Aernoud Fiolet

249 Short-term effect of low-dose colchicine on biomarkers trial. 7,28–30 A causative role for these two cytokines in disease progression is further implied by the absence of clinical benefit using the anti-inflammatory drug methotrexate, which did not yield a change in hs-CRP or IL-6 levels. 8 IL– 1 beta is an upstream biomarker of IL-6 and there are data suggesting that high doses of colchicine can reduce IL– 1 beta release. However, such an effect has not been described in patients with chronic coronary artery disease. 31 The absence of a clinical effect in the low dose canakinumab arm with the smallest change in inflammatory biomarkers may suggest a certain biomarker threshold to reach clinical effect. This hypothesis is further substantiated by the absence of clinical effect in patients not reaching below-median levels of IL-6 in the CANTOS trial. 32 Blood count effects A small reduction in leukocyte and thrombocyte count was observed during one month of colchicine exposure. This finding is not unexpected. Colchicine affects leukocyte adhesion and chemotaxis and also has an anti-proliferative effect on leukocytes, mediated by the ability to disrupt the cytoskeleton. Colchicine irreversibly binds with tubulin to form an intracellular tubulin complex preventing the formation of microtubules. 33,34 In high doses the drug will arrest mitosis in metaphase as it precludes chromosome separation. 15 Data in acute myocardial infarction, gout or Familial Mediterranean Fever do not support the possibility that these changes translate into clinically relevant adverse effect such as increased likelihood of bleeding. 14,35 In patients with recent myocardial infarction, no numerical differences in total white blood count or lymphocytes between active and placebo drugs were seen twelve months after treatment initiation, and similar rates of infection in general were seen, but higher incidences of pneumonia (0.9% versus 0.4% in patients on placebo (p = 0.03). 14 Treatment with canakinumab resulted in a small increase in the incidence of fatal infection, albeit with a low absolute risk (0.31 versus 0.18 events per 100 person years). 7 Renal effects A small increase in serum creatinine and a corresponding decrease of eGFR was observed. Excretion of colchicine takes place mainly via the enterohepatic circulation (80%) and in part via renal excretion (20%). 9,36 Whether current observations are a direct drug effect on glomerular filtration should be investigated further. Future analysis should include to what extent renal function is affected during long-term administration. The absence of correlation between change in eGFR and magnitude of hs-CRP reduction suggests that the effect of colchicine on