Introduction
Psychological stress may alter immune function by activating physiological pathways of stress, such as the autonomic nervous system and the hypothalamus–pituitary–adrenal axis, which in turn interact with the immune system [
1‐
4]. Consequently, stress could have negative effects on health, particularly in populations with immune dysfunction, such as patients with rheumatoid arthritis (RA). The pathophysiological mechanisms involved in stress and disease exacerbation have not yet been elucidated.
Psychological responses to stress that might lead to immune dysregulation can be altered by interventions aimed at reducing psychological stress [
1,
5]. As yet there is no consensus about whether and to what extent stress management interventions are able to alter immune function. In an extensive meta-analysis by Miller and Cohen there was only modest evidence that different types of stress management interventions change basal immune function in healthy and clinical populations, with most consistent changes being found in basal total leukocyte counts and secretory immunoglobulin A levels [
6]. More recent studies reported that psychological interventions for patients with HIV or cancer changed basal lymphocyte proliferation and basal levels of proinflammatory cytokines [
7‐
10]. Even though the effects of psychological interventions in patients with RA have been extensively studied and reviewed [
11‐
16], there are only incidental reports of immune changes after psychological interventions in patients with RA, such as changes in interleukin (IL)-6 or interferon-gamma (IFNγ) [
17,
18], or in immune measures indicative of disease status, such as C-reactive protein and erythrocyte sedimentation rate [
19‐
24]. Potentially, previous effects in RA might be limited because changes in immune function in response to a real-life stressor have not yet been investigated combining both a stress management intervention and a stress induction paradigm. Particularly then, the benefits of stress management training can become evident because patients are challenged to cope with a stressful situation.
We previously showed that a short course of stress management training decreased the subjective distress response and stress-induced cortisol levels in patients with RA at a follow-up assessment, and especially in those patients psychologically at risk [
5]. In the present study, we explored the effects of the intervention on stress-induced levels of key cytokines involved in disease progression (for example, IL-6 and IL-8) in patients with RA, with stress being elicited by the Trier Social Stress Test. Building on our previous findings [
5], we expected that patients in the intervention group would show an altered cytokine response to acute psychosocial stress compared with controls at the 9-week follow-up assessment. We also explored immune effects specifically in patients psychologically at risk.
Discussion
This is the first study to explore the response of circulating cytokines to a psychosocial stress test after stress management training in patients with RA. Although no differences in basal and stress-induced levels of key cytokines were observed immediately after the intervention, patients in the intervention group had lower stress-induced IL-8 levels than patients in the control group at the follow-up assessment. Results suggest that a short individual training in stress management might alter immune parameters after a psychosocial stress task in a population with immune dysfunction; namely, patients with RA. This finding is in line with our previous report indicating that the stress management training improves psychological functioning and influences subjective and endocrine parameters of stress (that is, distress and cortisol levels) at the follow-up assessment [
5].
Stress-induced immune effects after a stress management intervention have not so far been investigated in rheumatic patients, including patients with RA. Stress induction paradigms using only a single stress exposure have yielded relatively robust effects on IL-6, IL-1β, and IFNγ levels in various healthy and patient populations [
28,
29]. Stress exposure also changes levels of these and other cytokines in rheumatic patients, but results are much less consistent [
2]. For example, IL-6 levels increased in response to a cold pressor task in patients with RA and juvenile idiopathic arthritis [
33,
34], but IL-6 and IFNγ levels remained unchanged after psychological stress was induced in patients with RA and systemic lupus erythematosus [
35‐
37]. Differences in stress induction paradigms and detection methods used and differences in the heterogeneity of patient samples might explain the inconsistent findings. Immune function after stress management training has only been measured incidentally in patients with RA and, moreover, has not been investigated in combination with stress exposure. One study reported altered basal IFNγ levels after emotional disclosure therapy for patients with RA [
17], while lower basal IL-6 levels were observed after cognitive behavioral therapy compared with meditation and education groups [
18]. Several other studies also reported other types of biological markers, mostly erythrocyte sedimentation rate and/or C-reactive protein, often as part of assessing overall disease activity, but did not find intervention-related changes [
21,
22,
24,
38‐
46]. In our study, the stress management intervention did not change basal or stress-induced cytokine levels, except for a decrease in stress-induced IL-8 levels at follow-up.
