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Pathogenesis of Sjögren's syndrome

Robert Fox, MD, PhD
Section Editor
Peter H Schur, MD
Deputy Editor
Paul L Romain, MD


Sjögren’s syndrome (SS) is a chronic, multisystem inflammatory disorder characterized by diminished lacrimal and salivary gland function due to lymphocytic infiltration of the secretory glands. This results in the “sicca complex,” a combination of dry eyes (keratoconjunctivitis sicca [KCS]) and dry mouth (xerostomia). Additional disease manifestations may also be present, including dryness of the skin and other mucosal surfaces. Systemic extraglandular features include arthritis, renal, hematopoietic, and pulmonary involvement, and vasculitis. Neurologic manifestations include peripheral neuropathy, myelopathy, and cognitive disturbances. These extraglandular manifestations may result from vasculitis, autoantibody-mediated mechanisms, or lymphocytic infiltration of the target organs. There is a marked increased risk of lymphoma in comparison with other autoimmune disorders. (See "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease" and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease".)

The pathogenesis of SS includes multiple genetic and nongenetic interacting factors. There is involvement of innate and adaptive immunity, as well as neuroendocrine and neuropathic processes. Biopsies of glandular and extraglandular sites are characterized by lymphocytic infiltration, with immunohistologic evidence for involvement of numerous elements of innate and adaptive immune responses. Further, cellular adhesive molecules, metalloproteinases, and neural transmitters show alterations in the affected target organs. Thus, SS represents an interface of autoimmunity with lymphoma, and of autoimmunity with neuroendocrine disorders.

Many aspects of SS are shared with other systemic autoimmune rheumatic diseases, including a female preponderance (9:1 female to male), distinctive HLA associations, familial clustering with other autoimmune conditions, the presence of characteristic autoantibodies, and the existence of shared clinical features (eg, arthritis, Raynaud phenomenon, serositis) with other autoimmune connective tissue diseases. There are strong similarities to the clinical manifestations and pathophysiology of systemic lupus erythematosus (SLE), but important differences between these disorders exist. Despite the areas of overlap between SS and SLE, differences include the autoantibody profiles (eg, anti-Ro/SSA and –La/SSB are not criteria for SLE), the intraglandular lymphoid infiltrates, and the frequency of lymphoma. (See "Epidemiology and pathogenesis of systemic lupus erythematosus".)

SS occurs in a primary form not associated with other well-defined autoimmune diseases and in a secondary form associated with other well-defined autoimmune conditions, such as rheumatoid arthritis, SLE, progressive systemic sclerosis, and primary biliary cirrhosis. Pathophysiologic distinctions between primary and secondary SS have been demonstrated in the genetic associations, serology, and histology of the salivary gland biopsies (See "Diagnosis and classification of Sjögren's syndrome".)

The pathogenesis of SS is reviewed here. The clinical manifestations, diagnosis, treatment, and prognosis of this disorder are discussed separately. (See "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease" and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease" and "Diagnosis and classification of Sjögren's syndrome" and "Treatment of systemic and extraglandular manifestations of Sjögren’s syndrome" and "Treatment of dry eye in Sjögren's syndrome" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren's syndrome".)


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