Abstract
Although the pathogenesis of autoimmunity is not fully understood, it is thought to involve genetic, hormonal, immunologic, and environmental factors. Stress has been evaluated as a potential trigger for autoimmunity and disease flares in patients with systemic lupus erythematosus (SLE). The physiologic changes that occur with stress involve numerous catecholamines, hormones, and cytokines that communicate intricately with the immune system. There is some evidence that these systems may be dysregulated in patients with autoimmune disease. Mindfulness-based techniques are practices aimed at mitigating stress response and have been shown to improve quality of life in general population. This review will discuss pathophysiology of chronic stress as it relates to SLE, evidence behind mindfulness-based practices in these patients, and directions for future research.
Introduction
The most commonly studied pathways involved in the stress response include the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), each of which participate in complex, bidirectional communication with the immune system via hormones, neurotransmitters, and cytokines. These pathways have been shown to directly and indirectly interact with immune cells and functioning1–4 and chronic stimulation may contribute to the onset of autoimmunity and immune dysregulation.5–9
Although the development of autoimmune disease requires a combination of genetic, hormonal, immunologic, and environmental factors,1,10 several studies have linked stress to the development of autoimmune disease.11–15 For example, patients with major depressive disorder are 10-times more likely to develop autoimmune skin conditions, such as lupus erythematosus, psoriasis, alopecia areata, dermatomyositis, and others. 16 Up to 80% of individuals report a significant emotional stress prior to disease onset.12,17 Among patients with systemic lupus erythematosus (SLEs), several have explored stress and stressful events as a precursor and mediator of SLE.11,18,19 A 24-years longitudinal cohort study found women who experienced post-traumatic stress disorder (PTSD) had almost three times the incidence of SLE compared to women with no history of PTSD. 19 Moreover, the association between stress and disease in SLE is relevant even after diagnosis, with daily stress being strongly correlated with SLE flares, 20 perceived worsening of SLE symptoms, 21 and greater lupus activity. 21 A retrospective analysis using the National Patient Register in Sweden showed stress-related disorders such as PTSD were associated with an increased risk of developing autoimmune disease, compared to matched unexposed individuals and to full siblings. 22 However, in this same study, the use of selective serotonin reuptake inhibitors (SSRIs) within the first year of diagnosis of PTSD reduced the risk of developing autoimmune disease, 22 emphasizing the interplay between environmental, genetic, and neurocognitive factors in developing autoimmunity and the potential for intervention and prevention. 23
Mindfulness-Based Interventions (MBIs) have been shown to modulate post-stress inflammatory response in healthy volunteers, 24 decrease symptoms of distress, and improve quality of life,25,26 as well as attenuate responses to stress.27,28 Mindfulness is defined as the awareness that emerges through purposeful, nonjudgmental attention to the present moment and the practice of mindfulness is thought to positively impact brain function and structure. 25 A recently published systematic review comparing over 1600 individuals in 20 randomized control trials concluded that MBIs may modulate inflammation, cell-mediated immunity, antibody production, and gene expression. 29 Mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) are two of the most well-studied MBIs, 26 though several variations of these have been used in the SLE case series and randomized control studies. In SLE specifically, studies have shown stress-reduction practices improve pain, 30 stress,31,32 anxiety31,33,34, depression,34–36 and quality of life.32,34,37–39 Moreover, SLE patients who engage in chronic disease self-management behaviors, such as increased exercise, improved diet, mindfulness, and relaxation techniques, felt subjective improvement in their ability to self-manage symptoms. 40
This article will summarize the pathophysiology associated with chronic stress as it relates to developing and exacerbating autoimmune disease, with a focus on SLE, as well as evaluate current evidence for MBIs and stress-reduction practices in SLE. Given the paucity of research on MBIs in SLE, our review provides implications for areas of future research in this population.
What is mindfulness?
