Jo Edwards MD, Professor of Connective Tissue Medicine
Research at University College, London
Jo Cambridge PhD, Senior Scientist
Centre for Rheumatology, University College London
Rheumatoid Arthritis and Autoimmunity: A new approach to their cause and how long term cure might be achieved
In autoimmune conditions, such as rheumatoid arthritis, the body produces antibodies to its own tissues - "autoantibodies". Until now it has not been clear why people make autoantibodies or whether autoantibodies cause the illness. This homepage gives an new explanation for autoimmunity and suggests a new treatment that may produce long term relief for conditions such as rheumatoid arthritis, lupus, and Crohn's disease. Promising results obtained in an initial trial of this treatment in rheumatoid arthritis are summarised in a scientific abstract at the end of the homepage.
Our conclusion is that autoantibodies are first made by chance but can set up a vicious cycle so that they go on being produced in large amounts, causing damage to body tissues. Removing the cells that make antibodies should break this cycle. It is now possible to remove most of these cells safely and effectively. Preliminary results are encouraging.
To explain how autoimmunity may work it is necessary to go into some detail about the immune system. However, we have tried to make this reasonably easy to follow. New opportunities for treatment are described at the end.
The immune system and autoimmunity
The immune system includes two types of white blood cell, B and T cells, which recognise the difference between "self" molecules belonging to the body and "non-self" molecules from bacteria and viruses. B cells make antibodies. Each B cell makes antibodies to one non-self molecule. However, it can only do so if given "help" by T cells recognising parts of the same non-self molecule. T cells are, therefore, seen as directing antibody production.
Because T cells direct normal immunity, it has been thought that autoimmunity starts with T cells mistaking self for non-self. These T cells would then direct the production of autoantibodies by helping B cells which recognise self molecules. This sort of autoimmunity can be created in animals if the animal is immunised with self molecules, but usually dies down after a few weeks. This is quite different from autoimmunity in people and we think that human autoimmunity works in a different way.
Most forms of autoimmunity in humans start up for no obvious reason, apparently by chance. Once autoimmunity has developed it often goes on for ever. There is nothing to suggest that anything from outside the body is fooling the T cells into confusing self and non-self. Hereditary factors make some people more at risk than others, but even within "autoimmune families" there is no way of knowing who will develop disease or when. This suggests that human autoimmunity starts with a chance event within the immune system, which develops into a perpetual vicious cycle. We believe that the chance event is the production of an autoantibody which can stimulate its own production.
Autoimmunity as a vicious cycle
The reason for thinking that the chance event which starts autoimmunity is the production of a new type of antibody is that all new antibodies are made by chance. B cells cannot deliberately make an antibody to a molecule. All they can do is make random changes in the antibody they are already making. If the changed antibody binds better to a non-self molecule the B cell is encouraged to go on making antibody. If the new antibody binds less well or binds to a self molecule the B cell is told to die. However, under rare circumstances, instead of dying, B cells making autoantibodies may be able to keep themselves alive.
This idea does not mean that T cells are not involved, because B cells can only make antibody with help from T cells. It means that T cells must be fooled into helping B cells to make autoantibodies, not by something from outside the body, but by autoantibodies themselves. The autoantibodies also need to fool the B cells, because B cells have their own means of checking they are making the right antibodies. Very few autoantibodies are likely to be able to fool both systems. This explains why autoimmunity does not develop all the time and why autoantibodies are only made to a few self molecules.
Autoantibodies and disease
Even if autoantibodies are made they may cause no harm. Many people make enough autoantibodies to be measurable in blood samples. (This can cause confusion because some people have a positive rheumatoid arthritis autoantibody blood test but never get arthritis.) As we get older we accumulate autoantibodies. These are probably autoantibodies which can stimulate their own production but are of no importance because they are harmless to the tissues. If an antibody attaches to a self molecule most of the time it is probably cleared away without any problem. However, certain autoantibodies are dangerous. Increasingly, it is possible to see how different autoantibodies can cause particular illnesses. The mechanisms are pretty clear for rheumatoid arthritis and lupus, but for other conditions there is still some way to go.
In rheumatoid arthritis there are antibodies against antibodies - which is perhaps the most obvious way of setting up a vicious cycle. Antibodies come in five types: IgM, IgG, IgA, IgD or IgE. The autoantibodies in rheumatoid arthritis, known as rheumatoid factors, are antibodies against IgG.
