Stress means different things to different people, but it generally has a negative connotation. At this time, we focus on stress as a constellation of events that begins with a stimulus (stressor) that causes a reaction in the brain (stress perception), which subsequently activates physiologic systems in the body (stress response) (1). The stress response results in release of neurotransmitters, hormones, and immune cells that serve to send an efferent message from the brain to the periphery. Several authors have reviewed the literature in order to link psychological stress in animal models to inflammatory diseases (2–10). This information from animal models was necessary in order to begin to understand the situation in human diseases. In this review, we attempt to integrate these experimental findings and lessons learned regarding stress in patients with rheumatoid arthritis (RA) and inflammatory diseases (11–13), in order to formulate a clinical viewpoint relevant to daily care in clinical rheumatology.
Obviously, 2 paradoxes present themselves when one reviews the extensive literature examining the relationship between psychological stress and inflammatory diseases. First, opposite results exist from studies on experimental acute, minor, short-lived stress compared with chronic, major, long-lived stress: acute minor stress is accompanied by an enhancement of immune function, whereas sustained major stress is linked to immunosuppression. In the first situation, it seems as if the time integral of stress axes mediators is small, whereas the time integral is huge during sustained stress. Second, there seems to be a fundamental difference between consequences of stress in healthy subjects compared with patients with chronic inflammatory diseases. The question arises whether the obvious discrepancy depends on defects of stress axes in patients with chronic inflammatory diseases.
In this review article, we attempt to delineate the physical connections between the central nervous system (CNS) and the periphery, with a particular focus on cortisol and norepinephrine. RA and juvenile idiopathic arthritis (JIA) are presented as prototypic diseases, because most of the relevant data in humans have been collected in patients with these diseases.
Human studies on RA or JIA and stress
This section provides a brief overview of whether or not psychological stress may be a permissive or an aggravating factor in RA and JIA. First, it should be a prerequisite to appreciate why studying psychological stress in inflammatory diseases is a real clinical problem. Second, such an overview may also provide readers with an idea of why oscillations in disease activity can depend on psychological factors. In this section, we focus on cross-sectional surveys of patients with RA or JIA but not on studies with controlled stress exposure (see below). The term minor stress refers to an acute minor stress over a few hours (i.e., daily hassles), whereas major stress is a long-standing stress over days and even weeks (e.g., providing care to a handicapped family member).
Stress as a disease-permissive factor.
For patients with RA, the role of stress as a disease-permissive factor seems to be equivocal (for review, see ref. 12). The picture is clearer in JIA. Among studies of patients with JIA (involving ∼500 children), all showed that stressful life events played a permissive role (for review, see ref. 12). For example, one such study showed that children growing up with only one parent due to divorce, separation, or death comprised 28% of the JIA population compared with 11% of the control group (14). Adoption occurred 3-fold more often in the JIA population, and 51% of these events (divorce, separation, death, or adoption) occurred near the date of onset of the disease (14). In one study of monozygotic twins who were discordant for JIA, the authors observed that psychological stress was more prominent in the afflicted twin before disease onset (15). Thus, in a large proportion of children with JIA, stressful life events preceded the onset of disease. All of the existing studies were retrospective, and it is obvious that in this research field longitudinal, prospective, population-based studies are needed, with the spotlight on RA or JIA.
At the moment, we do not know why stress can be a permissive factor in JIA but is less so in RA. One may speculate that immune system activity is different in young persons compared with elderly individuals. For example, stress induced an increase in natural killer (NK) cell activity in young persons but not in elderly individuals (16). A similar picture of delayed stress responses was observed in old compared with young rats (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Furthermore, the immune response is typically stronger in young people compared with elderly persons (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm), and, thus, stress-induced changes of immune system activity may affect young persons more than it affects elderly persons.
Stress as an aggravating factor.