The concept of mindfulness has roots dating back over 2000 years in Buddhist tradition. 41 Although the definition may vary among some scholars and has been the subject of lively discussion in recent years, mindfulness is thought to be a moment-to-moment awareness of the present moment in a nonjudgmental, non-reactionary manner. 42 In a theoretical sense, it may be a state of being; however, in a pragmatic sense, it is an active practice or process in which one focuses the mind on the present moment, giving rise to a greater awareness of situation and self. It is this attentional and meditative practice of mindfulness that has been championed as the “heart” of Buddhism. 42 Additionally, more recent conceptualizations of mindfulness include not only the attentional and meditative practice, but also a perception of acceptance and open-mindedness. 43 This then becomes a shift in focus not only on the self and mind, but also on socioemotional relations outside of the self. It is by incorporating both of these aspects that the practice of mindfulness has become operationalized in the last several decades and includes more than traditional meditative practices.
Jon Kabat-Zinn founded the Center for Mindfulness in 1979, and subsequently developed MBSR practices as a therapeutic intervention program. 41 Since then, several other mindfulness-based programs have been developed and are each aimed at cultivating the psychological benefits from ancient practices. 44 Collectively, in growing medical literature, these programs have been termed MBIs as they involve specific, structured programs that can be replicated and studied. The most common MBIs are MBSR and MBCT, but also include other stress-reduction practices and exercise programs such as Tai Chi and yoga. Overall, there has been a sharp increase in research focusing on MBIs in recent years, 44 and an effort to incorporate interdisciplinary understanding of these practices and potential benefits is of major interest and warrants further attention.
What is a stress response?
During a stressful event, both catecholamines and glucocorticoids are released in parallel, each of which exert various effects on immune cells and alter the cytokine profile via the SNS and the HPA axis.1,45,46 These mechanisms are in place to aid the host in coping with the stressor, yet each have both direct and indirect effects on the immune system and inflammatory responses.
Hypothalamic-pituitary-adrenal axis
Psychological stress is associated with increased concentration of ACTH and cortisol in both serum and saliva. 47 For this reason, salivary cortisol levels have been used as a marker for acute stress response. 48
The HPA axis is regulated by the limbic system, which includes the amygdala, hippocampus, and pre-frontal cortex, all of which have intricate positive and negative feedback mechanisms to attenuate and exacerbate stress response via glucocorticoid release. 49 However, once in a state of chronic stress, the HPA axis itself undergoes physiologic changes, both in basal functioning and in responsiveness to stress.50,51 Some of these changes include hypertrophy of the adrenal gland, increased central tone of the HPA axis via increased corticotropin releasing hormone (CRH) production, down-regulation of glucocorticoid receptors and decreased efficacy of glucocorticoid negative feedback.49,50,52 Cumulatively, these result in a “less flexible” (decreased responsiveness to glucocorticoids) and “more fatigued” (hypo-functioning) HPA axis. Given these changes, some authors have postulated that decreased functioning of the HPA axis is associated with the pathogenesis of autoimmune diseases, as the body allows a type of “permissive” inflammation unchecked by the now desensitized glucocorticoid receptors in the hypo-functioning, hyper-toned state.5,11
Moreover, as the HPA axis is integrally connected with the immune system, it stands to reason that sustained changes in stress responsiveness would also affect immune-mediated or inflammatory pathways. Chronic stress has been associated with elevated IL-6 and CRP 14 though the mechanism for this is thought to be multifactorial. 53 Activation of glucocorticoid receptors is known to inhibit NF-kappa B (NF-kB), 54 a transcription factor that regulates pro-inflammatory cytokine and chemokine production. 55 Thus, down-regulating glucocorticoid receptors would decrease inhibition of this pro-inflammatory pathway in leukocytes. In fact, even in healthy adults, higher NF-kB activity in acute and chronic stress was correlated with increased levels of IL-6. 56 Interestingly, another study showed healthy adults who had less cortisol production in response to a social stress were also more likely to have elevated levels of IL-6 and IL-1a pro-inflammatory cytokines due to stress. 