Research – The Future
IntroductionResearch is 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 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.
Factors in the development of LupusAn extensive search for genetic factors that predispose to lupus have confirmed that lupus is a polygenic disorder and the research challenge is to unravel the complex interplay between gene products that produce the milieu that fosters the varied clinical condition we recognise as lupus.
Lupus is characterised by the production of autoantibodies particularly to nuclear antigens and certain enzymes related to nucleic acid function. Detection of these antibodies in blood is crucial in the investigation of patients suspected of having lupus. The ascertainment that the major auto-antigens involved, namely DNA, histones, Sm, SS-A, SS-B and RNP are clustered in surface blebs on apoptotic cells (cells undergoing programmed cell death) has led to the hypothesis that these surface blebs are critical immunogens in lupus. Furthermore, aberrations in the apoptotic process itself may be central to lupus immunopathogenesis.
It has long been recognised that immune complexes play an important role in the tissue damage, particularly in lupus nephritis, however, there is now evidence of abnormalities in the pathways by which immune complexes are cleared by lupus patients and this has fostered a whole new research front.
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, one might argue that there is no contest. However, this would be premature.The crucial role of the T cell is exemplified by the demonstration of self-reactive B cells in normal human blood - 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. Furthermore, there has been an upsurge of interest in the role of T regulatory cells (CD4+ CD25+) to explain the disruption of immunological self tolerance notable in lupus.These specialised T regulatory cells appear to be decreased in active lupus compared to inactive lupus and normal controls. This may appear to be compelling evidence for a central role for T regulatory cells, however, the current challenge is to develop reagents to assist in the further dissection of this intriguing observation.
Expansions of certain families of T lymphocytes in the blood of lupus patients have also been identified. Similar profiles of T cells in juvenile onset diabetes mellitus led to the identification of a candidate retrovirus. A viral aetiology for lupus has long been suspected and, despite the technical difficulties, prospects now exist for the detailed and systematic investigation of this subject.
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 female with joint pains. Regrettably, in many patients the time from onset of symptoms to diagnosis is several years and earlier diagnosis would be beneficial. Serological tests (antinuclear antibodies and Ro antibodies) can be very helpful in screening for lupus as ANA negative Ro negative lupus is extremely 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 ongoing research into a number of new markers of disease activity.
Management of LupusNew therapies for lupus are being regularly introduced and old ones refined.The use of certain anti-transplant rejection therapies such as cyclosporine A (neoral) and tacrolimus (prograf) have shown significant benefit in lupus. More recently, another anti-rejection agent, mycophenolate mofetil, has been demonstrated to be a useful therapy, especially for lupus nephritis. Mycophenolate mofetil works by selectively blocking lymphocyte proliferation and, hence, T cell dependent antibody responses. Where in the treatment ladder mycophenolate should be placed will require further careful observation and clinical trials are in progress.
The prognosis in lupus has improved dramatically over the last 20 years and, hopefully, the long term complications of drugs, particularly steroids, will be further reduced by these new therapies. The use of new antagonists of ovulation may protect the woman’s ovarian function whilst chemotherapy with cyclophosphamide is ongoing.
Information given to patients with lupus must be accurate and, regrettably, misinformation abounds. Well designed studies, using appropriate control groups, have now shown that true allergy is not more common in lupus, that stress does contribute to flares of lupus, that smoking is a risk factor and that alcohol may even be protective.
Depletion of B cells in lupus with rituximab (an anti-CD20 monoclonal antibody) is now a reality but its place in the therapeutic arsenal, and the timing of this therapy, needs further clinical research. Biologic therapies to costimulatory molecules, complement (C5b) and cytokines are all currently being considered/tested in lupus patients.
Haemopoietic stem cell transplantation and extracorporeal photochemotherapy are two novel treatment modalities that have been used successfully in small numbers of lupus cases. Their application is currently limited by availability of expertise and expense but may offer hope to individuals with disease at the most severe end of the spectrum.The survival after autologous haemopoietic stem cell transplantation for malignancy continues to improve and real possibilities for lupus exist.
The FutureTo those individuals who kindly donate to the "tin rattlers" outside the 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.The last 5 years have certainly confirmed this!
Nottingham University Hospitals
Professor of Clinical Immunology & Allergy
Clinical Immunology Unit
Queens Medical Centre
Nottingham University Hospitals