Two different types of stress events have been defined. Major life events (e.g., death of a spouse, severe illness of a spouse) are strong stressors over days and weeks (sustained stress), while minor life events are daily hassles with less intensity over a few hours (acute stress). These stress events are not exactly defined by readout parameters of the stress axes such as cortisol, norepinephrine, or others. In a review of 27 independent studies with an interest in minor stress (involving ∼3,000 patients with RA) (for a summary, see ref. 12), the authors concluded that minor stress can be related to an increase of disease activity. A longitudinal study over a period of 5 years showed that patients with RA who had a higher daily stress level at baseline had a poorer outcome and significantly more bony erosions after 5 years (17). Similar findings were described in a more recent study of JIA (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Only 5 studies, involving ∼150 patients with RA, did not support the link between minor stress and disease flare-ups (for review, see refs. 12 and18). In contrast, sustained major stress, which is likely accompanied by a large and long-lived release of stress axes mediators (large time integral), was associated with a decrease in disease activity, but other studies have indicated inconclusive results (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). At this point, the question arises of what can we learn from animal models of stress.
The dual role of stress on immune function in animal models
Studies (in rodents) on delayed-type hypersensitivity (DTH), a Th1-dominated immune response of the skin with similarities to RA and JIA, demonstrated that acute minor stress over a few hours is accompanied by an enhancement of immune function (1, 19) (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). It was pointed out that early redistribution of leukocytes to the site of inflammation plays the most important proinflammatory role in DTH (for review, see ref. 5). In contrast, sustained major stress can decrease DTH (20). Similarly, acute minor stress over a few hours enhanced humoral immunity to different stressors and antigens (21), while sustained stress suppressed antibody production (22) (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). More recent studies have beautifully delineated the dual role of acute minor stress over a few hours and sustained stress over days in a single animal model (23, 24) (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Such a dual role of minor and major stress was also demonstrated for influenza vaccination responses in healthy humans (25).
In experimental arthritis, acute minor stress over a few hours and sustained stress over days can also lead to dual effects on disease activity in type II collagen–induced arthritis (26). Repeated stress (and thus sustained stress), but not acute stress over a few hours, suppressed bradykinin-induced inflammatory plasma extravasation (27). In one study in rats with acute minor stress, the authors demonstrated the influence of learned helplessness on disease activity in rats with adjuvant-induced arthritis (28). Compared with animals with learned helplessness, those without learned helplessness that were undergoing acute stress, with increased corticosterone plasma levels at the time point of acute stress, demonstrated increased disease activity. This indicates that good responsiveness of the stress axes may even increase arthritis. In a model of sustained stress attributable to food restriction, with persistently elevated corticosterone levels, adjuvant-induced arthritis was significantly diminished (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). In this context, arthritis induced in Fischer rats, which mount a strong and long-term elevated corticosterone response over many days after challenge with either antigen or stress (29, 30), resembles a situation with arthritis under sustained stress conditions due to prolonged increased hypothalamic–pituitary–adrenocortical (HPA) axis activity. In contrast, Lewis rats, which do not mount a long-term exaggerated corticosterone response, demonstrate arthritis under conditions of acute minor stress (Figure 1).
In conclusion, in consideration of the above-mentioned studies, acute stress over a few hours stimulates, and sustained stress over days and weeks suppresses, immune responses and inflammatory reactions. We do not have exact laboratory criteria for acute stress and sustained stress in human subjects, but these terms may well fit with the concept of minor and major stress mentioned above for patients with RA or JIA. Probably most critical for these contrasting findings is the dual role of hormones and neurotransmitters of the HPA axis and the sympathetic nervous system, which is discussed in the following sections.
The dual role of cortisol and norepinephrine on immune function
This section should provide a solution for the apparent paradox that acute minor stress is accompanied by an enhancement of immune function, whereas sustained major stress is linked to immunosuppression in the healthy subject. Many aspects of this discrepancy are probably linked to the obviously dual role of cortisol and norepinephrine on immune function.
Cortisol, corticosterone, and glucocorticoids.
