Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Gout flares are characteristically mediated by the pro-inflammatory cytokine interleukin (IL)-1β. Uptake of monosodium urate (MSU) crystals by macrophages activates the nucleotide-binding domain and leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, which converts intracellular pro-interleukin-1β (pro-IL-1β) to mature bioactive IL-1β by proteolytic cleavage. In the presence of concomitant pro-inflammatory stimuli, i.e., Toll-Like Receptor (TLR) agonists, transcription of IL-1β gene is induced and pro-IL-1β is rapidly converted into its active form. IL-1β binds to its receptor (IL-1R1) and induces a cascade of secondary inflammatory mediators including prostaglandins, cytokines and chemokines, resulting in a fulminant joint inflammation. Recently, OLT1177™, a β-sulfonyl nitrile compound, safe in humans, was shown to inhibit the NLRP3 inflammasome and inhibit joint inflammation in murine models of acute arthritis. This study explores the mechanisms by which oral OLT1177™ inhibits joint inflammation in humans with gout flares.
Methods: 29 patients with a gout flare were treated according to protocol with four different doses of OLT1177™ for 8 days (EudraCT: 2016-000943-14). Blood was drawn at baseline, days 3, 7 and 14 (7 days after finishing treatment). Haematology was evaluated as a marker of systemic inflammation. Plasma was collected for assessment of circulating cytokines. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured under unstimulated or stimulated conditions with a TLR ligand in combination with MSU crystals after which intra- and extracellular cytokine production were assessed.
Results: Treatment of acute gout flares in humans with oral OLT1177™ demonstrates a reduction in white blood cell counts, mainly neutrophils, in all cohorts. In cohorts receiving 2000mg, 1000mg or 300mg, both circulating IL-1β and IL-6 and ex vivo IL-1β and IL-6 production by stimulated PBMCs were reduced during treatment with the strongest effect in the cohort with the highest dose OLT1177™. In unstimulated PBMCs on day 3, ratio of intracellular pro-IL-1β and IL-1β revealed inhibition of the NLRP3 inflammasome by oral OLT1177™ treatment. All these markers of inflammation are relevant parameters that correlate with target joint pain.
Conclusion: Oral OLT1177™, safe in humans, is a potential drug for the treatment of gout flares and other NLRP3 mediated diseases.
To cite this abstract in AMA style:Kluck V, Jansen T, Janssen M, Tengensdal I, Schraa K, Cleophas M, Skouras D, Marchetti C, Dinarello C, Joosten L. Treatment with OLT1177™, an Oral NLRP3 Inflammasome Inhibitor, Reduces Systemic Inflammation During Gout Flares in Humans [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/treatment-with-olt1177-an-oral-nlrp3-inflammasome-inhibitor-reduces-systemic-inflammation-during-gout-flares-in-humans/. Accessed August 5, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-with-olt1177-an-oral-nlrp3-inflammasome-inhibitor-reduces-systemic-inflammation-during-gout-flares-in-humans/