{
  "abstract": "Background Inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Individuals who have residual inflammation following acute coronary syndromes (ACS) are at higher risk of further major adverse cardiovascular events (MACE). Anti-inflammatory therapies such as colchicine and canakinumab have reduced MACE in chronic coronary syndromes but their use is limited by significant side-effects. In ACS the data is less robust with colchicine failing to reduce MACE in a recent trial, leaving an unmet clinical need. Regulatory T-cells (Tregs) are powerful endogenous regulators of the immune system. Low-dose interleukin-2 (IL-2 LD) increases Tregs, potentially providing a novel immuno-modulatory strategy in ACS to reduce inflammation and MACE.Methods The IL-2 LD for the reduction of vascular inflammation in ACS (IVORY) trial was a double-blind, randomised, placebo-controlled, Phase IIb trial. ACS patients with high-sensitivity CRP levels ≧ 2mg/L were randomised to receive 1.5 ×106IU IL-2 or placebo, at a 1:1 ratio. Dosing consisted of a daily induction phase (5 days) and a maintenance phase (7 weeks of once weekly dosing). 18F-FDG-PET/CT imaging of the ascending aorta and carotid arteries was performed before and after treatment. The primary outcome of IVORY was the difference in arterial inflammation in the index vessel at follow-up. The index vessel was the vessel with the highest inflammation at baseline. IVORY-FINALE study reports MACE up to 5 years in participants who completed the IVORY trial.Results Of the 106 patients screened for the IVORY trial, 69 were randomised to treatment and 63 received IL-2 LD or placebo. Baseline characteristics were well matched between the groups. 60 patients (IL-2 LD:placebo, n=31:29) completed the trial. Arterial inflammation was significantly lower (figure 1c) at the end of treatment in the IL2 group than in placebo (-7.7%, P=0.015). In more inflamed arterial segments, the difference between the groups was greater (-8.3%, P=0.009). Overall, higher the arterial inflammation at baseline, greater the placebo & baseline corrected treatment effect of IL-2 LD. There was also a reduction in bone-marrow 18F-FDG activity at the end of treatment. IL-2 LD significantly increased circulating Tregs compared to placebo (P<0.001), without changes in pro-inflammatory effector T cells. IL-2 LD was well-tolerated, with mild transient side-effects. There was no difference in the frequency of infections observed between the groups. In the IVORY-FINALE study at median follow-up of 2.6 years, no individuals experienced MACE in the IL-2 group, whilst 4 individuals experienced MACE in the placebo group.Conclusion In ACS, IL2 LD was safe and resulted in a significant reduction in arterial inflammation, compared to placebo. Whilst a trend toward a reduction in MACE was observed in the IVORY-FINALE study, larger trials are needed to confirm the impact of low-dose IL- 2 therapy on cardiovascular outcomes.",
  "authors": [
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom",
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Rouchelle Sriranjan-Rothwell"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Stephen Hoole"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Tian Zhao"
    },
    {
      "affiliations": [
        "Cambridge Clinical Trials Unit, Cambridge, United Kingdom"
      ],
      "name": "Simon Bond"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Jason Tarkin"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Jacob Brubert"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "Annette Hubsch"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "Joanna Helmy"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "Elaine Bumanlag-Amis"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "Jalaludeen Navazh"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "Heike Templin"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "James O’Brien"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "Christopher Wall"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "James Rudd"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "Joseph Cheriyan"
    },
    {
      "affiliations": [
        "Cambridge University Hospital, Cambridge, United Kingdom"
      ],
      "name": "Ziad Mallat"
    }
  ],
  "title": "418 Anti-inflammatory therapy with Low-dose interleukin-2 (IL-2) in acute coronary syndromes: the results of the IVORY trial and IVORY-FINALE study",
  "uid": "58de9bcd-af38-5c16-aa14-58a885093ec9"
}