Between 1940 and the 1980s, it was thought that an initial cortisol surge serves to stimulate defense mechanisms that included the first attack of the immune system (mentioned in ref. 31). Since publication of the research of Munck and Guyre in 1986 (31) until 1995, the pendulum swung to the opposite side, and it was correctly realized that cortisol has also a prominent immunosuppressive role: “There is overwhelming evidence that glucocorticoids generally suppress defense mechanisms [leading to immunosuppression], rather than enhance them, as assumed in the traditional view [according to Selye]. … Our alternative to the traditional hypothesis is almost its opposite, namely, that—what the glucocorticoids really protect us from in stress—is our own defense mechanisms” (31).
Munck and Guyre proved the concept by demonstrating that dexamethasone doses of 10−8M to 10−7M, which are biologically equivalent to 3 × 10−7 to 3 × 10−6M of cortisol, suppressed cytokine secretion in vitro (31). Other similar studies demonstrated many immunosuppressive effects of cortisol, in vitro and in vivo (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Generally, most of these studies were carried out with relatively high doses of cortisol. This immunosuppressive concept was also confirmed by studies in patients with RA who were receiving glucocorticoid treatment (32). The therapeutic dose typically leads to serum concentrations of cortisol equivalents of 5 × 10−7M up to 10−4M (32), and the levels remain high over weeks with the typical top–down dosage of glucocorticoids. The top–down therapy regimen generates immunosuppressive concentrations that can be compared with concentrations reached during sustained major stress.
In recent years, the immunomodulating role of this hormone has been critically reexamined, because several studies using lower cortisol concentrations applied in vitro and in vivo demonstrated immunostimulating effects in both humans and rodents (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Alveolar macrophages from glucocorticoid-treated rats were highly sensitive to lipopolysaccharide (LPS) and released large amounts of tumor necrosis factor α (TNFα) ex vivo. A very similar relationship between prior cortisol infusion and subsequent LPS-stimulated levels of interleukin-6 (IL-6) and TNF was described in humans (33). The influence of glucocorticoids on leukocyte redistribution is probably the most important factor in supporting immune responses (1, 19). Many more similar immunostimulating effects of stress-induced cortisol release have been described (for review, see ref. 5). In conclusion, these opposite effects of cortisol are fact, and it is not realistic to overlook either its immunosuppressive or its immunostimulating effects. Both effects are dependent on dosing over time (time integral).
A very similar paradox emerged for norepinephrine, the immunosuppressive role of which, via β-adrenergic receptors at concentrations of 10−6M to 10−5M, has been repeatedly demonstrated (for review, see ref. 34). This neurotransmitter inhibits TNF secretion from macrophages via β-adrenoceptors (35); however, it enhances TNF production via α2-adrenergic receptors (35) (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Moreover, norepinephrine stimulates complement production from macrophages via α1-adrenoceptors (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Norepinephrine inhibits many functions of the innate immune system, such as macrophages, NK cells, and neutrophils via β-adrenoceptors (summarized in ref. 36), but it also stimulates chemotaxis by increasing IL-8 secretion (37) and by its own chemotactic properties (38). Concerning the adaptive immune system, it also has stimulating effects on B cells and Th2 immune cells via the β-adrenergic receptor (39).
As Figures 2A and B schematically demonstrate, the stress response concerning cortisol and norepinephrine can be very different depending on response amplitude and duration (time integral of stress axes mediators). During acute experimental stress, a brief increase in the levels of cortisol and norepinephrine over a few hours can be observed (Figure 2A), while during sustained major stress a huge release of cortisol and norepinephrine is expected over a prolonged period of time (Figure 2B). It is interesting that the main mediators of the HPA axis and the sympathetic nervous system axis—cortisol and norepinephrine—act at similar concentrations in order to exert stimulatory and inhibitory effects on the immune system (Figure 2C). Furthermore, release of cortisol is typically coupled to release of norepinephrine, which leads to stronger signaling through the β-adrenoceptor. Several studies have shown cooperativity of cortisol and norepinephrine on a molecular level (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm).
