Session Type: Abstract Submissions (ACR)
Background/Purpose: The pathogenesis of rheumatoid arthritis (RA) is unclear, and treatment options can be improved. Gonadotropin-releasing hormone (GnRH) stimulates immune responses (1) and therefore might be pro-inflammatory in RA. We investigated the short-term effects of a GnRH-antagonist, cetrorelix (which rapidly decreases luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), in a proof-of-concept study in RA.
Methods: In this double-blinded, single-site study in Norway (ClinicalTrials.gov NCT00667758), 99 patients with active longstanding RA, were randomised to predefined intention-to-treat populations using computer-generated allocation (1:1) in dynamic blocks stratified for sex. Patients were assigned to subcutaneous cetrorelix (n=48) (5 mg days 1–2, 3 mg days 3–5) or placebo (n=51). The primary endpoint was the change in disease activity score (DAS28CRP) by day 5, when the greatest LH and FSH suppression was anticipated. Secondary endpoints included change in tumour necrosis factor-α (TNF-α), American College of Rheumatology (ACR) responses, and DAS28CRP<2.6 remission by day 5. Patients were followed up on days 10 and 15.
Results: By day 5, the change in DAS28CRP was −0.82 (95% CI –1.06, –0.58) in the cetrorelix group and –0.57 (–0.76, –0.37) in the placebo group, between-group difference 0.26 (–0.04, 0.57, p=0.091). By day 5, TNF-α (log pg/mL) was significantly decreased in the cetrorelix group (–0.58) compared with the placebo group (–0.02; difference 0.55 [0.08, 1.01], p=0.023), and more patients on cetrorelix achieved ACR20 responses (40% vs 18%; p=0.015) and DAS28CRP<2.6 remission (13% vs0%; p=0.009). Serum CRP levels were clinically relevantly reduced in the cetrorelix group versus placebo (-0.28 vs. 0.045mg/dL, p=0.060); followed by a reduction in ESR levels by day 15 (-1.06 vs. 5.04, p=0.051). Disease activity markers rebounded towards baseline after cetrorelix withdrawal, except erythrocyte sedimentation rate, which is slower to change. Adverse event rates were similar between groups.
Conclusion: This study demonstrates antagonizing GnRH with cetrorelix lowers TNF-α, and improves signs and symptoms of RA. The novel association between GnRH and TNF-α may improve insights into the pathogenesis and treatment of RA, and potentially other autoimmune diseases. Larger, long-term studies on the efficacy and safety of GnRH antagonists in RA patients are warranted.
Reference: Chen A et al. The neuropeptides of GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs. Nat Med 2002; 8: 1421-6.
H. C. Gulseth,
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ACR Meeting Abstracts - http://acrabstracts.org/abstract/cetrorelix-a-gonadotropin-releasing-hormone-antagonist-significantly-reduces-tumour-necrosis-factor-alpha-and-demonstrates-efficacy-in-patients-with-active-rheumatoid-arthritis-a-proof-of-concept/