57 This was further noted at the genetic level, as Miller et al. 58 showed genome-wide microarray analysis of peripheral blood monocytes in individuals with chronic stress had diminished responses to glucocorticoids and heightened expression of NF-kB transcription elements, including IL-1a and CRP. It should be noted that monocytes were chosen for analysis given intimate relationship with toll-like receptors (TLRs), which are also up-regulated in chronic stress via NF-kB. 59 Moreover, pro-inflammatory cytokines IL-6, TNF-α, and IL-1 stimulate production of glucocorticoids. 60 It is thought inflammation from chronic stress may be at play in increased cardiovascular disease and atherosclerosis, 61 especially in autoimmune disease. 62 One study showed those with chronic stress measured by cortisol levels had greater progression of carotid intima media thickness over a 4-years follow-up. 63
Taken together, these findings are consistent with the idea that maladaptive HPA axis in chronic stress is associated with elevated levels of inflammation, potentially increasing risk of systemic disease. Tian et al. 64 further describe the relationship of stress to inflammatory cytokines and NK-kB signaling, noting that up-regulation of pro-inflammatory cytokines is stage-dependent and as such, only occurs once maladaptive patterns as described have become the norm.
In SLE, Gutiérrez et al. 65 showed that although healthy controls and undertreated SLE patients had similar basal levels of ACTH and cortisol, the SLE patients had a significantly blunted response to stress, as induced by hypoglycemia. These patients also had significantly elevated prolactin in response to stress. 65 Prolactin is considered a pro-inflammatory marker. HPA dysfunction and hypo-responsiveness is also seen in patients with other rheumatologic conditions, such as rheumatoid arthritis (RA) and Sjögren’s syndrome (SS).5,66–69
A study exploring reduced stress response in long-term meditation practitioners noted these individuals had more rapid clearance of salivary cortisol, 70 suggesting quicker recovery from stress. A systematic review and meta-analysis that included five randomized control trials evaluated MBIs and found that in healthy adults, engaging in MBIs decreases overall salivary cortisol production, suggesting an attenuated stress response. 71 However, these results have not been consistent. 72 One issue has been related to difficulty in interpreting cortisol levels as stand-alone values. 72 Some authors have proposed evaluating cortisol flexibility, or adaptiveness of cortisol response to stressful stimuli, instead of cortisol magnitude. 73 This model would be preferential in patients with autoimmune conditions or known HPA dysfunction, as basal cortisol levels may not be indicative of stress reactivity, and thus may not be applicable to patients with known autoimmune disease. While a recent study showed lonely older adults who engaged in an 8-weeks mindfulness-based stress reduction (MBSR) program had a nonsignificant decrease in glucocorticoid resistance, 74 there was a trend towards decreased glucocorticoid resistance, suggesting MBIs could be beneficial and warrant further research.
Sympathetic nervous system
From premature hair graying 75 to stress cardiomyopathy (Takotsubo), 76 the effects of the SNS play a significant role in acute and chronic stress response.7,8,46 Although less is known about how the SNS regulates inflammation, adrenergic receptor actions on immune cells have been gaining more attention, as they interact intimately with neural and endocrine pathways. 77 Pongratz et al. 3 review examples of direct sympathetic neurotransmitter actions on immune cells and down-stream effects, including increasing IL-6 and decreasing IL-12 via dendritic cell stimulation, and increasing T-regulatory cell apoptosis via T-cell stimulation. 3 Modulation of inflammation via the SNS occurs primarily via norepinephrine (NE) stimulation of β2-adrenoreceptors on various immune cells.78,79 In acute stress, Bierhaus et al. 80 showed that NE stimulation of peripheral blood mononuclear cells may increase NF-kB-dependent gene expression, thus activating pro-inflammatory cytokines. Interestingly, this was suppressed by both α1-and β-adrenergic inhibitors. 80 These authors further discuss that expression of β2-AR is also NF-kB-dependent, suggesting that termination of the inflammatory NF-kB cascade may in fact be driven by α-adrenergic stimulation of the NF-kB pathway inducing increased expression of β2-AR, which in turn antagonizes the pro-inflammatory challenge. Elevated NE may be associated with pro-inflammatory state of memory T-cells, suggesting chronically stressed individuals may be more susceptible to previously encountered antigens. 81 These complex communications shed light on how the variability of individual sensitivity to stress may alter the immune system’s ability to regulate the inflammatory response to stress effectively.