The usual blood test for rheumatoid arthritis measures IgM antibodies against IgG (IgM-anti-IgG). These antibodies are probably harmless because they do not get out of the bloodstream and can be cleared away by a set of molecules called the complement system. However, some antibodies in rheumatoid arthritis are IgG anti-IgG i.e. they bind to themselves. These are more difficult to measure but are likely to be more important.
Inflammation in joints
Pairs of IgG anti-IgG antibodies stuck to each other are dangerous because they are not cleared away by the complement system. They are small enough to pass out of the bloodstream into the tissues. Once in certain tissues they probably cause inflammation by stimulating macrophage cells. They do this by binding to a receptor, known as CD16a, on the macrophage surface. Macrophages only carry this receptor in the tissues affected by rheumatoid arthritis, including joint lining, the lungs and the pericardial lining of the heart, so inflammation only occurs in these tissues. The situation is made worse in the joints by the fact that, during inflammation, cells which make anti-IgG antibodies come into the joint lining and make autoantibodies inside the joint.
Fooling the T cells
It has been known for a long time that B cells that make anti-IgG antibodies can "borrow" help from T cells which recognise non-self molecules, breaking the normal rules.
A B cell normally gets help only from a T cell that recognises the same non-self molecule. The B cell does this by carrying some antibody on its surface. This surface antibody picks up the non-self molecule, which the cell then digests. The broken down fragments of the non-self molecule are then "presented", attached to a carrier molecule on the B cell surface, to nearby T cells. If a T cell recognises the fragment as non-self it gives the B cell a "help" signal to make more antibody. (The B cell divides and daughter cells known as plasma cells make most of the antibody.)
B cells that make anti-IgG antibodies (rheumatoid factors) can cheat the system. The anti-IgG antibodies on the B cell surface pick up IgG molecules, which are themselves antibodies already attached to non-self molecules. The B cell digests the non-self molecule, presents it, and gets help from a T cell recognising a non-self molecule fragment. The carrier molecule that the B cell uses to present fragments, known as MHC Class II, is different in different people, with the result that molecule fragments are presented differently. Perhaps not surprisingly, the type of MHC Class II a person carries has an effect on how likely they are to develop rheumatoid arthritis. Other genetic factors probably influence the likelihood of the development of arthritis , but they are as yet unknown.
Fooling the B cells
Luckily, there is another checking system which ensures that B cells that make anti-IgG antibodies only last for short periods. If a B cell is given help by a T cell it then moves into an area of a lymph node (lymph gland) called a follicle centre. If at this time it picks up unattached self molecules with its surface antibody it will die. This means certain death for most B cells that make anti-IgG antibodies because there is plenty of unattached IgG around.
Unfortunately, if the B cell is making IgG anti-IgG antibodies the situation is more complicated. When a B cell first makes antibody it makes the IgM type. Before it can change to making IgG antibody the B cell has to run the gauntlet of the follicle centre. This is probably why very few people have B cells that make IgG anti-IgG, they will have died before they have a chance to change to IgG. However, very occasionally it may be possible for B cells already making useful IgG antibodies to a non-self molecule from a virus or bacteria to change to making IgG anti-IgG antibodies by making a random change in the structure of their antibody. These cells can return to the follicle centre bathed not only in unattached IgG but also in their own IgG anti-IgG antibodies clumped together.
Although picking up unattached molecules via cell surface antibody is lethal to the B cell in the follicle centre, picking up molecules stuck to antibody (and complement, which follows the antibody attachment) will keep the B cell alive. This means that a B cell that makes IgG anti-IgG may survive the death signals from unattached IgG. In other words, if an anti-IgG antibody producing B cell has switched to making IgG, its own antibodies may keep it alive both in the company of T cells and in the follicle centre so that it can produce more antibody. The vicious cycle is complete.
Lupus is a condition rather like rheumatoid arthritis in which several sorts of autoantibodies can occur. Perhaps the most important of these are antibodies to a complement system molecule known as C1q.
The complement system has three uses. It can kill bacteria. It clears away antibodies bound to unwanted material. It is also involved in selecting which B cells are allowed to survive in the follicle centre and make antibodies. Binding of autoantibodies to C1q has the effect of using up complement proteins. As a result people with lupus have difficulty fighting infections. They cannot clear away antibodies bound to unwanted material in the blood, which end up depositing in the walls of blood vessels in tissues such as the kidney. The production of other autoantibodies in lupus may be due partly to poor clearance of unwanted material and partly to poor selection of antibody-forming B cells.
