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DEFINITION, INCIDENCE, AND PREVALENCE

Sjögren’s syndrome is a chronic, slowly progressing autoimmune disease characterized by lymphocytic infiltration of the exocrine glands resulting in xerostomia and dry eyes (keratoconjunctivitis sicca). The syndrome has unique features since it presents with a wide clinical spectrum from organ-specific autoimmune exocrinopathy to systemic disease. A small but significant number of patients develop malignant lymphoma. The disease can present as an entity alone or in association with other autoimmune diseases (Table 354-1). Finally, the histopathologic lesion in the labial minor salivary glands is easily accessible aiding the diagnosis, prognosis and disease pathogenesis.

TABLE 354-1Association of Sjögren’s Syndrome with Other Autoimmune Diseases

Middle-aged women (female-to-male ratio, 9:1) are primarily affected, although Sjögren’s syndrome may occur at any age, including childhood. The prevalence of primary Sjögren’s syndrome is ~0.5–1%, while 5–20% of patients with other autoimmune diseases suffer from Sjögren’s syndrome (secondary).

PATHOGENESIS

Sjögren’s syndrome is characterized by both lymphocytic infiltration of the exocrine glands and B lymphocyte hyperreactivity. An oligomonoclonal B cell process, which is characterized by cryoprecipitable monoclonal immunoglobulins (IgMκ or IgAκ) with rheumatoid factor activity, is evident in up to 10% of patients.

Sera from patients with Sjögren’s syndrome often contain autoantibodies to non-organ-specific antigens such as immunoglobulins (rheumatoid factors) and extractable nuclear and cytoplasmic antigens (Ro/SS-A, La/SS-B). Ro/SS-A autoantigen consists of two polypeptides (52 and 60 kDa, respectively) in conjunction with cytoplasmic RNAs, whereas the 48-kDa La/SS-B protein is bound to RNA III polymerase transcripts. Autoantibodies to Ro/SS-A and La/SS-B antigens are usually present prior to diagnosis and are associated with earlier disease onset, longer disease duration, salivary gland enlargement, extraglandular (systemic) manifestations, and more intense lymphocytic infiltration of minor salivary glands.

The major infiltrating cells in the affected exocrine glands are activated T lymphocytes in mild lesions, whereas B cells prevail in severe lesions. Macrophages and dendritic cells are also found. The number of macrophages positive for interleukin (IL) 18 has been shown to be associated with parotid gland enlargement and low serum levels of the C4 component of complement, both of which are adverse predictors for lymphoma development.

Ductal and acinar epithelial cells appear to play a significant role in the initiation and perpetuation of autoimmune injury. These cells (1) express costimulatory molecules, and inappropriately the intracellular autoantigens Ro/SS-A and La/SS-B on their membranes, acquiring the capacity to provide signals essential for lymphocytic activation; (2) produce proinflammatory cytokines and lymphocyte attracting chemokines necessary for sustaining the autoimmune lesion and allowing the formation of ectopic germinal centers, a finding predicting lymphoma development; and (3) express functional receptors of innate immunity, particularly Toll-like ...

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