Dysregulation of the SNS has been implicated in pathogenesis of autoimmunity.79,82–84 Most attention in autoimmune pathogenesis has been focused on the β2-adrenergic receptor, as these receptors have been shown to cause bidirectional inflammatory responses depending on cell type and tissue of action. 79 Moreover, NE-mediated modulation of B-cells for antibody production is regulated by β2-adrenergic receptors. 85 Elenkov et al. 78 discussed that NE stimulation of β2-adrenergic receptors on T helper 1 (Th1) cells inhibited production of pro-inflammatory cytokines, such as TNF-α, interferon-γ (IFN- γ), IL-12, and simultaneously stimulated anti-inflammatory IL-10. As IL-12 is considered a Th1 response, and IL-10 a T helper 2 (Th2) one, these findings further suggest that NE stimulation may shift the T-cell dominance towards Th2 and humoral immunity. 78 This and other studies have thus suggested that stress via adrenergic stimulation may alter ratio of new CD4+ T-cells,1,7,82,86 which are critical in SLE as severity of disease often correlates to humoral response and antibody titer.87,88 One study even found that βadrenergic stimulation may increase anti-dsDNA antibodies in murine lupus models. 89
In SLE specifically, patients have also been shown to have heightened sympathetic responses to stress. 90 Some have suggested that this may be related to decreased ability to modulate the stress response. Such that, while the HPA axis is depleted and unable to produce the anti-inflammatory glucocorticoids in chronic stress, the SNS pathway is hyper-responsive, resulting in these systems becoming uncoupled. 91 In fact, in patients with other chronic rheumatic diseases, there is evidence of an impaired sympathetic response in B-lymphocytes. 92 RA patients are also more likely to have polymorphisms in β-adrenergic receptors, 93 further emphasizing individual risk for maladaptive stress response at a genetic level.
The sympathetic response can be difficult to measure, as plasma NE has organ-specific and regional differences in activity. 94 A clinical example of this is Raynaud’s syndrome, in which patients have been shown to have elevated heart rate and venous NE concentrations in the hand. 95 A common method to evaluate overall tone of autonomic nervous system has been heart rate variability (HRV), although this correlates more specifically with parasympathetic nervous system (PSNS) activity. 96 Nevertheless, mindfulness has been associated with improved PSNS activity, which in turn, regulates the SNS. 97
A recent study of pregnant women showed that those who engaged in weekly mindfulness meditation sessions for 5-week had decreased perceived stress scores and improved HRV. 98 SLE patients have abnormal HRV at baseline, which has been attributed to inflammatory changes, but not necessarily disease activity. 99 A study evaluating 24-weeks meditation program in lupus nephritis patients with CKD showed that meditation improved quality of life and HRV. 100 Decreased HRV has been associated with increased all-cause and cardiovascular mortality in diabetes, cardiovascular disease and essential hypertension. 101 Stress, although not in solidarity, has been implicated in development of each of these disorders. 102
The inflammatory modulation of stress via the SNS is complex, and varies by chronicity and tone of the PSNS. However, with the potential benefits of MBIs attenuating stress response via this pathway, further research is needed to more fully understand how this impacts SLE pathogenesis and activity.
Other systems associated with stress and inflammation
While the HPA axis and SNS pathways are the most commonly studied systems in the stress response, stress has varied effects throughout the body. Here, we discuss some of these changes as they have been implicated in SLE pathology and potential response to MBIs as areas of future research.
