Fatigue in patients with systemic lupus erythematosus: the role of dehydroepiandrosterone sulphate.

Fatigue is a major problem in systemic lupus erythematosus (SLE), but the physiological substrate of this fatigue is largely unclear. To examine if low levels of dehydroepiandrosterone (DHEA) and its sulphate DHEAS play a role in SLE fatigue, we compared: 1) DHEAS levels and fatigue between 60 female patients with SLE with low disease activity (31 using, 29 not using prednisone) and 60 age-matched healthy women, and 2) fatigue between patients with SLE with low and normal DHEAS levels. Serum DHEAS levels were determined with an Advantage Chemiluminescense System. The Multidimensional Fatigue Inventory (MFI) was used to assess fatigue. Patients were more fatigued (p ≤ 0.001) than healthy women and more often had below-normal DHEAS levels (p < 0.001). Patients using prednisone with low and normal DHEAS levels reported a similar level of fatigue (p ≥ 0.39). Patients with low DHEAS levels not using prednisone reported less fatigue than those with normal DHEAS levels (p ≤ 0.03). Thus, our results indicate that low DHEAS levels in SLE are not - or even inversely - related to fatigue. After our previous finding that DHEA administration does not reduce fatigue, this result further indicates that low serum DHEA(S) levels alone do not offer an explanation for SLE fatigue.

Serum dehydroepiandrosterone sulphate levels and laboratory and clinical parameters indicating expression of disease are not associated with fatigue, well-being and functioning in patients with primary Sjögren's syndrome.

OBJECTIVES: The aim of this study was to compare serum dehydroepiandrosterone sulphate (DHEAS) levels and clinical and laboratory parameters reflecting expression of disease between female patients with primary Sjögren's syndrome (pSS) and age-matched healthy women and to examine in pSS patients the correlation of these variables with fatigue, well-being, and functioning. METHODS: Comparisons were made between 60 female pSS patients and 60 age-matched healthy women. We assessed questionnaire scores of general fatigue, depressed mood, mental wellbeing, and physical functioning, tear production (Schirmer I test), tender point counts, serum DHEAS level, haemoglobin concentration, erythrocyte sedimentation rate, and serum immunoglobulin G. RESULTS: As compared to healthy participants, patients had more fatigue and depressed mood, reduced well-being and functioning, more dryness and pain, lower serum DHEAS levels, and more expression of disease as reflected by laboratory assessments (p≤0.001). In pSS patients, fatigue, well-being, and functioning correlated with tender point counts, but not with the extent of dryness and also not with laboratory assessments including serum DHEAS levels. CONCLUSIONS: The high prevalence of fatigue and reduced functioning in pSS patients might suggest a mediating role of generalised autoimmune processes. In the present study, clinical observations and laboratory assessments are not correlated with persistent fatigue and reduced functioning. Our results suggest that treatment of fatigue, well-being, and functioning, should target other variables than those examined in this study, preferably psychological variables or perhaps specific immunologic parameters.

Variability of fatigue during the day in patients with primary Sjögren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis.

OBJECTIVES: Fatigue is a common complaint of patients with primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). The aim of this study was to examine and compare in patients with these diseases the course of fatigue within the first hour after awakening and during the day, and to examine sleep disturbance as a potential determinant of fatigue. METHODS: Eight repeated measurements at 5 fatigue dimensions were assessed on 2 consecutive days in the natural environment of female patients with pSS (n=29), SLE (n=23), RA (n=19), and healthy women (n=52). Sleep disturbance of the previous night was assessed. Fatigue levels and the change of fatigue after awakening and during the day were analysed with analyses of variance (adjusted for age). RESULTS: The patients showed significantly elevated levels at all fatigue dimensions as compared to healthy participants. Fatigue levels decreased in the first hour after awakening in patients with SLE and RA, but increased or did not change in patients with pSS. Fatigue progressively increased during the remainder of the day for all patient groups. Sleep disturbance correlated with overall fatigue levels, but hardly with the change of fatigue within the first hour after awakening. CONCLUSIONS: Our study confirms the presence of increased fatigue in patients with pSS, SLE, and RA. Patients with pSS failed to show a decrease in fatigue in the first hour after awakening. Future research should examine the causes of this difference in fatigue after awakening.

