Links Between Inflammatory Activity, Autoantibodies and Development of Cardiovascular Disease in Patients with SLE

Grant Holders - Dr Anisur Rahman, Dr Sean O'Neill, Dr Ashley Groves, Dr Simon Woldman, Dr Andrew Taylor

Patients with lupus have an increased risk of developing heart disease and stroke compared to other people. Heart disease and stroke are often referred to as cardiovascular disease (CVD). There is currently no reliable way to predict which patients with lupus will develop CVD. We need a reliable way to identify and treat the patients with lupus who are at the highest risk of CVD and we need to understand what causes this increased risk in those patients.

LUPUS UK has been funding a research team at University College London to look at these questions.

Our research was in three parts:

Can we use conventional risk factors to help us work out which patients with lupus could benefit from treatment to reduce their risk of cvd?

By conventional risk factors, we mean increasing age, being male, smoking, high blood pressure, high cholesterol, enlarged heart, diabetes and a family history of CVD. These factors are responsible for most of the risk of developing CVD in people who do not have SLE. Someone with all those factors would be at very high risk of CVD and someone with none of those factors would have almost no risk. In fact doctors can take down details of these factors and use them to calculate a person's risk of developing CVD in the next 10 years. This calculation is done using a special mathematical method, often using a computer. If this calculated risk is greater than a certain number (which is usually somewhere between 15 and 30%) then it is generally accepted that patients should be offered treatments such as drugs to reduce cholesterol. However, most patients with lupus have calculated risks of less than 15% because they are young women (in general, older men have the highest risk of CVD). We decided to calculate the risk scores in all the patients attending our clinic at University College Hospital London to find out how high they were and whether we could use these scores to help us identify and treat lupus patients at high risk of CVD. Our idea was that we should consider treating people who had a 7.5% or greater risk of getting CVD in the next 10 years, which is a lower risk than that used to decide on treatment in the general population. By setting a lower risk value for treatment we hoped to allow for the extra risk due to lupus itself, which is not reflected in the calculated risk score.

Over the three-year period 2005-2007 we calculated risk for 308 patients with lupus (about 90% of the patients who attended our clinic). We found that about 30% had high blood pressure, 28% had high cholesterol and 17% smoked. However, the calculated risk scores were usually very low even in people who had these risk factors. Only 11% had a predicted risk of developing CVD in the next ten years of 7.5% or more and most of these people were already having heart treatment for a reason other than SLE (for example a previous heart attack). Overall we found that calculating risk scores would have helped us change the treatment of no more than 11 out of the 308 patients that we studied. This does not mean that we are going to ignore smoking, blood pressure and cholesterol. We just have to find a better way of working out which patients are at such high risk of CVD that they would benefit from treatment of these risk factors. This could involve scans of the heart, blood tests or both.

Can magnetic resonance scans of the heart help us to identify lupus patients who have heart problems before they develop any heart symptoms?

There are several different types of scan that doctors can do to look at people's hearts. Ultrasound scans (echocardiographs) are commonly done and don't involve radiation but they don't show damage to the muscle in the wall of the heart very clearly. Angiograms are very good at showing up problems in the blood supply of the heart but they involve radiation and putting a tube from the groin into the heart itself so are only used in a minority of cases. A new type of scanning called cardiac magnetic resonance (MR) is now available. This does not involve radiation and is very good at showing damage to the wall of the heart caused by poor blood supply. It is only available in a few research centres but may be much more widely available in the future. We started a project with a cardiac MR centre to look at MR scans of the hearts of people with lupus and we compared these scans with echocardiographs taken on the same day. This was to see whether MR scans show more information than echocardiographs in these patients.

22 patients kindly agreed to have scans. These were 11 pairs of patients chosen by us so that one member of each pair was known to have suffered from CVD and the other member had similar age, sex and duration of lupus but had never suffered from CVD.

We found MR scan abnormalities in the hearts of six patients, and in four cases these were not seen by echocardiography. In five of these six patients the damage to the heart shown on MR scanning was in exactly the pattern that is caused by heart attacks but only four of the five were known to have had heart attacks. This means that MR scanning showed heart damage in one patient who did not know that she had heart problems. She had never had any heart symptoms. We sent her to see a heart specialist. This patient had antiphospholipid syndrome (APS) as well as lupus. One very reassuring finding was that we did not find widespread small scars in the heart in the patients with lupus - some people have suggested that this could happen due to inflammation of the heart. It does not seem to have happened in these patients.

From this part of our study we learnt that MR scanning can show up heart damage in patients with SLE but most (10/11) patients without previous heart disease did not have this sort of damage. We think MR scanning may well be helpful in detecting heart problems in some patients with lupus before they get symptoms and are going to do more scans, especially in other patients with antiphospholipid syndrome.

Can testing blood for antibodies show a link between very active lupus and the development of cvd?

Why do patients with lupus have an increased risk of developing CVD? One theory is that when patients have flares of lupus their blood vessels get inflamed and this leads to CVD. Patients with lupus have antibodies in their blood. The most commonly tested antibodies are anti-DNA antibodies and levels of anti-DNA usually go up when people have flares of active disease. However, anti-DNA antibodies have not been shown to affect blood vessels or to cause CVD. On the other hand there are some antibodies that are more likely to be linked to development of CVD in people with heart disease. These are antibodies that stick to high-density lipoprotein (HDL). HDL is sometimes called "good cholesterol" because it is the type of cholesterol that protects people against CVD. HDL is made up of different components and one of the main components is called apolipoprotein A1 (apo A1).We are very interested in anti-HDL and anti-apo A1 antibodies in our patients with lupus. In the third part of our study we measured levels of these antibodies in the blood of patients with lupus.

We found that average levels of both anti-HDL and anti-apo A1 were higher in 37 patients who had had persistently active lupus over the previous two years than in 40 patients who had persistently inactive lupus over the same period of time. We also looked at samples from individual patients taken before and during a flare of lupus and found that in 73% the level of anti-apo A1 went up during the flare. Therefore it is possible that increased production of anti- HDL and anti-apo A1 could be a link between flares of disease and increased risk of developing CVD. In the future we plan to do cardiac MR scans of patients with high levels of these antibodies to see if they have heart problems that have not yet caused symptoms.

How have these results been disseminated?

We were invited to give lectures about these results at both the American College of Rheumatology and the Australian Rheumatology Association and we are writing three papers for publication in medical journals. We are planning to carry on this work both in the UK and in Australia, as one of the doctors who was involved in the project is Australian and has returned there.

Dr Anisur Rahman Phd FRCP

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