Section 1. Epidemiology and aetiology
Its clinical manifestations range from arthralgia, photosensitivity and the classic malar or 'butterfly' rash to internal organ involvement, most notably renal and CNS disease.
SLE is often considered a rare disease, but is actually fairly common, especially in certain ethnic groups.
SLE typically affects young women of childbearing age, but all ages can be affected. The overall female:male ratio is 9:1. In paediatric populations and those aged >50, the ratio is 4:1.
The female predominance in SLE may indicate that hormonal influences play a part, but the precise role of estrogens is unclear.
The prevalence of SLE ranges from 40 to 200 per 100,000 population, varying considerably in different ancestral groups. It is more common in African, Asian and Hispanic populations than in those of European ancestry.2-4 Overall prevalence in the UK is approximately 28 per 100,000, rising to about 200 per 100,000 in African-Caribbean females.5 Patients from these ethnic groups are more likely to develop internal organ complications, such as lupus nephritis.6,7
There is a clear familial tendency in SLE, with a disease concordance of 24-57% in monozygotic twins and 2-5% in dizygotic twins, and a sibling risk ratio of 20-29, indicating that a genetic contribution is important.8,9
A number of lupus susceptibility genes have been identified, including polymorphisms involved in antigen presentation, Tand B-cell signalling, immune complex clearance and toll-like receptor pathways.
A wide variety of autoantibodies occur in SLE and their role in diagnosis is well established. Antinuclear antibodies (ANA) are the hallmark of SLE, while high-affinity antibodies to double-stranded DNA (anti-dsDNA) correlate with clinical activity, particularly renal disease.
The interplay between genetic, hormonal and environmental factors results in T-cell dysfunction and B-cell activation, autoantibody production and the clinicopathological manifestations of SLE.
Section 2. Making the diagnosis
No single clinical feature or laboratory test is diagnostic of SLE because no two patients present alike. Diagnosis requires a careful review of symptoms, detailed physical examination and appropriate investigations.
The 2012 Systemic Lupus International Collaborating Clinics classification requires the patient to fulfil four criteria, including at least one clinical and one immunological. Alternatively, the patient must have biopsy-proven lupus nephritis in the presence of ANA or anti-dsDNA.10
Although the criteria are useful for enrolling patients in research studies, they should not be used to diagnose patients because they are designed to be highly specific at the cost of sensitivity. There are no diagnostic criteria for SLE, so patients with mild or early SLE may not be diagnosed.
When to refer depends on the clinical presentation. In general, patients with acute presentations, for example, severe skin disease, arthritis, nephrotic syndrome, cardiopulmonary disease or neurological manifestations, are usually referred rapidly, often through A&E.
The more challenging situation is the patient who presents in primary care with a long history of malaise, fatigue, oral ulcers, arthralgia and non-specific skin rashes.
Clues to the diagnosis (see box 1) include the development of an asymmetrical pattern of Raynaud's phenomenon, recurrent oral ulcers, characteristic discoid skin lesions, scarring alopecia or photosensitivity and a symmetrical pattern of arthritis or arthralgia. Although the butterfly rash is characteristic, it is in fact an uncommon presentation.
If in doubt, a careful history, supplemented by simple screening investigations, may lead to an appropriate early referral. Laboratory investigations that suggest an early presentation of SLE include finding a high ESR with a normal CRP, cytopenias and a positive ANA. Urinalysis for proteinuria is an important screening test.
Laboratory investigations at baseline and regular follow-up should include FBC with differential WCC, ESR, CRP, serum creatinine, serum albumin and urinalysis.
A baseline immunology screen should include ANA, anti-dsDNA, antibodies to extractable nuclear antigens (ENA), anticardiolipin antibodies, and lupus anticoagulant and complement levels.
It is useful to repeat anti-dsDNA antibody and complement levels (C3, C4) at routine review because rising anti-dsDNA antibody levels and falling complement levels may indicate active disease. If a patient is taking a particular drug, for example, azathioprine or mycophenolate mofetil, specific monitoring is warranted.
Section 3. Managing the condition
Corticosteroids are often used in managing SLE. Mild disease may respond well to low-dose prednisolone 5-10mg daily. For more severe disease, higher doses of 20-40mg may be required, or pulse therapy with IV methylprednisolone.
Every effort should be made to taper the dosage to the lowest sufficient to maintain disease control, to minimise potential side-effects.
Hydroxychloroquine is extremely useful in the management of musculoskeletal and dermatological symptoms in SLE.