People with lupus have repeated attacks of illness of different types, depending on how much the complement system has been used up and what autoantibodies are being made. For instance, antibodies to red blood cells can cause anaemia, antibodies to DNA are often associated with kidney problems, and antibodies to phospholipids in the blood can cause thrombosis.
Vicious cycles in Lupus
When an antibody binds to a molecule, complement system molecules tend to attach as well. C1q is the first to attach. The details are quite complicated, but this means that the ways in which rheumatoid factor anti-IgG antibodies can fool T and B cells are also available to anti-C1q antibodies. A B cell making anti-C1q antibodies can pick up non-self molecules stuck to antibody and C1q, just as the anti-IgG B cell can. In the follicle centre anti-C1q B cells will tend to find C1q bound to antibody and the key rescuing complement molecule, called C3d.
Another vicious cycle has already been mentioned. Anti-C1q antibodies help to generate other autoantibodies by using up complement. These other autoantibodies can also use up complement by binding to self molecules. Lupus probably represents a whole series of vicious cycles which can feed off each other and which have one thing in common - running out of complement.
The importance of complement is supported by the fact that people who are born lacking complement proteins often get lupus. A genetic lack of the C1q protein almost always leads to a form of lupus. In most lupus sufferers there is no genetic lack of complement but there is increasing evidence of other genetic factors which may alter the balance of the immune system. These may affect complement, messenger molecules known as cytokines, or molecules on the surface of cells through which cells interact, such as CD40.
The anti-phospholipid antibody syndrome is another condition which may depend on very similar vicious cycles to those in lupus. Thrombosis and miscarriage are the commonest features. The two conditions often occur together. It may be that low complement levels can generate vicious cycles either with the antibodies to DNA which are typical of lupus, or antibodies to phospholipid.
Scleroderma, myositis and Sjögren's syndrome
In several autoimmune conditions autoantibodies are found which bind to molecules found inside the nucleus of cells. These molecules are often involved in the handling of DNA in chromosomes or the rather similar RNA, which carries the genetic code to be translated for making proteins. Most antibodies cannot get in to cells, but a few can. By getting into cells and attaching to target proteins autoantibodies of this type may damage the cell when it is dividing or making protein. The cells lining blood vessels are bathed in a high concentration of antibody because they exposed directly to blood plasma. This may be why in the condition scleroderma, in which there are antibodies to proteins used for cell division, small blood vessels die and cannot be replaced. Antibodies to molecules involved in protein synthesis are often linked to the muscle disease polymyositis, which may be because muscle cells make large amounts of protein all the time. In childhood dermatomyositis antibodies to other molecules linked to DNA and RNA occur with both blood vessel damage similar to scleroderma and muscle damage.
Antibodies to proteins found in cells are associated with other conditions. In Sjögren's syndrome, dryness of the mouth and eyes and often arthritis, the molecule is called Ro. In one form of juvenile arthritis there are antibodies to a molecule called DEK. It is not known why antibodies to these molecules cause the patterns of illness we see. However, an important point is that when illness is due to antibodies getting in to cells blood tests for inflammation, such as the ESR, may well be normal. This may lead to a delay in diagnosis because the physician may only take note of autoantibodies if the ESR test is high.
How these antibodies might cause vicious cycles is not certain but several possibilities exist. If autoantibodies cause cells to die while dividing, cell proteins may be released alongside a "danger" signal which fools the T cells into treating them as non-self. If autoantibodies were to interfere with molecules involved in cell survival or activity they might also persuade both T and B cells to allow the autoantibody producing B cells to stay alive. In Sjögren's syndrome excessive survival of B cells is a major feature - often with excessive production of all sorts of antibodies. In some cases this gets to the stage that groups of B cells get completely out of control and behave like a malignant lymphoma.
Antibodies to receptors - myasthenia and thyrotoxicosis
The most clearly understood effect of autoantibodies is at the site where signals from nerves are transmitted to muscle - the muscle end plate. Antibodies to the signalling receptor cause a condition of muscle weakness known as myasthenia gravis. The antibodies prevent the signalling chemicals from nerves reaching the muscle. Antibodies to receptors on thyroid gland cells are probably also the cause of excessive production of thyroid hormone, in Grave's disease, or thyrotoxicosis.