Effects of dehydroepiandrosterone on fatigue and well-being in women with quiescent systemic lupus erythematosus: a randomised controlled trial.

OBJECTIVE: Dehydroepiandrosterone (DHEA) has been reported to improve fatigue and reduced well-being. Both are major problems in patients with systemic lupus erythematosus (SLE), even with quiescent disease. Low serum DHEA levels are common in SLE. The present work investigates the effects of DHEA administration on fatigue, well-being and functioning in women with inactive SLE. METHODS: In a double-blind, randomised, placebo-controlled study, 60 female patients with inactive SLE received 200 mg oral DHEA or placebo. Primary outcome measures were general fatigue, depressive mood, mental well-being and physical functioning. Assessments were made before treatment, after 3, 6 and 12 months on medication, and 6 months after cessation of treatment. RESULTS: Patients from the DHEA and placebo group improved on general fatigue (p<0.001) and mental well-being (p=0.04). There was no differential effect of DHEA. The belief that DHEA had been used was a stronger predictor for improvement of general fatigue than the actual use of DHEA (p=0.04). CONCLUSIONS: The trial does not indicate an effect of daily 200 mg oral DHEA on fatigue and well-being, and therefore DHEA treatment is not recommended in unselected female patients with quiescent SLE. Clinical Trials Registration Number NCT00391924.

Effect of dehydroepiandrosterone administration on fatigue, well-being, and functioning in women with primary Sjögren syndrome: a randomised controlled trial.

OBJECTIVE: Dehydroepiandrosterone (DHEA) administration has been reported to improve fatigue, psychological distress, and physical disability. These are common features of primary Sjögren syndrome (pSS). We investigated the effects of DHEA administration on fatigue, well-being, and functioning in women with pSS. METHODS: In a double-blind, randomised placebo-controlled clinical trial, 60 female patients with pSS received 200 mg oral DHEA or placebo. Primary outcome measures were general fatigue, depressive mood, mental well-being, and physical functioning. In addition, pain, sicca complaints and disease activity parameters were measured. Patients were assessed before treatment, after 3, 6, and 12 months on study medication, and 6 months after cessation of treatment. RESULTS: Patients from both the DHEA- and placebo-treated group improved on general fatigue (p<0.001), mental well-being (p = 0.04), and depressive mood (p = 0.008). Physical functioning did not change (p = 0.44). Of the secondary outcome variables, complaints of a dry mouth diminished during treatment in both groups (p = 0.006), the erythrocyte sedimentation rate showed a decrease for the DHEA group (p = 0.02), and complaints of dry eyes improved in the placebo group (p = 0.01). The belief to have used DHEA was a stronger predictor for improvement of fatigue and well-being than the actual use of DHEA. CONCLUSIONS: Our study does not support a superior effect of DHEA over placebo in female patients with pSS. Both DHEA and placebo induce improvement of fatigue and well-being. This may suggest possibilities for cognitive behavioural interventions.

The effect of dehydroepiandrosterone on lumbar spine bone mineral density in patients with quiescent systemic lupus erythematosus.

