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Clinical Efficacy of Acupuncture on Rheumatoid Arthritis and Associated Mechanisms: A Systemic Review

Objective The objective of this review is to investigate the detailed existing scientific information about the clinical efficacy of acupuncture on rheumatoid arthritis (RA) conditions and to reveal the proposed mechanisms. Methods We searched the PubMed, EMBASE, Cochrane, AMED (Allied and Complementary Medicine), NCCAM (The National Center for Complementary and Alternative Medicine), and CNKI (China National Knowledge Infrastructure) databases to identify relevant monographs and related references from 1974 to 2018. Chinese journals and theses/dissertations were hand searched. Results 43 studies were recruited. Each research was analyzed for study design, subject characteristics, intervention, selected acupoints, assessment parameters, proposed mechanisms, and results/conclusions. Conclusions In our review, we concluded that acupuncture alone or combined with other treatment modalities is beneficial to the clinical conditions of RA without adverse effects reported and can improve 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 regarding the clinical efficacy and lack of well-designed human/animal double-blinded RCTs. Future discussion for further agreement on taking traditional Chinese medicine (TCM) theory into consideration as much as possible is a top priority.


Introduction
Rheumatoid arthritis (RA) is the most common inflammatory arthritis and has been known as a chronic and autoimmune disease involving inflammatory condition characterized with symmetrical and persistent synovitis and destructive polyarthritis [1]. RA is also associated with morbidity, chronic disability, and poor quality of life and the cost of care is huge [2,3]. The estimated prevalence of RA is 0.2-1% [4]. As many factors like susceptibility genes, disease-causing immune cells, cytokine, and signal transduction networks are involved in the pathogenesis of RA [5], the treatment of RA has always been a challenge. The mainstream of the management regarding RA is the use of nonsteroid anti-inflammatory drugs, disease-modifying antirheumatic drugs, analgesics, and biological agents [3]. But the concerns may arise when taking accompanying side effects and toxicity into consideration [6]. Given the fact of the expanding awareness of unwanted side effects of pharmaceutical treatment, there has been an increased utilization of acupuncture as a contemporary healthcare option which has been reported as a kind of safe management 2 Evidence-Based Complementary and Alternative Medicine of rheumatic patients used CAM [9]. In the United States, a small but significant linear increase in the use of acupuncture (from 1.4% in 2007 to 1.5% in 2012 of the US adults) was reported [10]. About 41% of patients with rheumatic diseases sought the help from acupuncture in Israel [11]. In Taiwan, a recent population-based study revealed the high prevalence and specific usage patterns of TCM including acupuncture in the RA patients [12]. 54.6% of the newly RA user of CAM selected acupuncture only in Korea [13].
However, discrepancy exists between previously conducted investigations and reviews regarding clinical efficacy of acupuncture for RA [14,15]. As early as in 1985, a literature analysis of the efficacy using acupuncture for RA was done by Bhatt-Sanders and no conclusion was drawn [16]. Ernst and Posadzki suggested that the evidence to support the effectiveness of CAM as a treatment option for RA has also been ambiguous [17]. On the other hand, Hughes concluded that acupuncture elicited a range of effects which contributed to improvements in RA patients' quality of life [18].
The actual mechanism by which acupuncture works also remains controversial. Among all the proposed mechanisms, anti-inflammatory effect has been the most often mentioned which was supposed to provide nonanalgesic effects via suppression of inflammatory response, improvement of blood flow, or relaxation of muscle tone, but they are still largely conjectural [19]. Others include regulating plasma adrenocorticotropic hormone, serum cortisol levels, activity of synovial nuclear factor kappa B (NF-B), and the release of endorphins [20][21][22].
In this article, we provide a descriptive and critical systemic review of the current researches available on the clinical efficacy of acupuncture for RA conditions. We analyzed the details of each investigation in terms of study designs, subject characteristics, interventions, outcome assessments, and results/conclusions. We wish to reveal the possible underlying mechanisms as well.

