Rheumatology in 21st Century

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Rheumatology is a branch of general medicine which only became recognised as a specialty during the 1950s. At this time there were only a few pioneering centres in the United Kingdom, the most influential ones being at Edinburgh, Aberdeen, Glasgow, London, Manchester, Aylesbury, Bath, Slough, Leamington Spa and Buxton. Yet rheumatic diseases are the most universally complained of and spa treatments have been in existence for hundreds of years. This paper will give you a brief run through the initial development of the modern specialty and show the changes that have taken place in the last sixty years to bring us to modern day science. This is the span of my life and a brief description of my family gives an insight into this history also.

First however let us look at a timeline which illustrates treatments. The most notable discoveries prior to this century were of the effects of willow bark on rheumatic fever, discovered by a parson from Oxfordshire in the 18th.century. In those days many parsons were in fact scientists as well as classical scholars and spent their life outside their church work in studying plants, animals, geology or, in this case, folk remedies. This discovery was in fact of the salicy¬lates which have powerful effects on fever but also pain,

We then skip over 100 years to the dying years of the 19th.century. Aspirin was first manufactured then and became the backbone of treatment for fever and pain for the next 50 years. In Victorian times laudanum (a form of morphine) was freely available and used for anything from toothache in a young child to sleeplessness. As its use increased, its addictive properties became obvious and gradually it became available only on a doctor’s prescription. Aspirin was one of the few commercially manufactured drugs at this time and can really be said to be the first specific ‘anti¬rheumatic drug’, for all its side effects. When I first went into rheumatology we had to learn how to measure the right amount of aspirin to give to patients with arthritis or rheumatic fever. This was mostly done by giving the patient toxic effects and then reducing the dose marginally. The worst toxic effect experienced was ringing in the ears and deafness although bleeding and bruising occurred and in some cases was life threatening. Now this effect of aspirin is used therapeutically to prevent heart attacks and strokes.

The first major breakthrough in the 20th.century occurred in the 1920s and was a chance discovery. At that time tuberculosis was the scourge of the world and the death rate from it was high. A Frenchmen began experimenting with the use of heavy metals (earlier arsenic and mercury had been found to help some infections) for tuberculosis. When he tried gold it did nothing for the tuberculosis but patients reported that it did wonders for their arthritis. He believed them and carried out a very careful trial which showed that gold salts did indeed help inflammatory arthritis. Gold became established as the standard treatment for arthritis quite quickly in Europe but did not move to this country until the 1940s.

This brings me to my family. My mother’s mother was one of five sisters. They were born in Yorkshire of farming parents. All five suffered from crippling arthritis that began when they were about 45 years old and progressed so that by the time they were 70, they had problems walking and in personal care. As a child I remember watching my grandmother struggling to put on a coat or shirt because of her shoulders. She was an ingenious and intelligent lady and invented an aid to dressing that really worked (a coat hanger with a cup hook on the end for pulling on sleeves and pulling up zips!). She was one of the very first people in Devon to be given gold injections by her doctor, in about 1944, and always swore that it helped her. Certainly she did not become as crippled as her sisters or even her daughter. But she did have to give up playing the piano because, as a professional musician, she could not bear to have lost her facility and accuracy.

In Britain the Empire Rheumatism Council was in existence then and was responsible for research and development. This council carried out a careful study of gold using a ‘placebo’ (dummy) dose for comparison and showed that it worked in rheumatoid arthritis. Thereafter gold did indeed become the ‘gold standard’ for arthritis treatment.

The time line begins to gallop at this point. It is interesting to see why this was so. There is clear evidence that war brings about an explosion of medial advances which would only otherwise be discovered over a long period. This is partly because of the urgency of medical need in wartime but also the concentration of research money and researchers available in one place. The first world war brought mustard gas, a truly terrible weapon but the forerunner of oncology (cancer) drugs including one very familiar to many of you, methotrexate. This drug was available by the 1940s but used for cancer until in the 1970s people began using it for arthritis.

The Second World War brought two major advances, blood transfusion and antibiotics. For a blood transfusion to be safely given, some knowledge of blood groups and therefore of the immune system is required. This discovery has led to immunisations and modern immunology and genetics, both at the forefront of modern medicine’s search for a cause and cure of arthritis in all its forms. More of that later.