OBJECTIVE: Because dehydroepiandrosterone (DHEA) is an adrenal steroid hormone with weak intrinsic androgenic properties that can be converted in peripheral tissues into more potent sex hormones, one might expect a positive effect of DHEA on bone mineral density (BMD). We evaluated the effects on lumbar BMD of oral DHEA, 200 mg/day, for 1 year in female patients with quiescent systemic lupus erythematosus (SLE). METHODS: The study subjects were 60 women with SLE. All participants gave informed consent to participate in a double-blind, placebo-controlled study on the effects of DHEA on fatigue and general well-being. BMD was measured with dual-energy x-ray absorptiometry (DEXA) at baseline and after 12 months. RESULTS: Fifty-eight patients (mean age 42.6 years) could be evaluated; 2 patients (both in the DHEA group) refused to undergo DEXA a second time. In premenopausal women, DHEA did not influence BMD significantly. There was a significant increase in BMD with use of DHEA in postmenopausal women who were not receiving bisphosphonates or estrogen-containing medications. This increase was not observed in the group receiving placebo. CONCLUSION: In premenopausal women with quiescent SLE, use of DHEA does not have a significant effect on BMD. DHEA may increase BMD in postmenopausal SLE patients if they are not already protected from bone loss by use of estrogens or bisphosphonates. Small numbers, due to the absence of stratification for menopausal status, and the use of antiresorptive agents at randomization preclude firmer conclusions based on the results of this study.

Serum cytokine levels related to multiple dimensions of fatigue in patients with primary Sjogren's syndrome.

OBJECTIVE: To test whether serum levels of selected cytokines relate to different dimensions of fatigue in patients with primary Sjögren's syndrome (pSS). METHODS: Sixty female patients with pSS filled out a questionnaire to assess multiple dimensions of fatigue. Scores were compared with values in a population based control group (n = 139). Levels of interleukin (IL)1beta, IL2, IL6, IL10, and tumour necrosis factor alpha were measured in serum with commercial sandwich ELISAs. The relationship between self reported dimensions of fatigue and these serum cytokine levels was determined. RESULTS: Patients with pSS had high scores at all dimensions of fatigue (p<0.001): general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. Fatigue levels were not related to serum cytokine levels. The incidental finding that reduced motivation was higher in patients with detectable serum levels of IL10 (p = 0.04) disappeared after correction for multiple testing. CONCLUSION: Fatigue is prominent in patients with pSS and involves all dimensions of fatigue. The findings do not suggest a widespread effect of circulating cytokines on multiple aspects of fatigue.

Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease.

OBJECTIVE: To investigate sympathetic (SNS) and parasympathetic (PNS) nervous system activity in patients with recently diagnosed rheumatoid arthritis (RA), and to analyze the association between activity of these systems and disease activity, and complaints that frequently occur in RA, viz., pain, fatigue, negative mood, and stiffness. METHODS: To assess sympathetic and parasympathetic nervous activity, the Pre-Ejection-Period (PEP) and Respiratory Sinus arrhythmia (RSA) were measured on two consecutive nights in a real-life environment in 25 patients with RA [19 female (f), 6 male (m), mean age 55.2 years) and 28 healthy controls (20f, 8m, mean age 55.8 years]. RESULTS: Patients showed a significantly shorter PEP (reflecting elevated SNS activity) compared to healthy controls, an effect that was most pronounced in those with active disease. RSA and the heart period did not differ between patients and healthy controls. The heart period was significantly associated with stiffness, but neither PEP nor RSA were associated with pain, fatigue, mood, or stiffness. CONCLUSION: Our study showed that cardiac sympathetic nervous system activity is elevated in RA, whereas cardiac parasympathetic activity remains at a normal level. Our results suggest that inflammatory stress rather than the common symptoms of RA challenge the SNS.

Fatigue in daily life in patients with primary Sjögren's syndrome and systemic lupus erythematosus.

Fatigue is a well-recognized complaint with major impact on daily life in primary Sjögren's syndrome (PSS) and systemic lupus erythematosus (SLE). Previous research has not taken into account several crucial aspects of fatigue. This study examined various aspects of fatigue in the daily life of patients with PSS and SLE and in healthy controls. We compared age-adjusted, repeated measurements of fatigue across the day of female patients with SLE (n = 20, mean age 43.4 +/- 11.3), with PSS (n = 28, mean age 53.7 +/- 13.9) and healthy participants (n = 30, mean age 50.5 +/- 13.4). General and physical fatigue was significantly higher in patients than in healthy participants. Groups did not differ with respect to average levels of reduced motivation or mental fatigue. Both general and physical fatigue and reduced activity varied significantly during the day. Adjusting for depressive symptoms, groups showed significantly different time courses during the day. In healthy participants and patients with SLE, fatigue first decreased and then increased, whereas a rather opposite course-at least for the first part of the day-was observed in patients with PSS. Using an ecologically valid assessment method, we demonstrated substantially higher levels of daily fatigue in SLE and PSS patients as compared to healthy participants, thereby jeopardizing these patients' quality of life. The effect of disease on variations in fatigue over the day should be the subject of further inquiry, especially as it might clarify underlying mechanisms.

