Introduction

Rheumatoid arthritis (RA) is an immune-related disease that affects 1% population in the world and associated with severe morbidity, functional impairment, permanent disability and increased mortality. As to its therapy, disease-modifying anti-rheumatic drugs (DMARDs) are most commonly used [1, 2]. While because of the limited success of DMARDs in the prevention of RA development and the potential risk for infection, malignancies and autoantibody production, the exploration of new anti-rheumatic drugs with high efficacy and less toxicity are eagerly needed. Furthermore, the adjuvant effects of alternative and complementary therapies have been proved. Now it has become the mainstream for RA therapy combining drug administration with adjuvant therapies. As to this point, we believed that the traditional Chinese medicine (TCM) which mainly includes Chinese herbs, acupuncture and massage is another new approach for the treatment of RA. Thus, it is helpful to review the current research status about the treatment of RA using TCM. In detail, PubMed search on ‘traditional chinese medicine AND rheumatoid arthritis’, ‘chinese herbs AND rheumatoid arthritis’, ‘acupuncture AND rheumatoid arthritis’, ‘massage AND rheumatoid arthritis’ with the link of ‘clinical queries’ or not were collected and analyzed. The papers closely related to our topic were enclosed and cited.

The etiology of RA in TCM theory

In the view of modern medicine, RA is regarded as one of the immune-mediated diseases for which an understanding of the etiology is dependent on the definition of environmental triggers that may initiate immune reactions and having the potential to contribute to disease development. Whereas in the theory of TCM, three main factors contribute to the origination of RA are defined as ‘Wind (feng)’, ‘Damp (shi)’and ‘Cold (han)’ [3] (Fig. 1). ‘Wind’ refers to the sudden onset of the disease, mobility of the affected site, variability of the manifestation of symptoms and sensitivity to changes in the environment. Wind-dominant arthralgia most occurs in the early stage of RA and affects the upper body. ‘Damp’ mainly relates to the weather. Wading in water or sleeping on damp ground can initiate and worsen the symptoms because of the wet environment. ‘Cold’ refers to the worsening of symptoms with exposure to cold, which could be improved by applying heat. Cold-dominated arthritis prominently affects the extremities such as hands and feet. In these areas circulation is poor and easily yielding a cold syndrome. All of these three factors are related to weather which in accordance to the ideas about the origination of RA in modern rheumatology [4].

Fig. 1
figure 1

The pathological process of RA based on the traditional Chinese medicine theory

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Chinese herbs and RA

In the ancient past of China, formulas are most commonly used in the management of RA. Now, many Chinese herbs recorded effective in the therapy of RA have been analyzed and the related mechanisms have been further detected. In the following illustration, Tripterygium wilfordii Hook-F (TWHF) was exemplified to illustrate the anti-rheumatic effect of Chinese herbs.

TWHF is one of the most popularly used herbs in Chinese formulas for RA treatment. Commonly, water extract is used in form of formulas, while ethyl acetate and chloroform–methanol extract are preferred to avoid its serious side effects and reduce its toxicity [5, 6]. Besides formulas, new forms of the effective ingredients such as capsules and powders have been available in market and have become the mainstream in China (Fig. 2). It is well known that diterpenoid, triptolide, tripdiolide, triptonide and triptophenolide in the TWHF are the main ingredients that contribute to its anti-rheumatic function. Triptolide has been shown to suppress inflammation and cartilage destruction in collagen-induced arthritis (CIA) mice [7]. Furthermore, apoptosis of rheumatoid synovial fibroblasts was found after triptolide treatment [8]. The inhibition of inflammatory cytokines (or proteins) such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-17 (IL-17), cycloxygenase-2 (COX-2), matrix metalloproteinases-3 (MMP-3), matrix metalloproteinases-13 (MMP-13) were observed after TWHF administration [9, 10]. Furthermore, the existence of other approaches which may contribute to the anti-inflammatory function of TWHF was proved. For example, iNOS gene expression which resulted from the down-regulating of NF-κB DNA-binding activity and JNK pathway was observed after triptolide treatment [11]. Besides the above, down-regulated expression of adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were seen [12]. Overall, most aspects of RA pathological development were ameliorated due to the multi-targeted function of TWHF or its active ingredients. However, complications co-existed in the clinical application of TWHF which were mainly expressed as skin rashes, cheilosis, diarrhea, amenorrhea and myelosuppression [13, 14]. Besides TWHF, many other Chinese herbs such as Stephania tetrandra S Moore, cat’s claw, etc. are normally used in clinic (Table 1).The new drug exploration in Chinese herbs may even enrich the family of DMARDs.

