All Grand Rounds
Journal Club
CANTOS and the Inflammation Hypothesis of Atherosclerosis
CANTOS gave the first large randomized proof that targeting inflammation alone, without lowering cholesterol, can reduce cardiovascular events, a result with direct relevance to patients with rheumatic disease.
Recording
The discussion
Background. For decades, atherosclerosis was framed mainly as a lipid disorder. Pathology and biomarker work, including the link between hsCRP and future events, suggested that inflammation drives plaque formation and rupture. In rheumatology we see the clinical consequence every day: patients with RA, psoriatic disease, gout and SLE have excess cardiovascular risk that traditional factors do not fully explain.
What CANTOS showed. CANTOS randomized roughly 10,000 patients with prior myocardial infarction and hsCRP of 2 mg/L or higher to canakinumab, an IL-1 beta antibody, or placebo. The 150 mg dose modestly reduced major adverse cardiovascular events with no effect on LDL cholesterol. The benefit was greatest in patients whose hsCRP fell most. The cost was more fatal infections, and canakinumab was not approved for cardiovascular prevention. Later trials sharpened the picture. Low-dose methotrexate in CIRT did not lower IL-6 or CRP and did not reduce events in patients without rheumatic disease. Colchicine reduced events in COLCOT and LoDoCo2, and a low-dose colchicine product is now FDA-approved for cardiovascular risk reduction, although a more recent large post-infarction trial did not show benefit.
How it changes practice. For our patients, CANTOS supports treating inflammation as part of cardiovascular prevention. Achieving remission, minimizing glucocorticoids and NSAIDs, and managing lipids and blood pressure aggressively all matter. It also reminds us that the specific pathway targeted matters: lowering inflammation through IL-1 and the NLRP3 inflammasome is not the same as broad immunosuppression.
Open questions. Which patients benefit most from anti-inflammatory cardiovascular therapy? Does the IL-6 pathway, now being tested in cardiovascular outcome trials, offer a better balance of benefit and infection risk? And how should we interpret colchicine’s mixed trial results for patients with gout, who already take it for different reasons?
Key takeaways
• CANTOS showed that IL-1 beta inhibition reduced cardiovascular events without lowering LDL, supporting the inflammation hypothesis.
• The benefit came with more fatal infections, so anti-inflammatory cardiovascular therapy needs careful patient selection.
• Not every anti-inflammatory drug works: low-dose methotrexate did not reduce events in CIRT.
• For rheumatology patients, disease control is part of cardiovascular prevention, alongside lipids, blood pressure and smoking cessation.
Questions for peers
1. Should hsCRP measured during remission inform statin or colchicine decisions in our patients with inflammatory arthritis?
2. How do we reconcile the positive colchicine trials with the more recent negative post-infarction trial when counseling patients with gout and coronary disease?
3. Does the TNF and IL-6 inhibition we already use in RA provide cardiovascular benefit beyond disease control, and how would we prove it?
4. Who in our system owns cardiovascular prevention for patients who see rheumatology more often than primary care?
References
1. CANTOS: Ridker PM et al. N Engl J Med 2017. IL-1 beta inhibition with canakinumab reduced recurrent cardiovascular events without lowering LDL. PubMed
2. CIRT: Ridker PM et al. N Engl J Med 2019. Low-dose methotrexate did not lower inflammatory markers or cardiovascular events in patients without rheumatic disease. PubMed
3. COLCOT: Tardif JC et al. N Engl J Med 2019. Low-dose colchicine after recent myocardial infarction reduced ischemic cardiovascular events. PubMed
4. LoDoCo2: Nidorf SM et al. N Engl J Med 2020. Low-dose colchicine reduced cardiovascular events in chronic coronary disease. PubMed
5. Atherosclerosis as an inflammatory disease: Ross R. N Engl J Med 1999. Influential review framing atherosclerosis as an inflammatory process. PubMed
At a glance
Format
Journal Club
Reviewed by Farhan Tahir, MD, FACR
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