status: physical activity, usual role functioning, pain, general health, vitality, social activity, role functioning difficulties caused by emotional problems, and mental health. The domain scores can be used to derive two summary measures of health status: physical (PCS) and mental (MCS) summary measures. The SF-36 has been applied in multiple rheumatic conditions for the purposes of assessing relative health status, the effectiveness of interventions, and the validity of new disease-specific questionnaires [61, 62].

Substantial reduction in all domains of health-related quality of life has been demonstrated in primary SS comparable to the reduction in quality of life in patients with RA and fibromyalgia.[31] Irrespective of the instrument used to assess fatigue, diminished quality of life is strikingly linked to fatigue in multiple autoimmune disorders including primary SS [31, 49, 57]. In a recent large community survey of primary SS subjects, Physical functioning (mean = 35.0), Energy/fatigue (mean = 38.9), and General Health (mean = 45.5) were the domains that were ranked lowest by primary SS patients [23]. General health among primary SS patients was uniquely predicted by somatic fatigue (pain, mental fatigue, depression, age, and sicca severity were not significant predictors in the model), whereas emotional well-being was predicted by depression and pain severity.

Oral sicca severity as measured by the PROFAD-SSI was also associated with reduced general health, social functioning, and lower energy levels and greater fatigue levels [63]. Patients with the most severe sicca symptoms report the greatest impact on all activities of daily life: physical activity, daily activities, social interactions, mental alertness, sexual relations, career productivity, and choice of occupation. Interestingly, in a large survey of patients with RA, noninflammatory rheumatic disorders, and fibromyalgia, the prevalence of sicca symptoms was increased in all three patient groups. The likelihood of self-reported sicca symptoms was related to illness severity, therapy, and psychological distress [64].

9.4Relationship of Fatigue to Cognitive Symptoms and to Depression

Affective disorder is associated with fatigue in essentially all studies. In a recent survey of persons with primary SS in the United States, the prevalence of depressive symptoms was 37% [22]. This figure is similar to the prevalence of self-reported depression in SLE (32%) [65]. Fatigue and depression have a dual interaction in that depressed patients typically report the most severe fatigue and patients with fatigue are more likely to be depressed. However, clinicians should be cautious in attributing pain and fatigue to depression in primary SS, because the nature of the relationship between fatigue and depression has not been elucidated. Further, the majority of primary SS patients with fatigue are not depressed [22]. Depression could contribute to fatigue through psychological effects: for example, the patient’s reaction to having a chronic illness. It is also possible that parallel but independent biological mechanisms such as dysregulated cytokine networks contribute to the underlying pathophysiology of both fatigue and depression [19].

Patients with primary SS and SLE often refer to a symptom colloquially referred to as “brain fog.” Although subjective memory loss and concentration difficulties are frequently reported by primary SS patients, the contribution of cognitive dysfunction to quality of life and to fatigue is less clear. Cognitive symptoms do not contribute to disability independently of depression [23]. Attention and memory are cognitive domains that are very sensitive to depression. Cognitive function measured objectively, particularly performance on verbal memory and attention tests, correlates with perceived problems in memory and attention in primary SS, but larger studies are needed to assess the contribution of depression to mild cognitive dysfunction [66].

The neuroanatomic substrate of cognitive difficulties in primary SS has been explored recently. In unselected primary SS patients, conventional magnetic resonance imaging of the brain did not demonstrate clinically relevant abnormalities [21]. However, two recent pilot studies that combined detailed neuropsychometric assessment with sensitive brain imaging modalities suggest a different picture of neuropathology in primary SS. Cerebral perfusion abnormalities in brain single photon emission computerized tomography (SPECT) imaging in primary SS patients correlated with deficits on psychometric tests of executive function and attention [67]. In addition, a high-resolution quantitative diffusion tensor imaging (MR-DTI) study suggested a very localized pattern of white matter injury in primary SS subjects who complained of subtle cognitive impairment. MR-DTI demonstrated abnormalities localized to the inferior frontal white matter in primary SS patients with mild difficulties in verbal memory and attention [68]. The inferior frontal region is involved in memory processing and regulation of the impact of negative emotion on memory [69–71]. Observation of abnormality localized to inferior frontal white matter in primary SS is especially intriguing in light of recent data that link fatigue in primary SS with elevated levels of inflammatory cytokines within the cerebrospinal fluid [72].

