Purpose: Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology predominately affecting synovial joints. Significant reductions in disease manifestations may be achieved using anti-inflammatory drugs. Among the therapeutic agents commonly used to treat patients with RA is sulfasalazine. The major focus of this study is to determine the potential mechanisms by which sulfasalazine mediates its beneficial effects in RA. We hypothesize that sulfasalazine exerts its anti-inflammatory effects by inhibiting nitric oxide (NO) and prostaglandin (PG) formation, which are important mediators in the pathogenesis of RA. The study objectives are: 1) To determine if sulfasalazine treatment of patients with RA decreases nitric oxide synthase type 2 (NOS2) mRNA and protein expression, and NOS enzyme activity in PBMC. 2) To determine if sulfasalazine treatment of patients with RA decreases inducible (COX-2) mRNA and protein expression, and Cox enzyme activity in PBMC. Methods This is a prospective, 10-week open pilot trial in fifteen patients with RA. Ten patients whose physicians have decided to initiate sulfasalazine treatment as part of their routine care will sulfasalazine 500 mg twice daily for 2 weeks, 1,000 mg twice daily for 4 weeks, and then 1,500 mg twice daily. There will be five control patients with RA. Results: Four patients were enrolled between April and November 1998 and three patients have completed the study. One patient withdrew from the study prematurely because his physician had to increase his Prednisone dosage due to worsening of his arthritis symptoms. The increase in Prednisone dosage was a protocol violation. Three subjects were female and 1 subject was male. Two patients were Caucasian and two patients were African-American. No patient enrolled in the study has had a serious adverse event. Enrollment for the study remains open. Significance: Sulfasalazine may derive its treatment efficacy in RA through actions that lower PBMC NOS2 and COX-2 activity. The mechanisms regulating NOS2 and COX-2 activity in RA are not known. In RA TNF most likely plays an important role in the upregulation of NOS2 and COX-2 expression since it is overproduced in this disease and stimulates the transcription of NOS2 and COX-2 mRNAs. However, the regulation of NOS2 and COX-2 is likely to be more complex than simply a direct effect of TNF on transcription. TNF is a pleiotropic cytokine with downstream effects on a variety of pathways. Moreover, the regulatory signals subject to TNF modulation are influenced by the presence of other cytokines. Thus, neutralization of TNF may reduce NOS2 and COX-2 expression by direct and indirect means. If sulfasalazine can be shown to inhibit PBMC NOS2 and COX-2 expression, then further studies would be necessary to elucidate the precise mechanisms of this effect. Future plans: No further studies are planned at this time.

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Duke University
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