Over the past two decades, reliable instruments for fatigue measurement have been developed that can be used both in day-to-day clinical practice and in clinical trials. Persistent fatigue is a common symptom reported by 15–22% of persons in the general population [5, 6]. Abnormal fatigue, defined as a sense of exhaustion that is not relieved by rest, is also a ubiquitous concomitant of chronic illness. Among patients with autoimmune disease, fatigue is a particularly prevalent and debilitating symptom. It has a profoundly negative impact on quality of life [7].

9.2Assessing Fatigue

Tools used to measure fatigue include a simple 10 cm visual analog scale (VAS) that provides a global rating, and brief questionnaires in which patients are asked to respond to a series of questions [8–10]. Among the “uni-dimensional” questionnaires that have been used in primary Sjögren’s syndrome (SS) studies (Table 9.1), the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale and the Fatigue Severity Scale (FSS) have acceptable psychometric properties, [9, 39]. Each of these instruments provides a composite fatigue score comparable to the global fatigue rating provided by a VAS [8, 9, 42]. The different questionnaires address slightly different aspects of fatigue, but comparisons between scales demonstrate convergent validity [15, 22] (Table 9.1). The reliability and validity of the FACITFatigue instrument (FACIT-F) and the FSS have been established in a variety of chronic rheumatic and nonrheumatic illnesses [9, 43]. The smallest difference in fatigue score that patients perceive as beneficial (minimal clinically important difference or MCID) has been evaluated with the FSS in RA and in SLE [44, 45]. The MCID of the FACIT-F was assessed in a sample of RA patients [9]. A minimally important difference for a fatigue visual analog scale of about 10% has been suggested for use in RA clinical trials and for interpretation of the fatigue VAS in day-to-day clinical practice [33]. There is need for agreement on a standardized version of a fatigue VAS and additional research to establish the sensitivity to change for the fatigue questionnaires in SS.

Fatigue influences the physical, emotional, cognitive, and even social aspects of life. Moreover, it frequently coexists with factors such as stress, mood disturbance, and sleep disorder that complicate the measurement of fatigue. Instruments with more complex structure such as the Multidimensional Fatigue Inventory and Profile of Fatigue provide a means to investigate relationships between different aspects (domains) of fatigue and physiologic or psychosocial variables [11, 46]. The Profile of Fatigue and Discomfort (PROFAD-SSI) provides specific profile of symptoms based upon descriptors used by patients with primary SS. Examples include fatigue, joint and muscle pain, and cold hands. Important domains are the physical (needing to rest, low stamina, weak muscles) and the mental experience of fatigue (difficulty concentrating and poor memory). The individual domains of physical and mental fatigue obtained with the Profile of Fatigue can vary independently of each other.

The FSS is simple to administer and has been widely used by investigators interested in the impact of fatigue among patients with multiple sclerosis and SLE, as well as primary SS, primary biliary cirrhosis (PBC), and chronic hepatitis C [47–50]. The nine item FSS index emphasizes the behavioral aspects of fatigue and assesses an individual’s perception of the degree to which fatigue limits his or her ability to function on a 7-point scale [8]. A score of ³4 indicates abnormal fatigue that limits physical activity [51]. Interestingly, nearly identical mean FSS scores of between 4.6 and 4.8 have been reported in primary SS, SLE, RA, multiple sclerosis, and primary biliary cirrhosis, disorders with heterogeneous organ manifestations and quite different demographics. The severity of fatigue experienced by persons with chronic inflammatory illness is similar despite differences in gender, age, and disease-specific organ manifestations [21, 39, 45, 47, 48].

Multiple studies have, in fact, demonstrated that psychosocial variables are significant predictors of fatigue in patients with rheumatic disease [27, 52, 53]. In a large cohort of primary SS patients, the predominant factors associated with fatigue as measured by the FSS were pain, depression, and helplessness [22]. Those same three variables predicted 71% of the variance in physical fatigue. Helplessness, a concept defined as the perception that patients have very little control over their symptoms, has been identified as a significant risk factor for fatigue in SLE and in multiple sclerosis as well as in primary SS. The relationship between fatigue and helplessness is consistent with cognitive theory that suggests that persons who see themselves as unable to influence or control their condition are more susceptible to fatigue and depression [54, 55].

In contrast to the associations detected between fatigue and behavioral variables, correlations between fatigue and laboratory variables such as the Westergren erythrocyte sedimentation rate and autoantibody titers are weak or inconsistent [25, 47, 52, 56, 57]. In SLE, variables associated with fatigue include older age, helplessness, abnormal illness behavior, and any previous neurologic disease manifestation, but not laboratory measures or disease activity [58]. Similarly, multiple diseaserelated variables, including sicca symptom severity, salivary gland function, immunoglobulin titer, hemoglobin concentration, and absolute lymphocyte count were not associated with physical or “mental” fatigue in primary SS [22].

9.3Prevalence of Fatigue and Impact of Fatigue

on Health-Related Quality of Life in Primary SS

In persons with primary SS, the prevalence of abnormal fatigue is about 70% [11, 20, 22, 31]. Seropositive and seronegative patients are equally likely to report clinically significant fatigue [22]. The prevalence of chronic fatigue was reported to be 22% among healthy working adults in a population-based study [59]. Fatigue, pain, and cognitive symptoms comprise a commonly experienced set of overlapping symptoms. The mechanisms underlying such symptom clusters are largely unknown (Table 9.2).

Table 9.2 Hypothesized individual risk factors for symptom clusters associated with primary Sjögren’s syndrome

Possible Outcomes

Fatigue

Sleep disorder

Central sensitization (allodynia and hyperalgesia)

Depression

Cognitive Dysfunction

Patients with similar fatigue intensity can have widely divergent levels of disability [26]. Stratification of subjects according to the level of disability is therefore important in assessing fatigue. The SF-36 is a widely used measure of health-related quality of life designed for use in population surveys [60]. Each of the eight SF-36 subscales has a range of 0–100, with 100 indicating very good health status. Any score below 50 is considered below the population average. Population norms are available for demographic subsets categorized by age and gender. SF-36 scale scores provide a means to measure the effects of illness on each of eight domains of health