Biopsychosocial mediators and moderators of stress-health relationships in patients with recently diagnosed rheumatoid arthritis.

OBJECTIVE: To investigate the mediating and moderating roles of social support, coping, and physiological variables in the relationship between life events and health status. METHODS: Psychological and biological measurements were taken in 54 patients (38 women, 16 men, mean age +/- SD 56 +/-14.4 years) with recently diagnosed rheumatoid arthritis (RA). RESULTS: Life events were correlated with psychological distress, but not with disease activity. No mediators for the relationship of life events with psychological well-being and disease activity were observed. In 40 tests, 4 moderators were found: Problem-focused coping, perceived support, diastolic blood pressure, and total number of lymphocytes were moderators of the relationship between daily hassles and health status (P < or = 0.05). CONCLUSION: Our study provides limited support for the notion that the interactions of life stress with biopsychosocial variables have an impact on health. None of these variables were found to be crucial mediators of stress-health associations in recently diagnosed patients with RA, but some provocative evidence was given that biopsychosocial variables may have a minor impact on stress-health relationships.

Experimentally challenged reactivity of the hypothalamic pituitary adrenal axis in patients with recently diagnosed rheumatoid arthritis.

OBJECTIVE: There is evidence that the hypothalamic pituitary adrenal (HPA) axis is subresponsive in patients with rheumatoid arthritis (RA). We assessed HPA axis responses to experimental stressors mimicking daily life challenges in patients with RA to determine whether HPA axis activity is associated with Th1 and Th2 activity. METHODS: ACTH and cortisol responses in reaction to the succession of a bicycle ergometer task, a cold pressor task, and a computerized Stroop Color-Word interference test, as well as basal Th1 and Th2 cell activity, were assessed in 29 patients (21 female, 8 male) with recently diagnosed RA (mean disease duration 29 wks, range 5-69), mean age 55.7 years, none receiving glucocorticoid treatment, and 30 (20 female, 10 male) healthy age and sex matched controls (mean age 54.1 yrs). RESULTS: Mean ACTH and cortisol levels did not differ between the groups (p > 0.10). Patients tended to have a less pronounced ACTH response (F2.50 = 2.7, p = 0.08) and had a significantly smaller cortisol response (P F2.50 = 6.1, p < 0.01) than healthy controls in reaction to the stressors. This difference in cortisol response was reduced, but remained significant when ACTH responsiveness was accounted for by entering it as a covariate (P F2.49 = 3.7, p = 0.03). ACTH and cortisol levels and responses were not associated (all p > 0.19) with basal interferon-gamma and interleukin 4 as reflections of Th1 and Th2 cell activity, respectively. HPA axis activity was not linked to current disease activity. CONCLUSION: Our findings show reduced HPA axis responsiveness in RA patients with recent diagnosis receiving longterm medication that is suggested to be located both at a hypothalamic/pituitary and at an adrenal level. It appears that common HPA axis activity accomplishes low amounts of cortisol release, which makes it difficult to determine an influence of endogenous cortisol changes on the Th1/Th2 balance.

Vagal cardiac control throughout the day: the relative importance of effort-reward imbalance and within-day measurements of mood, demand and satisfaction.

