When the FDA put a black box warning on tofacitinib in 2021, the message was blunt: more heart attacks, more cancers, and more blood clots. The warning came from the ORAL Surveillance trial, which followed over 4,000 patients with rheumatoid arthritis already at high cardiovascular risk. Compared to TNF blockers, patients on tofacitinib had:
- Heart attacks and strokes: About one extra event for every 111 patients treated over four years.
- Cancers: About one extra case for every 83 patients treated.
- Blood clots: higher risk, especially with the higher dose.
On the surface, it looks like another drug safety story. But the deeper lesson is about how the heart and immune system are connected.
The paradox
Patients with rheumatoid arthritis already face two to three times the usual risk of cardiovascular disease. That is not fully explained by cholesterol or hypertension. Interestingly, TNF blockers (anti-inflammatory drugs) often reduce heart attack risk compared to standard care. So why would another anti-inflammatory drug, a JAK inhibitor, make things worse?
The infectious angle
Atherosclerosis may not just be clogged plumbing. It may also be the footprint of a chronic infection, with Chlamydia pneumoniae a leading suspect. Suppress TNF? You calm inflammation but leave enough immune firepower to control hidden bugs. Block JAK-STAT broadly? You silence interferons and other pathways that are vital for keeping intracellular infections in check. The result: TNF blockers may promote healing, while JAK inhibitors may give pathogens inside the vessel wall free rein.
Why this matters
The JAK story reminds us that the heart is an immune organ. When you tinker with immune pathways, cardiovascular outcomes change, sometimes for the better, sometimes for the worse. Notice what is missing: cholesterol barely moves, yet heart attack rates shift. If we continue to treat atherosclerosis as only a lipid problem, we will keep missing the bigger story.
Where we go next
- We need trials that test antibiotic and anti-inflammatory combinations, the same way we already treat TB or H. pylori.
- We should use coronary CT angiography as a fast, affordable way to measure whether therapies actually shrink or stabilize plaque.
- We should remember the Korean War autopsies: young, healthy soldiers in their late teens and twenties already had arteries that looked decades older. Plaque starts early, even in the fittest among us.
Closing thought
The JAK inhibitor warning is not just about drug safety. It is a flashing neon sign pointing us back to the immune system and to the microbes it battles. Until we confront the possibility that infection is the hidden driver of atherosclerosis, we will keep mistaking shadows for the real disease.
Larry Kaskel is an internist and “lipidologist in recovery” who has been practicing medicine for more than thirty-five years. He operates a concierge practice in the Chicago area and serves on the teaching faculty at the Northwestern University Feinberg School of Medicine. In addition, he is affiliated with Northwestern Lake Forest Hospital.
Before podcasts entered mainstream culture, Dr. Kaskel hosted Lipid Luminations on ReachMD, where he produced a library of more than four hundred programs featuring leading voices in cardiology, lipidology, and preventive medicine.
He is the author of Dr. Kaskel’s Living in Wellness, Volume One: Let Food Be Thy Medicine, works that combine evidence-based medical practice with accessible strategies for improving healthspan. His current projects focus on reevaluating the cholesterol hypothesis and investigating the infectious origins of atherosclerosis. More information is available at larrykaskel.com.
