Why is life span shortened by

Rheumatoid Arthritis?

Dr Holly John BM BS MRCP, Research Fellow,  Dr Karen Douglas  MBChB, MRCP, MD Consultant Rheumatologist, Prof George Kitas MD, PhD, FRCP, Consultant Rheumatologist, Dudley Group of Hospitals Foundation Trust, Dudley
Original article: 14/08/2001
Reviewed: 07/10/2010
Next review due: 07/10/2013

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 the general population. This excess mortality appears to have remained unchanged over the last 2-3 decades, despite significant alterations of treatment. 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 presence of other health problems, and characteristics of severe RA – such as poor quality of life, a lot of joint damage on x-rays, or involvement of organs other than the joints – have been shown to associate with higher mortality. In contrast, patients who see a rheumatologist 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.

RA patients appear to have a higher risk of dying from lung, heart or stomach problems, as well as infections and cancers.

The reasons for excess deaths from infections and cancers may be related to the altered function of the body’s defence system (the immune system). However, as many of the drugs used for treatment of RA also have an impact on the immune system these are also implicated. Firstly, let us discuss risk of infection. Most infections in patients with RA are not serious and in recent years studies have shown that the more commonly used drugs such as methotrexate, sulphasalazine and hydroxychloroquine do not significantly increase the risk of serious infections. However azathioprine, cyclophosphamide and corticosteroids do appear to increase the risk of infections. There is also ongoing concern about the “biologic” therapies, such as infliximab, etanercept, adalimumab and rituximab and risk of infection. The British Society for Rheumatology Biologics Register (BSRBR), and other similar registers across the world are monitoring this very carefully. Thus far, the Register has shown that people treated with anti-TNF drugs are up to twice as likely to develop a serious infection, usually within the first 6 months of treatment. Skin infections in particular seem to be associated with 2 of the anti-TNF drugs (infliximab and adalimumab) and these drugs are also linked with an increased risk for re-activation of tuberculosis, in people who had been exposed to TB in the past (whether they were aware of it or not).

Lung conditions account for about 10-20% of deaths in people with RA. Patients with RA may develop inflammation or scarring in their lungs which causes gradually worsening breathlessness. Breathlessness can also be due to inflammation of the blood vessels supplying the lungs, or of the membrane that covers the lungs. Other causes include getting unusual chest infections or scarring of the lungs as a side-effect of certain medications.

Like anyone, patients with RA may develop cancer. The rates of some cancers are higher in RA than in the general population and the outcome sadly is also potentially worse. Most notably increases are seen in lung cancer and lymphoma (a cancer of the blood and lymph glands). On average the risk of lymphoma is twice that of the general population. These cancers are commonest in patients with the most aggressive arthritis, who are more likely to receive the most aggressive treatments; it is therefore still not clear if the increased risk of cancer is due to the RA, its treatment or both. Specific to anti-TNF therapies there appears to be a slight increase in skin cancer. Until more is known, biologic treatments are best avoided in patients with a history of cancer, with a few exceptions. On a more positive note we must add that patients with RA have a reduced risk of cancers of the bowel and breast.

In the past there were an excess number of deaths from stomach or bowel problems (usually bleeding or perforated ulcers) most probably due to side effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the lining of the stomach. However development of other drugs that protect the stomach from the side effects of anti-inflammatories and also with improvements in other treatments for RA may have reduced mortality from such causes. Recent evidence suggests that anti-inflammatory drugs may also associate with high blood pressure, kidney disease and ultimately with an increase in disease and death due to heart disease (see below).

By far the most important single contributor to mortality in RA is heart disease. This accounts for almost half of all deaths in RA. Death from heart disease occurs in patients with RA when they are 10 years younger, on average, compared to controls. The exact reasons for this are still unclear. What we do know, however, is that the most likely cause is ischaemic heart disease (IHD), that is furring up of the blood vessels supplying the heart, making it harder for blood to reach the heart and deliver necessary oxygen to the heart cells. Furring of the arteries occurs in everyone, not only patients with RA, and is due to several “risk factors” including old age, male sex, family history as well as smoking, high blood pressure, high cholesterol, diabetes, increased weight and reduced exercise. This can lead to angina and heart attacks, sudden death, or heart failure. This may occur within the first 10 years of being diagnosed with RA, and may be more severe in people with RA than in people without RA, even if they have the same risk factors. RA patients also seem to have less in the way of warning symptoms (such as chest pain on exertion), probably because they are limited by their physical disability, or pain being attributed to other causes such as their arthritis. Hence they may not receive the most appropriate investigations and treatment.

The reasons for the increased frequency and earlier development of IHD in RA are not known but are being actively researched. Patients with RA may have more of the traditional “risk factors” described above but also other very important explanations relate to the RA itself. Changes of the function of blood vessels due to the inflammation of RA, inflammation of the blood vessels themselves (called vasculitis), changes to the type and levels of cholesterol, altered clotting mechanisms of the blood due to inflammation or genetic differences are likely contributors. It is therefore important to both modify any traditional “risk factors” for example, by stopping smoking or lowering cholesterol (initial research in patients with RA suggests that cholesterol-lowering tablets may lower the chance of having a heart attack) but also to treat RA as effectively as possible to minimize the level of inflammation. Interestingly there are some early signs to suggest that patients who respond well to anti-TNF medication are at lower risk of a future heart attack than patients in whom anti-TNF treatment doesn’t work.

We, as rheumatologists, anticipate that more effective control of RA will not only improve quality of life but also improve life expectancy in patients, and with databases such as the BSR biologics register, and similar registers across the world, in future years this story will no doubt become clearer. In the meantime, several practical steps that make common sense 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.