Background 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).
Objectives 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.
Methods 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)<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.
Results 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<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<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.
Conclusions 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
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.
Disclosure of Interest None Declared