symptoms in pSS, as might be expected in a chronic rheumatic disease, but that there is still some uncertainty as to the extent to which symptoms of fatigue and pain in pSS correlate with symptoms of low mood and psychological distress.

21.3.2.2 Fibromyalgia

Fibromyalgia (FMA) is another area of potential controversy due to the wildly different reported prevalence of FMA in pSS. Vitali et al. identiÞed FMA in 14 out of 30 patients (47%) [28]. In another Italian study, the prevalence was 22% [29]. In a single-center UK study, however, the prevalence was reported as 7Ð12% dependent on the criteria used and 5% in a comparator group of SLE patients [30]. In our UK cohort, the prevalence was 4.4% in pSS, 4.5% in SLE, 1.4% in RA, and 0% in the controls [2]. One potential explanation for these differences is the extent to which narrower criteria, such as the American College of Rheumatology (ACR) criteria, were used for the diagnosis of FMA. Similar controversies apply to SLE where many studies suggest a comparable prevalence of FMA of approximately 5% [2, 30], while other studies suggest a higher Þgure (e.g., 22% in Ref. [31]). Another possibility is that these are ÒrealÓ differences in FMA prevalence but reßect cultural factors in different countries. Nevertheless, the two UK studies are consistent in methodology and results in demonstrating a prevalence of 5Ð12% of patients fulÞlling ACR criteria for Þbromyalgia and demonstrating that Þbromyalgia does not, of itself, account for the symptoms of fatigue in pSS [2, 15].

21.4Measurement of Fatigue and Other Extraglandular Symptoms

The simplest way of measuring fatigue (or indeed other symptoms such as joint/muscle pain or RaynaudÕs phenomenon) is to use a 10-cm visual analog scale (VAS) or Likert rating scale (0, 1, 2, 3, etc.) asking the patient to rate their fatigue (e.g., from ÒnoneÓ at minimum to Òworst fatigue

imaginableÓ at most). Another approach is to use a questionnaire comprising a series of questions, each of which addresses some different component of the symptom under evaluation. Some of these fatigue questionnaires, e.g., FACIT-F scale [32] and the Fatigue Severity Scale (FSS) [33] are described as Òuni-dimensional,Ó i.e., they give a total score for fatigue much as the fatigue VAS does. In the context of clinical trials in rheumatoid arthritis, there is evidence that a VAS may be just as effective as using a longer questionnaire [34], particularly in relation to sensitivity to change. This may well be the case in therapeutic studies in pSS as well [35]. One might conclude, therefore, that a simple VAS is all that is needed as a primary outcome measure for the symptom of interest. Using even a simple, uni-dimensional, fatigue questionnaire in parallel with the VAS, however, offers reassurance that the VAS Þndings are valid and can, therefore, be a useful conÞrmatory secondary outcome tool.

Other questionnaires are Òmultidimensional,Ó i.e., they have a series of domains or subscales that try and assess different aspects of fatigue [2, 36Ð40]. In some of these questionnaires a total score can also be calculated. The individual questions that make-up these questionnaires and the resulting domains offer a useful insight into what is meant by the term fatigue. One common theme is the differentiation of physical fatigue (e.g., lack of energy, difÞculty in getting started, easily worn out, feeling weak) and mental fatigue (e.g., difÞculty in concentrating or thinking) and, although the exact phraseology differs between questionnaires, these two basic concepts are reßected in all Þve of the above multidimensional fatigue questionnaires. In addition some questionnaires such as the Fatigue Assessment Instrument (FAI) [37], Piper Fatigue Scale (PFS) [38], and Fatigue Impact Scale [40] explore other concepts such as fatigue severity, the consequences of fatigue on daily activities, or the emotional consequences of fatigue.

In practical terms, however, such as the consideration of fatigue as a potential outcome in clinical trials [35], as will be discussed below, the predominant concepts are that of ÒtotalÓ or ÒglobalÓ fatigue measured either by the

VAS, or by questionnaires and the domains of Òphysical fatigueÓ and Òmental fatigueÓ typically measured by multidimensional questionnaires. Another widely used questionnaire in rheumatology research is the Medical Outcomes Study Short-Form 36-item questionnaire (SF-36) [41] (see below). This eight domain questionnaire includes a ÒvitalityÓ domain, which generally correlates reasonably well with fatigue questionnaires [2]. Fatigue, however, is just one component of health-related quality of life and should not be equated as an identical concept.

In terms of the decision as to which questionnaire to use to measure fatigue (and other symptoms) the reality is that in comparing Òlike- to-like,Ó e.g., the physical fatigue or mental fatigue domains of two different questionnaires, they are likely to generate very similar results, e.g., MFI versus PROFAD [42]. One important note is that fatigue in pSS/RA measured by VAS appears to correlate better with Òsomatic fatigueÓ domain scores of multidimensional fatigue questionnaires than with Òmental fatigueÓ domain scores [43Ð45]. It looks, therefore, as though patients with pSS or RA generally associate the

term ÒfatigueÓ (e.g., measured by the VAS) primarily with physical rather than mental fatigue.

In order to examine how best to measure fatigue as well as other symptoms in pSS we started in 2000 by reviewing the literature and interviewing patients to get an idea of key disease symptoms. We then constructed and reÞned a symptom questionnaire, which was then completed by patients with pSS, RA, SLE, and community controls without rheumatic disease. This included a wide range of symptoms including constitutional, pulmonary, neurological, urological, and other general and organ-speciÞc symptoms of potential relevance to pSS. By eliminating symptoms that were either infrequent, or common to the community control group (i.e., not disease speciÞc), we were able to produce a ProÞle of Fatigue and Discomfort (PROFAD) that captured the symptomatic component of pSS [2]. This demonstrated a very similar background ProÞle of Fatigue among pSS and SLE patients with the RA group showing higher levels of physical fatigue (likely related to the physical component of arthritis) and clearly different to controls (Fig. 21.1).

