Sjögren's syndrome. Controversies and progress.

Diagnostic criteria for Sjögren's syndrome (SS) are required by both physicians and patients to (1) provide a rational basis for their symptoms, assess their prognosis, and guide therapy; (2) identify a group of patients who are most likely to share a common etiopathogenesis, in order to identify those genetic and environmental factors that are crucial in pathogenesis; (3) fill out the myriad medical insurance forms that require a diagnosis code; and (4) serve as a "shorthand" code that alerts specialists in different fields (oral medicine, ophthalmology, and a variety of specialists in internal medicine) to search for particular clinical problems found in the SS patient. The key question in this article is whether the term "Sjögren's syndrome" should apply to a rather restricted group of individuals (those with an autoimmune basis for exocrinopathy) or to a rather large group of individuals who share a similar symptom complex of dry eyes and mouth. Primary SS, as defined by San Diego criteria, is a systemic autoimmune disease that is characterized by keratoconjunctivitis sicca and xerostomia resulting from lymphocytic infiltrates of the lacrimal and salivary glands. The criteria for the diagnosis of SS continues to be controversial, leading to confusion in the clinical and research literature. It is important to distinguish SS (an idiopathic autoimmune process) from other processes including hepatitis C infection, retroviral infection, lymphoma, autonomic neuropathy, depression, primary fibromyalgia, and drug side effects that can result in sicca symptoms. Recent studies on pathogenesis of SS in human and animal models have examined the clonality of the T-cell infiltrates, the production of cytokines by lymphocytes and glandular epithelial cells, neuroendocrine and hormonal factors that affect glandular secretion, and the fine structure of antigens recognized by T cells and B cells. Studies in SS have allowed comparison of lymphocytes in blood and in the glandular tissue lesions; important differences in the gland microenvironment play an important role in the initiation and perpetuation of the autoimmune process. For example, apoptotic death depends on the balance of Fas, Fas ligand, nuclear factors (such as bcl-2, bax, and myc), cytokines, neuropeptides, and cell membrane interactions with extracellular matrix. Although increased rates of apoptosis may be present in the blood T cells of SS patients, some glandular T cells are resistant to apoptosis. Recent advances have led to improved understanding of signal transduction in response to cytokines and hormones that play a role in the local and systemic manifestations of SS.