Fig. 2
figure 2

The research mode of Chinese herbs. All of these three types of anti-rheumatic drugs have been used in the treatment of RA and the active ingredient products will be the final destination

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Table 1 The summary of Chinese herbs mainly used for the treatment of RA
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Acupuncture and RA

When acupuncture is performed, thin needles are inserted in specific documented points believed to represent concentration of body energies. It based on the theory that an essential life energy called ‘qi’ flows through the body along invisible channels, called ‘meridians’. According to TCM theory, when RA occurs the flow of ‘qi’ is blocked or out of balance, stimulation of specific points along the ‘meridians’ can correct the flow of ‘qi’ to restore or optimize health. Acupuncture analgesia and curative acupuncture were included in clinical therapies which will lead to pain relief and inflammation subsidence. Besides the traditional Chinese acupuncture (TCA) which is manually operated, electroacupuncture is normally used.

Clinical effects research

Based on different sample sizes and conditions, acupuncture may result in different outcomes. A double-blind study of Russians suffering from RA and treated by auriculo-electropuncture (AEP) indicated that all the patients feel better and the statistically significant improvement in blood sample was observed after treatment [15]. Using positron-emission tomography (PET), a random trial was performed in Japanese. The final result confirmed the function of acupuncture in the management of RA patients to relieve symptom and improve quality of life with unchangeable regional inflammation [16]. While in other trials, contrary results were obtained [17–19]. These conclusions are limited by methodological considerations such as the type of acupuncture (TCA vs. electroacupuncture), the site of intervention, the shortage of clinical trials and the small sample size which indicated that a series of large-scale trials based on standard manipulation should be performed to further verify the existing evidence [20].

The possible mechanism

Studies indicated that the following pathways may contribute to the pain-relief function of acupuncture: the stimulation of Aδ and C afferent fibers on the skin and II and III afferent fibers on the muscle [21]; the release of endogenous opioid peptides (EOPs) [22–24], anti-inflammatory substances [25] or other neurotransmitters involved in pain suppression [26]. Besides the above, enhanced serum level of interferon-γ (IFN-γ), interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-6 (IL-6) were seen in RA patients after acupuncture treatment, accompanied with reduced level of TNF-α [27, 28]. Furthermore, production of anti-inflammatory cytokines such as interleukin-10 (IL-10) increased in this procedure [29]. Thus, the balance between Th1 and Th2 cell-derived pro-inflammatory and anti-inflammatory cytokines was modulated by acupuncture. The ‘broad parasympathetic effects’ of the vagus nerve may be another pathway that lead to the anti-inflammatory function of acupuncture and auriculotherapy [30]. Increased vagus nerve activity was observed during acupuncture treatment process by Tracey [31, 32]. As a further step, the anti-inflammatory function of vagus nerve stimulation and the cholinergic anti-inflammatory pathway were found. It has been found that the anti-inflammatory effect of acetylcholine is due to the combination of acetylcholine and α7 nicotinic receptor and the following down-regulation of NF-κB pathway and up-regulation of Jak2-STAT3 pathway [33–35] (Fig. 3).

Fig. 3
figure 3

The possible mechanism of acupuncture for the treatment of RA. TNFα tumor necrosis factor α, IL-1β interleukin-1β; IL-6 interleukin-6, IL-10 interleukin-10, α7nAchR α7 nicotinic acetylcholine receptor

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Chinese massage and RA

Ever since the “Shang” dynasty, Chinese massage (Tui-Na) has been used to the therapy of children’s diseases and digestive complaints in adults. Different from other types of massage, the therapeutic effect of Chinese massage derived from the accurate diagnosis of the clinical symptoms is based on the theory of TCM. In detail, blocked ‘qi’ and ‘blood’ may be eliminated after massage treatment so as to obtain equilibrium in our body. In the view of modern science, using massage may lead to the activity of the circulation and nervous system so as to relieve muscle tension and pain. In our opinion, although massage therapy cannot cure or stop the progression of RA, it can most assuredly ease the symptoms associated with inflammation and help to improve the quality of life. The following literature may support our idea. One group of preliminary findings suggested that massage was associated with improved psychological function in children with arthralgia in RA [36]. Improved symptoms of depression, anxiety, mood and pain in RA patients were found after massage treatment which indicated the possible effect of massage on the peripheral nociceptive perception and central information in RA [37, 38]. However, further study may be hampered by the lack of suitable control group in the study of massage in RA patients [39]. Thus, the medical authorities are reluctant to endorse manual therapies for RA due to a lack of scientific mechanism to verify its efficacy and safety [40]. Therefore, more researches are needed, be it clinical trials or detailed mechanism study.

Conclusion and prospect

Based on the above analysis, we are quite sure that RA treatment will benefit from the application of TCM. While the following suggestions should be particularly considered: (1) more active ingredients should be isolated from the anti-rheumatic Chinese herbs and be applied in clinic which will be useful supplement to the DMARDs family (Fig. 4); (2) as a further step, larger randomized trials should be performed to verify the effects of acupuncture and massage. At the same time, more in-depth studies of the related mechanisms are needed. It is glad to see that TCM has been playing more and more important role in the therapy of RA and further researches about this theme will bring more benefits to the RA patients.

Fig. 4
figure 4

The diagrammatic illustration of TCM in the therapy of RA. TCM Traditional Chinese medicine, DMARD disease-modifying anti-rheumatic drugs, CAM complementary and alternative medicine

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