OP0202 Cetrorelix, a gonadotropin-releasing hormone antagonist, significantly reduces TNF-alpha and demonstrates efficacy in patients with active rheumatoid arthritis: A proof-of-concept, double-blind randomised trial
Authors: A. Kåss, H.C. Gulseth, I. Hollan, M. Fagerland, P. Torjesen, Ø. Førre
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Cetrorelix is a gonadotropin-releasing hormone (GnRH) antagonist, which rapidly decreases luteinising hormone (LH) and follicle-stimulating hormone (FSH). A potential effect of GnRH in immune system regulation has been suggested previously (1). <h3>Objectives</h3> The aim of this proof-of-concept study was to examine whether cetrorelix can give a beneficial clinical response by reducing TNF-α in RA patients, and to characterise the relationship between the endocrinological and immunological effects of decreasing GnRH after a short course of treatment in RA patients. We present proof-of-concept biochemical, efficacy and safety data of GnRH-antagonist use in active RA patients. <h3>Methods</h3> Active RA patients on stable DMARDs were randomised 1:1 to receive daily s.c. injections of cetrorelix, n=48 (5mg days 1-3, 3mg days 4-5 to achieve a rapid substantial reduction in LH/FSH) or placebo (PBO), n=51. The primary endpoint was the change in DAS28-4 (CRP) score by day 5 (when LH/FSH levels are lowest). Secondary endpoints included the relative change in TNF-α, ACR20 response rates, and proportion of patients with DAS28-4 (CRP)&lt;2.6, all by day 5. Statistical analyses were based on the ITT principle. Patients were followed up on day 10 and 15. This study is registered with ClinicalTrials.gov, number NCT00667758. <h3>Results</h3> 99 patients with active RA were randomised; mean age 55; 72% patients female, mean disease duration 141 months; characteristics similar between groups. In the cetrorelix group vs. PBO, serum LH/FSH was significantly reduced (p&lt;0.0001) and mean relative change in TNF-α was also significantly reduced (-25% vs. 13% [diff -37%, 95%CI: -64%, -10%] p=0.008), both by day 5. Although not reaching statistical significance, the change in DAS28-4 (CRP) by day 5 was greater in the cetrorelix group vs. PBO (-0.82 vs. -0.57 [-0.25, 95%CI:-0.57, 0.04] p=0.091). The proportion of ACR20 responders by day 5 was significantly higher in the cetrorelix group compared to PBO (40% vs. 18%, p=0.015). A significantly higher proportion of patients achieved DAS28-CRP&lt;2.6 (13% vs. 0% p=0.009) and SJC=0 (21% vs. 6% p=0.028) in the cetrorelix group. Serum CRP levels by day 5 were clinically relevantly reduced in the cetrorelix group vs. PBO (-0.28 vs. 0.045 mg/l, p=0.060); followed by a reduction in ESR levels by day 15 (-1.06 vs. 5.04, p=0.051). Occurrence of AEs between groups was similar, and there were no serious AE’s. <h3>Conclusions</h3> This study demonstrates antagonising GnRH with cetrorelix lowers TNF-α, and improves signs and symptoms of RA. This study suggests that clinically relevant interactions between GnRH and the immune system exist; which may improve insights into the pathogenesis of RA. Larger, long-term studies on the efficacy and safety of GnRH antagonists in RA patients are warranted. Funding: Norwegian Health and Rehabilitation Organisation <h3>References</h3> Chen A, Ganor Y, Rahimipour S, Ben-Aroya N, Koch Y, Levite M. The neuropeptides 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. <h3>Disclosure of Interest</h3> None Declared