What is the Cause of Rheumatoid Arthritis? Non-Genetic Factors

Introduction

It is seldom possible to say why a particular person has developed rheumatoid arthritis (RA) but, in general terms, the pieces of the jigsaw are coming together.

It is clear that there is a tendency for RA to run in families. If one member of a pair of identical twins has RA then the other member has a 15% chance of developing the disease. This is substantially higher than the risk in the general population, which is approximately 0.8%. Since identical twins have identical genes, this high degree of what is called 'concordance' points to a major genetic contribution to the cause of RA. The fact that the concordance is not 100% means that other non-genetic or "environmental" factors also play a part. We are using the term "environmental" in a somewhat broader way than is common in everyday language. We are referring to the environment in which the genes have influence and so we might include, for example, psychological stress, other medical illnesses and factors in the external environment such as pollution.

There is no single gene which is the cause of RA. There have been major advances in the last 5 years in terms of understanding the genetic factors which predispose to RA. Many of these have come from whole genome scans in large cohorts of people with RA. More than 10 genes have now been identified and work is currently in progress to establish exactly what these genes do and how they interact with one another and environmental factors. Similarly, there is no single environmental factor which is sufficient, by itself, to cause RA. We can think of RA as being like a plant. Firstly it needs the soil in which to grow. The soil is equivalent to the genetic factors. Then there are the seeds which have to be planted in the soil. The seeds are equivalent to the non-genetic risk factors. The richer the soil (i.e. the more genes associated with RA a person has), the fewer the quantity of seeds needed for a plant to grow. Thus, within families with several cases of RA, it is likely that there are many of the genes which are associated with RA and so environmental risk factors play a smaller part in triggering the disease than in so-called 'sporadic' cases of RA. Also, since genetic factors are present from birth, whereas environmental factors are encountered throughout life, people who develop RA early in life are more likely to have a high number of genetic risk factors than those who develop RA later in life.

The Course of Rheumatoid Arthritis

There are three stages in the course of RA in which genetic or environmental factors may play a part. The first is the time leading up to the onset of RA. Factors which act during this time are called susceptibility genes or environmental risk factors. It is only these factors which can be thought of as truly contributing to the cause of RA. The next phase, which takes three to twelve months is termed the persistence phase. Many people who develop joint inflammation after, for example a viral infection, get better within a few weeks. In other people the arthritis persists and develops into RA. Various genetic and environmental factors influence whether arthritis becomes persistent. Finally there is the chronic phase of RA. In this stage genetic or environmental factors (including treatment) may influence the severity of the disease. It is very important to distinguish in which of the three phases of RA any particular gene or environmental factor plays a part. Only then can we know what the likely outcome would be of removing or modifying this particular factor. For example, if eating plums were a risk factor for developing RA (it isn't as far as we know!) but had no effect on the severity of the disease once RA had developed, then there would be no point in advising people who had RA to stop eating plums. There might, however, be some merit in advising the non-affected member of an identical twin pair to stop eating plums in order to try and prevent the development of RA.

In order to find risk factors for the development of RA we need to study people as close as possible to the onset of their symptoms. If we continue to study these people as their arthritis either gets better or progresses we can learn about the genetic and environmental influences on the course of RA.

Clues from History and Geography

A study of the history and geography of RA provides some intriguing clues with regards to the cause of the disease. Within Europe there are no definite descriptions of RA before 1800. It is surprising that the typical hand deformities which often develop after many years of disease particularly if it is untreated, do not appear in medical or ordinary literature, paintings, or skeletal remains. This suggests that RA may be a "modern disease". By contrast, in North America, skeletons have been found dating back several thousand years which do show evidence of RA. To this day the highest frequency of RA is found amongst Native American peoples. This suggests that RA may have originated in the New World and been transported to the Old World. The first candidate that springs to mind is an infection. However, we must not forget that other items such as tobacco and the potato were also transported from the New World to the Old.

