Sjogren's Syndrome (SS) is an autoimmune disease, characterized as a widespread epitheliitis, which results in dryness of the lining surfaces of the body, producing, most notably, dry mouth and dry eyes. Under this project, the SS Clinic conducts clinical investigation and clinical trials, and collaborates with laboratory investigators in GTTB and Johns Hopkins in order to elucidate pathogenic mechanisms operative in this disease. A major achievement during this FY is the near completion of a secure, integrated, relational database incorporating research records since the inception of the SS Clinic in 1985. The entry of clinical data on 1800 subjects, who have participated in studies of SS and salivary dysfunction, is almost finished. The database includes information on hundreds of variables from: questionnaires completed by patients on history and symptoms; data forms completed by clinicians, such as physical findings and salivary flow rates; and information imported from the NIH Clinical Center?s Medical Information System. The importation of laboratory and pathology data relies on specific computer programs that automatically detect inconsistencies and duplicates. In addition, sophisticated algorithms have been developed within statistical computer programs to allow for the automated classification of cases to determine whether or not they meet accepted criteria of SS, and whether the cases are primary or secondary SS. When fully completed, this data-base will be a rich resource and allow rapid and convenient access to important research information. SS also can involve the skin, lungs, kidneys, and peripheral nerves, and the risk of developing lymphoma is much higher in patients with SS than in the general population. Polyclonal activation of B cells tends to evolve toward the development of monoclonality and ultimately lymphoma. We hypothesized that increased inflammation in salivary tissue, manifesting as higher focus scores, as well as increased serological activity and higher immunoglobulin levels, may be risk factors in SS patients for monoclonal expansion of B cells. We are examining gene rearrangements in minor salivary gland B cells from SS patients to address this issue. Also, in collaboration with colleagues at Johns Hopkins, the hypothesis that subsets of SS are associated with antibodies specific for distinct autoantigens has been affirmed. Primary SS and limited scleroderma patients were found to differ markedly in their pattern of centromere protein (CENP) recognition. Antibodies to CENPs were found in 26% of SS patients. While CENP-positive SS patients recognize predominantly CENP-C in isolation, this pattern was very uncommon in CENP-positive patients with scleroderma. SS patients with antibodies recognizing CENP-C were uniformly associated with the presence of antibodies to Ro and La. Dual recognition of both CENP-B and CENP-C occurred much more frequently in patients with scleroderma. Both CENP-C recognition alone and dual CENP-B and CENP-C recognition are patterns that correctly identified the phenotype in the vast majority (positive predictive value 88%) of these anti-CENP positive patients with primary SS and limited scleroderma. In clinical investigations at the SS Clinic, we have hypothesized that immunomodulatory treatments may favorably alter the course of this disease. Accordingly, we conducted a placebo-controlled, randomized clinical trial (RCT) of a new biologic agent, etanercept. Etanercept is an inhibitor of (soluble receptor for) tumor necrosis factor a, a cytokine found in increased amounts in salivary and lacrimal glands of SS patients. This RCT has recently been completed. Our results show that the drug is safe to use in SS patients, but we found no evidence for efficacy of etanercept in treatment of the exocrine component of SS. Finally, with the collaboration and support of an international group of SS investigators, the National Eye Institute, the Office of Women's Health, the Sjogren's Syndrome Foundation, and industry, the SS Clinic led a workshop to develop an international consensus on outcome measures for clinical trials in SS. From this endeavor, a framework has been established for the validation of a core set of outcome measures, as well as for the evaluation of newer potential outcome measures for which there are currently insufficient data.
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