Brain imaging studies have also demonstrated interesting correlations between fatigue and imaging parameters in both multiple sclerosis (MS) and SLE [73, 74]. Functional MRI demonstrated different brain activation patterns in fatigued versus nonfatigued MS patients [75]. Moreover, abnormal recruitment of frontal-thalamic circuitry was associated with interferon-induced fatigue [75]. Another functional MRI study demonstrated that cognitive fatigue in MS, operationally defined by slowed performance on a specific mental task, relates to impaired interactions between functionally related cortical and subcortical areas [76]. Evidence of correlation between decreased perfusion of the thalamus and increased fatigue provides further structural support to theories relating fatigue to impaired connectivity between cortical and subcortical regions [77]. In MS patients studied with proton magnetic resonance spectroscopy, fatigue (FSS) was associated with diffuse axonal injury. This association was independent of T2 lesion volume, age, disease duration, and disability score. These findings suggest that increased recruitment of cortical areas is responsible for the patients’ sense that the effort required to perform actions is disproportionately high [78]. In primary SS, a pilot brain diffusion tensor imaging study demonstrated correlation of white matter injury in the caudal anterior cingulate gyrus with physical

fatigue (FSS) and with pain severity [79]. Although additional work is needed to confirm the DTI data, quantitative computer-assisted brain imaging has the potential to provide a window into brain microstructure and to provide clues to the origin of the subtle cognitive dysfunction in primary SS.

9.5Fatigue Viewed From the Physiological Perspective: Relationships Between Fatigue, Sleep Quality, and Neuroendocrine Function

Since the 1920s, attempts to evaluate fatigue from a physiologic perspective have been viewed skeptically. Although fatigue is a subjective experience that can be measured only by asking patients to describe how they feel, the experience of fatigue assessed through the use of fatigue questionnaires has been shown to correlate with physiologic variables. Several studies have addressed cardiopulmonary exercise performance [41, 51, 80]. There are limited data on sleep quality in primary SS and SLE, yet poor sleep quality is reported by as many as 62% of patients with SLE and 75% of patients with primary SS [81–83]. In primary SS and in SLE, fatigue is associated with both reduction in aerobic capacity and with poor sleep quality [41, 73, 84].

Sleep quality is amenable to measurement with validated self-report questionnaires such as the Pittsburg Sleep Quality Index (PSQI) [85] and by objective assessments such as polysomnography and actigraphy. Polysomnography, the classic “sleep study,” represents the gold standard for evaluation of sleep quality. However, because of its high cost and intrusive nature, relatively few data are available regarding the effect of sleep quality on daytime fatigue in patients with autoimmune disease. Actigraphy involves the analysis of data obtained with a laser wrist band worn by the subject during the night. The subject records the time he or she goes to bed and the time of awakening in a sleep diary. The propulsive movements of the upper extremity are recorded on a computer chip. Actigraphy, which provides a reliable record of sleep duration and sleep fragmentation, correlates well with polysomnography studies conducted in a sleep laboratory [86]. Recently the relationship between daytime fatigue and objectively measured sleep quality was reported in primary SS and RA subjects [35]. For individuals with both conditions, a night of worse discomfort and poor sleep was followed by more severe fatigue compared with the individual’s average.