The antibiotic penicillin, discovered by chance by Alexander Fleming while working in a basement in London (because he refused to be evacuated with the rest of the hospital) has with others, along with immunisations and more healthy diets, been responsible for the present excellent health enjoyed by the majority of the people of the developed world and for their longevity. Antibiotics saved many of those wounded in the forces in the war. Again by chance one of the modern remedies for arthritis, sulphasalazine was developed during the war. Originally it was tried as an antibiotic but was not very effective. People felt that arthritis was an infection so all the antibi­otics in turn were tried out. The idea of chronic infection in the teeth, tonsils, gall bladder, appendix and womb was also born at this time and it became the vogue for many years thereafter to subject sufferers from arthritis to unnecessary surgery to remove these ‘hidden’ infections. A trial of sulphasalazine was published in 1944 which conclusively showed its effects in rheumatoid arthritis. Interestingly this trial was lost for many years and sulphasalazine gained its place in the national formulary as a treatment for ulcerative colitis. Finally in the early 1970s when the toxicity of gold and steroids was clear, an enterprising group turned up the evidence for sulphasalazine, tried it out and the drug was introduced widely for all types of early arthritis. Anti-malarial drugs, also still used for some cases of arthritis, were first used for much the same reasons and found to help.

So after the war my family split up across England and the arthritis of my youngest great aunt developed apace in the damp of lowland Devon. Sadly she never benefited from any modern treatments because she distrusted science. She ended her life completely bed bound with fixed hips. The only treatment she might have accepted, hip surgery was denied her because her heart was so weak from childhood rheumatic fever. But she became my inspiration in years to come.

What did the 1950s bring to arthritis sufferers; probably the most exciting and dangerous but life saving discovery of all time-steroids or ‘cortisone’ as the first one was called. This was the ‘take up your bed and walk’ drug. In order to understand its effects you have to know something of the impact of arthritis at that time. Rheumatic fever was rampant but beginning to diminish because of the use of antibiotics and high dose aspirin. But rheumatoid arthritis and ankylosing spondylitis (psoriatic arthritis and other types of inflammatory arthritis were all called rheumatoid arthritis at that time) were only able to be treated by aspirin and gold, both with frequent toxic effects that meant that patients gave up on active treatment. The standard treatment for arthritis was bed rest and often splinting. Patients became bed bound, weak and fixed in whatever position was the most comfortable. In long stay hospitals at that time, thin stiff people of all ages were a common sight. Cortisone was found to save the lives of those with Addison’s disease (the wasting disease produced by total loss of the body’s production of cortisone) so it was tried in wasted arthritis sufferers with truly dramatic results. Anyone who has tried it for their arthritis will know the wonderful relief it brings to pain and stiffness. It was hailed as the cure for arthritis and everyone took it. In my family one of my great aunts tried it but it did not work because by then her arthritis had destroyed her hip and knee joints and she had osteoarthritis. My grandmother greatly benefited, as did my father by having local joint injections of cortisone. Many years later my mother had the drug for another condition; ‘polymyalgia rheumatica' and did very well.

What then was wrong with this miracle drug? I think we all now know that in doses high enough to suppress the arthritis it put on weight, weakened muscles, thinned the skin, caused bowel ulcers and caused dependency so that the body could not manage without it and collapse occurred at times of crisis such as surgery. Once this was realised operations were covered by an increase of dose but the overall effects of high dose cortisone were too devastating for it to be used long term. For a time it fell into total disrepute, then its benefits were shown to be there to some extent at low doses. Then again it was overtaken by other miracle ‘cures’ such as methotrexate. Finally in the 1980s it was shown to have long term suppressive effects in arthritis and it is now used as a second line dug in many people at very low doses. Its latest toxic effects now measurable are on the bones. It is a potent cause of osteoporosis. Again this has caused some lessening of prescribing but for those who really benefit from the drug, any side effects are worthwhile and most can be countered by some means such as other prescriptions.

