Stress and SLE

by Nathan Wei, MD, FACP, FACR

Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.

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Lupus is an autoimmune disease. In autoimmune diseases, the body attacks its own healthy cells and tissues.

This leads to inflammation and damage of body tissue. Lupus can affect all parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain. Although people with the disease may have many different symptoms, some of the most common ones include extreme fatigue, painful or swollen joints (arthritis), unexplained fever, skin rashes, and kidney problems. Lupus is a rheumatic disease. The rheumatic diseases are a group of disorders that cause aches, pain, and stiffness in the joints, muscles, and bones.

At present, there is no cure for lupus. However, the symptoms of lupus can be controlled with appropriate treatment. Lupus is characterized by periods of illness, called flares, and periods of remission. Understanding how to prevent flares and how to treat them when they do occur helps people with lupus maintain better health. Intense research is underway and scientists funded by the NIH are continuing to make great strides in understanding the disease, which ultimately may lead to a cure.

Adams, Dammers, Saia, Brantley, and Gaydos (1994) researched the effect of perceived stress on patients of Systemic Lupus Erythematosus (SLE). Earlier research in this area found a link between a high level of reported stress and worsening of Lupus patients' condition. In fact, a very high percentage of patients actually attributed their condition's worsening to a major stressful event in their lives. These early studies however, have three major flaws (as reported by Adams et al. (1994)). "First most studies regarding psychiatric symptoms are solely descriptive in nature...Second, studies have utilized only retrospective report of major life events as a measure of stress. As noted by Zimmerman (1983), medical patients may report more stress during times of illness... Third, the use of psychometrically validated stress measures is sorely lacking... Additionally, the potential role of minor life events has been ignored." This study attempts to address each of these shortcomings. Subjects in this experiment completed surveys that assessed major life events (number and intensity), minor daily stressors (number, intensity), and symptom history. The findings of this research were that there is support for a correlation between stress and SLE intensity. Also, a relationship was shown between major stress, minor stress, and SLE symptom levels. A surprising finding was that minor life events seemed to account for most of the effect on the severity of the symptoms.

P1.41, Abstract #24


C. Pawlak, R. Jacobs, M.S. Lombardi, A. Kavelaars, C.J. Heijnen, R.E. Schmidt, and M. Schedlowski

Hannover Medical School, Divisions of Medical Psychology, and Clinical Immunology, Germany; Division of Immunology/Hematology, Utrecht University Hospital for Children and Youth, The Netherlands; and Division of Medical Psychology, University of Essen, Germany

Experimental data demonstrate an abnormal stress-induced reactivity in the sympathetic nervous system and cellular immune functions in patients with chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Therefore, our study analyzed sympathetic activity, catecholamine production, lymphocyte subpopulations, cytokine production, and adrenergic receptor expression before and after exposure to acute psychological stress (public speaking) in SLE (n=15) and RA (n=9) patients, and healthy controls (n=15). Blood samples were drawn before, immediately after, and one hour after stress exposure and analyzed for catecholamine concentrations, lymphocyte subpopulations, intracellular cytokines and mitogen-induced cytokine production (IL-2, IL-4, IL-6, IL-10, IFNg) as well as adrenergic receptor expression on PBMC. Data show pronounced stress-induced increases in heart rate and blood pressure in all groups. However, lymphocyte numbers, in particular NK cell numbers (CD16+/CD56+), increased in healthy subjects and RA patients but significantly less in SLE patients. NK activity increased in controls but not in patient groups. Adrenoceptor expression after acute stress was enhanced in healthy individuals and RA patients but not in SLE patients. The number of IL-4+ cells increased after stress in SLE patients but not in RA and healthy control subjects. These data suggest that healthy subjects and patients with chronic inflammatory diseases, in particular SLE, differ in their immunological response to acute psychological stress.

Supported by Volkswagen-Foundation, Germany, grant I/72 032/031.

Autoimmune disorders result from the combination of several predisposing factors, that include the relationships between epitopes of the trigger agent (i.e. virus) and histocompatibility epitopes (i.e. HLA), the status of the stress response system including the hypothalamic-pituitary-adrenocortical axis (HPA) and the sympathetic nervous system (SNS), as well as the gonadal hormones (hypothalamic-pituitary-gonadal axis = HPG).

The activation of the hypothalamic-pituitary-adrenocortical- sympathetic nervous system (HPA-SNS) axes in SLE, has already been discussed as one of the factors generally involved in the complex pathogenensis of this autoimmune disease.