It has benefits in terms of reducing the risk of disease flares, increased long-term survival and protection against thrombosis and loss of bone mass.11 It also reduces damage accrual over time and has a protective effect on renal damage in patients with lupus nephritis.12,13
While hydroxychloroquine associated retinopathy is rare, it is recommended that patients have a baseline visual field examination. Thereafter, in low-risk patients, no further testing is required for the next five years. After five years of therapy, annual eye examination is recommended.
In high-risk patients, those with macular degeneration, retinal dystrophy or more than five years of therapy, annual eye examinations are recommended.14
Cyclophosphamide is the mainstay of treatment in secondary care in rash, severe renal and CNS involvement in SLE.
The Euro-Lupus regimen of a fixed low dose of cyclophosphamide for a short period, followed by maintenance therapy with azathioprine or mycophenolate mofetil, is now widely used and achieves comparable results to the high-dose cyclophosphamide protocol, with a low rate of endstage renal failure at 10 years.15,16
Azathioprine is frequently used in the management of moderate to severe SLE. Patients taking it also require regular FBC and liver function monitoring. Azathioprine can be continued during pregnancy.
Mycophenolate mofetil has become one of the most frequently used immunosuppressive agents in SLE. It is less likely than cyclophosphamide to cause toxicity, such as ovarian failure and infection. It is, however, contraindicated in pregnancy and patients should be switched to azathioprine during pregnancy planning.
Methotrexate is useful in the treatment of SLE, particularly in those with predominantly musculoskeletal and cutaneous involvement. It is given once weekly in conjunction with folic acid. Regular monitoring of liver function and FBC is required.
Increased understanding of the immunopathogenesis of SLE has led to the introduction of new biologics.
Rituximab has been used in SLE for almost a decade and has led to dramatic improvement in some patients with refractory disease.
Disappointingly, RCTs in non- renal SLE and lupus nephritis failed to meet their primary endpoints.17,18
More recently, corticosteroid-sparing regimens in lupus nephritis have been introduced with some success, with rituximab as induction therapy followed by maintenance mycophenolate mofetil. A large RCT is currently running.19
B-cell survival factors, such as B-lymphocyte stimulator protein (BLyS), have also been used as a therapeutic target.
Belimumab, a fully humanised monoclonal antibody against BLyS, has been shown to be effective in SLE patients with musculoskeletal, mucocutaneous, haematological and general constitutional features and has been approved by the US Food and Drug Administration and the European Medicines Agency for use in non-renal SLE.20,21
Other biologics are in clinical trials, including those targeting costimulatory interactions between Tand B-lymphocytes and therapies that target cytokines, such as interleukin-6 and interferon-alpha.
Section 4. Prognosis
Recent decades have seen major improvements, from a four-year overall survival rate of 50% in 1950 to a 15-year survival rate of 80% in the 1990s. Despite this, a patient diagnosed with SLE at 20 years of age still has a one in six chance of dying from disease activity or infection by the age of 35 years.
The bimodal pattern of mortality in SLE is well recognised, with early deaths due to active disease or infectious complications and deaths later in the course of disease due to cardiovascular disease (CVD).
There is a fivefold greater risk of atherosclerosis in SLE patients, with OR estimated at 4.8 to 9.8, making it critical to address classical risk factors such as smoking, obesity, hypertension, dyslipidaemia and diabetes mellitus in these patients.
The primary care physician has a major contribution to make in terms of assessing and managing these risk factors in patients with SLE.
As more targeted therapies are developed and patient survival increases, it is likely that CVD will become the primary cause of mortality in SLE, emphasising the need for cardiovascular risk modification early in the disease course.
Section 5. Case study
A 22-year-old female presented with new-onset arthralgia, fatigue, aphthous ulcerations, photosensitive skin rash and alopecia.
Investigations revealed positive ANA, anti-dsDNA, anti-Ro and anti-Sm antibodies. Complement levels were mildly reduced. Tests also indicated haemolytic anaemia (Hb 9.5mg/dL). A diagnosis of SLE was made and treatment with hydroxychloroquine, low-dose prednisolone and azathioprine commenced.
Cardiovascular risk factors, including lipid and glucose levels, were normal. Anticardiolipin antibodies and lupus anticoagulant were negative and she had no previous thromboembolic events or miscarriages, so a coexisting diagnosis of antiphospholipid syndrome was excluded.
The patient remained stable for a year, but then presented with increasing malaise and ankle swelling. She was hypertensive and had pitting oedema of the ankles.