The vicious cycles in these conditions may involve antibody binding to receptors on other cells involved in the immune system. The muscle end plate acetylcholine receptors are also present on cells in the thymus. The thymus is the organ where T cells undergo their "education" i.e. they choose which molecule they will recognise and are selected according to whether they see self or non-self. The unique feature of myasthenia is that the B cells making autoantibody take over the thymus gland where they interact with T cells and also form follicle centres. It seems that the antibodies to the receptor cause changes in the thymus that completely confuse the normal rules about B cell survival. If the thymus gland is removed myasthenia often gets better, but it is not a reliable cure.
Autoimmune disorders without typical autoantibodies - multiple sclerosis, sarcoidosis, Crohn's disease
Certain other conditions, including multiple sclerosis, sarcoidosis and Crohn's disease give the impression of being autoimmune, but are not linked to typical autoantibodies. However, unusual types of antibody do occur in each. There is more of a suggestion that these conditions are triggered by immunity to non-self molecules from viruses, bacteria or foodstuffs, but antibody-based vicious cycles may still be important.
In multiple sclerosis, antibodies are made within the fluid bathing the brain and spinal cord. The antibodies come from a small group of B cells and tend to remain the same throughout the illness. Nobody knows what they bind to. This may not be the point. The brain and spinal cord cannot cope with large amounts of any type of antibody in the surrounding fluid. Large amounts of antibody may cause phagocytic microglial cells to destroy the myelin which surrounds nerves. Although it has been thought that damage to the brain in multiple sclerosis is due to a direct attack by T cells, recent studies suggest that when the damage first starts antibody and active microglia may be present, but not T cells.
Multiple sclerosis is more common in some places than others and sometimes seems to occur in epidemics. One explanation for this is that it depends on a previous infection with a virus such as measles. The problem may be that some of the B cells making antibody to the virus make antibodies which give their B cell the ability to get into and live in the brain. The ability of B cells to get into tissues and survive there depends on the binding of one cell to another through surface proteins called adhesion molecules. Viruses often mimic or bind to these adhesion molecules. It may be that the B cells that survive in the brain make antibody which also mimics an adhesion molecule. If so, surface antibody on the B cells may not only allow the cells to survive in the brain, but may also lead to activation of microglia or other brain cells. This would be not so much an autoantibody stimulating its own production as an antibody creating the possibility of its own production in the brain.
The cells that make the antibodies found in the fluid around the brain in multiple sclerosis appear to be only found in the brain and spinal cord. However, they must come from cells in the lymphoid system. There may be a pool of cells outside the nervous system which do not make antibody most of the time, but every now and again some may get into the brain or spinal cord and start making antibody. This may result in a patch of myelin damage or "demyelination" which is the cause of symptoms in multiple sclerosis.
In sarcoidosis, clusters of phagocytic macrophage cells form in various body tissues, apparently stimulated by material they have taken up and by nearby T lymphocytes. However, there is no reaction if non-self proteins are injected into the skin, suggesting that the T cells have lost the ability to respond properly to non-self proteins. Even more strangely, particles from the tissue of one person with sarcoidosis injected into the skin of another sufferer cause a cluster of macrophages to form.
It seems likely that some form of autoantibody is binding to the surface of T cells and interfering with the way T cells interact with cells called accessory cells, which include macrophages and B cells. People with sarcoidosis often have antibodies to a type of sugar molecule (galactose) which is present attached to proteins on cell surfaces. The presence of this sugar on the surface of T cells is closely linked to their level of activity. The sugar is also present on B cells, but only when they are in follicle centres.
A number of plants make proteins called lectins which bind to specific sugars. Galactose is bound by a lectin in peanuts called PNA. When lectins bind to sugars on cells they can have powerful effects on the way the cell behaves. As suggested by Pilatte and Lambre, the autoantibodies in sarcoid may be interfering with the behaviour of T cells by behaving like lectins. The effect would seem to be to cause T cells to overstimulate accessory cells, but fail in other functions, and perhaps to cause follicle centre B cells to stimulate each other. This would set the scene for a vicious cycle of antibody production, explain the formation of macrophage clusters in the tissues and also the lack of response to non-self proteins.
In Crohn's disease, similar clusters of macrophages occur to those in sarcoidosis, but in the bowel. People with Crohn's disease often have antibodies to different sugar molecules (mannose) in a specific grouping. Interestingly, the bacteria that cause rather similar clusters of macrophages ("tubercles") in tuberculosis use mannose and galactose containing sugar molecules on their surface to interfere with the way macrophages and T cells behave.