These dual effects play an important role in acute stress-induced immunostimulation and sustained stress-induced immunosuppression. In addition, the endogenous tone of the HPA axis and the sympathetic nervous system prior to an immune challenge plays a supplementary role (Figure 3). At this point, the concept of the stress spectrum hypothesis needs to be slightly modified (5). One region of the stress spectrum is characterized by a normal to mildly increased endogenous tone (eustress), while the other 2 ends of the spectrum are characterized by either a low or strongly increased tone (distress). Thus, we hypothesize that the relationship between endogenous tone (degree of stress) and susceptibility to autoimmune diseases follows a bell-shaped response curve, while the response curve for susceptibility to cancer and infection is U-shaped (for review, see ref. 5) (Figure 3).
Consequences of stress in asymptomatic “healthy” subjects versus patients with RA or JIA
In the asymptomatic phase of an immune-mediated joint disease (during which patients are still “healthy”), a limited number of cell types are involved. If, as in the case of RA, we accept the etiologic concept of an antigen-driven disease (self or foreign), T cells, B cells, and antigen-presenting cells will play the major role in the asymptomatic phase (as easily recognized in animal models). In this context, it must be noted that in a recent important study it was demonstrated that autoantibodies against possible RA autoantigens (cyclic citrullinated peptide and IgA rheumatoid factor) were detectable many years before the first joint symptoms in the “healthy” phase (40). This indicates that autoantigenicity is not instantaneously accompanied by symptomatic inflammatory joint disease. One can say, “The immune response is restricted to secret players during a possibly long time of tolerance.” In this particular phase, acute stress may play a disease-permissive role, as observed in animal models and suspected in patients with JIA (see above) (Figure 4).
At the time point when the disease becomes symptomatic, many other local cell types are now involved in the destructive process. These include neutrophils, fibroblasts, osteoclasts, endothelial cells, chondrocytes, mast cells, osteoblasts, nerve fibers, stem cells, fat cells, and others. The roles of the initial secret players—the T cell, B cell, and dendritic cell—simultaneously decrease while other cell types step in. The characteristics of the disease gradually change. Thus, we may separate a more or less “healthy” asymptomatic phase from a proinflammatory symptomatic phase of arthritis (Figure 4). In these 2 phases the stress responses may have very different effects. This should be exemplified by experiments with abolition of the sympathetic nervous system and arthritis. Elimination of the sympathetic nervous system before induction of arthritis leads to a marked reduction of disease severity (41, 42), whereas abolition of the sympathetic nervous system during the chronic phase of arthritis leads to a dramatic increase of disease activity (42). Depending on different immune mechanisms in the different phases, the sympathetic nervous system has a completely different influence on arthritis.
In addition, stress axes markedly change during chronic inflammatory diseases, which may elicit unexpected stress responses during the symptomatic phase of the disease. This is discussed in the next section. From an ethical standpoint, one may conduct studies with RA and JIA patients under acute stress conditions, but it may be questionable to experimentally apply sustained major stress conditions in these patients. Thus, at the moment, only studies on acute stress conditions in RA and JIA are available (see below).
Response of stress axis under acute stress conditions in RA and JIA
The HPA axis under stress in RA and JIA.
We know that in patients with RA the responsivity of the HPA axis is diminished in relation to ongoing inflammation (43–45) (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Another important phenomenon is the dramatic change of circadian rhythmicity in patients with RA (46), which is also a good marker of deleterious amounts of stress in animals (5). We recall that inflammatory stress is a continuous stimulus of the HPA axis that leads to typical habituation phenomena (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). We also know that psychological stress leads to habituation phenomena in the CNS, and, thus, psychological stress due to the appearance of a chronic disease such as RA and JIA may also add to habituation in the CNS.
In addition, in healthy individuals, immune and other cells are receptive to stress hormones due to normal densities of hormone and neurotransmitter receptors. However, in some patients with RA we observe glucocorticoid receptor abnormalities, with lower density of intracellular receptors and increased density of membrane-bound receptors independent of glucocorticoid therapy (32, 47). These abnormalities may lead to cortisol resistance, which has been supposed to play a role in patients with RA (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). At this point, the question arises of whether or not patients with RA, compared with controls, are able to mount an adequate cortisol response during stress conditions.