Amygdala activity
Increasing research has been dedicated to identifying connections between psychological stressors, neurological signaling, and inflammatory responses. The amygdala is a nucleus in the brain that is activated during a stress response. Interestingly, heightened neural activity in the amygdala in response to a stressor is associated with greater increases in inflammation by IL-6 levels. 103 It has also been shown that increased amygdala activity has been associated with increased risk for cardiovascular disease 104 and preclinical atherosclerosis. 105
In SLE, patients have evidence of higher amygdala activity. 106 Although it is uncertain whether this is related to chronic stress, inflammation or is a manifestation of disease pathology, it has been found that SLE patients with anti-NMDAR antibodies had more severe amygdala damage suggesting at least an element of inflammatory changes driving this. 107 Interestingly, in healthy individuals, participants in an 8-weeks MBSR program decreased amygdala activation in response to negative images. 108 In a review study examining brain function and activity before and after mindfulness interventions, some studies found increased activity in the pre-frontal cortex, hippocampus, insula, and cingulate cortex, areas involved in executive functioning, memory, perception, and emotional regulation. 109 There was simultaneously decreased activity in the amygdala and earlier deactivation to emotional stimuli. 109 These findings suggest that mindfulness may alter neuronal processing after only 8-week of regular practice.
There are no studies to-date evaluating amygdala responsiveness in SLE after MBIs, though as SLE patients have a heightened risk of cardiovascular disease, this intervention warrants further investigation in this population.
Sleep
Circadian rhythms intricately interact with both HPA axis and neural components of the SNSs. 110 Disturbed sleep patterns have been associated with increases in cortisol and activation of SNS. 111 Sleep loss accelerates aging and inflammation via activation of NF-kB in mononuclear cells. 112 This effect is more pronounced in women, which is thought to be related to sex differences in monocyte IL-6 production. 113 In mouse models, sleep deprivation was shown to accelerate disease onset of SLE as noted by earlier production of antinuclear antibodies (ANA) antibodies in NZB/NZW F1 mice. 114 Clinically, less than 7 h of sleep per night was associated with increased risk of developing SLE. 115 A systematic review found sleep disorders occur in more than half of patients with SLE and are associated with disease activity. 116 Moreover, poor sleep is associated with worse depression and fatigue in SLE. 117 SLE patients with insomnia symptoms had increased levels of perceived stress. 118
A recent systematic review showed that MBIs may improve sleep quality. 119 As several authors have noted the importance of sleep in rheumatologic disorders,120,121 evaluating MBIs on sleep quality and inflammatory changes in SLE would be needed further research.
Dopaminergic pathway
The dopaminergic system has also been linked to autoimmunity. 122 The function of dopamine receptors (DRs) depends on experimental conditions, specific subtype, and cell type. 123 Furthermore, even similar classes of receptors may have varying down-stream pathways and biological effects. Stress can induce hyperactivity of the ventral hippocampus to activate dopaminergic neuron activity in the ventral tegmental area; however, once stress has withdrawn, there is a long-standing compensatory decrease in dopamine neuron activity causing attenuation. 124 This aforementioned study suggests that afferent structures cause dysregulation of dopaminergic system; thus, targeting this system itself may not be as effective in uncovering and addressing originating pathology. Nevertheless, dopamine can modulate immune system directly via binding dopaminergic receptors on immune cells, and indirectly via modulation of prolactin release. 125 Prolactin can promote T-cell maturation, 126 modulates CD4+ T-cell response in a dose-dependent manner, 127 and can increase antibody production which may contribute to autoimmunity. 128 In fact, prolactin is now considered pathogenic in SLE. 129 Hyperprolactinemia has been found in 20%–30% of SLE patients, which is thought to be related to pituitary stimulation and inflammation. 130
In SLE, DR2 is under-expressed, and DR4 is over-expressed compared to controls. 131 As activation of DR2 may be effective at regulating and differentiating naïve CD4+ cells, these authors speculate that under-expression of DR2 may partly explain decreased regulatory T-cells (Treg) in SLE. Although the underlying mechanism for this imbalance is likely multifactorial, mouse studies have shown DR2 in the amygdala are crucial in modulating hormonal responses to stress. 132 Meditation has been shown to increase dopamine in midbrain structures; 133 however, the effect of MBIs on the dopaminergic pathway in SLE and prolactin release has not been explored.
