cetrorelix and Arthritis--Rheumatoid

Gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins, which appear to be proinflammatory, undergo profound secretory changes during events associated with rheumatoid arthritis (RA) onset, flares, or improvement e.g. menopausal transition, postpartum, or pregnancy. Potential anti-inflammatory effects of GnRH-antagonists may be most pronounced in patients with high GnRH and gonadotropin levels. Therefore, we investigated the efficacy and safety of a GnRH-antagonist, cetrorelix, in RA patients with high gonadotropin levels.. We report intention-to-treat post hoc analyses among patients with high gonadotropin levels (N = 53), i.e. gonadotropin levels>median, from our proof-of-concept, double-blind AGRA-study (N = 99). Patients with active longstanding RA, randomized to subcutaneous cetrorelix (5mg days1-2; 3mg days 3-5) or placebo, were followed through day 15. Only predefined primary and secondary endpoints were analyzed.. The primary endpoint, Disease Activity Score of 28-joint counts with C-reactive protein (DAS28-CRP), improved with cetrorelix compared with placebo by day 5 (-1.0 vs. -0.4, P = 0∙010). By day 5, more patients on cetrorelix achieved at least a 20% improvement in the American College of Rheumatology scale (44% vs. 19%, P = 0.049), DAS28-CRP≤3.2 (24% vs. 0%, P = 0.012), and European League against Rheumatism 'Good-responses' (19% vs. 0%, P = 0.026). Tumor necrosis factor-α, interleukin-1β, interleukin-10, and CRP decreased with cetrorelix (P = 0.045, P = 0.034, P = 0.020 and P = 0.042 respectively) compared with placebo by day 15. Adverse event rates were similar between groups.. GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA.. ClinicalTrials.gov NCT00667758.

Topics: Adult; Aged; Anti-Infective Agents; Arthritis, Rheumatoid; C-Reactive Protein; Cytokines; Double-Blind Method; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Male; Middle Aged; Pregnancy

Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients.. In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3-5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15.. By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08-1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups.. Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Administration Schedule; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Middle Aged; Severity of Illness Index; Treatment Outcome