New Therapies for Systemic Lupus
Introduction: SLE and overactivity of the immune system
The disease SLE (lupus) is characterised by an overactive immune system that produces an excess of molecules called antibodies. Antibodies normally target proteins from infecting organisms but, in SLE, the antibodies recognise components of normal cells and are called autoantibodies as they recognise 'self'. This leads to the formation of complexes that activate another set of proteins called complement which in turn initiate a lot of the inflammation that causes the symptoms of lupus. The aim of new therapies currently being tested in lupus is to find a treatment which is more effective at reducing the formation of autoantibodies and suppresses the inflammation while having less side-effects than current therapy.
Current treatment
Treatment of SLE involves damping down the overactive immune system but it is important to retain the ability to fight infection and to avoid other side-effects of the treatment. Steroids revolutionised the treatment of SLE in the 1950s and remain the mainstay of therapy for all but the mildest cases. Before the advent of steroids there were no effective therapies for controlling lupus at all. In order to reduce the dose of steroids needed to control the disease, many patients are currently given another drug to work with the steroids such as an anti-malarial, for example hydroxychloroquine, or for more troublesome cases azathioprine (Imuran), cyclosporin A (Neoral) or methotrexate. Cyclophosphamide is used for kidney and other serious manifestations of lupus. Apart from hydroxychloroquine, all of these drugs are associated with a risk of infection due to suppression of the normal immune system. Each drug has other possible side-effects such as nausea with azathioprine, high blood pressure with cyclosporin A, or infertility with cyclophosphamide (especially in women over the age of 30).
Mycophenolate mofetil (MMF)
The drug which is already coming into use as an alternative to cyclophosphamide or azathioprine is mycophenolate mofetil (MMF). The first published trial comparing oral MMF (tablets by mouth) with oral cyclophosphamide in lupus kidney disease suggested similar benefit with less infections, no infertility and other side-effects were reduced. Unfortunately more people deteriorated when the MMF was changed to low dose azathioprine after a year than those given oral cyclophosphamide followed by azathioprine. A 6 month trial comparing MMF and intravenous (IV) pulses of cyclophosphamide is likely to be presented at the American College of Rheumatology meeting in October 2003. However, previous work suggests that you need much longer studies than 6 months to really compare the outcome of two treatments for lupus kidney disease. It takes at least 5 years of follow-up to assess whether or not there is going to be a significant difference in the number of patients likely to get long-term complications such as kidney failure requiring dialysis. Thus longer trials comparing MMF to IV cyclophosphamide are still required but getting funding for this is difficult. MMF may also be helpful for other types of lupus but there are no formal trials to demonstrate this at present.
Anti-cytokine therapy
Following the success of anti-TNF therapy in most patients with rheumatoid arthritis, many people have been asking whether either this drug or an alternative is going to have such dramatic effects in SLE. Unfortunately the role of the cytokine (inflammatory mediator/messenger molecule) TNF in SLE is somewhat debatable and most people feel that anti-TNF therapy might do more harm than good in SLE as it can cause the formation of autoantibodies. Nevertheless some small trials are underway in Austria. The results of short-term anti-TNF therapy is promising so far in a few patients but more studies are needed before this method of treatment can be recommended. Blocking another messenger molecule called interleukin-10 may be more helpful but again more work is required to be sure that this treatment method will block autoantibody formation and suppress the disease. These drugs have to be given by injection.
Other biological therapies that interfere with cells producing autoantibodies
There are two main cell types involved in the generation of autoantibodies, T cells (T lymphocytes) and B cells (B lymphocytes). There are small studies underway and larger trials being planned for 2004 in which therapy directed against the B cells is used to stop autoantibody formation. There is more experience with Rituximab (anti-CD20) than with anti-Blys (LymphoStat-B) therapy at present, especially in the UK. Therapy designed to remove T cells has proved disappointing although it worked in animals with lupus-like disease in the past. Newer therapies have been designed to interfere with the molecules on T and B cells that are involved in generating immune responses such as anti-CD40L and CTLA4-Ig without getting rid of the cells. This may reduce the risk of infection but it may prove necessary to combine these therapies with each other or with short courses of cyclophosphamide as they are not very powerful on their own and further trials are needed. Another approach is to specifically reduce the formation of anti- DNA antibodies, the autoantibodies that are most associated with kidney disease. This can be achieved by the use of a compound called LJP394 which is undergoing trials in lupus, but so far has not been as effective at preventing kidney disease as had been hoped.
Conclusion
These are exciting times as there is the potential for the treatment of lupus to change but there will not be any sudden changes. There are a number of new therapies under trial for SLE and more will undoubtedly follow. Unfortunately it takes some time to test a new compound and to show that it is as safe and as good as existing therapies. All the new therapies are much more expensive than the current drugs so it is essential to demonstrate that they are actually better than current treatments, either more effective or safer, or preferably both. In the next few years an increasing number of doctors and patients will be approached to take part in these clinical trials and we hope that they will feel able to do so after appropriate discussion, otherwise progress will be slow.
Dr Gordon is always very supportive of LUPUS UK and the West Midlands Lupus Group. Her professional role extends into being a member of a number of advisory committees on SLE and also Chairing the American College of Rheumatology abstract selection committee for clinical aspects of lupus.
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