Therefore, the activation of the stress response system (HPA = SNS) has been evaluated in different clinical stages of the disease and its alteration has been implicated in the pathogenesis of the neuropsychiatric SLE (NP-SLE).

A number of studies have found that a high proportion of individuals with SLE report that major stressful life events and daily hassles exacerbate their SLE symptoms, including greater levels of disease activity and severity, joint pain, abdominal distress, rash, and disability. In fact, a recent investigation found that the majority of individuals with SLE believed that stress played a role in the onset and flare-up of their condition.

A recent study examined the link between major and minor stressors, disease activity and damage variables, and changes in functional disability in women with SLE over an eight month period. Hierarchical multiple regression indicated that major negative life events, preceding six months before baseline measures were predictive of changes (13% of the variance) in disability in SLE even after accounting for baseline disability scores and depression. However, minor daily hassles were not found to be related to changes in disability levels over time. The authors concluded that there may be a differential role of various forms of stress on SLE-related outcomes.

Recently, a study examined the role of disease-related and psychosocial variables, including self-reported distress and severity of daily hassles, in the overall health of individuals with SLE. The results indicated that the severity of daily hassles and SLE disease were the best predictors of individual’s perceptions of their global physical health.

Further, psychological distress accounted for a significant proportion of variance in both disease activity and damage. An elegant study with a computer supported questionnaire conducted during a period of 6 consecutive months reported the influences of daily stress (and obviously effects on HPA activation) in 41 patients with SLE. The study found a positive correlation between the variables sleep quality, psychophysical health, mood, stress and anti-double-stranded DNA antibodies or antinuclear activity in SLE patients.

In other words, individuals who experienced greater levels of distress and severity of daily hassles reported poorer global physical health and had greater levels of SLE disease activity and damage further supporting the role of stress in both the etiology and exacerbation of SLE.

We already discussed that generalized, systemic immune activation in SLE stimulates the HPA axis as a normal mechanism to minimize the damaging effects of inflammation.

However, chronic activation of the HPA axis has also neurologic side-effects that share some feature s with NP-SLE. Brain structures bearing the brunt of injury in chronic stress are the hippocampus and amygdala and their connections. Clinical features of chronic stress include abnormalities such as anxiety, memory loss, and behavior disturbances.

Chronic stress in patients with SLE could results from chronic immune stimulation, chronic ischemia, and seizure activity.

There are several reasons to hypothesize that the HPA axis and particularly a regulatory limb from the hippocampus, is involved in the genesis of symptoms of NP-SLE. For example: cytokines IL-1 and IL-6 are elevated in the CSF of patients with SLE; prolactin appears elevated and bromocriptine (although toxic) may influence disease activity; seizures are a frequent and often presenting feature of SLE and imaging abnormalities in the temporal lobe are prominent.

Recently, adrenocorticotropin, androstenedione (ASD), cortisol, or dehydroepiandrosterone sulfate (DHEAS) before and during a human corticotropin releasing hormone (hCRH) test in patients with moderately active SLE undergoing low dose longterm glucocorticoid therapy were studied to examine these hormones in relation to interleukin 6 (IL-6) or tumor necrosis factor (TNF).

Serum levels of hormones and cytokines were measured before and during an hCRH test. The results of 12 patients with SLE were compared to 12 healthy subjects (HS) and 12 healthy subjects given prior short term prednisolone (HS+P). Baseline and stimulated serum ASD, cortisol, and DHEAS were found lower in patients with SLE vs. HS (p<0.005), but baseline and stimulated plasma adrenocorticotropin was normal in SLE. In SLE, but not in HS+P or HS, baseline and stimulated DHEAS was low in relation to cortisol or ASD (i.e., shift from DHEAS to cortisol or ASD). In patients with SLE, baseline and stimulated serum levels of adrenal hormones were lower in relation to IL-6 or TNF compared to HS or HS+P (p< 0.001). In contrast, in SLE patients, the baseline and stimulated pituitary hormone adrenocorticotropin was normal in relation to these cytokines. The study showed a marked adrenal insufficiency and a shift in steroidogenesis to cortisol in patients with SLE, but a completely normal pituitary function (in absolute values and in relation to IL-6 or TNF)

This may depend in part on prior longterm glucocorticoid therapy and changes of steroidogenesis due to cytokines. The situation in patients with SLE was not mimicked by high dose short term prednisolone in healthy subjects.

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