min

TA

TA

TA

Needle insertion time: 40 min

Abbreviations: EA= electro acupuncture; TA= traditional acupuncture; ND= No data; RA=Rheumatoid

aMean or median difference or improvement was calculated between groups and confidence interval cannot be calculated from published data. b Votalin ointment components not reported.\*Sham

acupuncture: needles inserted up to 2 mm, shorter insertion duration, and minimal needle stimulation.

In the past two decades, the literature has consistently recognized the potential therapeutic benefits of Tai Chi mind-body exercise. Significant improvements have been reported in balance, strength, flexibility, cardiovascular and respiratory function, mood, depression and anxiety, self-efficacy, pain reduction and health-related quality of life in diverse eastern and western populations for a variety of chronic conditions (Wang et al., 2004). Several recent reviews have further suggested that Tai Chi appears to improve a variety of medical conditions (Adler & Roberts, 2006; Jahnke et al., 2010; Rogers et al., 2009; Wang et al., 2010a;

Tai Chi, a traditional Chinese mind-body exercise, has grown in popularity in the United States. According to the 2007 National Health Interview Survey, around 2.5 million

Table 1. Randomized Controlled Trials Evaluating the Effect of Acupuncture on RA

Needle insertion time: 30 min

Needle insertion time: 20- 30min

(14 sessions)

(90 sessions)

(15 sessions)

Indomethacin (50 mg tid) plus triptolide (20 mg tid)

Votalin ointment (bid)b

Indomethacin (25 mg tid)

3

12

4

**3. Mind-body therapy for rheumatoid arthritis** 

**3.1 Tai Chi mind-body therapeutics** 

Difference between groups: 4.5

Significant improvement of total effective rate

TA: 8.3 Control group:

TA: 7.1

Difference between groups: 1.5

Control group: 4.0 Difference between groups: 3.1

6.8

mean disease

Wang, 2002 China

Cui, 2001 China

Zhou, 2000 China

arthritis;

\*\*Median difference.

Yeh et al., 2009).

duration 4.5 years. N= 60 Age=45

RA with mean disease duration

Functional class 1 and 2 patients with RA, with mean disease duration 3 years

N= 45 Age=18-65

10 years. N= 61 Age=ND

RA (1987 ACR criteria and no data for disease duration. N= 60 Age=ND


**Placebo-controlled Randomized Controlled Trials** 

TA

TA

EA (3 AP/ 1 session)

Needle insertion time: 15 min

**Randomized Controlled Trials Compared to Active Comparators** 

Needle insertion time: 30 min

(180 sessions)

(15 sessions) Indomethacin

TA

TA

Needle insertion time: 20 min

(10 sessions)

(5 sessions)

Needle insertion time: 4 min

Group 1: EA Group 2: TA (20 sessions) Needle insertion time: 30 min

10

9

22

16

12

4

**(weeks) Acupuncture Control\* Findings a** 

Sham acupuncture Placebo needles (20 sessions)

Superficial acupuncture at

acupuncture points (10 sessions)

non-

Placebo needles ( 5 sessions)

Placebo needles (1 session)

Methotrexate IM injection - week 1: 5 mg - week 2: 10 mg - week 3: 15 mg + Diclofenac (20 mg/day)

(25 mg tid)

EA: 5.5 TA: 4

0.5

5.0

3.5

2.45

TA: 8.35 Control group:

Control group:

TA vs. control:

Difference between groups: 5.9

Treatment effect: ↑ 0.5 (-1, 1.5)\*\*

EA (24h): 51% improvement EA (3 months): 23% improvement Control group: 0% improvement in pain scale (0-4)

TA: 16.6 Control group:

TA: 5.1

Difference between groups: 6.5

Control group: +

10.1

0.6

Difference between groups at week 10: EA vs. control:

**Ref. RA Patients Duration** 

Active RA, mean disease duration

RA for at least 6 months with stable drug treatment for at least 1 month

N= 40 Age>50

RA, mean disease duration

10 years.

Patients with seropositive RA for ≥ 5 years, for whom bilateral knee pain was a major problem

RA with mean disease duration 3.6 years. N= 240 Age=42

Functional class 1 and 2 patients with RA with

N= 64 Age=18-75

N= 64 Age=18-75

9.3 years

N= 36 Age= 58

Tam, 2007 Hong Kong

Zanette Sde, 2007 Brazil

David, 1999 UK

Man, 1974 Canada

Liu, 2003 China

Jiang, 2003 China


Abbreviations: EA= electro acupuncture; TA= traditional acupuncture; ND= No data; RA=Rheumatoid arthritis;

aMean or median difference or improvement was calculated between groups and confidence interval cannot be calculated from published data. b Votalin ointment components not reported.\*Sham acupuncture: needles inserted up to 2 mm, shorter insertion duration, and minimal needle stimulation. \*\*Median difference.

Table 1. Randomized Controlled Trials Evaluating the Effect of Acupuncture on RA
