Summary from Dr. Walter Maksymowych's presentation at the October 23, 1993 Workshop on Scleroderma
Dr. Maksymowych is a Rheumatologist at the University of Alberta Hospital in Edmonton.
I would like to highlight some of the advances and some of the successes that have occurred in the research area of scleroderma in the last 10 years.
There certainly does seem to be some genetic factors involved. The confusion is that people believe that this means that children and relatives are going to be affected by the disease. When we talk about genetics, we're really talking about interactions between the genetics of an individual and the environment. So even if you have certain genes that are related to scleroderma, that does not mean to say that if you pass on these genes to your children, that they are going to be at increase risk of developing the disease. Genetics, when it comes to arthritis and related disorders, is a very complex issue. We are often looking at not just one gene, but a combination of genes. If you have these genes it does not mean you will automatically get scleroderma. What it means is that they slightly increase your risk of getting scleroderma.
All your cells of your body are completely different than other people's,and the immune system recognizes the cells of your body as being different. How does it do that? On the surface of the cells of your body are these recognition molecules. They have a very unique structure. Each one of you possesses different recognition molecules on the surface of your cells. The immune system recognizes the uniqueness of these different molecules. If they are foreign to your body the immune system will destroy them. If we look at the genes that produce these recognition molecules, they appear quite different in patients with scleroderma. There are certain recognition molecules on the surface of the cells of the body, and certain genes that produce these molecules which increase your risk of getting scleroderma. And there are certain environmental things that presumably interact with the genetics that increase the risk of getting scleroderma-type illnesses. These are not absolutely identical to scleroderma but very close. These include things like the agent Poly Vinyl Chloride (PVC is now banned in many countries). There was a very interesting illness in Spain in the 1980's: the contamination of a certain type of oil that they used in the preparation of different types of food products. This oil was contaminated with a particular substance that caused a syndrome almost identical to scleroderma. There are certain agents that we use to treat certain types of cancers: for example Bleomycin. In high doses it certainly gives you the skin changes of scleroderma. We are beginning to understand the interaction between the genetics and certain environmental factors that cause scleroderma.
What actually happens pathologically?
The interior of the blood vessel is lined by a very fine membrane which we call the endothelium. In scleroderma patients, something damages that endothelial membrane. After the damage, you get repair, and scar tissue formation. It is this scar tissue that is encroaching on the lumen or interior space of the blood vessel. The lumen of the blood vessel get narrower. If this occurs in the blood vessels of the kidney for example, the blood flow to the kidneys gradually diminishes. That could potentially happen in a number of organs in the body.
In the early stages, this damage causes an irritation to the blood vessel. The blood vessels become unstable, and this is manifested as Raynauds Phenomenon, which is a spasm of the blood vessel. In the early stages of Raynauds Phenomenon, the blood vessels are just a little bit unstable, so they will contract but they will open up. Certain things, like cold weather will trigger this. We can also see this visually when we put a drop of oil on the base of a person's finger nail, and look at it under the microscope. Normally you would see loops of blood vessels. In scleroderma some of the capillary loops disappears due to scarring and narrowing of the blood vessel which causes a decrease in blood flow. The blood flow tries to increase through the remaining capillary loops. So you can imagine if some of them are closing down completely, the blood still tries to get through, trying to go which ever way it can, so some of the remaining capillary loops become hypertrophied, in other words they increase in size to try and accommodate the resulting increase in blood flow. So some of them are dying off, and others are increasing in size.
Kidney involvement used to be a major problem for physicians. One of the problems that ensures from this, is when the kidney lacks blood flow, it releases a substance that increases the blood pressure. You try to increase the blood pressure so that more blood pours through the kidney. This could potentially become a very serious emergency situation very rapidly. One of the major advances is with a group of drugs called ace inhibitors. These drugs basically stop the production of these substances that cause high blood pressure. These drugs have radically altered the management of kidney disease and high blood pressure in patients with scleroderma. Capoten or Vasotec are drugs that have recently become available for the treatment of scleroderma kidney. This has made a major impact because we are seeing far fewer problems with scleroderma kidneys than we used to. When blood flow is diminished to any organ of the body, there is one outcome: a gradual fibrosis of that organ.
All the tissues of our body are highly specialized to perform different functions. All these specialized tissues' function depend on an adequate blood supply and adequate nutrition. If they don't get adequate nutrition, these various organs start to lose their specialized function. The cells gradually, slowly die off, and the cells are replaced by fibrous tissue. Essentially, this means that these organs no longer perform their specialized function. In scleroderma, for reasons that are not yet clear, this fibrosis occurs specifically in certain organs, it doesn't occur in all the organs of the body. It occurs in the kidneys as already mentioned. It occurs in the gastro-intestinal tract. For example the esophagus (that tube that connects the throat to the stomach) is very important. It propels the food that you ingest into your stomach and into the intestine. If it looses it's blood supply, it slowly looses it's ability to propel food, an eventually it becomes more and more dilated, then it becomes very difficult to swallow. The other thing that the esophagus does that is very important is that there is a little sphincter (a valve made of circular muscle separating the esophagus and the stomach) when it contracts, prevents regurgitation of contents of the stomach back into the esophagus. That's when you feel heartburn: a temporary relaxation of that sphincter muscle and regurgitation of these acid contents of the stomach into the esophegus. In most people that sphincter works fairly well, and by and large keeps the food into the stomach, prevents anything from getting back into the esophagus. These mechanisms can potentially break down in scleroderma. The esophagus can become quite dilated and loose it's ability to propel food. The sphincter looses it's ability to close properly, allowing contents of the stomach to get back into the esophagus. The acid from the stomach can cause a lot of problems at the lower end of the esophagus. There are now a powerful group that drugs that stop acid secretion in the stomach. Examples are Zantac and especially Lozec, seem very effective for this type of problem. The one that gives us the biggest problem is with the lungs. Fibrous tissue accumulates in the lung creating difficulty in breathing. There are many clinical trials ongoing to assess certain therapeutic agents in the management of the scleroderma lung.