The effects of variables derived from a work stress theory (the effort-reward imbalance theory) on the power in the high frequency (HF_HRV) band of heart rate (0.14-0.40 Hz) throughout a work day, were determined using multilevel analysis. Explanatory variables were analysed at two levels: at the lowest level (within-day level), the effects of positive mood, negative mood, demand, satisfaction, demand-satisfaction ratio, and time of day were assessed. At the highest level (the subject level), the effects of sleep quality, effort, reward, effort-reward imbalance, need for control, type of work (profession), negative affectivity, gender and smoking on HF_HRV were assessed. Need for control has a negative effect on HF_HRV after controlling for time of day effects, i.e. subjects with a high need for control have a lower vagal control of the heart. In the long run, these subjects may be considered to be at increased health risk, because they have less of the health protective effects of vagal tone. The interaction between effort-reward imbalance and time of day has a positive effect on HF_HRV, i.e. the cardiac vagal control of subjects with a high effort-reward imbalance increases as the day progresses. It is discussed that this probably reflects reduced effort allocation, ensuing from disengagement from the work demands.

Chronic stress affects blood pressure and speed of short-term memory.

Subjects high and low on chronic stress (daily hassles) were engaged in a short-term memory-scanning task with (n = 12) or without (n = 12) an active listening task. Blood pressure and heart rate were obtained before and during the experiment. Subjects with high stress were slower in short-term memory processing, had higher systolic blood pressure and heart rate (at baseline and during task performance), and reported more health complaints than those low in stress. The processing efficiency theory may predict slower memory scanning in subjects with high chronic stress, as part of these subjects' working memory capacity is taken up by more worries than that of the other subjects. Speed of short-term memory was even lower for subjects with high stress when performing the memory task in the active listening condition.

The validity and reliability of the Dutch Effort-Reward Imbalance Questionnaire.

The reliability and validity of the Effort-Reward Imbalance Questionnaire were tested in 775 blue- and white-collar workers in the Netherlands. Cronbach's alpha revealed sufficient internal consistency of all subscales except Need for Control. With exploratory probabilistic scaling (Mokken) analysis, the psychometric qualities of the Need for Control scale were improved. With confirmatory factor analysis, the factorial validity of the Extrinsic Effort and Reward subscales was confirmed. A model with 3 separate dimensions for reward (status control, esteem reward, and monetary gratification) proved adequate, emphasizing the importance of distinguishing subscales. The congruent validity of the subscales and a hypothesized relationship with an external construct, health functioning, were confirmed.

Cortisol secretion throughout the day, perceptions of the work environment, and negative affect.

The effects of explanatory variables derived from a work stress model (the effort-reward imbalance model) on salivary cortisol were assessed. A multilevel analysis was used to distinguish the effects of single occasion and multiple occasion measurements of work stress and effect on cortisol. The single (or cross-sectional) factors include Effort-Reward Imbalance (ERI), need for control, negative affect, and other enduring factors (type of occupation, gender, and smoking). The multiple occasion measurements include momentary negative mood, Momentary Demand-Satisfaction Ratio (MD-SR), sleep quality, work load (workday versus day off), at work (versus not being at the workplace), and lunch. The effect of time of day on cortisol was controlled for before the effects of these variables were determined. Momentary negative mood but not trait negative affect was positively associated with ambulatory measured cortisol. The variables from the work stress model--effort, reward, need for control, and the multiple occasion measurements of demand and satisfaction--did not affect cortisol. As could be expected, time of day had an effect on cortisol, but a hypothesised interaction with momentary negative mood was not found. Additionally, the results show that the time course of cortisol differs between individuals and that the effect of sleep quality on cortisol can vary from person to person. This points to the necessity of continued efforts to single out sources of individual variability. The finding that variables derived from the effort-reward imbalance model are not related with cortisol does not support the hypothesis that ERI leads to short-term changes in cortisol, indicating no relation with hypothalamic-pituitary-adrenal (HPA) axis activity. On the other hand, the present results invite further qualification of negative affect as a potential determinant of HPA activity, at least, as far as can be deduced from cortisol measurements.

Immune responses to experimental stress: effects of mental effort and uncontrollability.

