From the National Magazine

SLE Then and Now

One of the UK's leading experts, Professor David Isenberg, ARC Diamond Jubilee Professor of Rheumatology at University College, London, looks at how treatment of lupus is improving.

What is lupus?
One hundred years ago syphilis was thought of as the great masquerader - the disease that could mimic any other. Its modern equivalent is systemic lupus erythematosus (SLE), or lupus. As well as rheumatologists, other specialists seeing patients with the disease include dermatologists, nephrologists, cardiologists and neurologists. Virtually all patients with lupus have arthritis and a skin rash frequently induced by sunlight exposure. In addition 30-40 per cent develop some degree of kidney involvement and around 50 per cent have disease affecting their lungs and/or heart. The central nervous system is involved in a potentially serious way in about a quarter of the patients. Morbidity and mortality.

Although the overall outlook for patients with lupus has improved substantially (50 years ago the five-year survival was approximately 50 per cent, the 15 year survival is now around 85 per cent) it continues to have a major effect on the quality of the lives of those who have it and a smaller, but significant, number of patients continue to die from lupus. For example of out of 361 patients with SLE treated at the UCH/Middlesex lupus clinic from 1978 when Michael Snaith first started the clinic to December 2002, 50 patients have died ranging in age from 16 to 87 years. Tragically this group includes several teenagers. The mean age of those who have died is 50, which is approximately 30 years younger than the average age of death of women in this country. Thus although the prognosis for patients with lupus is much improved it remains a disease that must be monitored very carefully.

When looking after patients with lupus, rheumatologists and other physicians are required, in effect, to place their patients on a fence between two fields, one marked effects of the disease and the other marked side-effects of the treatment. The disease itself - especially when it affects the kidney, heart, lungs and central nervous system - can cause significant ill health, which can last for months and years. As well as the short-term consequences of active inflammation, longer-term concerns including development of atherosclerosis and possible links to malignancy continue to cause great concern. Since the disease frequently requires treatment with major immunosuppressive drugs, patients with lupus have an increased risk of infection and, as a result of steroid use, osteoporosis. Developments in the assessment of lupus.

In order to understand the totality of the effects of disease on a patient we need to have means of measuring disease activity i.e. active ongoing inflammation; damage, meaning permanent change; and the patients' perception of the disease (often very different from that of their physician!) Lupus researchers have led the way in developing tools which do precisely these things. As we enter an exciting era for lupus research (see later) it is now possible to gauge the success, or otherwise, of new methods of treatment in a far more sophisticated and accurate method than seemed possible twenty years ago. Amongst the more successful activity indices for patients with lupus is one devised by the British Isles Lupus Assessment Group (BILAG) and a damage index devised by the Systemic Lupus International Collaborating Clinics group (to which several British rheumatologists belong) is widely used. To capture patients' views of lupus a questionnaire known as the SF-36 is often applied. Although not developed specifically for assessing patients with lupus it captures the key concerns including the major problem of fatigue.

Current research
Lupus is caused by complex interplay of genetic, environmental, hormonal and other factors. The complexity of this interplay has made determining the precise cause of lupus extremely difficult. Nevertheless, the powerful newer technologies which enable us to identify individual genes, study the structure and function of individual antibodies and explore the critical interactions between different cell populations within the immune system are now increasing our understanding about how lupus actually develops. Furthermore some of this research is "translational" i.e. it can move relatively quickly from basic research undertaken at the laboratory bench to the introduction of new therapies in the clinic. It is thus a very exciting time to be involved in taking care of patients with lupus and in studying its origins.

Examples of translational research include the introduction in America of new hormonal approaches to treat active lupus and, especially in the United Kingdom, the use of B cell depletion to treat severe disease. B lymphocyte cells are intimately involved in the production of antibodies, notably those which bind nuclear targets such as DNA which are thought to be an integral part of the pathological process that results in the disease. A combination of old (intravenous cyclophosphamide and oral steroids) and new (anti-CD 20, this being the marker for some types of B cells, also called rituximab) drugs have been combined to achieve significant depletion of B cells for patients with lupus who have failed conventional therapy. This form of therapy was actually introduced initially for the treatment of rheumatoid arthritis by my colleague Jo Edwards. Although much larger double blind and ideally placebo control trials are needed the results of the "open" studies published to date are encouraging.

However, much work remains to be done to explore our understanding of the critical involvement of other cells and molecules including the so-called T lymphocytes and cytokines, chemical messengers which enable cells to talk to each other. How is ARC (Arthritis Research Campaign) contributing to this effort? ARC has made a significant investment in lupus research over the past 20 years. Major research efforts are going on throughout the UK notably in the BILAG centres (Bath, University College London, St Thomas' Hospital, London, Birmingham, Newcastle, Leeds, Manchester, Bangor and Glasgow). ARC, through its project, fellowship, integrated centre and programme grant schemes has provided essential support to clinicians and scientists in these centres to enable the struggle both to understand lupus better and to improve its treatment to carry on - long may it continue!

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