19.1Introduction

SjšgrenÕs syndrome (SS) is a chronic, slowly progressing autoimmune disease, affecting

A.G. Tzioufas ( )

Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece

e-mail: agtzi@med.uoa.gr

0.5−1.0% of the population, predominantly middle-aged women [1]. SS is characterized by lymphocytic inÞltration of the exocrine glands, mainly the lacrimal and salivary glands resulting in impaired secretory function. Systemic features of cutaneous, respiratory, renal, hepatic, neurologic, and vascular nature are seen in more than 50% of patients. The syndrome can present either alone (connoted primary SjšgrenÕs syndrome

[pSS]) or in association with another systemic autoimmune disease, for example, rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis (secondary SjšgrenÕs syndrome [sSS]) [2].

Prognosis and appropriate treatment planning are important issues because of the complexity and varying nature of the disease [3]. During the past few years, two types of SjšgrenÕs syndrome have been identiÞed: a localized disease that affects quality of life and a systemic syndrome that is associated with increased morbidity and mortality due to the high risk of malignant transformation. Systemic SjšgrenÕs syndrome is deÞned by the presence of palpable purpura, mixed monoclonal cryoglobulinemia, and low complement C4 levels at presentation [4]. So far, treatment for both types of SjšgrenÕs syndrome is empiric. Nevertheless, a more frequent and thorough follow-up plan is needed for patients who are at increased risk of severe disease.

In Chapter 19, we discuss the current treatments for the systemic manifestations of the disease, excluding the treatment with the newer biologic agents that will be discussed in Chapter.

a result of the ongoing B-cell hyperreactivity. Clinical Þndings associated with this process include palpable purpura, glomerulonephritis, and peripheral neuropathy, and they are associated with increased morbidity and risk for lymphoma development.

Based on this classiÞcation, the prognostic factors of outcome and survival have been determined. Skopouli et al. [4] studied the evolution of the clinical picture and laboratory proÞle, the incidence, and predictors for systemic disease, as well as the impact of clinical and laboratory Þndings on overall survival of the disease in a prospective cohort study of 261 Greek patients with primary SjšgrenÕs syndrome followed for 10 years. The results were compared with the general Greek population, adjusting for age and sex. The glandular manifestations of the syndrome were typically present at the time of diagnosis, and the serological proÞle of patients did not signiÞcantly change during the follow-up. The extraglandular manifestations were grouped into two different populations with regard to disease outcome. Arthritis, RaynaudÕs phenomenon, interstitial nephritis, and lung and liver involvement appear early in the disease process. Purpura, glomerulonephritis, decreased C4

and Outcome of Patients

Systemic manifestations are seen frequently in primary SjšgrenÕs syndrome patients and may include general symptoms such as easy fatigue, low-grade fever, myalgias, and arthralgias and other organ involvement. Easy fatigue is often a severe problem affecting the quality of life of patients with SjšgrenÕs syndrome [5].

The extraglandular manifestations in primary SjšgrenÕs syndrome can be divided into two major categories.

1.The periepithelial organ involvement, such as interstitial nephritis, liver involvement, and obstructive bronchiolitis, is the result of lymphocytic invasion in the epithelia of organs beyond the affected exocrine glands. These clinical features appear early in the disease and usually have a stable and benign course.

2.The extraepithelial manifestations are produced from an immune complex deposition as

globulinemia were identiÞed as adverse prognostic factors (Table 19.1). The overall mortality of patients with primary SjšgrenÕs syndrome compared with that of the general population was

Table 19.1 Extraglandular manifestations of pSS. Cumulative prevalence of extraglandular manifestations in primary SjšgrenÕs syndrome [4]

increased only in patients with adverse predictors. Similar results were reported by two other important studies that identiÞed hypocomplementemia and palpable purpura as signiÞcant predictors of death, largely due to lymphoproliferative malignancy [6, 7].