Let us now return to the 1950s because this was really the birth time of modern rheumatology. Centres for rheumatic disease were specifically set up then at Aylesbury, Edinburgh, and Slough amongst others to join the established spa centres. I have been privileged to know and work with many of these pioneers. All bar one are now dead but their work set the scene for the scientific development of the speciality which had previously been merely full of folklore and endurance as a part of life. They studied, they tried remedies and they sought for causes. In the name of science they tried remedies on themselves and I was told by one if them how he and a friend extracted joint fluid from the knees of an arthritis sufferer and injected into their own joints to see if they ‘caught’ arthritis! You would not find this happening today I feel! What they achieved was the evidence base for a regime of treatment that would dominate the rheumatology scene for the next 30 years. This regime was of painkillers, rest and exercise at the right time, gold or other long term agents and short courses of high dose cortisone for quick relief of inflammation. They discovered that short high doses of cortisone did not make you dependent on the drug and that if you ‘hit’ the arthritis with everything you had got there was a chance that the disease would disappear for a while. They also found out that one third of all patients presenting with acute arthritis had few or no signs of it after one year no matter what you did.

The late 1950s and early 1960s were the era of the development of anti-inflammatory and pain killing drugs. Butazolidine was the first after aspirin, known now only in the animal world as ‘Bute’. This is a very powerful drug but also very toxic and was at first used in far too high doses. I can vividly remember in my first visit to the rheumatology ward in Edinburgh, where I trained, a young man of 21 who was dying because the Bute had killed his bone marrow.

Indomethacin and ibuprofen (Brufen) were the next. The latter still survives and can now be bought across the counter in this country, a reflection of its weakness as an anti-inflammatory drug rather than its usefulness. But it is an excellent pain killer and useful for mild osteoarthritis. It keeps me going at any rate now!

Indomethacin is still available but seldom used. Again it was introduced while I was a medical student and became widely available after I had qualified. My memories of it are of a patient I looked after in the medical wards at Stoke Mandeville Hospital, one year after I had qualified, who only just survived acute liver failure from the drug. These individual memories of patients have a very strong influence on one’s future behaviour as a doctor. I am very cautious of any new drug. However they have equally made me wish to trial new drugs for myself rather than rely on others glowing accounts. I have carefully studied and used the best methods of trying drugs, I have tried to be honest in my appraisal and I have tried not to use new drugs without this careful personal study and trial.

These three drugs were then followed by a plethora of anti­inflammatory drugs, getting on for 30 individual types in all. Some have survived, some not, all have proved a miracle drug to a few people. The newer ones are perhaps a bit safer on the stomach; all are effective for pain and inflam­mation. They are limited by their side effects on the stomach and kidney and by the fact that they do not influence the course of the arthritis. Nevertheless they are a major advance in the battle against arthritis because they have removed much of the burden of pain. That is not to say that arthritis sufferers do not get pain but it is certainly less burdensome than it was 40 years ago as a result of these drugs.

It was during the 1960s that psoriatic arthritis was distin­guished from rheumatoid arthritis. Gout and ankylosing spondylitis had been distinguished before. Now psoriatic arthritis in its various forms and other forms of arthritis and systemic rheumatic disease were discovered. The work on psoriatic arthritis went on at Stoke Mandeville Hospital at the Oxford centre for Rheumatic Diseases and later at Leeds. I was privileged to join the team at Stoke Mandeville in 1967 as this work was published. The centre was at that time active and full of enthusiastic doctors and scientists. As a very junior doctor I was nevertheless expected to undertake a research project and publish it, as well as talk at interna­tional conferences. It was there that I first became interested in rehabilitation following a project to look at recovery of knee function and strength after surgery. I also began work on the drug penicil­lamine for rheumatoid arthritis which I continued for the next four years at Oxford and later as a consultant at Wycombe General Hospital. Rheumatology was a small world when I joined it; there were only 34 consultants in the UK. There are now nearly 500.

One of my principle roles in Stoke Mandeville was to prepare and look after patients with arthritis who were having surgery to their joints. This was my first experience of waiting lists! The ward for arthritis admitted patients for surgery also because of the medical complica­tions of arthritis that make surgery a hazard. I assisted at operations which allowed me a first hand insight into the type of joint damage that active arthritis can produce. The surgeon was a pioneer and developed the first half joint replacement for the knee in this country. Joint replacement began just before this for hips. From then onwards orthopaedic surgery moved forward rapidly in this country, with joint replacements of virtually every joint in the body available somewhere. There was also a hand surgeon at Stoke Mandeville who was a plastic surgeon; his surgery was wonderful to see. He tried finger and wrist replacements as they became available. Joint replacements have revolutionised life for arthritis sufferers in much the same way as have drug therapies, particularly for those with osteoarthritis for whom there are few effective treatments. Back to my family, my mother had a very successful knee replacement in the last year of the twentieth century.

