Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial

<div><p>Objectives</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00667758" target="_blank">NCT00667758</a></p></div

Change in Hormonal and Immunological Variables from Baseline.

<p>P values represent the baseline-adjusted between-group difference using analysis-of-covariance between the high-gonadotropin cetrorelix group (N = 27) and high-gonadotropin placebo group (N = 26) on day 15. There were no significant differences between the high-gonadotropin groups at baseline, day 2, day 5, or day 10; except for luteinizing hormone, which was significantly reduced in the cetrorelix groups compared to placebo groups already by day 2 onwards. Panels A-F show the change from baseline in luteinizing hormone, tumor necrosis factor-α, interleukin-1β, interleukin-2, interleukin-10, and C-reactive protein respectively. A: Change from Baseline in Luteinizing Hormone Between Groups. B: Change from Baseline in Tumor Necrosis Factor-α Between Groups. C: Change from Baseline in Interleukin-1β Between Groups. D: Change from Baseline in Interleukin-2 Between Groups. E: Change from Baseline in Interleukin-10 Between Groups. F: Change from Baseline in C-Reactive Protein (CRP) Between Groups.</p

Efficacy Variables by Day 5 Between Groups.

<p>Fig 2 shows the percentage of patients achieving at least a 20%, 50%, 70% improvement in the American College of Rheumatology scale (ACR20, ACR50, and ACR70 respectively), the percentage of patients achieving ≤ 3.2 on the Disease Activity Score for 28-joint counts, based on C-reactive protein ([DAS28-CRP ≤ 3.2], in which scores range from 2 to 9, with higher scores indicating more disease activity), the percentage of patients achieving DAS28-CRP<2.6, European League Against Rheumatism ‘Good-Responses’ (EULAR good). All patients, N = 53, are included in these intention-to-treat analyses. There were no significant differences in disease activity measured by DAS28-CRP at baseline between groups.</p

Baseline Characteristics of the Participants^*.

<p>* Plus—minus values are means ±SD. There were no significant differences between groups in baseline characteristics, except for age and sex.</p><p>^† CCP denotes Cyclic Citrullinated Peptide.</p><p>^‡ DAS28-CRP Disease Activity Score for 28-joint counts based on C-reactive protein (in which scores range from 2 to 9, with higher scores indicating more disease activity).</p><p>^§ LH denotes Luteinizing Hormone.</p><p>^¶ FSH denotes Follicle-Stimulating Hormone, Based on detectable FSH values <256 IU/L; N = 48 (cetrorelix), N = 50 (placebo).</p><p>ESR denotes Erythrocyte Sedimentation Rate.</p><p>** NSAIDs denotes Nonsteroidal Anti-Inflammatory Drugs.</p><p>^†† DMARDs denotes Disease-Modifying Anti-Rheumatic Drugs; MTX Methotrexate; SSZ Sulfasalazine; HCQ Hydroxychloroquine; and LEF Leflunomide.</p><p>^‡‡ Previous failure includes inefficacy or intolerability.</p><p>Baseline Characteristics of the Participants^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139439#t001fn001" target="_blank">*</a>}.</p

Trial Flow Chart.

<p>Trial Flow Chart.</p

All Adverse Events during the Study Period in the High-Gonadotropin Cetrorelix and Placebo Groups.

<p>* There were no significant between-group differences.</p><p>All Adverse Events during the Study Period in the High-Gonadotropin Cetrorelix and Placebo Groups.</p