LUPUS: A GP Guide to Diagnosis
Research is defined as the systematic investigation into and the study of materials, sources, and the like, in order to establish facts and reach new conclusions. This chapter will address the main areas of lupus research namely causation, epidemiology and new therapies. Although mouse models give clues and insight into disease processes, they are not an adequate substitute for the naturally occurring human disease. Hence, without the generous donation of blood, tissue and time by the patients themselves, little of what follows would be possible.
Lupus is characterised by the production of autoantibodies particularly to nuclear antigens and some enzymes related to nucleic acid function. Detection of these antibodies in blood is crucial in the investigation of patients suspected of having lupus. The recent finding that the major auto-antigens involved namely DNA, histones, Sm, SS-A, SS-B and RNP are clustered in 2 populations of surface structures on apoptotic cells (cells undergoing programmed cell death) has led to the hypothesis that these surface blebs on apoptotic cells are important immunogens in lupus patients. Indeed, the identification of phosphatidylserine on the outside of these blebs has generated the proposal that such substances could lead to the production of antiphospholipid antibodies which are an important clinical predictor of thrombosis in lupus. The fact that such thrombogenic autoantibodies can trigger apoptosis, together with the observation that there are large numbers of apoptotic cells in lupus patients, suggests that there may be a self-perpetuating cycle of events pivotal to the inflammation notable in the disease. It has also been postulated that immune complexes may play an important role in tissue damage in lupus and there is now evidence of abnormalities in the pathways by which immune complexes are cleared in lupus patients.
The debate concerning which type of lymphocyte is more important in the immunopathogenesis of lupus has reigned for decades and as all antibodies are products of B lymphocyte derived cells, you may feel from the information presented so far that the contest is over. However, this would be premature. The crucial role of the T cell is exemplified by the demonstration of self-reactive B cells in normal humans - i.e. do they matter? - and the observation that HIV infection may ameliorate lupus presumably via CD4+ T cell depletion. Mouse data also strongly supports the role of the T cell in lupus, as T lymphocyte depletion by genetic or biological routes prevents the development of murine lupus. Expansions of certain families of T lymphocytes in the blood of lupus patients have also recently been identified. Similar profiles of T cells in juvenile onset diabetes mellitus recently led to the identification of a candidate retrovirus. A viral aetiology for lupus has long been suspected and despite the technical difficulties real prospects now exist for the detailed and systematic investigation of this subject.
New therapies for lupus are being regularly introduced and old ones refined. The use of certain anti-transplant rejection therapies such as cyclosporin A (neoral) and tacrolimus (prograf) have shown significant benefit in lupus. The place of these agents in the therapeutic ladder makes them worthy of a special mention. Previously, patients failing to have their disease activity adequately controlled by hydroxychloroquine, azathioprine and methotrexate received cyclophosphamide with attendant problems of premature menopause/sterility which are very emotive areas for lupus sufferers who classically are females in the child-bearing years. Therefore, we are now able to offer treatment with either cyclosporin or tacrolimus before considering cyclophosphamide. The prognosis in lupus has improved dramatically over the last 20 years, hopefully, the long term complications of drugs, particularly steroids, will be further reduced by these new therapies.
Epidemiological studies in the last decade have identified that the memorable young sick woman with a butterfly rash is less common than the middle aged (40-60 years) female with joint pains. Regrettably, in many patients the time from onset of symptoms to diagnosis is several years and earlier diagnosis would be of benefit. Serological tests (antinuclear antibodies and Ro antibodies) can be very helpful in screening for lupus as ANA negative Ro negative lupus is rare. It is also important for patients that their disease activity is accurately assessed so that adequate additional therapy can be introduced when necessary and there is research into a number of new markers of disease activity in the serum and urine such as neopterin which show promise.
Information given to patients with lupus must be accurate but, unfortunately, misinformation abounds. Well designed studies, using appropriate control groups, have now shown that true allergy is no more common in lupus, that stress does contribute to the majority of flares, that smoking is a risk factor and that alcohol may be protective.
Haemopoietic stem cell transplantation and extracorporeal photochemotherapy are two novel treatment modalities that have been used successfully in a small number of lupus cases. Their application is currently limited by availability of expertise and expense, but therapies like these may offer hope to individuals with disease at the severe end of the spectrum. The survival after autologous haemopoietic stem cell transplantation for malignancy continues to improve and real possibilities for lupus exist.
Research into more specific immunosuppression is currently underway. Trials of T cell receptor peptide therapy are ongoing in multiple sclerosis and with the new data on the expansions of certain T cell families in lupus, this therapeutic modality may well be applicable to this disease. A new purine analogue which acts specifically on lymphocytes, namely mycophenolate mofetil (cellcept), has been shown to be of benefit in murine lupus and is well studied in humans as an anti-transplant rejection drug and, therefore, may prove beneficial in human lupus. The use of dsDNA-anti-dsDNA antibody complexes in murine lupus has also been shown to reduce anti-dsDNA antibody production and extend life.
To those individuals who kindly donate to the "tin rattlers" outside your local supermarkets and generously support coffee mornings, research means finding a cure for the disease in question. Sufferers from lupus demand no less, however, the nature of research, especially laboratory research, is that it often poses more questions than it answers. Consequently, in the next 5 years or so the above may be superseded, only time will tell!
Dr. Richard Powell
Consultant/Senior Lecturer in Clinical Immunology & Allergy
Clinical Immunology Unit
Queen's Medical Centre
Nottingham, NG7 2UH