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Sjögren syndrome (SS), the second most common autoimmune rheumatic disease, refers to keratoconjunctivitis sicca and xerostomia resulting from immune lymphocytes that infiltrate the lacrimal and salivary glands. However, differential diagnosis remains confusing due to the high prevalence of vague symptoms of dryness, fatigue, and myalgias in the general population. The problems of diagnosis are further compounded by the finding of "positive" antinuclear antibodies in a high percent of the general population. Unless minor salivary gland biopsies are read by experienced observers, nonspecific changes of sialadenitis are frequently confused with the focal lymphocytic infiltrates that are characteristic of SS. The distinction between fibromyalgia patients with low titer antinuclear antibodies and primary SS remains difficult. Even in patients fulfilling strict criteria for SS, the genomic search for critical genes has proven difficult due to the multigenic pattern of inheritance and strong role of currently undefined environmental factors. No single environmental factor has been detected in the majority of SS patients. SS-like syndrome has been detected in certain patients with HTLV-1 and hepatitis C infection, providing clues to pathogenesis. Even in SS patients with marked sicca symptoms, minor salivary gland biopsy shows that almost 50% of glandular cells are still detected on biopsy. These results imply the importance of immune factors such as cytokines and autoantibodies in decreasing neuro-secretory circuits and induction of glandular dysfunction. Of potential importance, an antibody against muscarinic M3 receptor that can decrease secretory function when injected into rodents is frequently found in the sera of SS patients. Newly developed topical and oral therapies can ease the oral and ocular dryness. Orally administered agonists of the muscarinic M3 receptor (pilocarpine and cevimeline) have recently been approved by the US Food and Drug Administration to increase salivary secretion. Topical ocular use of low-dose corticosteroids or cyclosporin may decrease conjunctival surface inflammation. In a Phase II double-blind study, orally administered interferon alpha (150 U) led to improved saliva flow and symptoms. In pregnant patients with evidence of fetal distress, oral dexamethasone is preferred because this agent crosses the placenta effectively. In animal models, antagonists of tumor necrosis factor and inhibitors of de novo pyrimidine synthesis appear promising.