The lymphocytes that provide immunity in the gut have different molecules on their surface from those in the rest of the body. It may be that the difference between sarcoidosis and Crohn's disease is due to antibodies to different sugar molecules having more effect on one set of lymphocytes than another.
Diabetes in young people is often caused by a lack of insulin due to damage to the islet cells of the pancreas. Autoantibodies to these cells are often found. However, both in diabetes and some forms of thyroid disease it may be that the damage to the tissue is done by T cells directly. Experiments in animals suggest that under unusual circumstances excessive numbers of T cells can accumulate in the pancreatic islets, rather in the way that excessive numbers of B cells can accumulate in the thymus, brain or joint in different autoimmune diseases. This suggests that diabetes may involve a vicious cycle involving T cells alone. Nevertheless it is possible that the autoantibodies present contribute to this cycle.
Are autoimmune diseases bugs in our immune software?
It appears that many autoimmune diseases may result from the chance production of antibodies which stimulate their own production in various ways. It is clear that only a tiny number of antibodies can do this - perhaps one in a million million possible types of antibody. We make many million types every day. Over seventy years our chances of getting autoimmunity are about one in twenty to one in fifty. It is likely that the antibody not only has to bind to the wrong molecule, it must be of the right subtype and bind in exactly the right way. Making one of these antibodies is just bad luck.
If so, autoimmune diseases may be a bit like bugs in a computer programme. Most of the time the programme can take cope with any numbers you put into it and it will do its job. However, if you happen to press certain keys in a particular order (i.e. make a dangerous antibody) the programme crashes - often going in to a "loop" in which it keeps doing the same thing for ever. The solution is to turn everything off, wipe out all the numbers you have put in and start up afresh. For autoimmune disease this may mean getting rid of all the B cells in the body, which will include the ones making the dangerous antibodies causing the loop, and start again. Fortunately, this may be possible.
How should autoimmunity be treated?
Most autoimmune diseases are being treated at present with drugs which damp down the activity of immune cells. There may be improvement, but in the long term the treatment has to go on being given. It is a bit like keeping the weeds in the lawn down by mowing - it works quite well but the weeds always come back.
In the last few years a number of people have suggested that we should think in terms of curing autoimmune disorders. This is partly because we feel we know enough about the immune system to think this might be possible and partly because successful cures have been achieved in some other conditions. Hodgkin's disease, for instance, which is a disease of immune system cells, can quite often be cured. Moreover, certain autoimmune conditions seem to be cured by the very high doses of chemotherapy given to patients who need bone marrow transplants. The evidence is not clear, but some people with rheumatoid arthritis who have had bone marrow transplants for other reasons find that their arthritis may go away for long periods and perhaps for good.
If it is accepted that it may be possible to produce permanent remission in autoimmune disorders then it seems fair to say that we should direct our efforts to this rather than simply to damping the condition down. The key question is how to achieve long term remission safely and surely. We believe that clearing away B cells is the best hope, for the reasons given above, but other ideas have already been tried.
One approach has been to try to get rid of T cells. However, if the explanation given here is correct this is not very logical. It is also likely to be dangerous because T cells carry our immune memory and are not readily replaced. Removing T cells can produce some benefit, but now that many studies have been done, the general impression is that it has no lasting effect - rather as we would expect.
A second approach is to get rid of all immune cells, on the basis that we do not know for sure which ones are most important. This is what happens when people have high dose chemotherapy before getting a bone marrow transplant. The same high dose chemotherapy is now being used in patients with autoimmunity. The difference is that they are being given their own bone marrow back - so there is no risk of rejection of the marrow. So far, several patients seem to have had benefit, but no clear picture has emerged. Very often patients are given rather smaller doses of chemotherapy to avoid too much risk. Unfortunately this may mean that they do not get lasting benefit.
B cell depletion
The approach we are favouring, getting rid of B cells, has not been tried in autoimmunity, but has been tried in other diseases. It has some enormous advantages, quite apart from being logical. If only B cells are removed, there is no risk from infection, of the sort that occurs if all immune cells are killed. The phagocytic cells that destroy bacteria are unharmed. There is enough antibody in the blood to last for a good while. This means that it is theoretically feasible to get rid of every single B cell without any danger. This is quite different from T cells. If a high proportion of T cells are removed immunodeficiency results. (The AIDS virus causes illness by removing T cells.) What is more, B cells regrow very quickly. After about 3 months the numbers are back to normal. The new B cells will be making a different set of antibodies. They will be directed by T cells only to make useful antibodies.