Chemotactic IL-8 is a key player in the acute exacerbation of inflammatory conditions, directing neutrophils and other cell types (for example, monocytes and lymphocytes) to sites of inflammation when homeostasis is disrupted [
47]. Blocking the actions of IL-8 has been shown to prevent acute inflammation in animal models [
48]. The lipopolysaccharide-stimulated production of IL-8 has been found to be positively correlated with perceived stress in healthy adults, and this could be primarily attributed to negative affect [
49,
50]. However, IL-8 levels did not change after the induction of stress with the cold pressor task in patients with juvenile idiopathic arthritis and healthy controls [
34]. Whether IL-8 acts as a more general marker of stress or whether it is specifically involved in the physiological stress response of patients with RA is not yet clear. Consequently, future studies should compare IL-8 responses to stress and stress management training in both healthy and clinical populations. Interestingly, the effect of the stress management training on stress-induced IL-8 levels tended to be particularly evident in patients with heightened levels of anxiety and negative mood. We found comparable effects for self-reported levels of tension and cortisol levels in our previous report [
5], but these measures were not related to IL-8 levels in this study. In addition, the effectiveness of psychological treatment for RA patients at risk was reported previously [
51], which warrants further research into the benefits of stress management on different types of psychophysiological parameters in high-risk patients.
This study had several limitations. The relatively homogeneous and small sample of patients with mild RA prevents generalization of our findings. The normal range for many immune parameters is very broad and psychological interventions, especially of short duration, might not induce physiological changes of sufficient magnitude or duration to move cytokine levels beyond this range [
6]. Nevertheless, intervention studies have demonstrated that immune alterations occur when people display a change in cognition [
52] and emotion [
7]. Moreover, intervention-related immune changes could have been masked by biological forces, such as disease flare-ups and biological treatments that affect the patients’ immune system [
6]. Although we tried to limit effects of disease flare-ups by monitoring the patients’ disease status and ruled out that treatment effects were caused by differences in biological treatment protocols through covariate analyses, we cannot preclude that this problem might have influenced our results. Prompted by earlier unequivocal findings of stress-induced changes to immune function in rheumatic patients [
2], the high intercorrelation of most cytokines, and the small sample size, Bonferroni correction for multiple testing was not applied in this explorative study. Future research should try to replicate our findings and, if possible, apply the Bonferroni correction to data with large sample sizes. Moreover, the direction of other cytokine responses observed in this study (for example, IFNγ) seems consistent with the stress literature and tentatively suggests a broader effect of stress management training on immune function, but larger studies are needed to validate this effect. Furthermore, no statements can be made about the clinical relevance of our results, especially since the intervention was of short duration (four 1-hour sessions over 2 weeks) and disease activity did not improve over the course of our study [
5]. A longer intervention that may produce more pronounced effects might overcome these problems. Another general problem concerning immune markers in stress research, particularly circulating cytokines, is the ambiguity regarding the interpretation of findings. Circulating levels of cytokines are thought to reflect levels of systemic inflammation and are correlated with disease activity and radiographic progression [
53]; however, changes in cytokine concentrations from baseline might not indicate
de novo cytokine production or clearance, but a redistribution of existing cytokines from or into the periphery [
54]. To what extent these alterations represent adaptive or maladaptive immune processes is not well understood and needs further investigation.
Acknowledgements
The authors acknowledge the contribution and support of patients, rheumatologists, and other health professionals from the participating study sites, and would particularly like to thank R van den Berg, C Blom, A van Burik, B Cranenbroek, E Fasse, S de Klerk, R van der Kolk, A van Laarhoven, R Siliakus, S Slebus, S Rösener, L Verhoeven, I Vermeulen, M Vogelaar, R te Winkel-Slotboom, and L Wirken for their assistance in collecting the data. This study was supported by grants from the Dutch Arthritis Association (Reumafonds).
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SJMdB, AWME, PLCMvR and FWK conceived and designed the experiments. SJMdB, AWME, SS-vK and AE were involved in the acquisition of data. SJMdB, AWME, ARTD, TRDJR, IJ and HvM contributed to the analyses and interpretation of data. SJMdB and AWME drafted the manuscript. All authors critically reviewed and approved the final manuscript.