Colchicine is an alkaloid derivative from the plant "colchicum autumnale" that has been traditionally used in treating rheumatologic conditions such as gout and Familial Mediterranean Fever.^1,2 However, growing evidence suggests that colchicine's mechanisms of action are multifaceted and hold promise for therapy in atherosclerotic cardiovascular disease (ASCVD), atrial fibrillation (AF), and more recently, treating COVID-19. Here, we review the evidence behind the use of colchicine in rheumatologic, cardiovascular, and infectious disease. We also explore additional future considerations for the use of colchicine.

Colchicine for the Treatment of Gout

Colchicine has most widely been used for the treatment of acute gout flares and other crystalline arthropathies. The clinical features of acute gout result from the inflammatory response to monosodium urate (MSU) crystals which form as a result of hyperuricemia.¹ These crystals interact with macrophages within the synovial lining cells, thereby activating the NOD-like receptor protein (NLRP3) inflammasome, a complex cytosolic multi-protein. Activated NLRP3 recruits caspase-1 which cleaves pro-interluekin-1β into its mature form, interleukin-1β (IL-1β).³ This promotes the secretion of pro-inflammatory chemokines and neutrophil influx into the synovium and joint fluid, resulting in gout.⁴

There are multiple mechanisms by which colchicine exerts its anti-inflammatory properties. Colchicine irreversibly binds tubulin, thereby blocking microtubule polymerization.¹ By binding tubulin, colchicine impairs migration of inflammatory cells via chemotaxis. By inhibiting mitosis, colchicine reduces growth of vascular smooth muscle cells and fibroblasts.

Platelet aggregation is impaired as cytoskeleton rearrangement is necessary for shape change and activation. By inhibiting intracellular signaling, colchicine prevents NLRP3 inflammasome assembly preventing release of IL-1β and other interleukins. Microtubules play an important role in cytokine and chemokine secretion, cell division, cytoskeletal re-arrangement, and intracellular signaling, all critical cellular processes involved in triggering the inflammatory cascade vital to innate immunity.⁴ Independent of tubulin binding, colchicine further impairs platelet-leukocyte interaction, decreases activation and adhesion of T lymphocytes, and reduces selectin expression on inflamed vascular endothelium.⁵

Colchicine for the Treatment of ASCVD

Atherosclerosis is partly an inflammatory disease.⁶ The initiation of atherosclerosis begins with the deposition of cholesterol crystals within vascular endothelium and progresses via inflammatory signals to form atherosclerotic plaque.⁷ The inflammatory cascade seen in acute gout flares is similar to that seen in the propagation of atherosclerosis. Like uric acid crystals, cholesterol crystals stimulate pro-inflammatory macrophages to assemble the NLRP3 inflammasome within the plaque, which increases the risk of acute plaque rupture.^5,7 Thus, colchicine may confer protection against plaque progression.

Three randomized controlled trials suggest that the anti-inflammatory properties of colchicine may eventually be US Food and Drug Administration (FDA) approved to be part of a secondary prevention strategy in patients with coronary artery disease. The Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo) trial was the first prospective randomized clinical trial that evaluated the use of colchicine to treat coronary artery disease (CAD).

This trial randomized 532 patients with stable coronary artery disease on statin and antiplatelet therapy to treatment with colchicine or placebo. Those treated with colchicine had a 67% relative risk reduction in the primary composite outcome of cardiovascular death, non-cardioembolic stroke, acute coronary syndrome, and out-of-hospital cardiac arrest (p<0.05).⁸ Subsequently, a much larger trial, LoDoCo-2, randomized 5,522 patients with stable coronary artery disease to receive colchicine versus placebo. Those who received colchicine had a 31% risk reduction in primary outcome measures including cardiovascular mortality, myocardial ischemia, ischemia-driven revascularization and stroke compared with placebo (p<0.05).⁹

While colchicine use was not associated with increased rate of hospitalization for infection, pneumonia, or gastrointestinal intolerance, there was a non-significant increased incidence in non-cardiovascular deaths. This was not explained by an increase in death from cancer or infection. It is unclear if this finding is due to chance and it warrants further study.

The Colchicine Cardiovascular Outcomes Trial (COLCOT) trial was the first large study evaluating colchicine's effects on secondary cardiovascular prevention. The trial randomized 4,745 patients who had suffered a recent myocardial infarction to receive low dose colchicine (0.5 mg once daily) or placebo. Those who received colchicine had a significant 23% risk reduction in the primary composite end point of cardiovascular death, cardiac arrest, myocardial infarction, stroke, or urgent coronary revascularization. Post-hoc analysis showed benefit of colchicine only among patients who were started on colchicine within the first 3 days after myocardial infarction, highlighting the importance of early initiation of therapy.¹⁰

Colchicine for the Treatment of Atrial Fibrillation

The NLRP3 inflammasome is also thought to play a significant role in the pathogenesis of AF. Mice models have shown that inhibition or ablation of NLRP3 prevented the development of AF.¹¹ Other studies have shown that elevated inflammatory markers such as hsCRP, IL-6, IL-1β, which are downstream of NLRP3 activation, are correlated with AF recurrence after ablation.¹²

Several randomized controlled trials have evaluated the role of colchicine for prevention of post-cardiothoracic surgery AF and the recurrence of AF after pulmonary vein isolation and AF ablation. Imazio et al. conducted a multicenter trial, Colchicine for the prevention of the Postpericardiotomy Syndrome Trial (COPPS), and showed that administering colchicine for 1 month after pericardiotomy reduced post-operative AF by 45%.¹³

Deftereos et al. conducted a randomized controlled trial showing that 3 month administration of colchicine was associated with reduced AF recurrence after pulmonary vein isolation (16% colchicine vs. 33.5% placebo, P=0.01).¹⁴ Currently the American College of Cardiology (ACC)/American Heart Association (AHA)/Heart and Rhythm Society (HRS) Guideline for the Management of AF recommends consideration of treating selective individuals after cardiac surgery with colchicine to reduce AF occurrence  (Class IIb recommendation).

