Elsevier

Autoimmunity Reviews

Volume 9, Issue 5, March 2010, Pages A305-A310
Autoimmunity Reviews

The geoepidemiology of Sjögren's syndrome

https://doi.org/10.1016/j.autrev.2009.11.004Get rights and content

Abstract

Sjogren's syndrome (SS) is a slowly progressing autoimmune disease, affecting predominantly middle-aged women, with a female to male ratio reaching 9:1. It is characterized by lymphocytic infiltration of the exocrine glands, mainly the lacrimal and salivary glands, resulting in reduced secretory functions and oral and ocular dryness. The syndrome can present alone as primary SS (pSS) or in the context of underlying connective tissue disease as secondary SS (sSS). While the pathogenesis of the disease remains elusive, environmental, genetic and hormonal contributors seem to be involved. Over the last years, compelling evidence has suggested a pivotal role of the epithelium in orchestrating the immune response in the histopathological lesion of Sjogren's syndrome and the term “autoimmune epithelitis” has been proposed as an etiological term. Although the clinical manifestations of pSS patients are mainly those of an autoimmune exocrinopathy, almost half of patients develop extraglandular disease, which may be manifested either by epithelial lymphocytic invasion of lung, liver, or kidney (resulting in interstitial nephritis) or by skin vasculitis, peripheral neuropathy, glomerulonephritis, and low C4 levels. The latter reflect immune-complex mediated disease and confer increased risk for lymphoma development.

Introduction

Sicca syndrome as a systemic disease has been first appreciated in the early thirties by the ophthalmologist Henrik Sjogren, when he observed extreme dryness of the mouth and eyes in a female patient with deforming arthritis. Since then, intense research efforts have revealed important clinical, serological and pathogenetic disease aspects, giving insights to novel therapeutic interventions. Sjogren's syndrome (SS) is a slowly progressing autoimmune disease, affecting predominantly middle-aged women, with a female to male ratio reaching 9:1. It is characterized by lymphocytic infiltration of the exocrine glands, mainly the lacrimal and salivary glands, resulting in reduced secretory functions [1].

To aid in the accurate diagnosis of the syndrome, several sets of SS diagnostic criteria had been proposed over the years; however, they lacked validation and wide acceptance. Subsequently, the European Study Group on classification criteria on SS have developed a set of diagnostic criteria – revised in 2002 by a group of American and European SS experts – in order to include the evaluation of subjective and objective sicca manifestations, autoantibody production against the ribonucleoproteinic complexes Ro/SSA and La/SSB and characteristic histopathological findings in the minor salivary glands (MSGs)[focus score > 1 (cluster of 50 or more lymphocytes per lobule when at least four lobules are assessed)][2], [3] (Table 1). Antibodies against Ro/SSA and La/SSB occur in approximately 60% of patients with SS and are associated with early disease onset, longer disease duration, parotid gland enlargement, higher frequency of extraglandular manifestations and more intense lymphocytic infiltration of the MSGs[4].

While sicca complaints in the setting of SS are quiet common in rheumatology, dental or ophthalmological practices, a relatively few number of studies have estimated the population prevalence of SS. As shown in the comprehensive Table 2, there is a widely reported range between different studies varying from 0.1 to 4.8%. The observed variability might reflect differences in the definition and application of diagnostic criteria between the studies, the diverse geographic study origin (implying the contribution of both genetic and environmental factors) as well as the different initial sample size and sex distribution. In a recent Japanese study, prevalence of SS was 2.3% among Nagasaki atomic bomb survivors and was not associated with radiation dose. The association between radiation dose and hyposalivation supported the possibility that radiation exposure damaged salivary gland function [5], [6], [7].

Systemic features of cutaneous, respiratory, renal, hepatic, neurological and vascular nature can also occur. The syndrome can present alone as primary SS (pSS) or in the context of underlying connective tissue disease as secondary SS (sSS). The multiple facets of the syndrome make it difficult to diagnose. As a consequence, it remains commonly either undiagnosed or diagnosed years after the onset of symptoms. Early recognition is of pivotal importance since it may prevent delay in diagnosis, allow appropriate diagnostic evaluation, and optimize therapeutic intervention [2].

The list of differential diagnosis is quiet extensive, including chronic HTLV-1, HCV, HIV infections, amyloidosis and sarcoidosis. When sicca symptoms are the prevailing presenting symptoms and no other pathology including SS can be identified, underlying thyroid autoimmunity should be also considered [8].

Section snippets

Histopathological lesion in primary SS-cellular populations and cytokine milieu

The histopathological hallmark of SS is periductal lymphocytic infiltration of the salivary and lachrymal glands; in earlier stages it consists mainly of T-cells of the CD4+ subtype, to a lesser extent of B-cells (CD20+) (approximately 20% of the total infiltrating population), whereas classical antigen-presenting cells (macrophages and DCs) producing proinflammatory cytokines (such as IL-6, TNF, IL-12, IL-18) are primarily observed in heavy infiltrates and their frequency is associated with

Etiological factors

The etiology of Sjogren's syndrome as well as of autoimmunity in general is unknown to date. According to the prevailing belief it is considered to be the result of environmental interactions with an appropriate genetic background. Given the compelling evidence of intrinsic activation of epithelium in various target organs [22], as evidenced by inappropriate expression of MHC molecules, overexpression of costimulatory molecules and ability of cytokine production, the term “autoimmune

Oral manifestations

Involvement of the major and minor salivary glands, in SS leads to decreased salivary secretion resulting in mouth dryness and increased incidence of oral infections, mucosal friability and dental caries due to loss of the lubricating, buffering and antimicrobial capacities of saliva. Fungal infections (primarily candidiasis) are also common, which can mainly be presented as pseudomembranous or erythematous mucosal lesions, fissured tongue, atrophy of filiform papillae, and angular cheilitis.

Therapy

Ocular involvement, manifested as keratoconjunctivitis sicca (KCS) is managed with local and systemic stimulators of tear secretion and supportive surgical procedures. Treatment of oral manifestations includes intense oral hygiene, prevention and treatment of oral infections, use of saliva substitutes and local and systematic stimulation of salivary secretion. Cholinergic agents, such as pilocarpine and cevimeline which stimulate saliva and tear production from the salivary and lachrymal glands

Take-home messages

  • Sjogren's syndrome (SS) is a chronic autoimmune disorder affecting mainly middle aged women characterized by lymphocytic infiltration of the salivary and lachrymal glands resulting in dry eyes and dry mouth.

  • Systemic (extraglandular disease), can be manifested either by epithelial lymphocytic invasion of lung, liver, or kidney (resulting in interstitial nephritis) or by skin vasculitis, peripheral neuropathy, glomerulonephritis, and low C4 levels (immune complex disease).

  • Among SS patients, the

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