Aernoud Fiolet

371 Clinical implications and future perspectives NCT02898610) trial, is designed to investigate the effect of colchicine 0.5 mg once daily on the risk of major adverse cerebrovascular and cardiac events in patients with prior cerebrovascular disease in particular. The trial is estimated to complete recruitment at the end of 2021. Other therapeutic agents Lastly, drugs targeting similar pathways with different pharmacokinetic properties maybecome increasingly relevant.The interleukin – 1 receptor antagonist anakinra and the interleukin – 6 antagonist tocilizumab were never able to progress to phase III studies in coronary disease. However, the novel interleukin-6 ligand monoclonal antibody ziltivekimab seems effective at reducing multiple inflammatory and thrombotic biomarkers relevant to atherosclerosis. These data have led to the initiation of a large-scale cardiovascular outcomes trial of ziltivekimab compared with placebo in patientswith chronic kidneydiseasewho have increased hsCRPand established cardiovascular disease. 16 Selective NLRP3 inflammasome inhibitors are being developed, but no clinical studies have been registered yet. FURTHER INSIGHTS IN MECHANISM AND DIRECTIONS FOR FUTURE RESEARCH In part III of this thesis, we have set out to distinguish various regular and in- depth biochemical mechanisms by which the protective effect of colchicine in atherosclerosis can be explained and identify clinical markers that could help to predict early (within 30 days) intolerance of the drug. Colchicine, originally extracted from the autumn crocus ( Colchicum autumnale ), is mostly used in chronic administration to prevent gout and treat familial Mediterranean fever. Administered intermittently it is used in the treatment of pericarditis. 17,18 In Chapter 9 , we have shown that low-dose colchicine is associated with a 30–40% reduction in median hsCRP levels and a 16% reduction in median interleukin – 6 levels in patients with chronic coronary disease. 19,20 These effects occur early after treatment initiation and are less pronounced than the anti-inflammatory response seen with canakinumab post-myocardial infarction. 21 In general, the mechanism of action of colchicine relates to the inhibition of microtubule self-assembly. Microtubules are structural components found in various static and dynamic processes of the cell. They form the cytoskeleton and contribute to shape and movement of the cells. They are also the structures