The worlds of research into therapies for cardiovascular disease and autoimmune disease are getting closer and closer as we gain understanding of the shared mechanisms and treatments, the ACR Convergence has heard.
Dr Susan Manzi, professor of medicine at Allegheny Health Network in Pittsburgh, said there was a “colliding of two worlds in terms of both mechanisms and treatment”.
“Whether you believe that atherosclerosis is just a growing relationship, or it’s an actual other autoimmune disease, the truth is that our mechanistic pathways and our therapeutic targets are coming together,” Dr Manzi said.
“The more we understand about the pathogenic mechanisms for our autoimmune diseases, as well as those same mechanisms in atherosclerotic vascular disease, the closer our worlds come together, because now we’re sharing therapeutic targets, which is really bringing things quite close.
“If we share these mechanisms and targets, why not define it as an autoimmune condition?
Dr Manzi told the conference that clinicians need to recognise patients’ cardiovascular risk, manage the known cardiovascular risk factors and adapt current risk assessment tools.
“The underlying message is you have got to control disease activity. Disease remission is more important than the agent used to get there, and I would just exclude corticosteroids in that statement.”
Dr Manzi said vascular diseases shared pathways with autoimmune conditions, whether it was the formation of plaque, thrombus formation or the loss of vessel elasticity.
“We know that cardiovascular diseases are greater than expected in autoimmune conditions, whether that’s actual events, or whether that’s preclinical by measuring plaque progression or looking at imaging for elasticity or vascular stiffness.”
There was evidence that having one autoimmune condition increased the risk of having another, she said.
Dr Manzi said a study in The Lancet last year found that people with an autoimmune disease had a 56% increased risk of any cardiovascular event compared to controls.
The UK study included almost 500,000 cases of 19 newly diagnosed autoimmune diseases and matched those cases to more than two million controls matched on traditional cardiovascular risk factors.
The researchers found that the incidence of any cardiovascular event was 23 per 1000 among people with an autoimmune condition, compared with 15 per 1000 in the control group over seven years.
“The more conditions you have, the higher the risk,” Dr Manzi said.
“They found that the younger patients less than 45, versus those that are older, had the highest relative risk. And the overall cardiovascular rates went down over time, but they were still greater than expected. And then finally, there was a greater risk of hospitalisation and death.”
As for rheumatology therapies, which ones increase CV risk, and which attenuate risk? Dr Manzi said a meta-analysis and systematic review including 34 studies – mostly in RA and psoriasis and psoriatic arthritis – found there was a 30% reduction in cardiovascular events in patients taking TNF inhibitors and a 28% reduction with methotrexate.
The study also saw a modest increase in risk with NSAIDs, mostly driven by COX-2 inhibitors, and a significant increase with corticosteroids.
Dr Manzi said corticosteroids increased cardiovascular risk “across the board”.
“No one’s going to disagree that we have to use corticosteroids at lowest effective dose, shortest period of time.”
Last year, EULAR recommended limiting glucocorticoid exposure, using the lowest effective dose and the shortest duration, and discontinuing if possible, to help reduce cardiovascular risk, she said.
The recommendations also stated that hydroxychloroquine should be used in lupus to reduce cardiovascular risk, and a recent meta-analysis and systematic review of antimalarials in RA and lupus showed that hydroxychloroquine gave a 60% reduction in cardiovascular events.
“Regardless of what disease you’re treating, hydroxychloroquine looks to be protective,” she said.
“We know that hydroxychloroquine and antimalarials have beneficial effects on lipids, glucose, coagulation, inflammation and endothelial function.”
One member of the audience asked whether it would be beneficial to paediatric patients to start anti-inflammatories such as colchicine early to decrease the future risk of cardiovascular disease.
Dr Manzi said the key message for young patients was disease control and biologic trials should be extended into the paediatric population.
“As soon as we start and get things under control, the better, and we have to push biologics to that group.”
The next speaker, Professor Johan Frostegard from the Karolinska Institutet in Sweden, focused on the immune-based pathogenesis of atherosclerosis, telling delegates that the idea that atherosclerosis was an inflammatory disease was first raised in the mid-1800s.
Professor Frostegard pointed out that brown bears had very high blood lipids and were totally immobilised and uremic during seven months of hibernation but had no signs of atherosclerosis.
That puzzling contradiction could be explained by their high levels of anti-phosphorylcholine autoantibodies (anti-PC), which was associated with protection in atherosclerosis and cardiovascular, autoimmune and chronic inflammatory diseases, he said.
“So why don’t they get atherosclerosis and CVD? It turns they develop high levels of anti-PC in the winter, which is probably related to the food for these animals which consists of continuously eating everything they get their claws on.”
Another study of a population with a traditional lifestyle in Papua New Guinea 30 years ago showed that they had very high anti-PC levels and no cardiovascular disease, he said.
Professor Frostegard said high anti-PC levels could be caused by the environment, diet, bacteria and microorganisms, and there was promising research into developing an anti-PC vaccine.
Mouse experiments with active and passive immunisation show atheroprotective effects, he said.
Professor Frostegard said everyone had antibodies against phosphorylcholine which were negatively associated with atherosclerosis progress, cardiovascular disease, SLE, RA and other chronic inflammation.
“Some other groups are showing that association in vasculitis and also in osteoarthritis.”
Professor Frostegard said human anti-PC had potential atheroprotective and anti-inflammatory mechanisms including inhibition of inflammatory phospholipid effects, decreased uptake of oxLDL in macrophages, inhibition of cell death caused by lysophosphatidylcholine (a major player in lesions), increased clearance of dying cells and promotion of T regulatory cell polarisation.
“I think we will see lots of new studies coming in this field,” he concluded.
14T131: Cardiovascular Rheumatology: Lessons Learned from Targeting Inflammation to Modulate CV Risk