There is no reason why any of the new B cells should make dangerous antibodies. The chance of rheumatoid arthritis occurring a second time is probably about the same as the chance in an identical twin, which we know to be about one in four. It may well be less, since it may take many years for the conditions to develop which will allow an autoimmune vicious cycle to occur. The situation for some of the other autoimmune disorders may be a bit different. If the T cells have developed immunity to a particular virus or bacteria this may help set a vicious cycle going again.
So far, depletion of B cells has been used in people with malignant growths of B cells called non-Hodgkin lymphoma. It has also been used in a few patients with rheumatoid arthritis and some with neuropathy (a disease of the nerves). Specific depletion of B cells depends on using a drug which is itself an antibody to B cells. The results are even better if this is combined with other drugs which have a more general effect on immune cells. Lymphoma sufferers receiving this combination have a very good chance of their disease being put into remission for many months and perhaps years.
Treatment of autoimmunity should be easier than treatment of malignant growths. To cure a malignant disease it may be necessary to kill every single diseased cell. In autoimmunity it may only be necessary to kill sufficient cells to break the vicious cycle.
If B cell depletion will work in autoimmunity the biggest question is how many B cells have to be killed. It may be 90%, 95%, or even 99.5%. It will probably be different in different autoimmune conditions. 90% should be well within the scope of current technology. 95% may be at the limit, but more efficient techniques should come along fairly soon. The conclusion must be that if the explanation for autoimmunity described above is correct, it is logical to think that long term remission in autoimmune disease may be possible within the next two or three years. Early results of treatment of neuropathy have already been published. Results in rheumatoid arthritis are described below. In at least 3 out of 5 patients remission of disease seems to be continuing.
SUSTAINED IMPROVEMENT IN RHEUMATOID ARTHRITIS FOLLOWING A B LYMPHOCYTE DEPLETION PROTOCOL
JCW Edwards, G Cambridge, University College London Centre for Rheumatology, Arthur Stanley House London W1P 9PG
Background: We have recently proposed that rheumatoid arthritis (RA) is propagated by a vicious cycle based on self-perpetuating autoreactive B lymphocytes . On this basis subtotal B lymphocyte depletion therapy might be expected to induce long term remission. B lymphocyte depletion has been shown to be safe in the treatment of lymphoma. To test the hypothesis an open study of B lymphocyte depletion in RA was undertaken.
Methods: 5 patients with refractory RA (mean duration 22 yrs) having failed at least 5 disease modifying drugs, underwent a 3 week course of B lymphocyte depletion using monoclonal anti-CD20 antibody (Mabthera 2.1gm), prednisolone (60mg p.o. reducing) and cyclophosphamide (750mg IV x 2). Mean follow up is now 49 weeks.
Results: All patients achieved substantial improvement (American College of Rheumatology improvement grades ACR70,70,70,50,50) at six months without introduction of further therapy. Patients 1,3,5 have maintained or extended improvement at 52,52 & 44 weeks (ACR70,70,70) and their rheumatoid factor titres are now either negative or borderline. Patient 2 (ACR70) relapsed at 7 months, coincident with B lymphocyte repopulation, but regained ACR50 following a single repeat dose of anti-CD20 under low dose steroid cover . Patient 4 (ACR50) has relapsed gradually from 10 months and will be retreated. B lymphocyte counts remained low for several months but significant numbers have returned in all cases. As predicted on the basis of a B cell/autoantibody vicious cycle, relapse coincided with the return of B lymphocytes only in cases where rheumatoid factor titres remained elevated. Adverse events were limited to respiratory infection in 2 patients with histories of similar previous episodes, and marginal thrombocytopenia in 1.
Conclusions: These findings suggest that B lymphocyte depletion may be safe and effective therapy for RA. If confirmed, it appears likely that a majority of RA patients could be maintained with minimal symptoms with intermittent B lymphocyte depletion. The inclusion of cyclophosphamide in the protocol probably increased the speed of remission and may be necessary to optimise long term improvement with a single course of treatment. However, re-induction of improvement with anti-CD20 under steroid cover suggests that it may not be essential.
Reference: 1. Edwards JCW, Cambridge G and Abrahams VM. Immunology , 1999,97,1868-96.
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