Material and Methods
A comprehensive search of literatures which were published from 1974 to 2018 was undertaken using the following key words: rheumatoid arthritis, rheumatism, rheumatic disease, acupuncture, electroacupuncture, laser acupuncture, traditional Chinese medicine (TCM), complementary and alternative medicine (CAM), moxibustion, therapeutic effect/efficacy, and their synonyms. These terms were used to search the following databases: PubMed, EMBASE, Cochrane, AME (Allied and Complementary Medicine), NCCAM (The National Center for Complementary and Alternative Medicine), and CNKI (China National Knowledge Infrastructure) databases. Additional articles were also identified from the reference list of identified articles. Chinese journals, theses, and dissertations that we thought might be relevant to our study were hand searched. In order to review as many investigations as possible, we reviewed any article in English or Chinese with full-text available including animal studies. There was no limitation regarding the study type. But we did exclude some articles using the following exclusion criteria: (1) interventions not involving traditional acupuncture needle insertion or electroacupuncture such as gold thread embedding or bee venom acupuncture but we kept the studies using acupoints stimulation with transcutaneous electric nerve stimulation (TENS), laser, or other herbs; (2) studies not aiming at the effect of acupuncture on RA such as reliability/validity tests for certain questionnaires; (3) study protocols not involving human or animal subjects such as expert's opinions or pure descriptive literature reviews/systemic reviews.

Results
149 studies from 1974 to 2018 were analyzed and 43 studies were recruited into the review. As there are not many researches specific for acupuncture and RA, we tried to include as many articles as possible. The study designs, subjects' characteristics and sample size, acupuncture and other intervention types, applied acupuncture points and their meridians, parameters used for comparison, proposed mechanisms, and the results/suggestions/conclusions of the researches were summarized in Table 1 classified in an order of the year when the study was done.
Liu et al. included 180 human RA subjects with peptic ulcer to investigate the efficacy of ginger-partitioned acupoint stimulation which is known to be the research with most subjects included [37]. 5 studies contained human subjects more than 100 [23,29,37,42,60]. 2 researches focused on elderly RA patients [24,50], one focused on 6 female RA patients [46], and 3 researches recruited healthy human subjects for control as well [33,34,66].
3.6. Details of Acupuncture Protocols. The details of the acupuncture protocol are summarized in Table 1. The following describes the detailed items summarized in the table: (1) Intervention type: traditional acupuncture with different manual techniques, laser acupuncture, electroacupuncture, buccal acupuncture, auricular electroacupuncture, warm needling with or without moxibustion, and acupoint stimulation with herbs.
(2) Modalities used for control or combined therapy: oral or injected form of Western medication, reflexology, moxibustion, 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 period of each research summarized in detail as shown in Table 1.
Wang et al. used the same acupuncture protocol but compared the treatment efficacy for 3 and 6 courses [53].

Primary Outcomes.
Most primary outcome assessments are associated with clinical RA symptoms (pain, morning stiffness, and so forth) and RA symptoms related scales such as pain threshold, visual analogue scale (VAS), pain disability index (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 of Rheumatology 20 (ACR 20, i.e., 20% of clinical improving rate), ACR 50, and ACR 70.
Parameters specifically used for animals include swelling volume of the joints, limb diameter, and number of swollen joints, arthritis index, skin temperature, and weight.
There are many questionnaires applied in each domain specifically for human RA subjects including quality of life such as the rheumatoid arthritis quality of life questionnaire (RAQoL), health assessment questionnaire (HAQ), short form-36 health survey (SF36), the Pittsburgh sleep quality index, depression, anxiety, and stress scale and face scale for mood, and modified health assessment questionnaire (MHAQ). Table 1 has the details of each assessment tool used in each study.

Special Imaging Tools.
One study employed positronemission tomography (PET) scan to detect the regional improvement of inflammation [46] and another study used X-ray of hands for before-after treatment comparison [63].
Please refer to Table 1 for more details.

Proposed
Mechanisms. Not every investigation proposed the possible mechanisms of how acupuncture works on the RA condition. Proposed mechanisms could be summarized as the following categories.  [24]. Specific regulation of the Krebs cycle (also known as the tricarboxylic acid cycle) and glycometabolism were also mentioned in the work of Du et al. [27]. Du et al. suggested the role of biological heat production by acupuncture [33]. For most researches in Chinese, the authors selected the treatment protocol and acupoints according to the TCM theory.