The occurrence of RA is not the same throughout the world. RA is rare in less developed and rural parts of the world. One large study in Nigeria failed to find a single case. RA is also rare in rural China and Indonesia. An intriguing pair of studies from South Africa found a low frequency of RA amongst members of an African tribal group in a rural area and similar rates to those found in Europeans amongst members of the same tribal group who had moved to live in the city. This led to a theory that RA might be related to an industrialised lifestyle. However the same pattern was not found amongst the Chinese. Low frequencies of RA were found in Hong Kong which is a highly industrialised society. Perhaps the African people changed their diet when they moved to the city whereas the Chinese people did not.

Environmental Risk Factors for the Development of RA

1. Hormonal factors
Throughout the world, RA is more common in women than in men. This suggests that hormonal factors may play a part in the development of the disease. RA usually goes into remission during pregnancy. It is also very unusual for the disease to begin during pregnancy. However, in the few weeks after delivery, women with RA often experience a relapse and there is a much higher frequency of development of RA. This may be because prolactin, the hormone which is responsible for milk production, enhances inflammation or it may be due to an over-production of immunosuppressive substances in the placenta, normally produced to help prevent the mother's immune system from rejecting the foetus.

The oral contraceptive pill has probably played a major part in reducing the occurrence of RA in younger women in the developed world over the last thirty to forty years. The incidence of RA in women who have ever taken the Pill is around half that in women who have never taken the Pill. It is not clear whether this protection will be lifelong. It is possible that the onset of RA has simply been delayed until after the menopause. There is as yet no evidence that hormone replacement therapy has any effect on the development of RA or that the Pill has any effect on the course of RA in women who have already developed the disease.

2. Other Medical Conditions
There has always been a widely held belief that RA ought to be caused by an infection. Many researchers have dedicated their lives to trying to identify that agent, without success. It seems clear now that no single germ causes all cases of RA. However, in a substantial proportion of cases RA begins within a few weeks of an infection of some sort. It is not that the infection persists but that the immune response to the infection does not "switch off" as it should. Arthritis is a consequence of that immune response.

Rarely, immunisation (which mimics, in a controlled way, the development of infection) can act as a trigger for RA in some people. However, it is likely that these people would have developed RA if they had caught the natural infection from which the immunisation was protecting them.

RA is more common in people who already have another auto-immune disease, probably because of the shared genetic background.

3. Personal Risk Factors for the Development of RA
The risk of developing RA is substantially higher in smokers. There is also some evidence that smoking influences the course of RA. Smoking appears to have beneficial effects on the amount of pain and joint tenderness which people with RA experience and this may be why people with RA find it difficult to stop smoking. However, people with RA who continue to smoke are more likely to develop what is called extra-articular disease (meaning that they occur outside of the joints), such as nodules, involvement of the lung or inflammation of the blood vessels. People with RA also have a higher death rate from lung cancer than the general population and this is probably explained by the higher proportion of smokers amongst people with RA.

By contrast there is no evidence that alcohol consumption has any influence on the development of RA or its subsequent course.

There is some evidence that certain components of the diet may increase the risk of RA in susceptible individuals. Diets high in red meat and low in vitamin C and other components of brightly coloured fruit and vegetables appear to carry an enhanced risk of RA. Conversely, the so-called Mediterranean diet appears to be relatively protective.

Conclusion

In people with many of the genetic risk factors for RA, exposure to a single environmental risk factor may trigger RA. However, in the majority of people these factors (and others which have not yet been identified) probably act cumulatively, slowly lowering the threshold for the development of RA.

References available on request

Professor Deborah Symmons MD FFPH FRCP, Professor of Rheumatology & Musculoskeletal Epidemiology, Deputy , Director of the Arthritis Research UK Epidemiology Unit, University of Manchester

Original article: 07/01/2004
Reviewed: 12/06/2013
Next review due: 12/06/2016 

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