Colchicine Attenuates Inflammation Beyond the Inflammasome in Chronic Coronary Artery Disease: A LoDoCo2 Proteomic Substudy

Abstract

disease ◼ inflammasomes ◼ inflammation Editorial, see p 1901 I nflammation has a crucial role in the progression of atherosclerosis.COLCOT (Colchicine Cardiovascular Outcome Trial) recently showed cardiovascular benefit of treatment with colchicine. 1 Colchicine is an established anti-inflammatory drug, which attenuates NLRP3 (nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3) inflammasome-mediated crystal-induced inflammation present in gout attributable to uric acid crystals and in atherosclerosis attributable to cholesterol crystals.2 Colchicine may inhibit phagocytosis and neutrophil activity.3 The effect of colchicine in human atherosclerosis is unclear.We studied the anti-inflammatory potential of colchicine in patients with chronic coronary artery disease by comparing serum samples before and after 30 days of colchicine treatment using targeted proteomics.We conducted a prospective open-label study during the 30-day run-in period of the LoDoCo2 trial (Low-Dose Colchicine 2; URL: https://www.anzctr.org.au/;identifier: ACTRN12614000093684), including 174 patients with a history (>6 months) of acute coronary syndrome.The study was approved by the Medical Research Ethics Comittees United (MEC-U) at Nieuwegein, the Netherlands.All patients provided informed consent.Patients with highly elevated high-sensitivity C-reactive protein (>10 mg/L) were excluded.All patients underwent blood sampling at baseline and after 30 days of colchicine 0.5 mg once daily in addition to regular care.Targeted proteomic analysis included 184 proteins measured in serum with Cardiovascular II and III panels (Olink; Uppsala, Sweden).The primary outcome was percent change in median protein levels from baseline after 30 days of colchicine treatment.Biomarker levels were presented using normalized protein expression, an arbitrary unit.Correction for multiple comparisons was performed by the Benjamini-Hochberg method with a false discovery rate (FDR) of 5%.The data that support the findings of this study are available from the corresponding author on reasonable request.The 30-day treatment period with colchicine resulted in a significant median reduction in serum expression of 37 proteins (P FDR <0.05).Attenuation of the NLRP3 inflammasome pathway was supported by a reduction of interleukin (IL)-18 (-4.8%;P FDR =0.020), IL-1 receptor antagonist (-8.6%;P FDR =0.006), and IL-6 (-9.7%;P FDR =0.009).The NLRP3 inflammasome cleaves pro-IL-18 and pro-IL-1β into their active form, and attenuation of IL-1β is reflected by attenuated levels of IL-1 receptor antagonist and IL-6.These effects may be partially upstream of the NLRP3 inflammasome inhibition, as suggested by a 10.7% reduction of NF-κB (nuclear factor-κB) essential modulator (P FDR =0.008), an activator of NF-κB, which is necessary for NLRP3 inflammasome activation.Eleven proteins showed a large median reduction (>10%) after colchicine (Figure).These proteins are not directly involved in the NLRP3 inflammasome pathway;