RA is more prevalent among women. Sex hormones were thought to play a role in the pathogenesis and also in the improvement of RA during pregnancy, due to their effects on the immune system [18] .

RA could be induced or aggravated by many factors, among which mental factors play a large part in terms of its development, aggravation and recurrence. Mental factors include negative emotions such as tension, anxiety, fear, anger, depression, worry, grief, etc.; stressful events such as family disputes, death of family members, job changes, impending tests, etc.; or over-fatigue or sleep disorders [2] .

In RA therapy, anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoid is one of these powerful drugs.

Accordingly, the neuronal function could be related to the processes involved in the course of RA and associated with fatigue and depression. Neuroendocrine hormones triggered during stress response may lead to immune dysregulation or altered or amplified cytokine production thus resulting in an increase in disease activity. Various types of transmitter substances in the neuroendocrine-immune network include human growth hormone, growth hormone releasing hormone, somatostatin, epinephrine, norepinephrine, acetylcholine, serotonin, substance P, vasoactive intestinal peptide, glucagon, insulin, cytokines, and growth factors [19] . The stress response and induction of a dysregulation in the cytokine balance can trigger the hypothalamic-pituitary-adrenal axis and sympathetic nervous system.

In conclusion, neuroendocrine-immune network is a general system. During the day, glucocorticoid plays an important role in controlling inflammation, and

human growth hormone plays an important role in eliminating inflammation during the slow-wave sleep at night. Mental factors can lead to the onset, recurrence or aggravation of RA through neuroendocrine and immune function disorders. Conversely, positive mental psychological activity could prevent or alleviate the state of RA [2] [5] [6] .

Cytokines carry out many crucial biological processes like cell growth, proliferation, differentiation, inflammation, tissue repair and regulation of the immune response [20] [21] . It is well known that they play an important role in the pathogenesis of RA and are responsible for inflammation and joint destruction that occur during arthritis [22] . There occurs an imbalance between the pro- and anti-inflammatory cytokine activities which leads to multisystem immune complications [20] .

The inflammatory milieu in the synovial compartment is regulated by a complex cytokine network. It is believed that B cells, T cells and over-production of various pro-inflammatory cytokines and de-regulation of anti-inflammatory cytokines regulate the pathophysiology of RA. Clinical interventions clearly demonstrate that of these components, tumour necrosis factor (TNF), interleukin 6 (IL-6), and probably granulocyte-monocyte colony stimulating factor are essential to the process. Cytokines lead to the induction or aggravation of the inflammatory response by activating endothelial cells and attracting immune cells to accumulate within the synovial compartment [3] .

Although immune system which is regulated by cytokine network is complex, many of cytokines such as TNF-α IL-6 IL-17 have been tested as therapeutic targets with notable success in RA and subsequently other inflammatory diseases, whereas targeting of other cytokines rendered low or no therapeutic success [3] .

In conclusion, it is important to recovery balance of cytokine network and to improve immune function [23] .

Recently, RA is described as an autoimmune disease mediated by T cells, especially effector The T helper 17 cells (Th17 cells) [24] . The protective role of T regulatory cells (Treg cells) and the pro-inflammatory role of Th17 (by secreting IL-17) have been elucidated and emphasized in the pathogenesis of RA. In patients with active RA increased Th17 levels and decreased Treg levels were found. Th17 and Treg cells (Th17/Treg balance) have a fundamental role in determining the outcome of RA.

Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces. In the case of autoimmune disorders, Th17 cell over activation can cause an inappropriate amount of inflammation. Treg cells are considered to have a protective role against bacterial and fungal infections and also in suppression of autoimmune response. They express forkhead box P3 (FoxP3), CD4, CD25 and produce TGF-β and IL-10. Treg cells do not promote immune function, but act to decrease it instead. Treg cells actively suppress activation of the immune system and prevent pathological self-reactivity. The critical role Treg cells play within the immune system is evidenced by the severe autoimmune syndrome (IPEX syndrome) that results from a genetic deficiency in Treg cells. Despite their low numbers during an infection, Treg cells are believed to play an important role in the self-limitation of the immune system, they have been shown to prevent the development of various autoimmune diseases.

