Research leading to new treatments for rheumatoid arthritis rewarded by the Royal Swedish Academy of Sciences with the 2000 Crafoord Prize.
Professor Ravinder N. Maini and Professor Marc Feldmann, both of the Kennedy Institute of Rheumatology, London, Great Britain, have in their research found mechanisms of importance for the pathogenesis of rheumatoid arthritis. Using these discoveries they have succeeded in developing principles for treating the disease. The new drugs block one of the key factors – TNF-alpha – in the inflammatory process.
The citation of the Academy runs: “for their definition of TNF-alpha as a therapeutic target in rheumatoid arthritis”.
The Crafoord Prize, consisting of a gold medal to each prizewinner and USD 500 000 to be divided between them, will be awarded on 18 September 2000 at a ceremony at the Royal Swedish Academy of Sciences. His Majesty the King will present the Prize.
This is the first time since the Crafoord Prize was instituted in 1982 that the Royal Swedish Academy of Sciences has awarded the Prize in the field of polyarthritis. According to the statutes, this area is to be rewarded when significant progress has been made. The donor Holger Crafoord himself suffered from rheumatoid arthritis and for this reason research in this area was of particular interest to him.
Fundamental immunological research leads to breakthrough in treatment of rheumatoid arthritis
Rheumatoid arthritis is the commonest and most severe of the inflammatory rheumatic joint diseases (together termed “polyarthritis”). It often leads to permanent handicap and shortened life expectancy. Until the 1980s the development of better methods of treatment was limited by our inadequate knowledge of the mechanisms by which the disease was induced. New knowledge from immunological research changed the situation, with growing understanding of the details of how the molecules in the immune system attack the organism’s own tissues. During the past ten years Ravinder N. Maini and Marc Feldmann have led an innovative development that has yielded the decisive new results.
Maini as a clinical rheumatologist and Feldmann as a basic research immunologist started co-operating in the middle of the 1980s at the Kennedy Institute in London. Their goal was to clarify the importance of certain signal molecules, termed cytokines, in rheumatoid arthritis. They found that one of these signal molecules, TNF-alpha, had a key function. (TNF is the abbreviation for tumour necrosis factor, the original signal substance discovered in studies of tumours). It now turned out that TNF also regulated the production of a series of other signal molecules of significance for inflammation and joint destruction. On the basis of these findings the researchers went on to show that TNF-blockade also inhibits the production of other inflammatory molecules in cultures of cells obtained from the inflamed joints. Subsequently they also found that blockade of TNF retarded the development of joint inflammation in experimental animals. This knowledge led Maini and Feldmann in 1992 to introduce treatment with monoclonal antibodies against TNF-alpha in patients with rheumatoid arthritis.
Following a pilot study with encouraging results, a series of more extensive clinical trials was undertaken, and these confirmed the original findings. It was found that blockade of TNF-alpha, either with monoclonal antibodies or with artificial parts of TNF-alpha receptors, had a very good effect on joint inflammation in a large majority of patients. During the past year, moreover, it has been shown that blockade of TNF in addition can delay joint destruction that otherwise may lead to handicap in many patients. Two different drugs with the ability to block TNF have recently been registered for practical clinical use against rheumatoid arthritis in the USA They are also expected to be registered for use in Europe and other parts of the world shortly.
The research now rewarded with the first Crafoord Prize for Polyarthritis is an example of how innovative contributions from researchers who have combined basic research and clinical application have rapidly transferred findings from basic molecular research to new effective treatment, in this case of rheumatoid arthritis.
Professor Ravinder Maini, born 1937 studied medicine at Cambridge and in London. He has been associated with the Kennedy Institute of Rheumatology since 1979 and is since 1990 its Director.
Professor Marc Feldmann, born 1944, studied medicine in Melbourne, Australia. He came to the Department of Zoology, University College, London in 1972 Has been Deputy Director and Head of the Immunology Unit at the Charing Cross Sunley Research Centre, and he joined the Kennedy Institute of Rheumatology in 1992.
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Rheumatoid arthritis is a serious disease. It affects approximately 1% of the population, often starts in middle age and afflicts three times more women than men. In the majority of patients the disease causes damage to various joints, with persisting disablement often associated with chronic pain. Further, the life expectancy of patients with the disease in active form is considerably reduced. Methods of treatment to date have had considerable success in reducing the severity of the disease but have been able only to a small extent to cure it and to effectively retard joint destruction.
Ever since the first description of rheumatoid arthritis as a defined disease at the end of the 19th century, researchers have wondered why some people are afflicted by this chronic, often life-long inflammation of the joints. It was early known that joint inflammation was associated with accumulation of white blood cells in the joints and that the reactions in the joints resembled the defence reactions the body uses to attack invading bacteria or viruses, with the difference that the defence reaction against infectious agents is in most cases self-limiting and disappears when the invading micro-organism has been eliminated.
Before the 1980s it was not understood how the chronic inflammation in the joint arises and why it persists. For this reason it was hard to develop any effective treatment. It was only in connection with breakthroughs in basic molecular research that the situation changed, and it became possible to identify molecules denoted cytokines which are active in the communication between the various white blood cells. This made it possible to follow the different inflammatory reactions in more detail, to see what cells and molecules that initiate an immune reaction, what cells and molecules carry out the attacks, and how the reactions are regulated.