Clinical Efficacy.
Almost every investigation found that any kind of acupuncture as the main treatment or adjuvant treatment tool could benefit clinical conditions of RA in human or animal subjects except one [62]. There were no adverse effects of acupuncture reported.

Discussion
RA has been regarded as a chronic inflammatory condition with various clinical manifestations and some of them could cause serious disabilities and handicaps. Clinicians have been working very hard to suspend the devastating disease progression and deal with the symptoms as well as the impaired function and accompanying stress and cost. However, the actual pathogenesis of rheumatoid arthritis remains incompletely understood. Previous researches have shed light into the cellular and molecular mechanisms and from that base modern Western medications have derived [3]. Contemporary use of medication is linked with the concern of adverse effect and may limit the compliance such as the case of methotrexate (MTX) [67]. An estimated 60-90% of arthritis patients are reported to use CAM including acupuncture [68]. There have been several reviews concerning the clinical efficacy of CAM on rheumatic diseases [8,9,17,[69][70][71][72] but the latest review specifically focused on the efficacy of acupuncture for RA conditions was conducted in 2008 [14,15].
Seca et al. suggested a protocol for systemic review focused on pain, physical function, and quality of life but will exclude animal studies and has not been completed [73]. To our knowledge, the present review is the most comprehensive one covering studies from 1974-2018 including human and animal studies and with discussion of the details of study designs, interventions, parameters used for comparison, and the possible proposed mechanisms as well as results and conclusions.
When taking study design into consideration, TCM theory was adapted substantially in most of the investigations. TCM represents the most significant component of complementary and alternative medicine [74]. According to the TCM theory, patients who suffer from the same disease may present different TCM syndrome patterns that also correspond to different biological processes and are associated with different related biomarkers [75]. Lu et al. indicated that RA patients may be divided into cold and heat pattern and they have different molecular signature processes and react differently to certain treatment [76], so theoretically RA patients may be treated by acupuncture without unanimous acupoints according to their TCM syndrome differentiation. These facts have led to obstacles when trying to conduct contemporary researches which critics may face in terms of methodology. Double-blinded RCT is thought to be the most optimal study design to establish scientific evidence, but acupoints selection by TCM theory would experience difficulties which may be the reason of the existing discrepancies between studies of human subjects. In addition, it is also difficult to classify animals into appropriate TCM syndrome categories like human. Another question is the standard localization of acupoints in animals and the correlation and difference between different species. A RA animal model is often established in animal studies by injection of substance such as bovine collagen [26], Freund's adjuvant [32], or ovalbumin and extra freezing process to imitate the cold syndrome as classified in TCM [27], the disease progression may not be the same in real RA patients, and most of the investigations did not have adequate 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 made the conclusions drawn less practical and applicable for RA patients. But Jie et al. used buccal acupuncture and found that central analgesic effect with upregulation of endorphin and CCK-8 in cerebrospinal fluid could be observed with needle retaining for 30 minutes in RA rabbits; this is the shortest observation but with good results [25].
We found an interesting fact that acupoint ST36 was used in almost every research and followed by GB34 and LI4. According to TCM theory, RA should fit the disease condition called "Bi" or impediment disease, which means any disease pattern that results from blockage of the meridians occurring when wind, cold, and dampness invade the fleshy exterior and the joints, and that manifests in symptoms such as joint pain, sinew and bone pain, and heaviness or numbness of the limbs as stated in Elementary Questions (Su Wen, bi lun). Distinction is made between three pattern types, each of which corresponds to a prevalence of one of those three evils: wind impediment (or moving impediment) characterized by wandering pain and attributed to a prevalence of wind; cold impediment (or painful impediment) characterized by acute pain and attributed to a prevalence of cold; damp impediment (or fixed impediment) characterized by heaviness and attributed to a prevalence of dampness. A fourth type, heat impediment, arises when the three evils transform into heat. The basic philosophy of how all the acupoints were selected derived from the above theory. As a result, the number of acupoints used seems not to affect the clinical efficacy.
