Progress in Scleroderma during the past 20 years
Professor Carol Black CBE
At the 20th Anniversary of The Scleroderma Society, 5th October, 2002
Part 2
Research
Of course, I could spend the entire afternoon on research but will have to settle for the short time available. You want to know if there have been developments in the disease and our research endeavours? And yes there have; some of them are displayed outside on posters. Have those developments lead to new treatments? Yes. There is a trial of anti bodies to Transforming Growth Factor B, a very potent growth factor in the UK and in other European countries. Suppression of this growth factor could be important in reducing fibrosis. We have another antibody which will suppress a compound called connective tissue growth factor (CTGF). This will, we believe, be trialled in the USA. We also have a compound that blocks the Endothelin 1 receptor. It is currently used for Pulmonary Hypertension and hopefully in the future for digital ulcers. Endothelin is a molecule which may drive the scleroderma process. These are 3 practicable examples of how research has informed treatment.
Scleroderma is a disease that can be triggered by external factors and therefore the history that patients give you is important. Several patients thought their disease might have started by paint strippers or weed killers. Their disease started very closely to an intense or prolonged exposure to these agents. There are also one or two drugs that can induce a scleroderma like illness and we are always questioning whether viruses might be a contributing factor.
We simply could not do without the Scientists in our Department so I am deeply indebted to David Abraham who is sitting at the front here. He has transformed our laboratory and I can thank him publicly. You need the best scientists you can get; these are the people who will translate science into possible practice. We are very reliant on scientists who help us in the field of cell biology, biochemistry, immunology, molecular genetics and other areas. For example with their help we have found that a little known cell — a pericyte, a cell which surrounds the blood vessels, may be important in driving scleroderma.
There is also much research in the area of fibrosis. Our own Laboratory is interested in how TGFb signals within the cell drive fibrosis and part of this is by stimulating CTGF. CTGF and also Endothelin stimulate fibrosis. There’s a lot of work going on in this area and blocking Endothelin may be a means of treating fibrosis. I think this is very exciting. Those small interesting cells called pericytes that cling to your blood vessels affect the strength and function of the blood vessel wall and they are also able to transform themselves with certain help from other stimuli into fibroblasts. It is possible that these cells are part of the problem in fibrosis in systemic sclerosis. Antibodies to a molecule on the surface of pericytes maybe a possible treatment to this problem.
What we are talking about is cells communicating with each other. They talk to each other and what we would like to do in scleroderma is prevent them talking too much! We need them to talk enough to keep each other healthy but to stop them giving messages that then make these other cells overwork. So putting it very simply we are trying to understand "cellular cross talk". It’s like a big talking shop and we want to cut off the noise and dampen it down and get them all back to behaving properly. They are a bit like unruly school children that need to be quietened down.
The three names for you to remember: Transforming Growth Factor B, Connective Tissue Growth factor and Endothelin. These are particularly important molecules, which are being targeted in scleroderma.
Gastro-Intestinal Tract
This is the most commonly involved organ after the skin. It makes life pretty miserable because it causes problems at the top, middle and bottom of the GI Tract. Excess collagen causes the muscle not to work properly. Our knowledge to date has been descriptive because it is impossible to biopsy the deeper tissues in the gut in life. Some advances have been made: for example a cause of bleeding in the stomach is a mass of dilated blood vessels (watermelon stomach) this causes an iron deficiency anaemia. It’s really miserable, patients feel tired and unwell. It is very easy to treat with a laser. We also have a much better awareness of the problem of incontinence. I know this is difficult to treat but at least we can try and prescribe the right drugs to reduce the problem. There is also some work with small electrodes that might stimulate the muscles and there is now more interest in understanding this very distressing problem.
We also know that a few patients with oesophageal disease are at risk of changes which lead to cancer of the oesophagus. Because of this increased awareness once we see any changes in the appearance of the Oesophagus then we would follow the patient yearly with an endoscopy. We know that Coeliac Disease occurs with scleroderma. We never used to think of that before but now we can look for Coeliac Disease with an easy blood test. There have been many improvements in specialised feeding methods for severe gut disease. There is also interest in looking at the epithelial cells that line the whole of the gut and how they communicate with the fibroblasts: this may provide a clue to why people get gut disease.
Kidney
To emphasise the advances in kidney failure in scleroderma, I must mention better education and better understanding of how to treat it, plus the knowledge that some patients develop kidney disease that isn’t always a hypertensive renal crisis. We now have a "credit card" which we developed at the Royal Free. If you are a patient who might develop kidney disease you carry it around in your handbag just like a credit card. One side tells the Doctor that the patient is ‘at risk’ and would they please use the right drugs such as ACE Inhibitors. The other side tells the patient that if they get new onset headaches, blurred vision, shortness of breath and/or confusion then they really need to speak to someone who understands what’s going on, preferably contact the scleroderma department that’s looking after them. Some patients also now monitor their blood pressure at home and feel comfortable with that.
Lung Fibrosis
There are now 2 interesting trials looking at the use of Cyclophosphamide in Lung Fibrosis one in the UK, one in the USA. The Endothelian 1 receptor antagonist Bosentan, is a possible new drug in this area. Placebo controlled trials are the way forward for new drugs for lung disease.
Rounding Up
Treatment has improved and we are trying to develop more targeted therapies. We have lots of different agents for Raynaud’s whereas 20 years ago we might have had just one drug and many patients didn’t get anything. We can use surgery (digital sympathectomies) in appropriate cases to heal an ulcer which is resistant to iloprost therapy. There are several new treatments being tried anti-TNF therapy, Beta Interferon and CTGF. There are a host of other things that are happening internationally. I think the understanding of scleroderma has developed and advanced. There are lots of good things going on, but of course it is not as complete as we would like it to be.
I would just like to pay tribute to the people who have influenced my life and have also done amazing things for the disease. Gerry Rodnan, Father of modern day scleroderma, a larger than life ebullient American who secured my interest in the disease. He sadly died of a coronary artery disease at far too early an age. Stephanie Jablonska for whom I have the greatest admiration. She is Polish and through the war Stephanie collected her scleroderma patients, looked after them, persuaded Gerry to do research with her, secured drugs that nobody else could get into Poland and really cared for hundreds of patients over more than 40 years. Carwile Le Roy sadly died this year. Carwile was the man who first gave us the vascular theory of scleroderma and he will be greatly missed. Dr Barbara Ansell also died. Barbara meant so much to so many of us in the audience. She was particularly important in my own career and that of Dr Denton’s as well. We will not forget Barbara, a Former Trustee of the Scleroderma Society, she is greatly missed.
I think the future is bright for scleroderma and I much prefer to think about the dreams of the future than the history of the past. Thank You.
This is the final part of the serialisation of Professor Carol Black’s talk at the Scleroderma Society’s 20th AGM on the 5th October 2002 at The John Lister Post Graduate Centre, Wexham Park, Reading UK.