We used PubMed to access articles on systemic lupus erythematosus and the antiphospholipid syndrome, covering January, 2001, until August, 2006, supplemented with review articles. (The Lancet published a Seminar on this subject in 2001).1 Search terms we used were “systemic lupus erythematosus”, “antiphospholipid syndrome”, “lupus nephritis”, “central nervous system disease in lupus”, and “fatigue”. Articles were selected according to their effect on clinical practice. We have not
SeminarSystemic lupus erythematosus
Section snippets
Epidemiology
The most striking studies of the epidemiology of lupus examined the development of autoantibodies years before the onset of clinical features of lupus and antiphospholipid syndrome.2, 3 The investigators used the US Department of Defense serum repository, which contains about 30 million samples from service personnel taken at baseline and on average alternate years. They identified 130 individuals with systemic lupus erythematosus and reported that 72 developed autoantibodies to DNA on average
Pathogenesis
The pathogenesis of lupus remains unclear, although the notion of apoptosis goes some way to explain how the immune system might recognise predominantly intracellular antigens. Autoantigens are released by both necrotic and apoptotic cells. Defects in the clearance of apoptotic cells have been described in this disorder and these defects could lead to aberrant uptake by macrophages, which then present the previously intracellular antigens to T and B cells, thus driving the autoimmune process.8
Genetics
Genetic susceptibility to lupus is inherited as a complex trait and studies have suggested that several genes could be important. In particular, an interval on the long arm of chromosome 1, 1q23–24, is linked with systemic lupus erythematosus in many populations. Clinically, active disease is accepted to be characterised by increased erythrocyte sedimentation rates but normal C-reactive protein (CRP) concentrations. CRP, complement, and serum amyloid P protein are important in clearing
Environmental factors
Sunlight is the most obvious environmental factor that can exacerbate the disease (panel 1). Other factors have been considered and crystalline silica was the focus of studies from southeast USA, where occupational exposure was postulated as a risk for development of lupus.14 A case control study showed that more patients than controls (19% vs 8%) had a history of medium-level or high-level silica exposure from farming or trades. This finding suggests that such exposure could be associated with
Hormonal factors
Systemic lupus erythematosus is a disease affecting women of childbearing age and there have been many anecdotal reports of exogenous oestrogens exacerbating lupus or increasing the risk of developing this disorder. Oral contraceptive use in the Nurses Health Study18 was associated with a slightly increased risk of disease with a relative risk for users versus never users of 1·9. Hormone replacement therapy (HRT) has been associated with an increased risk of systemic lupus erythematosus,19, 20
Cardiovascular risk
Over the past 5 years there has been an increase in published work assessing the prevalence and risk factors for the development of accelerated atherosclerosis in patients with systemic lupus erythematosus. Three case-control studies26, 27, 28 confirmed that atherosclerosis develops prematurely, independently of traditional risk factors for cardiovascular disease. Lupus itself seems to be a risk factor for the development of atherosclerosis, and a reasonable theory suggests that inflammatory
Lupus nephritis
The assessment and management of lupus nephritis has seen major advances over the past 5 years. WHO's classification for lupus nephritis has been updated to allow more accurate descriptions of renal histopathological specimens by the International Society of Nephrology and the Renal Pathology Society (figure).32 These descriptions allow better communication between pathologists translating static images from histology slides into meaningful descriptions of the huge variations in biopsy
Central nervous system lupus
CNS disease in lupus remains challenging in terms of pathogenesis, assessment, and treatment. A study by DeGiorgio and colleagues39 showed that antiDNA antibodies recognise a pentapeptide that is also present in the extracellular domain of murine and human N-methyl-D-aspartate (NMDA) receptor subunits NR2a and NR2b, which bind the neurotransmitter glutamate. Furthermore, they showed that the NR2 receptor is recognised by both murine and human antiDNA antibodies and that these crossreactive
Quality of life issues
Although survival has greatly improved in patients with lupus over the past 50 years, substantial challenges remain in improving quality of life for these patients. Indeed, actual measurement of quality of life has not been straightforward because there are very few validated instruments, which is an area that is being addressed.49 Fatigue severely affects quality of life. Factors contributing to fatigue remain complex and include depression, pain, poor sleep quality, poor physical fitness,
Pregnancy
Overall, pregnancies for patients with lupus have a greater risk of spontaneous miscarriage, preeclampsia, intrauterine growth restriction, fetal death, and preterm delivery. The degree of risk depends on several factors at the time of conception, including the presence of lupus nephritis, hypertension, antiphospholipid antibodies, and active disease. Pulmonary hypertension arises in up to 14% of patients with lupus and even mildly raised pulmonary artery pressures can be seen in 37% of
Antiphospholipid syndrome (Hughes' syndrome)
The description of the antiphospholipid syndrome in 1983 has, arguably, proved to be the pivotal advance in the management of lupus over the past half-century. The ramifications of the syndrome extend beyond lupus, to all disciplines of medicine. The classification criteria for this syndrome have been updated to include manifestations not previously classifiable.61 A description of the clinical features of 1000 patients with the syndrome remains the largest such series.62 The study documents
New treatments
Since 2001, there have been major advances in the treatment of this disorder. Newer, low dose cyclophosphamide regimens have already been described and biological agents are now having an effect.