Disturbed neuroendocrine function has been suggested as a cause of both fatigue and sleep disorder [87]. Adrenal axis hypofunction has been reported in primary SS [88], but the precise nature of the relationship between neuroendocrine function and fatigue in primary SS has been difficult to define. The role of the autonomic nervous system in mediating some aspects of fatigue also remains speculative. There is evidence of both parasympathetic and sympathetic nervous system dysfunction in primary SS compared to controls. Cardiovascular reflexes (tilt test, heart rate variability) are generally reduced in primary SS patients, but the clinical relevance of these

findings is unclear [89–91]. High levels of fatigue correlated with hypotension in one study [92]. However, data on autonomic nervous system function must be interpreted cautiously because the correlation between the results of autonomic reflex tests and autonomic nervous system symptoms is poor. Symptoms of autonomic dysfunction, but not the results of reflex tests, are significantly associated with fatigue, anxiety, and depression [36].

In animal models, the behavioral response to infection or injury is a stereotypical behavioral alteration termed sickness behavior [93]. Behavioral aspects of sickness include depression, lethargy, the need to sleep, failure to feed, reduced social behavior, and increased sensitivity to pain [94]. These behavioral manifestations are presumed to be mediated by the effects of inflammatory cytokines acting upon the hypothalamic-pituitary stress response system. Cytokine release provides a signal that triggers the set of metabolic and behavioral changes that are collectively called “sickness” [93]. For example, IL-1 can induce slow wave sleep, loss of appetite, and enhanced production of corticotrophin releasing hormone [88, 95]. The modulation of sleep by inflammatory cytokines is one example of altered homeostasis by centrally acting cytokines which has been well studied in human models of illness [96].

Increased levels of IL-1Ra in cerebral spinal fluid are associated with increasing fatigue in primary SS patients, indicating that the activated IL-1 system is a possible biological factor associated with fatigue [20]. Additional evidence for a link between inflammatory cytokines and fatigue is suggested by the finding that soluble IL6R had a strong inverse correlation with fatigue in one study of primary SS [14]. IL-6 stimulates the HPA axis via IL-6 receptors to produce stress hormones counteracting fatigue. Disruption in neuroendocrine function regulated by IL-6 could play a role in mediating fatigue. However, few studies have explored the link between circulating inflammatory cytokines and fatigue, and the data in primary SS are inconsistent [16]. The IL-6 system is thought to regulate dehydroepiandrosterone sulfate (DHEA-S). While DHEA levels are decreased in primary SS patients [87, 88], DHEA treatment had no effect on fatigue in primary SS in two studies [13, 89]. Although improvement in fatigue did not occur with DHEA, even at supraphysiologic doses, there is evidence consistent with the hypothesis that defective processing of DHEA could contribute to fatigue in primary SS [90].

9.6Relationship Between Fibromyalgia and SS

Features of fibromyalgia (FM) include fatigue, generalized pain, and the presence of multiple tender points on examination. Patients with chronic widespread pain and 11/18 tender points fulfill the ACR classification criteria for FM [101]. The reported prevalence of FM in the general population is about 2.0% [102]. Controversy continues as to whether FM is a distinct clinical disease entity or a universal human response to illness and stress. Irritable bowel syndrome, irritable bladder, and chronic fatigue syndrome overlap with FM, and clear differentiation between these disorders

is often difficult. It has been suggested that FM is not a specific disease entity but rather a condition in which the symptoms reflect difficulties in coping with various types of environmental stresses [103]. However, FM patients are not uniform, and the severity of psychological distress and behavioral disorders vary among patients meeting criteria for FM [104, 105]. Although no specific etiologic factors have been identified as causative of FM, a variety of stressors including trauma, history of abuse, and viral infection have been linked to the onset of the illness.