OBJECTIVE: Two important determinants of physiological stress responses have been identified, uncontrollability of the stressor and amount of effort involved in coping with the stressor. In the present experiment, we tried to identify the specific contributions of effort and uncontrollability to immune system responses to stress. METHODS: In a 2 x 2 design, effort and uncontrollability were manipulated independently of each other. Subjects participated in one of four experimental conditions, and their endocrine, immune, and sympathetic nervous system responses to the task were assessed. RESULTS: Effort had a stimulating effect on enumerative immunological parameters (CD8 and CD16+ cells) and on natural killer cell activity. The effect occurred immediately after the stressor and was transient. Regression models indicated that this effort effect may have been mediated by activation of the sympathetic nervous system. Uncontrollability influenced in vitro production of the cytokine interleukin-6, leading to decreased production 15 and 30 minutes after the stressor. Uncontrollability also led to an increased level of cortisol, but no evidence was found that the decrease in cytokine production was mediated by cortisol release. CONCLUSION: The results suggest that two major stressor characteristics, effort and uncontrollability, may have differential effects on the immune system.

High-density assessment of the IHS classification criteria for migraine without aura: a prospective study.

Fifty-six adult female patients with the clinical diagnosis of MwoA kept a diary 6 times per day for 10 consecutive weeks to record the occurrence, pain characteristics, and accompanying symptoms of headache. In order to avoid bias due to retrospection or expectancy the diary was programmed into palmtop computers which signaled the patients with a beep to enter the diary with a random-fixed time schedule: two signals occurred in, respectively, the morning, the afternoon, and the evening, but at different times for each day. The palmtop computers also warranted flawless data storage and automatic computations of response delay and missing values. Of the 339 attacks, 75% had a duration of 4-72 h and 94% confirmed the International Headache Society classification criteria for MwoA concerning pain characteristics and accompanying symptoms. Our results obtained for attacks in treated patients are highly comparable with the results of Rasmussen, Jensen, and Olesen (1991) obtained in the general population with unknown treatment of headache. Together, both studies support the IHS classification criteria for MwoA. The electronic Experience Sampling Method also allowed for an unbiased description of the course of treated MwoA attacks: 67% subsided in the first day. In the 16 attacks the characteristics and accompanying symptoms were present in 60-80% of the attacks at the first assessment (9.30 a.m.) with the exception of moderate to severe pain intensity (37%) and nausea or vomiting (31%). A waxing and waning of characteristics and symptoms over the day remained in about 30-40% of the attacks with a tendency towards increases in the evening (7.30 p.m. and 10 p.m.). The method is there for a replication of this study in untreated MwoA patients.

Experimentally induced stress in rheumatoid arthritis of recent onset: effects on peripheral blood lymphocytes.

OBJECTIVE: To examine the effects of experimentally-induced stress on the mobilization of peripheral blood lymphocytes (PBL) in patients with rheumatoid arthritis (RA) of recent onset. METHODS: Twenty-two (16 F, 6 M) patients (mean age 57.6 yrs.) and 23 (15 F, 8 M) healthy subjects (mean age 54.7 yrs.) were subjected to experimental stressors. The numbers of T-cells, B-cells, and NK-cells were determined before and after the completion of tasks inducing physical and mental effort. RESULTS: The change in PBL in response to stress was about equal for patients and healthy subjects (p > 0.75 in all PBL subsets). In patients as well as in healthy subjects, the correlations between PBL and cortisol changes in response to stress tended to be positive, while the correlations between PBL and cardiovascular changes were positive in healthy subjects, but zero or negative in patients. Moderate to high (0.32 < or = r < or = 0.55) correlations between PBL changes and pain were observed. CONCLUSION: Experimentally-induced changes in PBL (as well as cortisol) are normal in patients with early RA who are receiving long term medication, but correlations between these changes and autonomic nervous system responses are zero or negative. This apparent shift in the control of the change in PBL in response to stress is observed in particular in patients with more pain. The pathophysiological significance of these findings should be clarified in longitudinal studies.