When the first biological drugs arrived in 1999, some rheumatics could suddenly get up from their wheelchairs. It was revolutionary for both patients and medical science. Research now aims to, among other things, cure rheumatoid arthritis by nipping it in the bud.
For the most part of medical history, doctors and scientists have discovered curative and life-saving treatments by accident. The most classic example is perhaps when Alexander Fleming by chance got a bacterial culture contaminated by mould. When he noticed that the bacteria around the mould were dead, Fleming realised he was on to something important. Penicillin was to become our first antibiotic. But medical science no longer needs to rely on strokes of luck. Thanks to modern molecular biology, and increasingly detailed knowledge of the molecules’ interplay in the body, the development of new treatments can become more rational. One of the first examples of this revolution are the new, so called biological drugs for rheumatoid arthritis. Thanks to these, many rheumatics now can get rid of the pain in their joints. Some people have even been able to go back to their jobs.
"Patients who previously were completely broken down could suddenly get up again. It is absolutely amazing", says Lars Klareskog, Professor of Rheumatology and Director of CMM since 2008.
The history of these drugs begins at the Kennedy Institute of Rheumatology in London during the middle of the 1980s. Ravinder Maini, medical doctor and rheumatologist, and Marc Feldmann, a basic research immunologist, joined forces to understand the specific molecular mechanism behind rheumatoid arthritis. At the time, scientists knew that rheumatoid arthritis was an immunological disease; for some reason, the immune system attacked its own joints. They also knew a considerable amount about how the immune system worked; about how different signaling molecules, so called cytokines, activated different cells in the immune system. But no one knew exactly where in the molecular machinery things went awry with rheumatoid arthritis.
Ravinder Maini began collecting blood and tissue samples from the joints of his patients. Marc Feldmann analysed the samples. It turned out that many patients had too much of a substance known as TNF (tumor necrosis factor). TNF triggers the immune system. Hence, scientists tried in 1989 to wipe out TNF to see what effect it might have. Initially, they did the trial on cells in a tissue culture; in a test tube model of rheumatoid arthritis. They were thrilled to discover they could slow down the devastation.
From then on, development happened at a tremendous pace, by medical standards. In 1992, Maini and Feldman could demonstrate that the TNF-blocker had a powerful effect in animal models of rheumatoid arthritis. In 1993, Maini tested blocking TNF in his patients for the first time. In 1994, the first clinical trials started up, and in 1999 the first approved drugs were out on the market.
"This pioneering research showed that you could use knowledge about the molecular mechanisms to develop well-aimed therapies. It opened the door to this type of pharmaceutical development. Not just for rheumatoid arthritis, but also for a long list of other diseases. This is also the approach to work we take at CMM. We put molecular knowledge to clinical use", says Lars Klareskog.
Some people suffering from MS and psoriasis are now experiencing the same kind of therapy revolution as the rheumatics. CMM:s Marie Wahren Herlenius has also recently mapped the molecular mechanism behind SLE and Sjögren’s Syndrome, which may yield clues to how these diseases should be tackled.
Arthritis care and TNF-blockers serve as models, not just for developing new drugs, but also for following up new treatments. In order to monitor patients, the effect of care and potential side effects, doctors started to collect data for all patients in Stockholm who were treated with TNF-blockers in a dedicated registry: the STURE registry. Nowadays it is included in a large national registry called ARTIS. These registries are unique in the world and have brought about a lot of valuable knowledge. Among other things, scientists have been able to prove that expensive TNF-blocking drugs are worthwhile in the long run.
"Having this registry as well as a good follow-up of patients have contributed to us being able to prescribe these medications with a fair amount of liberty. The treatments have not been restricted from above", says Ronald van Vollenhoven, Associate Professor in Therapeutic Rheumatology and one of those responsible for the registry.
In Great Britain, the situation is different. The lack of follow-up and proof of long term benefits of the expensive drugs (which costs several hundreds of thousands of Swedish crowns per year) has resulted in treatment options being more limited. As a result, patients who might have felt a lot better from these drugs do not get access to them. The STURE registry and ARTIS have also been important in mapping potential side effects. One example of this is scientists suspecting that a TNF-blocker could increase the cancer frequency. There was no cause for alarm, as shown by registry research. On the other hand, it indicates that the risk of contracting a serious infection which needs hospital care increases with one patient per 100 treated patients and years.
"It is important to have an estimate of what risks are involved, so that the patient can weigh them against the expected benefit", says Ronald van Vollenhoven.
In later years, other similar registries have been founded in Sweden, for example for follow-up of MS patients.
Many doctors were sceptical when Maini and Feldmann were to test TNF-blockers on patients. They thought that if you wiped out TNF, other signaling molecules which also trigger the immune system would take over the role of TNF. Thus, the effect would not occur.
But that was not how it turned out. The effect was there. Not in all patients, however. Around 20 percent are not helped at all by TNF blockers. 40 percent get rid of their symptoms completely when they take the medication. The other 40 percent are helped, but still notice the disease. Rheumatoid Arthritis, as it turns out, is in fact several different diseases although with the same symptoms.
"The illness looks the same, but the mechanisms behind the disease differ a lot. Therefore, different patients need different therapies", says Lars Klareskog.
Now there is a new generation of drugs in the pipeline, which block other signaling molecules, such as IL-6, and different cells in the immune system. The next step for science is to quickly be able to differentiate one sufferer of rheumatoid arthritis from another. There are in fact signs that if you nip the disease in the bud, it seems the disease disappears completely. Some patients have now been off their medication for years.
"It has been demonstrated that if you deploy a TNF-blocker early, three or six months after the debut of the illness, there are some individuals who become completely symptom-free and no longer need any treatment", says Lars Klareskog.
In order to quickly prescribe the correct treatment, doctors must therefore be able to separate those who need a TNF-blocker from those who for example need an IL-6 blocker or something completely different. CMM:s Anca Catrina, research scientist at the Rheumatology Unit, is attempting to find markers in the blood or in the tissue from rheumatics, which can give clues to who should receive which treatment.
"When a patient comes into my surgery, I want a simple test, ideally a blood test, which I can use to decide which treatment would be best", says Anca Catrina.
If the scientists find a way to distinguish between patients, hopefully many more people can be cured from their disease.
Text: Ann Fernholm