In 1989, Strachan proposed his Hygiene Hypothesis Theory: the reduction of exposure to common pathogens such as helminthes increased the prevalence of allergic and autoimmune diseases in areas where sanitary conditions improved [25] .

The parasites related to protective effects of the aggressiveness of the disease in patients with RA, already described in the literature, are Schistosoma mansoni, Schistosoma japonicum, Ascaris suum, Heligmosomoides polygyrus bakeriand Hymenolepsis diminuta, Leishmania and Malaria. Such pathogens inhibit the secretion of Th17 cytokines, induce the appearance of tolerant dendritic cells and promote the proliferation of Treg cells [24] [25] .

In conclusion, intestinal immunity is a part of systemic immunity. In childhood, developing immune system must receive stimuli (from infectious agents, symbiotic bacteria, or parasites) to adequately develop Treg cells. In adulthood, eating food include probiotics would be useful.

RA is autoimmune disorder by immune complex precipitation. Taking adequate rest would be useful to the recovery of RA, but long-time rest would aggravate complex precipitation.

The available data suggest that physical activity (PA) is beneficial and should be encouraged in patients with RA [26] . Moderate exercise training is associated with improvement of expression of CD28 on Th cells and Th1/Th2 balances. Exercise also improves metabolism and helps to clear the immune complex. Therefore, exercise training could be helpful for a decrease in the risk of infections and in the progression of RA.

PA may diminish disease activity, improve bone mineral density, slow radio- graphic disease progression at the small joints, and slow the development of atherosclerosis. Engaging in PA also enhances self-esteem and decreases both fatigue and pain perception [27] . Regular exercise is recommended as both safe and useful to maintain muscles strength and overall physical function. PA is also beneficial for patients with RA complaining of fatigue [28] .

But, over exercise would be harmful. In RA, fatigue is reported in over 80% of RA patients. Fatigue is severer for patients with moderate to severe disease activity, compared with those with low disease activity. Then fatigue could induce sleep disorder. It is reported only 18.5% of RA patients had sleep of good quality.

In RA complex feedback loops involving cytokines, such as IL-1 and TNF-α produced in response to inflammatory, appear to play a role in the regulation of non-rapid eye movement (REM) sleep. Thus the inflammatory may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep. Most of RA patients do not have a good sleep quality. Several studies have found sleep fragmentation, low sleep efficiency, frequent awakenings and poor sleep quality in this group of patients [29] . Sleep is often considered a state of the brain that improves immune function. Sleep disorders could be detrimental to the metabolism and immune regulatory functions of the human body. High-quality and deep sleep can promote the secretion of growth hormone, affect the activity of thymus and other immune organs, and restore the immune balance [5] [30] [31] .

In conclusion, the clearance of immune complexes is limited by the total amount of phagocytes and the capacity of metabolism, exercise intensity would be increased gradually. Research has shown that aerobic exercise can improve PA in RA, while PA decreases chronic inflammation and reduces pain, all without adversely affecting disease activity.

RA is the local expression of the general imbalance of the human body. Once the abnormal immune response has become established (which may take several years before any symptoms occur), plasma cells derived from B lymphocytes produce RF and ACPA in large quantities. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begin to disintegrate and evidence of joint destruction accrues.

Typically in RA progression, the process of disease attack is often from small joints to large joints. Small joints of the hands and feet are most commonly involved (proximal interphalangeal joints, and metacarpophalangeal or metatarsophalangeal), followed by wrists and ankles, elbows, knees and shoulders, but almost any joint can be affected.

It is reported that 36 of 256 RA patients (14.1%) had self-limiting arthritis [32] . Within the process of improvement, the recovery process is often from large to small joints [1] [32] [33] .

In recovery process, massage and exercise can induce diffusion of the immune complex, then increased antigen would cause the secondary immunity.

Meanwhile, we must pay attention to the same shape trauma which can cause secondary response to the whole body just like Koebner response or the isomorphic response which were found in Psoriasis, Juvenile idiopathic arthritis, vascular inflammatory.

In conclusion, within the improvement of RA, we must pay attention to over-massage and over-exercise which can cause the secondary immunity. In addition, we must pay attention to local trauma which can cause Koebner response or the isomorphic response.