Early death is an important undesirable long-term outcome of Rheumatoid Arthritis (RA). It has been known since the early 1950s that RA shortens life span by about 10 years but, until recently, this received much less attention by the medical and scientific communities than control of physical disability and improvement of quality of life. RA mortality studies have been performed in most parts of the developed world, including the United Kingdom, USA, Canada, Holland, Scandinavia, Australia and Japan. They have shown consistently that mortality in patients with RA is up to 3 times higher than that expected in comparable sections of the general population of the same area (the control population). This excess mortality appears to have remained unchanged over the last 2-3 decades, despite significant alterations of treatment over the same period. The exact reasons for this remain unknown, but ongoing research is continuously adding important pieces to the puzzle.
Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality. In contrast, patients who present to rheumatological care early in the course of their disease have a better outcome. Many of these factors may be inter-related and more research is needed to tease out the most important of them. Using such information, health professionals should eventually be able to identify early on which individual patients are at high risk of early death and intervene appropriately, if possible, to control the relevant risk factors.
Some investigators have been able to examine the underlying causes for the excess mortality in RA. Compared with controls, RA patients appear to have a higher risk of dying from most possible causes of death, including stomach, lung or heart problems, infections and cancers (mainly of the blood).
Excess deaths from stomach or bowel problems (usually bleeding or perforated ulcers) are most probably due to adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the lining of the stomach. The development of other drugs that protect the stomach from NSAIDs (such as misoprostol and proton pump inhibitors), and of new generation NSAIDs that are kind to the stomach (for example the so called cyclooxygenase-2 selective drugs, or Coxibs) may reduce mortality from such causes. However, this may come at a cost: recent evidence suggests that these drugs may associate with increased heart problems and deaths from heart disease (see below).
The reasons for excess deaths from infections and blood cancers are much less clear. These are probably due to altered function of the body’s defence system (the immune system). However, it is very difficult to distinguish whether such alterations relate to intrinsic effects of the disease, or to the effects of drugs used for its treatment (such as methotrexate, cyclosporine, azathioprine, or others). It is also still unknown whether the introduction of the new “biologic” therapies, such as the anti-TNF drugs infliximab, etanercept and adalimumab, will have a significant impact on infection or cancer-related deaths. Answers to these questions may arise from further research, using initiatives such as the National Registry in Britain, which will enable comparison of the outcome of patients with RA who have been on various different sorts of treatment. Thus far, there have not been any significant warning signs, with the possible exception of the association of one of the anti-TNF drugs (infliximab) with an increased risk for re-activation of tuberculosis, in people who had been exposed to it in the past (whether they were aware of it or not).
By far the most important single contributor to mortality in RA is heart disease.This accounts for almost half of all deaths in RA. Several studies have shown that patients with RA are 2-5 times more likely than controls to die from heart disease. Death from heart disease occurs on average 10 years earlier in patients with RA than controls. The reasons for this are still unclear.
It has been known for a very long time that RA can affect the heart, by causing inflammation of the external lining of the heart (pericarditis), the heart muscle itself (myocarditis) or the heart valves (endocarditis). Such problems are common if one looks for them with special tests, but they rarely cause symptoms and even more rarely heart dysfunction, so they are unlikely to be the cause of increased death from heart disease. In contrast, most deaths appear to be due to heart attacks or due to heart failure. This suggests that the most likely cause is ischaemic heart disease (IHD). In this condition, the heart is starved of oxygen usually because blood cannot reach the heart easily due to hardening of the blood vessels (atherosclerosis). This occurs in most people and tends to associate with several “risk factors” including old age, male sex, family history (which cannot be modified) as well as smoking, high blood pressure, high cholesterol, increased weight and reduced exercise (that can be modified). This process of atherosclerosis and the resultant IHD appear to occur earlier and be more severe in RA than in controls with the same risk factors. Recent research suggests that almost half of RA patients attending hospital have evidence of IHD, compared with only one quarter of controls. Alarmingly, more than half of RA patients with IHD do not have any warning symptoms (such as chest pain on exertion), probably because they are limited by their physical disability. The reasons for the increased frequency and earlier development of IHD in RA are not known but are being actively researched. There are several possibilities including: changes of the function of blood vessels due to the inflammation of RA; inflammation of the blood vessels themselves (called vasculitis); changes of the type and levels of cholesterol; changes of the clotting mechanisms of the blood due to inflammation; adverse effects of drugs used for the treatment of RA; and genetic differences.
It is obvious that although we are aware of the problem of increased mortality in RA, we have a long way to go before we know the exact reasons and find ways to tackle them. In the meantime, there are several practical steps health professionals can take in every day practice and patients in every day life that make common sense. These include:
- Both patients and doctors should look out for new symptoms, such as excessive tiredness, sweats and fevers, weight loss – they may be due to RA but may also reflect chronic infection or cancer. Chest pain or breathlessness may also need to be investigated with special tests looking for heart or lung disease.
- Patients should try to stop smoking, control their weight and be as physically active as possible. Doctors in turn should check patients’ blood pressure and cholesterol and control them if necessary.
- Both patients and doctors should consider supporting further research addressing this important problem.