title: The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine.
abstract: OBJECTIVE
  Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity.
  
  
  METHODS
  A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28).
  
  
  RESULTS
  Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial.
  
  
  CONCLUSIONS
  The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: van Vollenhoven
authors.forename: Jos G A
authors.initials: JG
authors.lastname: Houbiers
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
authors.forename: Joanna
authors.initials: J
authors.lastname: In 't Hout
authors.forename: Maarten
authors.initials: M
authors.lastname: Boers
authors.forename: Susanne
authors.initials: S
authors.lastname: Leij
authors.forename: Tore K
authors.initials: TK
authors.lastname: Kvien
authors.forename: Ben A C
authors.initials: BA
authors.lastname: Dijkmans
authors.forename: Leszek
authors.initials: L
authors.lastname: Szczepański
authors.forename: Istvan
authors.initials: I
authors.lastname: Szombati
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Sierakowski
authors.forename: André M M
authors.initials: AM
authors.lastname: Miltenburg
mesh_terms: D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D047628:Estrogen Receptor alpha / Q000819:agonists*; D005260:Female; D006801:Humans; D055118:Medication Adherence; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged; D010919:Placebos; D017698:Postmenopause; D013256:Steroids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012460:Sulfasalazine / Q000008:administration & dosage*; D017211:Treatment Failure
chemical_list: D018501:Antirheumatic Agents; D047628:Estrogen Receptor alpha; C548093:Org 37663; D010919:Placebos; D013256:Steroids; D012460:Sulfasalazine; D008727:Methotrexate