Genetic variation
Toll-like receptors (TLRs) recognize specific patterns, are part of the innate immune system and have been implicated in several disease states. 134 Sex differences are also seen in TLR immune responses, 135 which may partly explain higher incidence of autoimmunity in females. However, TLR signaling pathways are necessary for induction of acquired immunity and transitioning to Th1 cell responses. 136 TLR7 and TLR9 are endogenous receptors that recognize viral RNA and DNA, respectively, and have been implicated in pathogenesis of SLE.137–139
TLR7 and TLR9 induce signaling via the myeloid differentiation primary-response protein 88 (MyD88), which then ultimately activates NF-kB signaling. 140 Interestingly, in MRL lpr/lpr mice which spontaneously produce ANA and anti-dsDNA antibodies, inactivation of MyD88 gene stopped production of these autoantibodies. 141 MyD88 pathway is responsible for down-stream activation of NF-kB, and, in a separate but related pathway, also activates type 1 interferon (IFN) 142 This is relevant, as type 1 IFN has been implicated in SLE pathogenesis and is not always responsive to glucocorticoids. 11
Clinically, SLE patients have been noted to have aberrant CD40-triggered NF-kB activity in B-cells. 143 Moreover, SLE patients in Mexico have been found to have higher levels of TLR7, MyD88 and IFN-α in B- and T-lymphocytes compared to age-matched healthy controls. 144 This suggests a genetic component may place these patients at greater risk for stress-induced inflammation. This has implications for treatment as hydroxychloroquine (HCQ) has multiple actions on TLRs, 145 though primarily acts on TLR9 receptor to modulate B-cell activity and decrease inflammation. 146 This is notable, as patients who are treated with HCQ prior to disease onset delay developing first clinical symptom and SLE classification. 147 Furthermore, lower serum HCQ levels in SLE patients also correlated with increased risk of disease exacerbation. 148 Interestingly, HCQ does decrease Th17 inflammatory cytokines, IL-6, IL-17, and IL-22. 149
Stress may also induce epigenetic changes associated with immune dysregulation. 150 Although few studies have evaluated genetics and mindfulness, one study did show that genetic variation in genes coding the muscarinic acetylcholine receptor M2, dopamine receptor D4, and μ1 opioid receptor was significantly associated with how responsive an individual would be to MBCT. 151 Another study identified epigenetic changes in long-term meditators compared to controls, finding 64 differentially methylated regions, 48.4% of which were linked to other common diseases such as psychiatric disorders, cardiovascular disease, and cancer. 152 Birmingham et al. 153 showed that lupus nephritis patients with specific serotonin receptor 1A-1019G allele were more susceptible to perceived stress, and had more frequent flares. This suggests that genetic variation may also contribute to risk of developing immune dysregulation due to stress and, once pathology develops, a subsequent flare. Therefore, understanding any stress-related pathology may not only be relevant in understanding disease pathogenesis, but becomes essential in disease management and may be more imperative in susceptible patients.
An extensive review discussing epigenetic changes associated with stress, HPA axis, SNS, and gut-barrier function suggested that mindfulness likely improves inflammation on multiple levels. 154 One hypothesis suggests that MBIs reverse or attenuate gene expression of inflammatory reactions induced by stress, specifically via the NF-kB pathway.155,156 Although these links are still not fully understood, mounting evidence suggests that stress may be a trigger for SLE onset and flares. Thus, exploring avenues for stress management in SLE, as well as in individuals with a predisposition towards autoimmune disease, is warranted.
