Methotrexate, despite the established anti-inflammatory effects in rheumatologic disease largely mediated through adenosine release, neither reduced IL-1β, IL-6, or hsCRP nor lowered MACE in the CIRT trial of 4786 patients with stable ASCVD and diabetes or metabolic syndrome (HR 0.96; 95% CI 0.79–1.16), potentially reflecting its limited activity on the NLRP3-IL-1β-IL-6 axis and inclusion of participants without elevated baseline inflammation [63]. This evidence concerns the gene IL1B and atherosclerosis.