Rituximab is a chimeric human-murine monoclonal antibody directed against CD20 on B cells and their precursors but not against plasma cells, which do not have this antigen. Rituximab has been widely used in the management of lymphoma and is fairly safe and well tolerated. There is increasing evidence
Assessment of disease activity and damage
The assessment of lupus in clinical trials has been dependent on several disease activity scoring systems, which usually provide one numeric value. The British Isles Lupus Assessment Group (BILAG) is useful in clinical trials because it describes disease activity on the basis of the physician's intention to treat the patient, and provides a clear picture of affected organs and systems. It has undergone revision and is being validated.88 Other disease activity scoring systems have been updated,
Conclusion
The next 5 years should see a consolidation of therapies, such as low-dose cyclophosphamide regimens, mycophenolate mofetil, and rituximab as well as the emergence of many potentially useful and highly targeted treatments. The major remaining challenges include improving the quality of life for patients with lupus, by keeping corticosteroids, infections, and fatigue to a minimum and reducing cardiovascular risk, which still claims substantial loss of life.
Search strategy and selection criteria
References (93)
- et al.
Systemic lupus erythematosus
Lancet
(2001) - et al.
Attempt to correct abnormal signal transduction in T lymphocytes from systemic lupus erythematosus patients
Autoimmun Rev
(2006) - et al.
Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodies
J Autoimmun
(2004) - et al.
Use of exogenous estrogens in systemic lupus erythematosus
Semin Arthritis Rheum
(2001) - et al.
Pregnancy in lupus nephritis
Am J Kidney Dis
(2002) - et al.
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)
J Thromb Haemost
(2006) - et al.
A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS)
J Thromb Haemost
(2005) - et al.
Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation
Blood
(2005) - et al.
Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med
(2003) - et al.
The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus
Arthritis Rheum
(2004)
Trends in the incidence and mortality of systemic lupus erythematosus, 1950–1992
Arthritis Rheum
Mortality and causes of death in systemic lupus erythematosus
Curr Opin Rheumatol
Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden
Lupus
Relation of risk of systemic lupus erythematosus to west African admixture in a Caribbean population
Hum Genet
SLE-a disease of clearance deficiency?
Rheumatology (Oxford)
Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies
Arthritis Rheum
A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus
Nat Genet
Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus
Hum Mol Genet
A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans
Nat Genet
Occupational exposure to crystalline silica and risk of systemic lupus erythematosus: a population-based, case-control study in the southeastern United States
Arthritis Rheum
Occupational risk factors for the development of systemic lupus erythematosus
J Rheumatol
EBV and systemic lupus erythematosus: a new perspective
J Immunol
Past use of oral contraceptives and the risk of developing systemic lupus erythematosus
Arthritis Rheum
Postmenopausal estrogen therapy and the risk for developing systemic lupus erythematosus
Ann Intern Med
Postmenopausal estrogen replacement therapy and the risk of developing systemic lupus erythematosus or discoid lupus
J Rheumatol
Hormonal and reproductive risk factors for development of systemic lupus erythematosus: results of a population-based, case-control study
Arthritis Rheum
The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial
Ann Intern Med
Combined oral contraceptives in women with systemic lupus erythematosus
N Engl J Med
A trial of contraceptive methods in women with systemic lupus erythematosus
N Engl J Med
Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus
N Engl J Med
Premature coronary-artery atherosclerosis in systemic lupus erythematosus
N Engl J Med
Systemic lupus erythematosus: an independent risk factor for endothelial dysfunction in women
Circulation
Prevention of cardiovascular disease in systemic lupus erythematosus—proposed guidelines for risk factor management
Rheumatology (Oxford)
Risk factors for cardiovascular disease in systemic lupus erythematosus
Circulation
Mannose-binding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus
N Engl J Med
The classification of glomerulonephritis in systemic lupus erythematosus revisited
J Am Soc Nephrol
Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide
Arthritis Rheum
Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial
Arthritis Rheum
Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong—Guangzhou Nephrology Study Group
N Engl J Med
Hong Kong Nephrology Study Group. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis
J Am Soc Nephrol
Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis
N Engl J Med
Sequential therapies for proliferative lupus nephritis
N Engl J Med
A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus
Nat Med
Quantitative magnetic resonance imaging in neuropsychiatric systemic lupus erythematosus
Lupus
Arthritis Rheum
Migraine, memory loss, and “multiple sclerosis”. Neurological features of the antiphospholipid (Hughes') syndrome
Postgrad Med J
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