Measurements of quality of life domain have gained more interest among RA patients than other disease-related parameters such as inflammatory biomarkers or joint counts [77]. In this review, some studies have adopted related questionnaires [24,30,36,37,46,62] and acupuncture was able to improve the quality of life except in one study [62].
Anti-inflammatory effect has been the most well-known mechanism of how acupuncture works for RA as many studies in this review used inflammatory biomarkers for comparison such as ESR, CRP, RF, IL, NF-B, and TNF-. Most of the studies comparing these biomarkers indicated the anti-inflammatory effect of acupuncture [22-24, 26, 31, 32, 37-39, 41, 43, 44, 50-55, 58, 59, 66]. Wang et al. indicated the reduction of ESR and CRP after acupuncture in RA subjects in their review as well [15]. Han et al. thought that acupuncture can lower TNF-and VEGF in peripheral blood and joint synovia to improve the internal environment which is beneficial for RA [41]. 18 Evidence-Based Complementary and Alternative Medicine Dong et al. indicated that toll-like receptor (TLR) signaling pathway contributed to the development and progression of RA and acupuncture could reduce the expression of TLR4, thus leading to anti-inflammation [31]. However, some authors did find clinical effect but not via anti-inflammation [46,49]. Efthimiou and Kukar indicated that even though no clear anti-inflammatory effect has been demonstrated, acupuncture may still be a useful adjuvant for pain [70]. In our review, we think anti-inflammatory effect acts in certain occasion to improve the RA conditions.
Another possible mechanisms could be attributed to the antioxidative effect (such as inducing the increased activities of SOD and catalase in the serum of RA, alleviating oxidative stress and inflammation, and improving antioxidant and energy metabolic status) [33,34,47] and triggered release of endorphins [25] and regulation of immune function as IgG, IgA, and IgM decreased, while IgE did not change evidently after acupuncture in 12 RA patients [23,32,[64][65][66].
Forestier et al. concluded in 2009 the evidence level of acupuncture for RA is limited to professional agreement with no scientific evidence [78]. Along with other inconclusive information regarding the clinical efficacy [54,72], welldesigned RCTs are warranted [79]. Most animal studies lack the consistency in establishing the RA model such as the standard injected substance, the dosage, the injected site, the duration of observation after injection, the treatment protocol including acupoints selection, animal acupuncture localization standard, TCM syndrome differentiation, the period of follow-up, and assessment parameters. As for human study, the most important thing is to decide if treatment protocol should vary according to TCM differentiation. Although different mechanism leads to different study design in terms of the parameters that will be assessed, efforts should be put on the standardization and it should be thought whether other methods like functional imaging test would be appropriate.
Acupuncture has its root in TCM and traditionally TCM has one distinguished character; that is, it does not completely seek the specific pathogen and pathological changes in a specific organ or individual, but it seeks the disturbances among the self-controlled systems by analyzing all symptoms and signs. The TCM intervention is based on the differentiation of symptoms to clarify what is wrong in the self-controlled system. TCM seeks the therapeutic mechanism from the integrity and balance, in each individual and between the individual and the environment. The therapeutics work by activating and improving system connection and enhancing human resistance. The mechanism in TCM is not like modern medicine that seeks the mechanism from cellular or molecular perspectives [80]. In light of this, to attend simultaneously to a well-designed RCT with every possible variable controlled and TCM theory is extremely difficult. Future agreement on this issue warrants extensive discussion.
Although we have tried our best searching and analyzing all the eligible articles, some earlier works are not available due to language barriers. We were not able to level the quality of each article as there are not many of them. We also exclude some investigations such as ones using venom acupuncture or gold thread embedding as more information about efficacy and mechanism may not be revealed. Some Chinese articles did bring about the treatment philosophy according to TCM, but it was very hard to organize and summarize well.

Conclusions
In our review, we concluded that acupuncture alone or combined with other treatment modalities is beneficial to the clinical conditions of RA without adverse effects reported and can improve 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 regarding the clinical efficacy and lack of well-designed human/animal double-blinded RCTs. Future discussion for further agreement on taking TCM theory into consideration as much as possible is a top priority.

Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this paper.