Why do people with rheumatoid arthritis die from cardiovascular disease up to ten years earlier than they should?
Rheumatoid arthritis (RA) is Australia’s most common significant autoimmune disease, affecting 1% of the adult population.1 Current treatment focuses on settling joint inflammation and allowing sufferers to return to work and perform daily activities, but there is no cure at present.
There is continuing development of new agents that target the inflammation in RA. These are proving to be increasingly effective, with up to 50% of patients obtaining clinical remission with combination therapy.2 However, despite treatment, patients with RA have increased mortality and morbidity because of their disease. They die on average 7–10 years earlier than their unaffected peers.3 RA is rarely the direct cause of death; infections and cardiovascular disease are the main causes.4 A US study following RA patients from 1965 to 2007 showed no change in their mortality over this time, compared to an 80% reduction in mortality in their peers.5
Cardiovascular disease (CVD) is recognised as an inflammatory disease of the blood vessels. Various risk factors will accelerate this process, including smoking and obesity. Importantly, RA is now recognised as an additional risk factor for CVD. It is thought that the inflammatory processes of RA, with its immune activation, cause further inflammation within the cardiovascular system.
We have no direct treatment for CVD – we can only slow it down by treating the known risk factors such as hypertension and smoking. We know that in diseases like diabetes, patients do best if we take an holistic approach to their cardiovascular risks rather than focusing wholly on their glycaemic control.
So what happens in RA if we tackle other CVD risk factors? The simple answer is that we don’t know. Currently, there are at least two trials underway examining the use of statins in the treatment of RA patients. The first is the TRACE RA trial in the UK, studying RA patients of any disease duration (http://www.dgoh.nhs.uk/tracera). The second, with which I am involved, is a trial in Brisbane through the Diamantina Institute, studying patients who have had RA for less than one year.
These trials are tackling the lipid profile because RA changes the lipid profile. A reduction in total cholesterol gives a false impression of a good lipid profile, and hides a disproportionate fall in the good high-density lipoprotein (HDL). Recent studies have also shown that in inflammatory disease, this good HDL often does not function normally and goes bad.6 Normally the HDL protects LDL from oxidation, thereby reducing the amount of oxidised LDL that can damage vessel walls. In SLE and RA, the HDL is often defective and is associated with increased risk of CVD. The abnormal lipid profile in RA may appear to be superficially normal, but it hides a defective lipid metabolism; importantly, these patients would not qualify for treatment with lipid modifying medications.
There are several reasons for using statins in RA-CVD risk reduction. There is good evidence for statins in primary and secondary CVD risk reduction in the general population. Statins also have more generalised effects than specifically lowering lipids. Statins have mild anti-inflammatory properties and reduce the inflammatory effects at the atherosclerotic plaque, which is thought to account for part of the CVD risk reduction. They have been studied as a disease modifier in RA, showing a statistical but not clinically significant reduction in disease activity.7 Therefore, there are theoretical mechanisms for using statins to reduce CVD risk in RA, and we await the outcomes of these trials.
What about other CVD risk factors? We now know that smoking predisposes patients to developing RA, so RA patients are more likely to be smokers. We should specifically address this with RA smokers (in an analogous way in which we attempt to encourage diabetics to stop smoking). However, a patient’s status as a smoker does not account for all of the CVD risk in RA. Therefore patients’ other risk factors also need to be addressed. Conditions like hypertension and diabetes can be partly treated with medication, but lack of exercise, poor diet and smoking all require a lifestyle change. Lifestyle factors are notoriously hard to treat in the general population, let alone in patients with RA who are stiff and sore. For most patients with RA, the diagnosis comes as a shock, and it takes a long time for them to come to accept it. To add to this, we are trying to correct behaviours of a lifetime, and this is a difficult area to address. However some patients welcome the opportunity to have some control over an aspect of their health after being dealt the RA card.
Currently we don’t know what happens if we tackle RA sufferers’ other CVD risk factors. When the results of the two current studies are analysed in the next few years, we will know if statins provide any significant benefits. Despite the lack of direct evidence, it would seem reasonable to focus therapeutic efforts on tackling other CVD risk factors. Hopefully, research within the next few years will elucidate new options in treating CVD in RA.
Article written by:
Dr Malcolm Turner, FRACP BMBS BSc(Hons)
Rheumatology Research Fellow, Diamantina Institute for Cancer, Princess Alexandra Hospital, Brisbane
Editorial Advisory Board Member of the Virtual Rheumatology Centre
Dr Malcolm Turner receives a research fellowship from the Princess Alexandra Foundation.
- Silman AJH, Hochberg MC (eds). Epidemiology of the Rheumatic Disease, 2nd Edition. Oxford: Oxford University Press, 2001.
- Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006; 54(1): 26-37.
- Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, et al. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994; 37(4): 481-94.
- Mikuls TR, Saag KG, Criswell LA, Merlino LA, Kaslow RA, Shelton BJ, et al. Mortality risk associated with rheumatoid arthritis in a prospective cohort of older women: results from the Iowa Women’s Health Study. Ann Rheum Dis. 2002; 61(11): 994-9.
- Gonzalez A, Maradit Kremers H, Crowson CS, Nicola PJ, Davis JM 3rd, Therneau TM, et al. The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum. 2007; 56(11): 3583-7.
- McMahon M, Grossman J, FitzGerald J, Dahlin-Lee E, Wallace DJ, Thong BY, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006; 54(8): 2541-9.
- McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004; 363(9426): 2015-21.