With respect to HPA axis stimuli, several studies of acute stress demonstrated inadequate adrenocorticotropic hormone (ACTH)/cortisol release after insulin-induced hypoglycemia and during a corticotropin-releasing hormone test (44, 48, 49). However, these studies are inconclusive, as was recently reported (50). Inconclusive results may depend on the inflammation status prior to or at the time point of the test, which has not been adequately reported. Furthermore, it may be that relatively strong stress stimuli do not reveal subtle alterations of the HPA axis, and only acute stress paradigms may reveal respective changes. Dekkers et al recently demonstrated that patients with RA, compared with controls, do not mount a significant ACTH response upon application of controlled psychological stress, which is also visible in the form of inadequate cortisol secretion during the test phase (51). It has been demonstrated that controlled exercise-induced release of cortisol is markedly decreased in patients with RA compared with controls (52). A subpopulation of patients with RA demonstrated impaired hypothalamic–pituitary regulation during a dexamethasone test (53). In addition, controlled adrenaline infusion, simulating a stress response, leads to a rapid decrease of cortisol serum levels in patients with RA but not in controls (54). Although the HPA axis is relatively robust, it seems that acute stress can lead to an unexpected decrease of HPA axis mediators in patients with RA compared with healthy subjects. This would yield an overall proinflammatory situation during the chronic symptomatic phase of the disease.
The sympathetic nervous system under stress in RA and JIA.
Similarly, as depicted for glucocorticoid receptors, a loss of β-adrenoceptors on peripheral and synovial immune cells has been described in patients with RA (55), and signaling through β-adrenoceptors seems to be disturbed (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). In contrast to the typically available β-adrenoceptors on immune cells, there seems to be up-regulation of α1-adrenoceptors in patients with JIA, which results in increased IL-6 secretion (56).
Due to this beta-to-alpha adrenergic shift, norepinephrine may not exert its typical immunosuppressive activities via β-adrenoceptors on macrophages, neutrophils, and NK cells. These phenomena are accompanied by a functional loss of sympathetic nerve fibers in inflamed RA synovial tissue. This is paralleled by a rather normal innervation with proinflammatory sensory nerve fibers (57) (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). According to the present point of view, functional loss of sympathetic nerve fibers would support a local proinflammatory situation due to an inflammation-induced beta-to-alpha adrenergic shift (Figure 5). A similar beta-to-alpha adrenergic shift may happen in lymphoid organs of patients with RA or JIA, because a loss of sympathetic nerve fibers has also been documented in the spleen in rats with adjuvant-induced arthritis (58). Functional loss of sympathetic nerve fibers will lead to uncoupled effects of cortisol and norepinephrine, which would support the beta-to-alpha adrenergic shift. Furthermore, functional loss of nerve fibers would also lead to uncoupling from the regulation of the CNS, and thus to uncoupling of the inflamed area from the rest of the body.
All of these factors would support the notion of a proinflammatory effect of norepinephrine in RA and JIA. On the basis of this information in the inflamed tissue, the question arises as to how the general sympathetic nervous system tone changes in RA, and how acute stress can change the sympathetic nervous system reactivity.
Several studies have demonstrated an increased baseline sympathetic tone in patients with RA and patients with JIA. One study showed that patients with RA had an increased heart rate at rest and increased systolic and diastolic blood pressures (59). Other investigators have noted an increased heart rate at rest in patients with JIA, which was interpreted as an increased central noradrenergic outflow (60). This study was supported by another study in patients with RA that demonstrated increased tonic pupillary autonomic activity with a relative sympathetic dominance and enhanced sympathetic sudomotor reaction (61). Hypersympathetic activity during sleep has recently been demonstrated in patients with RA (62). Furthermore, an increased basal tone of the sympathetic nervous system may also drive the renin–angiotensin system in order to release the major biologically active component angiotensin II, which was demonstrated to be a critical proinflammatory factor (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm). Interestingly, the sympathetic response to stimuli such as tilting (60), hypoglycemia (Imrich R, et al: unpublished observations), or stress tests (63) generated reduced sympathetic nervous system responses or increased responses (59). In RA and JIA, this may demonstrate the general inability of the sympathetic nervous system to adequately adapt to necessary needs under stress conditions.