In patient surveys, as many as 22.1% of patients with SLE and 17.0% of patients with arthritis appear to have clinical features consistent with the diagnosis of FM [106]. Patients recognized as meeting ACR criteria for FM typically present with high levels of polysymptomatic distress including fatigue, cognitive symptoms, sleep disturbance, and decreased pain threshold [107]. The prevalence of FM among patients with definite primary SS is between 12% and 22% [108, 109]. The reason for the increased frequency of FM in persons with rheumatic disease compared to the general population is not well understood. A population-based cohort study demonstrated that high levels of cortisol after dexamethasone and high levels of cortisol in evening saliva were associated with a moderately increased risk of developing chronic widespread pain [110]. Thus, a reasonable hypothesis is that adrenal axis hypofunction predisposes some individuals with systemic autoimmune disease to the development of FM.

FM patients exhibit physiologic disturbances in central pain processing including decreased pain threshold (allodynia) and increased sensitivity to subthreshold pain stimuli (hyperalgesia.) A decreased threshold to multiple types of noxious stimuli including heat and noise has also been demonstrated in FM and is characteristic of central sensitization. Dysregulation of the stress response system could be a final common pathway resulting in diffuse widespread pain and chronic fatigue which are then maintained by central sensitization mechanisms [111, 112]. A unifying hypothesis of FM and related disorders such as irritable bowel syndrome suggests that the somatic components represent biological amplification of sensory input, a paradigm that is supported by the results of functional imaging brain MRI studies in FM [113]. The cause of the abnormalities in central pain processing and the reason that disordered sensory processing at a central level is maintained in FM patients is not known.

The evaluation of pain mechanisms in primary SS patients is complex, because pain of nociceptive and neuropathic origin often coexist. Symptoms suggestive of neuropathic pain (burning, pins and needles sensation, numbness) are very frequently reported by patients with primary SS, but are also frequently reported by patients with FM in whom central sensitization is presumed to be the mechanism. Pain severity and pain interference with activities as measured by the Brief Pain Inventory were substantially greater in primary SS patients with positive sensory symptoms (paresthesia and burning discomfort.) Both positive and negative sensory symptoms (numbness) were more common in patients compared to controls in a recent large survey of primary SS [114]. These differences in sensory symptoms persisted between patients and controls when adjusted for depression and a history of FM, suggesting that nerve damage in the primary SS patients was the more likely explanation.

Distinguishing FM from primary SS with painful sensory neuropathy is especially challenging because the clinical neurological deficits in patients with primary SS and small-fiber neuropathy can be modest. In some patients with small-fiber neuropathy, the clinical examination is completely normal and ancillary tests (e.g., skin biopsy with evaluation of epidermal nerve fiber density) are required for diagnosis. Both neuropathic pain and nociceptive pain can lead to central sensitization, particularly in individuals with high anxiety and emotional distress [115].

Distinguishing FM from primary SS can also be problematic because of the overlap in clinical presentation. Fatigue is the presenting complaint in as many as 27% of primary SS patients; muscle pain is the presenting symptom in an additional 25% [63, 116]. Similarly, chronic fatigue, atypical Raynaud’s phenomenon, depression, and anxiety are highly prevalent in FM. Eighty to 90% of patients with either primary SS or FM are women, and routine laboratory testing, and results of radiologic studies are typically normal in both conditions [117]. Complaints of xerostomia may be present in as many as 70% of FM subjects [118]. The precise cause of the sicca symptoms in FM patients is not known, although it has been suggested that neurologic mechanisms could account for the sicca symptoms in the absence of gland inflammation.

Detailed bedside neurologic evaluation is especially helpful in those with complaints of neuropathic pain (Table 9.3). Evidence of small-fiber neuropathy (manifest by painful distal paresthesia and loss of distal sensation to pinprick) was found in 45% of outpatients with a definite diagnosis of primary SS [119]. The mechanism of sensory neuropathy is not known. Increased amounts of substance P and vasoactive intestinal peptide, in mast cells, plasma cells, and lymphocytes in primary SS, suggest that neuropeptides upregulated by inflammation may play a role in peripheral nerve damage [120]. Abnormalities on sensory testing are often subtle, and electrophysiologic studies are normal in patients with painful, predominantly,