21.1Introduction

Sicca (dryness) symptoms, reßecting reduced saliva and/or tear production, are the key features of primary SjšgrenÕs syndrome (pSS) and are reported by most patients [1]. Fatigue, however, is also a major problem and is often the symptom that patients complain about most bitterly. It is found in approximately 70% of patients and, as we will discuss below, is associated with a reduced sense of well-being (health-related quality of life/health status) [2Ð4]. Other common patient-reported extraglandular symptoms identiÞed in our and other studies include arthralgia, myalgia, and RaynaudÕs phenomenon [5Ð8].

In this chapter we will review the features of patient-reported symptoms in pSS, particularly fatigue and dryness, the extent to which they are associated with objective assessment of the disease, potential therapies for these symptoms, and the challenges of outcome assessment in clinical therapeutic trials in pSS.

Although patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or systemic sclerosis/scleroderma (SSc) who also have secondary SjšgrenÕs syndrome can have some or many of these symptoms, this chapter will focus only on primary SjšgrenÕs syndrome (pSS).

21.2What Is Fatigue?

The concept of fatigue can be approached in several different ways. In physiological terms isolated muscles demonstrate progressive biochemical (and measurable) fatigability with continued use, or if an individual person exercises, they are fatigued afterward, at least in part, from chemical changes in their muscles. In sports science, for example, this can be formally assessed in a standardized manner in a sports science laboratory.

In patients with a myopathic or neuropathic process, muscles can be weak, and some patients may feel fatigued as a consequence. Another patient, however, can have weakness but without having a perception of fatigue. One important

point, therefore, is to recognize that the concept of fatigue is a global one experienced by the patient as a whole, not simply the symptom component of biological muscle weakness.

There are also mental components of fatigue with difÞculty in thinking or concentrating. The term Òbrain-fogÓ is sometimes used. As we will discuss below, this is typically assessed using patient-completed questionnaires, although formal psychometric testing could be considered in parallel with this.

Furthermore, it is important to recognize that fatigue is common in the general population [9] and, in population terms, Òdisease-relatedÓ fatigue is the component of fatigue that is in excess of that already present in the background population. This, however, only deals with Òquantity,Ó and it is also important to consider whether there are qualitative features of the fatigue that differ between conditions or from the background fatigue described in the general population. This is where questionnaires that attempt to probe into different features of what is meant by fatigue can be helpful over and above a single question asking about the amount or ÒseverityÓ of the fatigue and will be discussed in detail below.

Fatigue can be a presentation of medical conditions such as hypothyroidism, anemia, or of sleep deprivation or a whole range of other disorders or medications (biological fatigue), or a manifestation of psychosocial factors such as psychiatric morbidity (e.g., depression) or social factors (life events, family circumstances). It can also be a feature of a personality disorder or be medically unexplained (chronic fatigue syndrome) [9, 10]. Fatigue is also commonly reported by patients with other rheumatic diseases such as RA and SLE [2Ð4].

21.3Potential Causes of Fatigue in pSS

21.3.1 Biological

21.3.1.1 Cytokines

In terms of how disease activity or biological factors might contribute to fatigue in pSS, one

approach is to look for associations between levels of fatigue and biological measures. A small number of studies have looked at this in pSS by examining correlations in crosssectional studies between levels of fatigue and levels of inßammatory markers (ESR, CRP), antibodies (immunoglobulin levels, anti-Ro/La antibody titres), or cytokines such as IL-1β(beta), IL-2, IL-6, IL-10, and TNF-α(alpha), [3, 11, 12]. These studies have not, however, identiÞed deÞnitive associations between fatigue and serological parameters in pSS. One study of 16 patients with pSS suggested that patients with pSS and myalgia had diminished cytokine release from peripheral blood mononuclear cells in vitro and increased serum levels of IL-18 [13]. There is, however, an important distinction between pSS and RA and SLE. In rheumatoid arthritis, for example, cytokines such as TNF-α(alpha), IL-1β(beta), and IL-6 (and the ESR and CRP) have clear relationships with disease activity and disease-modifying anti-rheumatic drugs and antiTNF therapies reduce fatigue levels as part of their beneÞcial effects on disease activity [14]. In pSS ÒßaresÓ are less well described, and, if they occur, are less common and less severe [15]. The raised ESR in pSS is mainly associated with antibody levels rather than clinical markers of disease activity [5] and there is no obvious link between the CRP level and systemic disease activity [5]. To this extent, therefore, existing serological markers in pSS such as immunoglobulin or anti-Ro/La antibody levels are more akin to the rheumatoid factor in RA, which is not a marker of disease activity per se.

Even in RA, however, the associations between disease activity and fatigue are relatively modest with the best predictors of fatigue being pain, depressive symptoms, and female sex [16]. In our study to develop and validate a systemic disease activity score, the SjšgrenÕs systemic clinical activity index (SCAI) [5], we demonstrated correlations between fatigue, arthritis, and RaynaudÕs phenomenon domains of the SCAI and comparable domains of the ProÞle of Fatigue and Discomfort (PROFAD) measure. There was not, however, a clear relationship between total fatigue and a total disease activity score, although

at this point our assessment of systemic disease activity is still advancing and this may become clearer as our tools develop.

Nevertheless, in comparing fatigue in pSS to that in RA and SLE the appropriate comparison is with the background levels of chronic fatigue in these conditions, rather than with the intermittently increased fatigue associated with increased disease activity. Since we do not know which cytokines might be involved in pSS, we are in the semi-darkness at present in terms of which cytokines to study. Currently, most of the focus in pSS at present is in the role of B cells and hence cytokines such as BlyS/BAFF would be logical to evaluate [17]. Our previous studies developing the PROFAD [2] have also shown that there is a very similar character or ProÞle of Fatigue among patients with pSS to that seen in patients with SLE [2]. While this does not directly address the core issue of biological versus psychosocial contributors to fatigue in pSS, it does suggest that fatigue in pSS has similar characteristics to that in SLE and may share a similar etiopathogenesis. Given our lack of understanding of many aspects of etiopathogenesis, the redundancy of many cytokines and the inherent difÞculties of disentangling psychosocial components, this may not be an area of research to expect quick answers, although the development of large-scale patient registries combining data on clinical, serological, genetic, and symptom may lead to some progress over the next few years.

21.3.1.2 Neuroendocrine

Another approach has been to examine the relationship between fatigue and neuroendocrine factorsÑparticularly the hypothalamicÐpituitary axis (HPA). There is a large and conßicting body of literature, particularly in the idiopathic chronic fatigue syndrome, arguing whether or not an underactive HPA, e.g., resulting in low cortisol levels, is related to chronic fatigue in some patients. There is some limited evidence of an underactive HPA in pSS with low cortisol and/or low dehydroepiandrosterone levels, suggested as a cause of reduced well-being [18, 19]. Another related consideration is that of autonomic dysfunction found in some patients with pSS. In a