Is there a new COVID-19 role for colchicine?
A long-established treatment for gout, colchicine – the world’s oldest anti-inflammatory drug – can attack COVID-19 inflammation at several points and has shown promising results in a clinical trial, reports Dr Susan Aldridge.
It’s well known by now that COVID-19 infection can lead to severe inflammatory disease, with manifestations similar to toxic shock syndrome, Kawasaki disease, macrophage-activation syndrome and myocarditis. Speaking at the latest World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease, Dr Norman Lepor, Clinical Professor of Medicine at Geffen-UCLA School of Medicine, said: “Whether a patient progresses to the inflammatory aspect of the disease really depends on activation of neutrophils, inflammasomes and the cytokine storm. That gives rise to injuries in a range of tissues – lung, cardiovascular, liver, kidney – leading to severe disease and death.”
The inflammatory picture in COVID-19 is very complex and the pieces are still falling into place. As Dr Lepor observed: “The virus is a real smart little rascal. It’s the smartest thing we have that doesn’t have a brain.” But the more researchers learn about the players, the more targets for new COVID-19 drugs are revealed. Dr Lepor singled out one particular macromolecule in the whole host of players in COVID-19 hyperinflammation. “The NLRP inflammasome really plays a pivotal role both in sensing the stress to the cell and also amplifying the inflammatory response.” It is known that NLRP can actually be primed and activated by a whole host of factors, including the virus. “So the NLPR3 inflammasome is something you’ll hear about more and more as we dig deeper into the effects of COVID-19.”
Colchicine – old drug, new role
There are several approaches to modifying the inflammatory response to COVID-19 infection – some, like the antiviral drug remdesivir, are already in clinical use while others, including the IL-1 receptor antagonist anakinra, are still in development. Dr Lepor wanted to talk about an old drug and one that has thus far received little press attention – colchicine.
Extracted from the autumn crocus, colchicine is the world’s oldest anti-inflammatory drug – its use dating back as far as 1500 BC. It has long been approved for the prevention and treatment of acute gout and is prescribed off label for Beçhet’s disease, pericarditis and other inflammatory conditions.
Dr Lepor noted a number of ways that colchicine has potential efficacy against COVID-19 inflammation. It stops neutrophil production, recruitment and adhesion to the endothelium – a key component of the inflammatory response. It also inhibits the NLRP inflammasome, mentioned earlier, which reduces cytokine production and so damps down the cytokine storm. Thus, it acts against several targets in the COVID-19 inflammation scenario.
Dr Lepor has been involved in the COLCORONA trial, led by the Montreal Heart Institute (see Lancet Respiratory No 9 August 2021). This was the first, and largest, randomised trial dealing with COVID-19. Participants, all of whom had at least one risk factor for severe disease, started on either colchicine (2075) or placebo (2084) within two days of their COVID-19 diagnosis. They were treated on an outpatient basis, so they weren’t very ill with the infection. “This was a really nice ‘no touch’ trial. Medicines were delivered by Uber and so on, and communications carried out by phone and Internet.” Among those patients whose COVID-19 status was confirmed by a PCR test, there was a statistically significant reduction of 25% (4.6% vs 6.0%) in the combined endpoint of hospitalisation and death with colchicine treatment.
There has also been the RECOVERY with colchicine, recently published in The Lancet Respiratory. This randomised controlled trial involved a cohort of inpatients who were more seriously ill with COVID-19 and found that colchicine did not have any efficacy. “We know that there are different stages of the COVID-19 infection in terms of the inflammatory state,” said Dr Lepor. “Patients who are very sick and hospitalised did not seem to have any impact in terms of colchicine in that particular stage of the disease process.” So, it is a matter of timing the administration of colchicine – earlier rather than later.
Fortunately, there are many more trials going on in terms of other approaches. “I think what we can all agree on is that the complications in terms of COVID-19 have an inflammatory basis,” said Dr Lepor. “The target of action of colchicine seem to be at sites that could mitigate some of the inflammation-based complications. The COLCORONA trial showed significant benefit in early, ambulatory COVID-19 subjects with confirmed infection.” He added that colchicine is, of course, a generic drug, which doesn’t really have that big pharma push you would see with a new molecule. But it is cheap and readily available – and could help cut hospitalisation and death in patients with COVID-19 infection before the inflammatory response takes hold.
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Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
Lancet Respir Med. 2021 Aug;9(8):924-932.
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Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
Lancet Respir Med. 2021 Dec;9(12):1419-1426.