Fig. 21.1 Mean and 95% conÞdence intervals for fatigue and general discomfort ratings at worst in the SjšgrenÕsbased questionnaire tool (7 = worst imaginable) for

healthy controls and three disease groups. Reproduced with permission from Ref. [2]

Clearly our bias is to recommend the use of a questionnaire developed speciÞcally to capture the symptoms of pSS in preference to a questionnaire developed for other diseases, but the practical reality is that in capturing similar data many of these questionnaires generate similar results and therefore the choice depends on the personal preferences of the researcher rather than there being one gold standard option.

Questionnaire (WHOQOL) [46]. This has four principal domains: physical (PHY), psychological (PSY), social relationships (SOC), and environment (ENV). Another more limited concept is that of Òhealth-related QOLÓ or Òhealth-statusÓ where the focus is on assessing how a disease affects an individual or group in a general way. The SF-36 [41] is probably the most widely used questionnaire designed to evaluate health-related quality of life in individuals with medical disorders. The 36-question items have been split

Quality of Life

Quality of life (QOL) is a difÞcult to deÞne concept but in general terms it describes an overall concept of Òwell-being.Ó This might include concepts of basic need such as access to clean water, food and shelter, psychological state, state of health, and relationships. It is not straightforward to measure in absolute termsÑ how does one compare the quality of life of a Kalahari bushman with that of a New York banker? Nevertheless attempts have been made to devise questionnaires that measure QOL such as the World Health Organization Quality of Life

(GH), physical functioning (PF), role-functioning physical (RP), bodily pain (BP), social functioning (SF), role-functioning emotional (RE), mental health (MH), and vitality (VT). There are now a series of papers in pSS showing fairly globally reduced SF-36 scores (i.e., lower healthrelated quality of life) compared to the general population and comparable to that of patients with SLE and rheumatoid arthritis [2, 4, 27, 47Ð49]. In our study [2], as well as reduced health-related quality of life/health status, we also demonstrated similar reductions in general quality of life measured by the WHOQOL-BREF [46] (Fig. 21.2).

21.6Potential Approaches to Treatment of Fatigue and Other Extraglandular Symptoms

Although hydroxychloroquine is frequently prescribed to treat fatigue in pSS, formal studies have been small in scale [50, 51] and there has never been a fully powered, double-blind, randomized, controlled clinical trial (RCT) of hydroxychloroquine in pSS. This omission, however, should be rectiÞed following a French trial currently in progress (www.clinicaltrials. gov, IdentiÞer: NCT00632866).

Inßiximab has been studied in an RCT of 103 patients with pSS [52]. The outcome chosen was an ad hoc composite of VAS of fatigue, pain, and dryness in which patients had to score >50 mm on at least two of these at baseline and demonstrate a 30% improvement at 10 weeks compared with baseline for at least two of the three components. The study outcome was negative, both in terms of this composite outcome and in terms of each of the individual components suggesting that TNF- α(alpha) is not a key driver of inßammation as it is in RA.

Results from another double-blind RCT, this time of dehydroepiandrosterone (DHEA) (see also the above section on the hypothalamicÐ pituitary axis), were reported by Hartkamp et al. [53]. Patients in both active therapy and placebo groups showed improvement in primary outcomes of fatigue, mental well-being, and depressive mood but without any difference between active treatment and placebo.

Taking a non-biological therapeutic approach, Strombeck et al. [54] examined the effect of exercise on fatigue and aerobic exercise capacity in nine patients with pSS over a 12-week period compared with ten patients who did not pursue an exercise regime over this period. Both of these components as well as depression improved although there was no relationship between the improvement in fatigue and in aerobic capacity in individual patients. This study suggests that non-medical approaches to treating fatigue may be successful.

Pilot clinical data for anti-CD20 (a B-cell marker) therapy, rituximab [35, 55Ð59], as well as from an open-label study of anti-CD22 antibody (epratuzumab) [60] paint an intriguing picture. In our study [35], 17 patients with pSS and a score on fatigue visual analog scale (VAS) > 50 mm were randomized to receive either two infusions of rituximab or placebo; patients also received oral and intravenous steroids. The results demonstrated significant improvement from baseline in fatigue VAS in the rituximab-treated group (p < 0.001) in contrast to the placebo group (p = 0.147), which became more apparent over time (see Figs. 21.3 and 21.4). There was also a signiÞcant difference between the groups at 6 months in the social functioning score of SF-36 (p = 0.01) and a trend to signiÞcant difference in the mental health domain score of SF-36 (p = 0.06). These data and studies by other groups suggest potential beneÞt in treating fatigue [35, 55, 58Ð60], dryness symptoms [55, 56], and systemic features [57]. If, therefore, fatigue improves following biologic therapy, one could argue that, in contradistinction to the above studies, this might suggest a biological mechanism for at least part of the fatigue symptoms in pSS.

21.7Measurement of Dryness (Sicca) Symptoms

Dryness is the key symptom of SjšgrenÕs syndrome with oral and ocular dryness as the most common and most troublesome components [1]. As with fatigue, pain, or other extraglandular symptoms, the simplest way to measure dryness is with a VAS, but questionnaires can add detail and reliability. A number of dryness questionnaires have been developed, although many are screening questionnaires to identify the presence or absence of dryness symptoms in the community or as part of classiÞcation criteria for SjšgrenÕs syndrome [61, 62]. There are, however, a number of questionnaires that have been developed to quantify oral [63Ð70] and ocular