Let us now move on to the 1970s and 80s, years when I was a consultant and see where science was taking us. During these years genetics grew as a specialism. The first rheumatic disease to be specif­ically associated with a gene was ankylosing spondylitis (the spinal disease associated with severe stiffness and in the worst cases fusion (fixing) of the spine). The discovery of the HLA B27 gene and its association with sufferers from ankylosing spondylitis occurred more or less simultaneously on both sides of the Atlantic. Since then genes associated with many rheumatic diseases have been described although none has quite the specific association of this first gene discovery. The promise that gene therapy would lead to a cure or at least specific drugs had not been realised yet but still may be.

However the discovery of genes, the science of immunology and the simultaneous development of knowledge about the so-called inflammatory cascade has led to significant developments in the treatment of disease- the biological drugs. For these various strands to come together in the 1990s we go first of all to the Second World War and blood transfusions. Firstly these can only be successfully used to treat people if the blood is of a compatible blood group and secondly there is a need to know about blood clotting. Both of these discoveries led to knowledge of immunology and inflammation, the development of anti-inflammatory drugs, the use of drugs such as methotrexate on the grounds of attacking the bodies own white blood cells which are said to be turning against the body (auto­immunity) and finally the present plethora of biological drugs that are attacking the inflammatory process itself and achieving miraculous ‘cures’ for many people.

Now that we are in the 21st.century where will we go next? Have we achieved that elusive state of being able to cure arthritis and relieve the pain and suffering endured by so many people? Sadly I fear not. Huge strides have been made but we have also discovered that we can cure many cases of childhood cancer only to find that in later life complications occur from the therapy. The latest biological treatments will take their toll although they are undoubtedly the greatest advance so far. We can relieve pain very successfully but at the expense of side effects. Suffering we understand far better and we know that in order to treat any chronic disease we must pay attention to the way each individual person responds in their mind to the diagnosis.

This present decade is the decade of the patient and of empowerment and self management. We have I believe learned that all drugs are powerful and will inevitably lead to side effects in some people. We also know that herbal remedies work but are not free of bad effects. We know that teamwork between professionals, patients, families and voluntary organisations will lead to best treatment and satisfaction for sufferers and assist them to understand and manage their disease better.

I hope that all those who strive to treat, investigate, cure or understand the rheumatic diseases will give sufferers choices and the knowledge to choose that treatment which they feel is right for them. If no treatment is chosen, then I hope that that decision is made with full knowledge. My family certainly chose where they could but was very accepting of the lack of available treatments for arthritis. They equally accepted the pain and suffering as part of life. Now we do not. We cannot get rid of pain altogether because it is a necessary physiological protection for the body but we should not accept chronic pain and disability as a fact if we have arthritis. There is an enormous amount that modern science can do for us and a lot that we can do for ourselves.

I have found my 60 years of rheumatology exciting, rewarding and sometimes painful. I went into rheumatology initially by chance, my husband and I were both ill and we decided we could not face yet another move to a job I had obtained in another hospital. I was intending at that time to be a pathologist and study diseases under the electron microscope. But after I had done a six months rheumatology post I felt that I had at last found what I wanted to do and remembered clearly the words of my great aunt when I told her I wanted to be a doctor. ‘Oh good now you can find a treatment and cure for the family arthritis’! Well I haven’t but in my career I have been able to give to patients the help of others and I believe we are certainly closer now to a cure than at any time in the last 60 years. I wish though that we actually knew the cause. My mother is far less crippled than either of her parents or aunts and I am better still. I hope that my children who already have some joint problems will be even better. All we really ask in life is for happiness and a degree of creature comfort. No one wants to live forever but we do want to enjoy life and be healthy right into old age so we can continue to be a plague to those around us but more particu­larly able to look after ourselves and continue to work at the pace we choose!

Dr. Virginia Camp PAA 10th anniversary conference September 2003