Ankylosing spondylitis: slow but steady progress in research
Reproduced from Issue 105 of Arthritis Today
Dr Paul Wordsworth
People with ankylosing spondylitis often wait for ten years before their condition is eventually diagnosed. But new arc research in Oxford tracking down the genes responsible for the disease may lead to new approaches to diagnosis and treatment. Dr Paul Wordsworth, of the Wellcome Trust Centre for Human Genetics, explains.
Ankylosing spondylitis is a relatively common inflammatory cause of back pain. It affects up to 0.5% of the population and is about three times more common in men than in women.
It is one of a group of conditions known as the spondyloarthropathies because of they affect the spine as well as peripheral joints.
Also included in this group of disorders are psoriatic arthritis, arthritis associated with inflammatory bowel disease (Crohn's disease and ulcerative colitis) and reactive arthritis.
Typically ankylosing spondylitis affects older teenagers, but the disease may also occur much earlier in life (when it frequently begins with peripheral joint problems rather than back pain).
The hallmark of the disease is inflammation of the sacroiliac joints (at the base of the spine) which may ultimately lead to them becoming fused.
Comedian Lee Hurst has ankylosing spondylitis
Typically in the early phases of the disease the paraspinal ligaments become inflamed, before fibrosis and eventually ossification of the ligaments leads to irreversible loss of movement. Immobility of the rib cage and chest pain is another common problem.
Early symptoms include low back, night pain and pronounced early morning stiffness. Anti-inflammatory drugs can provide excellent symptomatic relief and the performance of regular spinal exercises to preserve spinal mobility can also be helpful.
Unfortunately, even today there is typically a ten-year delay before the diagnosis is made and inappropriate management of back pain, including immobilisation, is still all too frequently employed.
However, early diagnosis of ankylosing spondylitis can be significantly enhanced by using magnetic resonance imaging (MRI) of the spine and sacroiliac joints which is capable of detecting very early changes of inflammation. In contrast, convincing X-ray changes may take months of years to develop.
Testing for the gene known as HLA-B27 is not routinely useful but may be helpful in excluding the diagnosis since ony 5–10 per cent of patients with ankylosing spondylitis will not carry HLA-B27.
In addition to the spine about 20% of individuals have significant involvement of peripheral joints including the hips, knees and shoulders and in some cases this may be sufficiently severe to require joint replacement surgery.
At least 25% of individuals with ankylosing spondylitis will develop a complication known as iritis, which involves inflammation of part of the eye including the iris. Patients should always be warned that this may happen, because it presents a potentially sight-threatening complication. Patients develop a pink painful eye which responds well to local steroids. If in doubt the patient should be assessed quickly by an ophthalmologist.
Over a long periods of time the spine tends to become stiffened in a fixed position which in its most extreme form may leave the patient staring at the floor. Osteoporosis of the spine is also a relatively early complication of ankylosing spondylitis. This represents another good reason for maintaining a regular exercise programme and also suggests that a diet containing adequate calcium (at least 1 gram per day) is sensible for patients with this condition.
As mentioned earlier, there is a strong genetic element to developing ankylosing spondylitis. Identical twin siblings of people with the disease have a 75% chance of also developing the disease. This risk is about 500 times that of the general population. There is also a seven per cent risk for other brothers and sisters of sufferers. The pattern of inheritance in families strongly suggests that several genes are involved and there has been substantial progress in recent years in identifying these.
Twenty-five years ago the association between ankylosing spondylitis and the gene HLA-B27 was first discovered. This immune response gene, which is found in over 90% of individuals with ankylosing spondylitis, plays an important role in determining the body's responsiveness to infections.
However, in ankylosing spondylitis it appears to trigger an abnormal inflammatory response against the body's own tissues, for reasons that are not well understood. Research in Canada and Oxford suggests that HLA-B27 contributes about one-third of the total genetic risk, and that other genes are also involved.
Work sponsored by the Arthritis Research Campaign has allowed substantial progress to be made towards identifying the other genes involved. My research group has recently completed the first stage of this work by identifying a number of human chromosomes which probably contain genes contributing susceptibility to ankylosing spondylitis.
This has involved the recruitment of a large number of families with at least two affected individuals, and then assessing the genes that have been inherited in common by these individuals from their parents.
Three regions on chromosomes 2, 10 and 16 look to be particularly promising, and a large world-wide effort is now on to recruit further families with two affected siblings to confirm these results and to try to narrow down the regions of interest to a manageable size.
Three hundred families with at least two affected siblings have been recruited in the UK and Germany while similar efforts are being pursued in France, the Netherlands and the USA.
Eventually a variety of techniques will be used to identify genes in these regions of the relevant chromosomes and to test whether they are involved in the disease. It may then prove possible to influence the actions of these genes and develop new forms of treatment.
Some of these genes may also be involved in psoriasis and inflammatory bowel disease, disorders from which about 10% of our patients with ankylosing spondylitis also suffer. Ultimately, a fuller knowledge of the genes involved in these disorders should yield new insights into their causes, allowing us either to develop new ways of beating the condition or avoiding it in the first place.
We still need more patients to take part in our study. We would like to hear from anyone with ankylosing spondylitis who also has a living brother or sister with the disease. We are also recruiting patients with ankylosing spondylitis who have two living parents. Further information can be obtained from Linda Bradbury, the project research nurse, on 01865 227325. |