What is it that a researcher does?
Researchers spend an awful lot of time trying to understand why the lining of the blood vessels for example, is irritated. Why is it that the immune system seems to target the lining of the blood vessels? Many researchers have been working on these hypotheses over the last two decades in particular. There have been some major advances, particularly with the speed at which research can now occur. You've probably all heard of terms like Òbio-technologyÓ and Òcloning genesÓ. Basically, it means that we can study the genes that are causing the immune system to function at an abnormal fashion. We can look at some of the proteins that the immune system cells product that causes damage. We can look at the genes that control, and make these proteins. For example, the group of chemicals that we are very interested in are called Lymphokines. There are certain Lymphokines that promote inflammation, and certain Lymphokines that fight inflammation. This is why the disease varies like this. Everyone of you has been through good and bad times. That's because during the bad times, the nasty Lymphokines take over, and through the good times, the good Lymphokines are predominant. The body is trying to call it's own defense mechanism to try and repair and return balance to the system.
So what has research in scleroderma been able to do?
Some of the experiments that used to take a couple of years to do, can now be done in about a month. Some of the new gene technology enables us to isolate a particular gene, grow large amounts of that gene, can study it's function, and see how it differs in patients with scleroderma as opposed to normal individuals. We can introduce that gene into cells grown in the laboratory, and we can see how that gene then alters the function of normal cells. We can alter genes in the laboratory to see how that influences the function of the cells. All this is done in very precisely defined experiments to see how some of these alterations that we see in patients with scleroderma, alter the function of normal cells. Once we understand this mechanism, we can counteract some of these changes. We may be able to produce new therapeutic compounds. This has spawned a new industry, the bio-technology industry, which is attracting billions of dollars on Wall Street, to look at new therapeutic agents for the treatment of disorders like scleroderma.
We have entered the era of the BIOLOGICS.
Our understanding has now advanced to the stage where we can actually make some of these natural substances produced in the body to fight inflammation. We are now using some of these biologics in clinical trials. For example, one of the factors, the Tumour Necrosis Factor, produced by the body as a natural mechanism against tumours, will kill certain tumour cells. What has been found is that it also causes inflammation. So if the body produces too much of it, it can cause inflammation in a variety of tissues. And this is one of the factors that has been pin-pointed as perhaps being of importance in some of the damage to the lining of the blood vessels in patients with scleroderma. There are certain monoclonal antibodies that are being produced that now target this Tumour Necrosis Factor. Early clinical trials in Europe are now being undertaken to see what effect these monoclonal antibodies may have in patients with Rheumatoid Arthritis. The very preliminary findings have been very encouraging. It's in very early days yet, but we are certainly entering the stage where some of these monoclonal antibodies are now being evaluated in patients with a variety of so-called auto-immune disorders.
I think that in the next five years, we are going to see a t more of these biologics being used. What these biologics really do is target certain types of proteins produced by these lymphokine genes that are important in triggering inflammation. We are now understanding some of these natural chemical processes that occur in the body that causes inflammation. We are developing technology and methodology that will specifically target certain parts of the immune system. When we give a patient one of these drugs, it doesn't automatically mean that the entire immune system is suppressed, as when we give someone Prednisone or Cortisone. Prednisone suppresses inflammation in a blanket fashion. What this type of technology has enabled us to do is to specifically target certain aspects of the immune system in such a way that we are using natural chemicals rather than artificial agents.
A PCR (Polymerase Chain Reaction) machine was donated to the Rheumatic Diseases lab by the Arthritis Association. This machine and it's technology has radically transformed research in arthritis related areas. With this machine, if I'm interested in a particular gene out of the billions of genes that exists in an individual, I can specifically look at one gene and produce large quantities of that gene in about one or two hours. We can then study it's action, we can introduce it into cells, we can modify it, we can see how it does what it does. We can see how it produces some of the pathological effects seen in patients with scleroderma. For example, we can look at one of those lymphokine genes in a highly specific fashion. In the old days we had to spend years looking, searching for that gene out of all those billions of genes that we all possess, until we found that one specific gene that we were interested in. And then it took us another few months to amplify that gene up in sufficient quantities that we could then study it. We can do all of this now in about two hours.
There is a lot of doom and gloom around lately due to budgetary cuts, and a lot of concern where our health care system is heading. In fact, I think the massive investment that has gone into the hugh area of arthritis research, will start having a payback very soon. I think that maybe 5 years from now, we will look back in the early 90's as the water-shed years. All the research involved in understanding the basic mechanisms of the cause of the disease will start to have a payback and will have an impact on the clinical care of patients with a variety of arthritis related diseases.
