title: Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00667758.
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Rheumatology, Betanien Hospital, Skien, Norway.
authors.forename: Anita
authors.initials: A
authors.lastname: Kåss
authors.affiliation: Department of Rheumatology, Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway.
authors.forename: Ivana
authors.initials: I
authors.lastname: Hollan
authors.affiliation: Unit of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
authors.forename: Morten Wang
authors.initials: MW
authors.lastname: Fagerland
authors.affiliation: Department of Rheumatology, Betanien Hospital, Skien, Norway.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Gulseth
authors.affiliation: Hormone Laboratory, Oslo University Hospital, Oslo, Norway.
authors.forename: Peter Abusdal
authors.initials: PA
authors.lastname: Torjesen
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
authors.forename: Øystein Torleiv
authors.initials: ØT
authors.lastname: Førre
mesh_terms: D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D006062:Gonadotropins / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011247:Pregnancy
chemical_list: D000890:Anti-Infective Agents; D016207:Cytokines; D006062:Gonadotropins; D007987:Gonadotropin-Releasing Hormone; D002097:C-Reactive Protein; C062876:cetrorelix