because of the lack of large, controlled, randomized studies. Instead, most of the regimens given are largely empiric and case dependent (Table 19.2) [8]. Most of the traditional diseasemodifying antirheumatic drugs (DMARDs) used in rheumatoid arthritis and systemic lupus erythematosus have been tried also in pSS with limited results, both in sicca syndrome and as disease-

19.3.1 Fatigue

Fatigue is observed in approximately 50% of patients with SjšgrenÕs syndrome and manifests as an increased need for resting hours [10, 11]. In these patients, concomitant hypothyroidism, Þbromyalgia, lymphoma, or underlying depression should be considered. In cases of Þbromyalgia, tricyclic antidepressants should be carefully used because they can exacerbate the dryness of patients; regular exercise and myofascial therapy could be of beneÞt [8].

19.3.2 Musculoskeletal

A half of patients with pSS experience intermittent episodes of arthritis during the course of their disease. In some instances, arthritis may precede sicca manifestations. Articular signs and symptoms include arthralgias, morning stiffness, intermittent synovitis, and chronic polyarthritis, which may sometimes lead to JaccoudÕs arthropathy [12]. In contrast to rheumatoid arthritis, radiographs of the hands usually do not reveal bone erosions.

Hydroxychloroquine has been successfully used for the treatment of constitutional and musculoskeletal symptoms as well as non-vasculitic cutaneous lesions in pSS. Its mechanism of action is not yet clariÞed, but experimental data have shown that hydroxychloroquine interferes with antigen presentation [13] and the production of pro-inßammatory cytokines (IL-1α and IL-6) [14]. Hydroxychloroquine may also inhibit glandular cholinesterase that may contribute to glandular hypofunction in SS [15]. In terms of laboratory Þndings, hydroxychloroquine has been shown to improve the levels of IgG, erythrocyte sedimentation rate, antinuclear antibody, rheumatoid factor, and IL-6 [16Ð20].

pSS patients should not be treated with steroids for long-time periods because, in addition to their well-known side effects, steroids may also accelerate the periodontal disease and oral candidiasis [21].

Methotrexate, the most widely used DMARD in rheumatoid arthritis, has also been used for the

treatment of polyarticular inßammatory arthritis of pSS. An open-label, non-controlled trial by Skopouli et al. in 17 patients with pSS showed improvement in sicca symptoms, frequency of parotid gland enlargement, and purpura but no beneÞt in objective parameters of dry eyes and mouth [22]. Immunoglobulin levels, autoantibody positivity, cryoglobulins, or complement levels remained unaffected. Persistent asymptomatic elevations of liver enzymes that occurred in methotrexate-treated individuals in higher frequency in pSS, compared with rheumatoid arthritis, led to dose reduction or discontinuation of treatment in 41% of patients. Other DMARDs including azathioprine, sulfasalazine, leßunomide, and cyclosporine have not shown any signiÞcant effect [9].

19.3.3 Raynaud’s Phenomenon

RaynaudÕs phenomenon is the most common manifestation of the skin, seen in one-third of patients with pSS. It usually precedes sicca manifestations by many years, and, therefore, patients with RaynaudÕs phenomenon should be regularly followed-up for subjective sicca manifestations. Patients with RaynaudÕs phenomenon present with swollen hands, but, in contrast to those with scleroderma, they do not develop telangiectasias or digital ulcers. Hand radiographs of these patients may show small tissue calciÞcations. Furthermore, these patients present more frequently with non-erosive arthritis, compared to those without RaynaudÕs phenomenon [23]. For the treatment of RaynaudÕs phenomenon, avoidance of physical and emotional stress, along with administration of calcium channel blockers or angiotensin-converting enzyme inhibitors, seems to be sufÞcient measures [23, 24].

19.3.4 Gastrointestinal Manifestations

Patients with SjšgrenÕs syndrome may frequently present with varying degrees of esophageal dysmotility, mainly manifesting as gastroesophageal reßux [25]. They may also develop