Colchicine for the Treatment of COVID-19

Colchicine's therapeutic role is now being explored in the realm of infectious disease to combat the cytokine storm that drives the clinical complications seen in patients with COVID-19. The severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), closely related to SARS-COV-2, activates the NLRP3 inflammasome triggering an inflammatory cascade associated with the cytokine storm syndrome.¹⁵ There is a therapeutic opportunity to target the NLRP3 inflammasome to reduce mortality in those with COVID-19.

The COLCORONA (COLchicine CORONAvirus SARS-CoV-2) trial is the first randomized, double-blind, placebo-controlled, investigator-initiated trial of 4,488 patients comparing colchicine and placebo in non-hospitalized patients. The primary endpoint was a composite of death or hospitalization due to COVID-19 within 30 days of randomization. Among the 4,159 patients with PCR-confirmed COVID-19, the primary end point occurred in 4.6% of those who received colchicine versus 6% in the placebo group. Notably there were fewer serious adverse events in the colchicine group (4.9%) compared to the placebo (6.3%).¹⁶

Future Considerations

There remains much to be learned about the full potential of this medication that has been used since the 6th century. Beyond arthropathies, cardiac disease, and infectious disease, any condition mediated by enhanced inflammatory signaling, especially by the NLRP3 inflammasome, deserves possible consideration for treatment with colchicine. Given its tolerable side effect profile, safety, and low cost, colchicine may eventually prove to be a mainstay therapeutic among anti-inflammatory agents.

References

1. Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet 2016;388:2039-52.
2. Slobodnick A, Shah B, Krasnokutsky S, Pillinger MH. Update on colchicine, 2017. Rheumatology 2018;57:i4-i11.
3. Kingsbury SR, Conaghan PG, McDermott MF. The role of the NLRP3 inflammasome in gout. J Inflamm Res 2011;4:39-49.
4. Kaul S, Gupta M, Bandyopadhyay D, et al. Gout pharmacotherapy in cardiovascular diseases: a review of utility and outcomes. Am J Cardiovasc Drugs 2020;Dec 28:[Epub ahead of print].
5. Deftereos S, Giannopoulos G, Papoutsidakis N, et al. Colchicine and the heart: pushing the envelope. J Am Coll Cardiol 2013;62:1817-25.
6. Boland J, Long C. Update on the inflammatory hypothesis of coronary artery disease. Curr Cardiol Rep 2021;23:6.
7. Nidorf SM, Thompson PL. Why colchicine should be considered for secondary prevention of atherosclerosis: an overview. Clin Ther 2019;41:41-48.
8. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-10.
9. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020.;383:1838-47.
10. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497-2505.
11. Yao C, Veleva T, Scott L Jr, et al. Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation 2018;138:2227-42.
12. Li N, Brundel BJJM. Inflammasomes and proteostasis novel molecular mechanisms associated with atrial fibrillation. Circ Res 2020;127:73-90.
13. Imazio M, Trinchero R, Brucato A, et al. COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial. Eur Heart J 2010;31:2749-54.
14. Deftereos S, Giannopoulos G, Kossyvakis C, et al. Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation: a randomized controlled study. J Am Coll Cardiol 2012;60:1790-96.
15. Freeman TL, Swartz TH. Targeting the NLRP3 inflammasome in severe COVID-19. Front Immunol 2020;11:1518.
16. Colchicine reduces the risk of COVID-19-related complications (Montreal Heart Institute). 2021. Available at: https://app.cyberimpact.com/newsletter-view-online?ct=guhsMu_jogsWK5zuKuZWMiFdWXxrNhn6Nkcjb1fm-HUAuS81ZbwD0N6bKX9bJ23ALFDAfrG83CWBnSzT41zxRA. Accessed 01/26/2021.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Cardiac Surgery, COVID-19 Hub, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Pericardial Disease, Prevention, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Coronary Artery Disease

Keywords: Dyslipidemias, Colchicine, Coronary Artery Disease, Postpericardiotomy Syndrome, Uric Acid, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Colchicum, Atrial Fibrillation, Tubulin, Pulmonary Veins, Inflammasomes, Plaque, Atherosclerotic, C-Reactive Protein, Interleukin-6, Platelet Aggregation Inhibitors, SARS-CoV-2, COVID-19, Secondary Prevention, Cardiovascular Diseases, Cytokines, Familial Mediterranean Fever, Acute Coronary Syndrome, Gout, Pericardiectomy, American Heart Association, Interleukin-1, Platelet Aggregation, Hyperuricemia, Chemotaxis, Neutrophils, Endothelium, Vascular, Double-Blind Method, United States Food and Drug Administration, Out-of-Hospital Cardiac Arrest, Galium, Muscle, Smooth, Vascular, Polymerization, Prospective Studies, Random Allocation, Myocardial Infarction, Atherosclerosis, Cardiac Surgical Procedures, Stroke, Anti-Inflammatory Agents, Microtubules, Neoplasms, Cholesterol, Cytoskeleton, Synovial Membrane, Selectins, Macrophages, Hospitalization, Immunity, Innate, Risk Reduction Behavior, Risk, T-Lymphocytes, Mitosis, Fibroblasts, Bodily Secretions, Polymerase Chain Reaction, Communicable Diseases, Outcome Assessment, Health Care, Arthritis, Rheumatoid

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