On the basis of the above-mentioned changes in the synovial tissue, one would expect that an increased basal sympathetic tone and local loss of sympathetic nerve fibers in these patients would support proinflammatory responses, which is described in the next section (Figure 5).
Stress and immune responses in RA and JIA
The changes of the HPA axis and of the sympathetic nervous system, as demonstrated above for RA and JIA, may lead to proinflammatory reactions during acute stress. Indeed, the first available studies in RA demonstrated that disease flare-ups were linked to a higher number of interpersonal stressors a few days prior to the visit to an outpatient clinic, and this was related to an increased number of circulating CD3+ cells and increased serum levels of soluble IL-2 receptor (64, 65). Results of other controlled studies of acute stress in JIA and RA indicate that the proinflammatory cytokine IL-6 is increased during stress situations. A strong noradrenergic stressor was accompanied by enhanced LPS-induced IL-6 production by peripheral blood cells, which may be mediated through α1-adrenergic receptors (66). This was supported in patients with RA, who demonstrated increased IL-6 levels during psychological stress before surgery (67). After adrenaline infusion in patients with RA, simulating a stress situation, the numbers of IL-8– and IL-10–producing monocytes were higher in the peripheral circulation (68).
These first studies may suggest that aberrations of stress axes in patients with RA or JIA may lead to increased proinflammatory responses. We hypothesize that sustained stress may also lead to proinflammatory effects, because no adequate long-term response of stress axes can be generated. Based on these prerequisites in RA and JIA, the stress response must be really strong in order to evoke an immunosuppressive effect. This may be the reason why only few studies demonstrated immunosuppressive effects of stress (and only with sustained major stress).
The following conclusions can be drawn: 1) Under normal (healthy) conditions, acute minor stress leads to immune system activation, and sustained major stress inhibits immune responses (the stress axes are largely intact). 2) Due to an immunostimulating effect of stress in the asymptomatic (healthy) patient, stress can be a disease-permissive factor, as demonstrated in JIA, and possibly also in RA (at least in some patients). Differences between JIA and RA are probably attributable to a stronger immune and stress axis response in younger individuals as compared with older individuals. 3) In conditions of chronic inflammation, we observe defects of the stress axes, with inadequate secretion of cortisol, an increased sympathetic tone at rest but an inadequate response during stress, functional loss of synovial sympathetic nerve fibers, a local beta-to-alpha adrenergic shift, local uncoupling of cortisol and norepinephrine, and an uncoupling of the body from the inflamed area, which generate the basis for stress-induced aggravation of the disease. 4) On the basis of these stress axes changes, one would expect that stress—either acute minor stress or sustained major stress—is most often an aggravating factor in JIA and RA, which has been repeatedly demonstrated.
Stress can be a real clinical problem for patients with RA or JIA, leading to an increase of disease activity and bony erosions (17). Furthermore, the factors discussed here begin to explain why patients have oscillations of disease activity in conjunction with stressful events. At this point, the question arises of how we can treat these patients. Three major therapeutic approaches were suggested. First, disease activity must be reduced in order to normalize responses of the stress axes (see ref. 45). Indeed, the insufficient effect of stress axes on reducing the inflammatory response in patients with RA or JIA represents one of the reasons for the successful long-term, low-dose “corticosteroid replacement therapy” in these patients (69, 70). Second, stress axes responses may be corrected in these patients by appropriate mild training programs, which must be the subject of further studies in patients with RA. Third, psychological stress management training can lead to improvements (71) (further citations available at http://www.uni-r.de/Fakultaeten/Medizin/Innere_1/aknei/table1.htm).
We hope that this article provides novel directions for further experimental studies and therapeutic approaches. A more wide-ranging and well-adjusted combination therapy, which comprises approaches outside the traditional immune system, needs to be implemented, because the immune system is not a lonely player in an empty body.
We thank J. Schölmerich for carefully reading the manuscript.