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Anti-IL-1 Therapy and Long-term Cardiovascular Risk

By: CARRA | February 18, 2016 | What Caught Our Eye

With newer biologics allowing us to more effectively treat JIA and put many more kids into remission, it’s worth taking a moment to think about whether there could be some innocent bystanders from our targeted attacks on the immune system. With that in mind, we were very intrigued by the work done by the IL-1 Genetics Consortium in a paper that must have set a record for the number of authors on one manuscript. They were curious about the effects of long-term IL-1 inhibition on the risk of cardiovascular disease. The problem with trying to answer this question by just seeing who gets a heart attack in a clinical trial of anakinra is that most clinical trials aren’t long enough and don’t have enough patients to see if there’s an increased risk. So this group did the next best thing: they looked at a huge (or “YOOOOOG” if you’re a certain American presidential candidate from New York) number of people who have variants in the gene that encodes IL-1 receptor antagonist (IL-1Ra). Because these variants are the strongest determinants of how much IL-1Ra is circulating, this is a great way to mimic giving anakinra. They then looked at whether these people were at increased risk of developing RA and 4 cardiovascular disorders.

Not surprisingly, they found that the more variant alleles a person inherited, the higher their IL-1Ra serum level was and the lower their IL-6 and C-reactive protein concentration was. This is what we see when we give our kids anakinra. What was really interesting was that there was a pretty powerful dose-response relationship between carrying an IL-1Ra-raising allele and developing coronary heart disease (CHD). People who carried 4 of these alleles had an odds ratio of 1.15 (1.08-1.22; p=1.08x10-6) of developing CHD. Proatherogenic lipids, especially LDL, were higher in these subjects. They also saw an increased risk of abdominal aortic aneurysms, but not of ischemic stroke or type-2 diabetes. Interestingly, the more IL-1Ra-raising alleles a person had, the less likely they were to get rheumatoid arthritis.

Before you go and start all your anakinra patients on statins, it’s important to remember that these are patients whose genetics means that they are, in a way, exposed to a lifetime of anakinra. In our kids, we’re using anakinra hopefully for only a few years. On the other hand, anakinra has more profound effects on inflammation than what was seen in these subjects. So while we’re not increasing their IL-1Ra levels for as long, we’re hitting them harder. If nothing else, this study reinforces the need to do long-term pharmacosurveillance on our patients on anti-IL-1 therapy and for studies looking at when is appropriate to wean or discontinue therapy in our diseases to prevent some of these long-term effects. Ongoing CARRA efforts in this regard include a JIA workgroup focused on inactive disease, and the new CARRA registry, which was developed, in part, to do pharmacosurveillance.