The new understanding of the normal inflammation process also opened possibilities for better understanding of how chronic inflammatory diseases, including rheumatoid arthritis, arise. At the same time there were – and remain – difficulties in applying the results of pure research to a clinical problem. It may be relatively easy to identify cells and molecules, e.g. in the rheumatic joint, but it is far harder to understand what role the many different molecules play in the complicated control of the inflammatory reaction developing in a pathological manner. And such knowledge is required for effective treatment that reduces the inflammation in rheumatoid arthritis without at the same time rendering patients defenceless against our common infections.
It was in the mid-1980s – just when these possibilities and problems were starting to become apparent – that Marc Feldmann as a basic researcher in immunology and Ravinder Maini as a researcher and physician within clinical rheumatology, started to co-operate. They focused their joint efforts on studying the role played by the various signal molecules, the cytokines, in regulating inflammation in rheumatoid arthritis. Particularly important were their studies of the order in which the various reactions occur. They were able to observe whether certain signal molecules were “superordinate” to others and whether there were signal substances that were particularly important in joint inflammation. At the end of the 1980s they found that one of the newly-discovered signal molecules, TNF-alpha, appeared particularly important in joint inflammation and this molecule might be one of the “superordinate”, controlling, molecules they had been seeking. They found that an antibody to TNF-alpha that “captures” the molecule and prevents it from reaching its target cell was also able to prevent large parts of the cascade of inflammatory reactions otherwise occurring in the cells cultured in the laboratory (in cascade reactions several factors are released in various orders, first a, then b, then c, etc. Blocking the release of one factor blocks the reactions at later stages).
The logical consequence of these findings, described by Maini and Feldmann in several articles around 1990, was to investigate whether it was possible to treat rheumatoid arthritis with blockade of TNF without inducing an unacceptable degree of susceptibility to infection.
From test-tube experiments to treatment of experimental animals
The “pecking order” between the different signal molecules may be observed in test-tube cultures of human cells, but this can never take us further than to hypotheses about how the signal molecules function in a living being (in vivo). Humans, like other mammals, are such complicated organisms that it is impossible to predict from cell cultures how far a similar “pecking order” also exist in the living organism. A necessary step in any investigation of principles that may eventually lead to a new treatment principle being tried on humans is thus to perform trials in experimental animals suffering from a disease similar to the one to be cured in man.
Feldmann and Maini continued blocking TNF-alpha with antibodies as a treatment for rheumatoid arthritis by treating mice that had polyarthritis. Together with other scientists they found that blockade of TNF-alpha really was an effective method to retard joint inflammation and – just as importantly – that there were no signs of side-effects, e.g. infections. The results of these experiments were published during 1992.
From mice to men
Encouraged by the successful results of TNF-alpha blockade in joint inflammation in animal experiments, Feldmann and Maini, in collaboration with their clinical colleagues at the Kennedy Institute, then started a small “open” study in which rheumatoid arthritis patients were treated with anti-TNF-alpha antibodies. This first clinical trial between 1992 and 1993 showed that the treatment appeared to be without untoward side effects and it seemed to have led to a dramatically positive effect on the disease. The patients often felt an appreciable effect of the treatment even after a few days/weeks, not only on the inflamed joints but on the fatigue which is a dominating symptom of rheumatoid arthritis. These results prompted Maini and Feldmann to seek contact with more clinical colleagues in Europe, and to run joint “double-blind” studies using injections of antibodies against TNF-alpha (a “double-blind” study is one in which, as opposed to the “open” study, neither the treating physician nor the treated patient know until after termination of the treatment whether the latter has received the active treatment or placebo). Under these well-controlled circumstances, the treatment also had a very good effect on both well-being and joint symptoms. This effect was particularly evident in patients who for many years had had severe rheumatism where treatment with the anti-rheumatic drugs so far available had not been successful.
This study, published in 1994, led to a number of larger clinical trials using both the monoclonal antibody in question and other principles for blocking TNF-alpha. It is these latter comprehensive clinical trials that during 1999 led to two drugs, including the first antibody used, being registered for regular clinical use against rheumatoid arthritis in the USA, and the two drugs are expected to soon be registered in Europe and other parts of the world.
Between inflammation and infection – an evolutionary dilemma
The ultimate importance of this new form of treatment for rheumatoid arthritis will depend on the balance between effect and potential side effects. As mentioned previously all the signal substances that cause chronic inflammation in rheumatoid arthritis also contribute to the normal defence against infection, and perhaps also to other defence reactions. One concern has thus been that individuals treated with TNF blockade might develop an increase susceptibility to infections, and that also other side effects may arise after long periods of treatment. Fortunately, the controlled trials conducted so far have indicated no appreciably increased risk of infection. At the same time it must be remembered that experience is still limited and has been gained during a relatively short time.
In summary entirely new methods of treating previously intractable inflammatory disease has been developed. The rapidly growing knowledge of immunology and inflammation provided by basic research has given opportunities for this significant development. This development has been possible by seminal scientific contributions by Marc Feldmann and Ravinder Maini. Hopefully there are great possibilities that the treatment principle now made available for patients with rheumatoid arthritis represents but the first of a long series of future specific treatments not only for rheumatic diseases but also for other chronic inflammatory diseases with elements of enhanced reactions against one’s own tissues.