Laboratory investigations revealed an elevated urea and creatinine, with eGFR 45mL/min, hypoalbuminaemia, raised anti-dsDNA antibodies and reduced complement levels.
Urinalysis revealed proteinuria and red cell casts. A urine sample was analysed for protein:creatinine ratio (PCR), which indicated an abnormal daily urinary protein loss of 6g.
She was referred to her local hospital, where a renal biopsy revealed class III nephritis. Induction therapy was initiated, with six doses of IV cyclophosphamide over a 12-week period. An ACE inhibitor was also commenced for optimisation of proteinuria and hypertensive control.
Gradually anti-dsDNA, complement levels and PCR improved, renal function normalised and hypertension was controlled. On completion of induction therapy, mycophenolate mofetil was introduced as maintenance immunosuppression. She remains under close observation.
Section 6. Evidence base
- Houssiau FA, Vasconcelos C, D'Cruz D et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002; 46: 2121-31
- Tamirou F, D'Cruz D, Sangle S et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann Rheum Dis 2015 doi:10.1136/annrheumdis-2014- 206897
- Furie R, Petri M, Zamani O et al. BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011; 63: 3918-30
- Navarra SV, Guzman RM, Gallacher AE et al. BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377: 721-31
- Mosca M, Tani C, Aringer M et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010; 69: 1269-74
These EULAR guidelines cover a number of key features, including patient assessment, cardiovascular risk factors, infection risk and immunisation, frequency of clinical assessments, laboratory tests, renal monitoring, neuropsychological manifestations and ophthalmology assessment.
- Hahn BH, McMahon MA, Wilkinson A et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012; 64: 797-808
These guidelines offer an overview of the principles of induction and maintenance immunosuppression in lupus nephritis.
- The Lupus UK website provides patient information and useful factsheets about the disease:
- Information is also available from St Thomas' Lupus Trust:
- Contributed by Dr Natasha Jordan, consultant rheumatologist, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, and Professor David D'Cruz, consultant rheumatologist, Guy's and St Thomas' Hospital NHS Foundation Trust.
|CPD IMPACT: EARN MORE CREDITS|
These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.
1. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008; 358: 929-39.
2. Feldman CH, Hiraki LT, Liu J et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004. Arthritis Rheum 2013; 65: 753-63.
3. Lim SS, Bayakly AR, Helmick CG et al. The incidence and prevalence of systemic lupus erythematosus, 2002-2004: the Georgia Lupus Registry. Arthritis Rheumatol 2014; 66: 357-68.
4. Somers EC, Marder W, Cagnoli P et al. Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan Lupus Epidemiology and Surveillance program. Arthritis Rheumatol 2014; 66: 369-78.
5. Johnson AE, Gordon C, Palmer RG et al. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Lancet 1996; 347: 367-9.
6. Hopkinson ND, Jenkinson C, Muir KR et al. Racial group, socioeconomic status, and the development of persistent proteinuria in systemic lupus erythematosus. Ann Rheum Dis 2000; 59: 116-19.
7. Alarcon GS, McGwin G Jr, Bartolucci AA et al. Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual. Arthritis Rheum 2001; 44: 2797-806.
8. Deapen D, Escalante A, Wienreb L et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992; 35: 311-18.
9. Hochberg MC. The application of genetic epidemiology to systemic lupus erythematosus. J Rheumatol 1987; 14: 867-9.
10. Petri M, Orbai AM, Alarcon GS et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677-86.
11. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010; 69: 20-8.
12. Fessler BJ, Alarcon GS, McGwin G Jr et al. LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum 2005; 52: 1473-80.
13. Pons-Estel GJ, Alarcon GS, McGwin G Jr et al. LUMINA Study Group. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum 2009; 61: 830-9.
14. Marmor MF, Carr RE, Easterbrook M et al. American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology 2002; 109: 1377-82.
15. Houssiau FA, Vasconcelos C, D'Cruz D et al. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term follow up of patients in the Euro-Lupus Nephritis Trial. Arthritis Rheum 2004; 50: 3934-40.
16. Houssiau FA, Vasconcelos C, D'Cruz D et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010; 69: 61-4.
17. Merrill JT, Neuwelt CM, Wallace DJ et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010; 62: 222-33.
18. Rovin BH, Furie R, Latinis K et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012; 64: 1215-26.
19. Condon MB, Ashby D, Pepper RJ et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 2013; 72: 1280-6.
20. Furie R, Petri M, Zamani O et al. BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011; 63: 3918-30.
21. Navarra SV, Guzman RM, Gallacher AE et al. BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377: 721-31.