- Welcome to peer to peer discussions. I'm JC Kaski, professor of cardiovascular science at St George's University of London. And my guest today is Dr. Aernoud Fiolet from the University Medical Centre, in Utrecht, the Netherlands. Dr. Fiolet thank you very much for joining me today to discuss anti-inflammatory therapy, current guidelines and clinical data. When you were looking at Colchicine and the mechanism of action, I remember some of your work says that Colchicine go beyond an action on the NLRP3 inflammasome. Why do you think this is so?

- Yeah the inflammasome actually is quite an important element in all those studies investigating anti-inflammatory drugs, particularly in atherosclerosis. But evaluating those effects can be quite challenging as one of the downstream markers of inflammasome activity interleukin 1 beta is notoriously hard to measure in regular blood samples. We did some research on NLRP3 in extracellular vesicles, but that's in that's something that's not available in clinical practise. But we also did some proteomics measurements so investigating a whole range range of laboratory measurements and proteins. And there we found something that was already known from previous literature that the effect of Colchicine is particularly strong in neutrophils and neutrophils activity and neutrophil movement. Something that relates to its the inhibition of the cytoskeleton of the cells and neutrophils in particular and also intercellular trafficking. So I think the, the those are things that underscored fact that the effect of Colchicine probably relates to more than the inflammasome alone and also relates to neutrophil activity and the roles of neutrophils in the progression of atherosclerosis.

- That is very, very important because I mean of course we want targeted therapies but an all round anti-inflammatory agent like Colchicine may offer very many advantages. Having said that the studies you carried out and other people have carried out with Colchicine show that there were some side effects some undesirable side effects. And also there was a question as to this trend of total mortality to, to go up in some of the studies and also the problem with CKD being Colchicine the drug that is excreted by the kidneys. Can you, can you comment on those two things?

- Yeah, I think that's an, that's a very relevant theme. Colchicine is excreted mainly via the gut but 20% is done by renal clearance. And we've known for many years that also in patients with gout that those patients that develop a temporary or permanent renal impairment develop higher levels of Colchicine and are at higher risk of toxicity. So it's, it's a drug that should be used in low doses in those patients with chronic kidney disease, or should be used not at all in those with strongly impaired renal function. Rheumatologists are a little bit more liberal in their using the drug, even at those having dialysis. But while the current evidence provides only rationale for using the drug and those with a clearance an estimated GFR of above 45 millilitres per minute. So that's, that's on the, on the renal clearance issue. Side effects seem to be benign. Most of them are gastrointestinal upset and when tolerated after the first week of treatment. We didn't see strong differences in the occurrence of later perceived side effects during the trial. No differences were noted in the occurrence of infections something that's relevant with an anti-inflammatory drug of course, or in the incidents of cancers. So we didn't pick up any strong signals on that matter. There was a numerical differences in non-cardiovascular deaths. The lower number of cardiovascular deaths was a little bit outbalanced by non-cardiovascular deaths. But the fact of the matter is that the patients were quite stable and the total number of non-cardiovascular deaths was quite low, less than 90 on a population of five and a half thousand. So, so whether we were looking at a true signal or it's more a sparse finding should, yeah, should be determined by future evidence, I guess. But those numbers are small and it's hard to say something on it and we haven't found a biological signal that represents it but in general, the drug is well tolerated without important signals on that first effects so far

- Do you thinking that the current international guidelines are fair in relation to the recommendations they give for anti-inflammatory treatments in ischemic heart disease?

- Well, I think that the authors of the guidelines and the guideline committee should be complemented, but the method they have introduced, they're looking at individual patient benefit introducing a a step one, a step two model. And while the recommendations now state that when a patient has, still has an elevated cardiovascular risk despite lifestyle modification, lipid lowering drugs adequate anti-hypertensives and thrombotic treatment one should be offered more intense lipid lowering and other secondary prevent strategies such as Colchicine. And I think it's, it's really, it's it's a very nuanced thing to do that based on an individual patient risk level. So I, that's something that's very interesting and I'm wondering what the guidelines for coronary disease will be, will be doing. These are the guidelines for secondary prevention of cardiovascular disease in clinical practise something that's used by general practitioners and vascular internists. But I think that's a nuanced way of introducing the drug for those people that still have an elevated risk despite the first steps of the secondary prevention.

- I reckon that the, I reckon that the guidelines will will actually be modified shortly. And I think that clinicians would be quite comfortable using Colchicine, for example, as opposed to perhaps other drugs, which require a bit more training for more targeted therapy. But I think that we are really on the right on the right direction. Thank you very much for having found the time to join me today. Thank you very much now.

- Thank you.