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 GTTB- SS Clinic conducts clinical investigations and clinical trials, and collaborates with laboratory investigators in GTTB, at the Academic Medical Center (University of Amsterdam) and at Johns Hopkins University in order to understand pathogenic mechanisms operative in this disease. Few rigorous clinical trials have been undertaken to develop treatments for SS patients, and agreed-upon outcome measures for such trials have only recently been defined. Our general approach has been to screen agents that have been used effectively in the treatment of other autoimmune diseases for their potential efficacy in SS. In addition to providing possible therapies for SS patients, these agents can also serve as probes of pathogenic mechanisms operative in this disease. We have generally hypothesized that immunomodulatory treatments may favorably alter the course of SS. As reported last year, we completed a placebo-controlled, randomized clinical trial of a new biologic agent, Etanercept, which is useful in treating rheumatoid arthritis, and during this reporting period finished all data analysis. Etanercept is an inhibitor of (and soluble receptor for) tumor necrosis factor (TNF)-alpha, a cytokine found in increased amounts in salivary and lacrimal glands of SS patients. This study was a 12-week double blind trial and patients meeting American-European Consensus Group criteria for SS received either 25 mg of Etanercept or placebo (vehicle) by twice-weekly subcutaneous injection. Five Etanercept-treated patients and three placebo-treated patients showed improvement from baseline in a primary outcome variable at 12 weeks, but this difference was not statistically significant. Additionally, there were no significant differences between the test groups for changes in subjective measures of oral or ocular symptoms (by visual analog scale), IgG levels, Schirmer I test results, van Bijsterveld scores, or salivary flow rates. However, at 12 weeks, erythrocyte sedimentation rates had decreased in the Etanercept group compared with baseline (P = 0.004). Our findings show that while this drug is safe to use in SS patients, there was no evidence for any efficacy of Etanercept in treating the exocrine component of SS. Furthermore, the results suggest that either therapeutic concentrations of Etanercept were unable to reach salivary tissue after systemic administration, or that the role of TNF-alpha in the pathogenesis of SS is less important than previously thought, or that a role for this cytokine is critical at an earlier time in the pathogenic mechanism. This reporting period also was marked by considerable change in the organization of the SS Clinic. After many years at NIH, the Head of the Clinic left to join a major biotech company, and the oral medicine research fellow left to assume a university faculty position. Nonetheless, SS Clinic activities were maintained at a high level thanks to our nursing and consultant oral medicine staff. We also were successful, after a national search, in recruiting an outstanding rheumatologist/clinical investigator to become the new Head of the SS Clinic.
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