Elsevier

The Lancet

Volume 369, Issue 9561, 17–23 February 2007, Pages 587-596
The Lancet

Seminar
Systemic lupus erythematosus

https://doi.org/10.1016/S0140-6736(07)60279-7Get rights and content

Summary

Systemic lupus erythematosus is an autoimmune connective-tissue disorder with a wide range of clinical features, which predominantly affects women, especially from certain ethnic groups. Diagnosis is based on clinical assessment supported by investigations, including the finding of autoantibodies. Treatments range from antimalarial agents to corticosteroids and immunosuppressive agents. This Seminar draws attention to advances in the epidemiology, genetics, cardiovascular risks, lupus nephritis, CNS disease, the antiphospholipid syndrome, assessment of disease activity and damage, and pregnancy related and quality of life issues. New therapeutic approaches, such as biological agents and mycophenolate mofetil, will also be discussed.

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

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

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