Discussion
Increasing research has been dedicated to identifying connections between psychological stressors, neurological signaling, and immune system responses. It is notable that despite unclear etiology for rheumatic diseases, there is increasing evidence that these patients have a maladaptive stress response. Sharif et al. 1 describe several mechanisms by which stress and autoimmune processes are linked, and discusses RA, SLE, thyroid disease, and others. While the relationship is intricate and complex, inflammatory changes in response to stress in a maladaptive or dysregulated pattern are common themes. In rheumatologic diseases, patients present with distinct phenotypic profiles that are differentiated clinically. Although the clinical phenotypes are likely more complex than currently understood, extrapolating that each syndrome may have distinct cytokine and immune cell profiles can be assumed. For example, in myositis, rheumatologists, and immunologists can make clinical decisions by including both myositis-specific and myositis-associated antibody information, as some of these have been associated with specific phenotypes within myositis patients. 157 Similarly, SLE patients have distinct cytokine and immune cell profiles.158,159 Dysregulation of regulatory T-cells (Treg) and an imbalance between Treg and Th17 cells has been implicated in the inflammatory response and pathogenesis of active SLE. 158 It has further been shown that IL-17, which is produced by Th17 cells, is over-expressed in undertreated SLE patients. 160 However, SLE patients are not completely homogeneous, with some developing comorbidities that others may not. For example, not all SLE patients have anti-NMDAR antibodies; yet, those who do, have more severe amygdala damage, 107 suggesting that the dysregulation pattern in these patients may be different. This further emphasizes the nuance of the stress response at an individual and potentially genetic level. This coincides with epidemiologic findings of overexpression of TLR7, MyD88, and NF-kB in SLE, 144 as well as more β2-adrenergic polymorphisms in RA patients. 93
Understanding overlapping drivers of pathology may not only aid in discovering ways to prevent or attenuate autoimmune activity, but also treat comorbid conditions in SLE patients. Depression is one of the most common psychological comorbidities in SLE that often goes undertreated. 161 Although the mechanism of depression in SLE is likely multifactorial, a clinical trial showed patients treated with adjunct celecoxib in addition to standard fluoxetine had significantly improved depression compared to patients on fluoxetine alone. 162 Another study found that severity of depression correlated with severity of disease in SLE. 163 While these findings suggest there may a component of inflammation contributing to depression in SLE patients, it is unclear if depression is a manifestation of neurologic disease in SLE, a consequence of generalized immune dysregulation, or an underlying predisposition in these patients. However, even outside of the realm of autoimmunity, immune dysregulation, and inflammation has been implicated in numerous mental health conditions, including depression, PTSD, and anxiety.164,165 Therefore, targeting underlying inflammatory and immune dysregulation mechanisms associated with stress would be a novel approach to prevent and treat morbidity in all patients with stress-related disorders, and may be particularly critical in those at risk for developing autoimmune disease.
Summary of studies of SLE and mindfulness-based interventions (n = 5)
Conclusion
Stress and autoimmunity share a complex, multifaceted relationship. Pathogenesis of autoimmunity involves genetic, hormonal, immunologic, and environmental factors. However, increasing evidence suggesting that stress contributes to SLE onset and flares is undeniable. Maladaptive stress responses due to chronic stress is seen on a physiologic level via decreased responsiveness of the HPA axis and increased tone of the SNS. These changes cause down-stream pro-inflammatory effects that alter the immune system and may affect some patients more severely than others. MBIs have been shown to improve stress response, and potentially induce anti-inflammatory changes at an epigenetic level. Although no studies to-date have shown anti-inflammatory effects or change in disease activity from MBIs in SLE, there is sufficient evidence that MBIs improve quality of life, anxiety, and depression symptoms in patients with SLE. More research is needed to evaluate whether regular practice of MBIs may alter inflammatory milieu in SLE.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
