Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial

• Published in: PloS one Vol. 10; no. 10; p. e0139439
• Main Authors: Kåss, Anita, Hollan, Ivana, Fagerland, Morten Wang, Gulseth, Hans Christian, Torjesen, Peter Abusdal, Førre, Øystein Torleiv
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.10.2015; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Analysis; Antagonists; Anti-Infective Agents - administration & dosage; Anti-inflammatory agents; Arthritis; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - drug therapy; C-reactive protein; C-Reactive Protein - metabolism; Care and treatment; Clinical medicine; Cytokines; Cytokines - blood; Development and progression; Diabetes; Double-Blind Method; Female; Follow-Up Studies; Gender differences; Gene expression; Genetic aspects; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - administration & dosage; Gonadotropin-Releasing Hormone - analogs & derivatives; Gonadotropin-Releasing Hormone - antagonists & inhibitors; Gonadotropins; Gonadotropins - blood; Health risk assessment; Hospitals; Humans; Inflammation; Interleukin; Interleukin 10; Male; Medicine; Middle Aged; Motivation; Patient outcomes; Patients; Physiological aspects; Pituitary; Pituitary (anterior); Pituitary hormones; Postpartum; Pregnancy; Proteins; Rheumatism; Rheumatoid arthritis; Rheumatology; Rodents; Studies; Testosterone; TNF inhibitors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Womens health; United States; Norway
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0139439

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.