Professor Richard Bruckdorfer

Department of Biochemistry and Molecular Biology

Royal Free and University College Medical School

University College London.

This short article contains the main points I raised at the last meeting of the Scleroderma Society last month. It is related to joint work being undertaken with Professor Black and Dr Abraham in the Department of Rheumatology at the Royal Free Hospital.

Whereas the origin of scleroderma is unknown, it is possible to find out something of the processes that are involved in the disease, so that some interventions may be devised that would be of therapeutic value. Our interests involve some reactive chemicals called free radicals which are know to be formed even in normal tissues, but their production is increased in certain diseases, especially inflammatory disorders. Oxygen itself is a free radical and the body produces even more reactive forms of oxygen. An example of such a chemical is hydrogen peroxide, which will bleach hair, but is also made in the body. Sometimes, free radicals have beneficial effects and are used by white blood cells to protect us from invading bacteria. One free radical called nitric oxide is normally produced by the cells lining the artery wall and is know to dilate arteries and to improve blood flow as well as preventing the coagulation of the blood. However, there is evidence that overproduction of free radicals (oxidative stress) can lead to damage of proteins and to DNA, the genetic material which is responsible for forming these proteins, and therefore could lead to derangement of our cells and tissues.

There is now significant evidence that there is oxidative stress in patients with scleroderma. We know this by making measurements of certain chemicals in the blood or urine. There seem to be some differences between subgroups of patients depending whether the scleroderma is diffuse or limited. We know that there is an overproduction of nitric oxide in the limited scleroderma patients, but not in diffuse scleroderma. However, some of the nitric oxide may have reacted with other free radicals to produce even more powerful chemicals, since we can detect characteristic changes in skin and blood proteins of some of the diffuse patients. We also know that some of these free radicals can increase the production of collagen in the skin leading to the thickening that is so characteristic of scleroderma. Still, we do not know why free radical production has been increased and that is something we are continuing to investigate. We believe it is part of a chain of events that contributes to the condition.

The question then arises whether this information leads to any new forms of intervention. The body has a number of ways in which it can defend itself against free radicals. One way is the use of special proteins, called enzymes, which neutralise the free radicals. We also consume antioxidant vitamins like vitamin C and E in our food, which contribute to our defence mechanisms. Indeed a number of investigators have found that the levels of vitamin C (but not vitamin E) are low in our scleroderma patient groups, even though they consume a diet very similar to everyone else. This is, therefore, a symptom of the oxidative stress and not due to a dietary deficiency of this vitamin. In other hospitals, supplementation with vitamin C and E have been tried but with no apparent improvement for the patients. At the Royal Free, we have shown that a powerful antioxidant drug probucol did give partial relief of Raynaud's symptoms in a short-term trial. Antioxidants are not identical and are effective in preventing reactions in different forms of oxidative stress. We therefore need to identify the precise nature of the chemical reactions occurring in the disease so that we can use the antioxidants intelligently. Certainly consuming large doses even of the antioxidant vitamins is not always productive and may be harmful if taken in very large amounts.

We are learning a great deal now about the role of free radicals in scleroderma and related disorders and hope that this will bring some benefit to patients.

This article was written for The Scleroderma Society’s newsletter ‘The Scleroderma News’ in the UK.