erb-041 and Arthritis--Rheumatoid

Selective estrogen receptor β (ERβ) agonists have demonstrated relevant antiinflammatory effects in different animal models. This study aimed to compare the efficacy and safety of one of these agonists, ERB-041, in subjects with rheumatoid arthritis (RA).. A total of 291 patients with active RA receiving stable doses of methotrexate were randomized to receive 5, 25, or 75 mg of ERB-041 or placebo for 12 weeks. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) at 12 weeks. Secondary end points included the ACR 50% improvement criteria (ACR50) and the ACR 70% improvement criteria (ACR70) responses, health outcomes measures, C-reactive protein (CRP) levels, and potential exposure-response relationships. Medical history, physical examination, and laboratory values were obtained at screening, baseline, and weeks 2, 4, 8, and 12.. No statistically significant difference for the ACR20 was found between the ERB-041 treatment and placebo groups (P = 0.518). Nor was a significant difference observed for ACR50 and ACR70 responses, health outcomes measures, CRP levels, and overall incidence of adverse events among all groups. Forty-four subjects (15.1%) discontinued the study and the rate of discontinuation was similar among the treatment groups. The most commonly reported treatment-emergent adverse events were headache (7.6%), nausea (6.2%), infection (4.8%), and bronchitis (4.1%). None of the adverse events was considered treatment related.. Although well tolerated and safe, ERB-041 failed to demonstrate antiinflammatory efficacy in RA patients, despite evidence of strong activity in preclinical arthritis models. These results suggest that selective ERβ agonists would not have effects on regulating inflammatory response in RA. Nevertheless, further studies are warranted to establish their efficacy in inflammatory arthritis.

Topics: Adult; Aged; Arthritis, Rheumatoid; Double-Blind Method; Estrogen Receptor beta; Female; Follow-Up Studies; Headache; Humans; Male; Middle Aged; Oxazoles; Treatment Outcome

Topics: Arthritis, Rheumatoid; Estrogen Receptor beta; Humans; Oxazoles; Severity of Illness Index; Treatment Outcome

Two receptors [estrogen receptor (ER)alpha and ERbeta] mediate the manifold effects of estrogens throughout the body. Although a clear role has been established for ERalpha in the classical effects of estrogen activity, the physiological role of ERbeta is less well understood. A small-molecule ERbeta selective agonist, ERB-041, has potent antiinflammatory activity in the Lewis rat model of adjuvant-induced arthritis. To characterize the response of target organs and pathways responsible for this antiinflammatory effect, mRNA expression profiling of the spleen, lymph node, and liver was performed, in conjunction with a global analysis of the plasma proteome. We find that the expression of a large number of genes and proteins are altered in the disease model and the majority of these are partially or fully reversed by ERB-041 treatment. Regulated pathways include the acute-phase response, eicosanoid synthesis, fatty acid metabolism, and iron metabolism. In addition, many of the regulated genes and proteins are known to be dysregulated in human rheumatoid arthritis, providing further evidence that the manifestations of the Lewis rat adjuvant-induced arthritis model bear similarity to the human disease.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Biomarkers; Blood Proteins; Estrogen Receptor beta; Gene Expression Profiling; Liver; Lymph Nodes; Male; Organ Specificity; Oxazoles; Random Allocation; Rats; Rats, Inbred Lew; RNA, Messenger; Spleen