Systemic lupus erythematosus (SLE) is a heterogeneous, inflammatory, multisystem autoimmune disease in which antinuclear antibodies occur (often years before clinical symptoms).Lupus erythematosus describes the typical rash of SLE and the term systemic emphasises the potential for multi-organ involvement. The cause of SLE is unknown.
Nov 2017 - Dr Hayley Willacy draws your attention to the recently published British Society for Rheumatology's first guideline dealing with the management of systemic lupus erythematosus in adults. Although SLE survival has improved over the last 40 years, people with SLE still die 25 years younger than average in the UK. This new BSR guideline includes recommendations on clinical and serological features prompting consideration of a diagnosis of SLE; assessment of SLE patients; monitoring of SLE and management of mild, moderate, and severe SLE.
- The age-standardised SLE incidence in the UK during the 1990s was 7.89 per 100,000 for females and 1.53 per 100,000 for males, with an overall female-to-male ratio of 5.2:1. Peak incidence occurred at age 50-54 years for females and 70-74 years for males.
- It is more common in those of Chinese, Southeast Asian (1 in 1,000) and Afro-Caribbean origin (1 in 500).
- Certain human leukocyte antigen DRB1 types are more common in lupus patients - eg, DR3 and DR2.
- Patients who have a defective C4 complement gene (C4A null allele) also develop a lupus-like illness.
- Environmental factors include ultraviolet light, viruses (eg, the Epstein-Barr virus) and some drugs. Drugs known to cause drug-induced lupus include chlorpromazine, methyldopa, hydralazine, isoniazid, d-penicillamine and minocycline.
- SLE is a remitting and relapsing illness, with a variety of different presentations.[5, 6]
- Symptoms and signs are often nonspecific - eg, fatigue (can be severe and debilitating), malaise, fever, splenomegaly, lymphadenopathy, weight loss, arthralgia and fatigue, oral ulcers, photosensitive skin rashes, pleuritic chest pains, headache, paraesthesiae, dry eyes and mouth, Raynaud's phenomenon, mild hair loss and myalgia.
- The symptoms of lupus can range from minor aching pains and rash to life-threatening disease.
- Any major organ involvement tends to develop within five years of the disease onset.
- Joint and muscle pains are common, often with early morning stiffness.
- Joint swelling is unusual and the arthritis is usually non-erosive.
- Some patients develop joint deformity and subluxation when tendons and peri-articular soft tissues are affected (Jaccoud's arthropathy).
- Peripheral, symmetrical, flitting polyarthritis is typical.
- Secondary fibromyalgia is common.
- Raynaud's phenomenon occurs in about one fifth of patients but is often mild.
- Photosensitivity rash.
- Classical feature is the malar (butterfly) rash, often precipitated by sunlight. It is erythematous and may be raised and pruritic. It spares the naso-labial folds:
- Discoid lupus erythematosus: can occur in the absence of any systemic features. It tends to occur in sun-exposed areas. It is erythematous, well demarcated and associated with scaling:
- Other manifestations include livedo reticularis, diffuse or patchy non-scarring alopecia and vasculitic rashes. Mouth ulcers can be large, multiple and painful.
- Pulmonary: pleurisy, fibrosing alveolitis, obliterative bronchiolitis. Patients with the secondary antiphospholipid syndrome (APLS) are at increased risk of pulmonary embolus.
- Cardiovascular: pericarditis, hypertension, Libman-Sacks endocarditis, an increased risk of coronary heart disease.
- Renal: nephritis is often asymptomatic and is detected by proteinuria, haematuria, hypertension or a raised serum urea or creatinine. Glomerulonephritis is common in lupus patients.
- Neuropsychiatric: anxiety and depression are common. Patients may also develop psychosis, seizures, neuropathy, meningitis and organic brain syndrome.
- Lupus can be associated with almost any neurological manifestation. Strokes may be due to vasculitis or thrombosis associated with APLS.
The American College of Rheumatology Classification system for SLE suggests that a person may be classified as having lupus if four or more of the following 11 criteria are present (which do not have to occur at the same time but can be cumulative over a number of years):
- Malar rash.
- Discoid lupus.
- Oral or nasopharyngeal ulcers.
- Non-erosive arthritis involving two or more peripheral joints.
- Pleuritis or pericarditis.
- Renal involvement with persistent proteinuria or cellular casts.
- Seizures or psychosis.
- Haematological disorder: haemolytic anaemia or leukopenia or lymphopenia or thrombocytopenia.
- Immunological disorder: anti-DNA antibody or anti-Sm or antiphospholipid antibodies.
- A positive antinuclear antibody.
However, the Systemic Lupus International Collaborating Clinic Index 2012 (SLICC'12) is more sensitive and may allow patients to be classified as having SLE earlier in the disease course.
- When SLE is suspected, useful screening investigations are urinalysis, FBC, ESR or plasma viscosity and antinuclear factor.
- Urinalysis: as initial test for proteinuria/haematuria.
- FBC and ESR:
- Mild normochromic normocytic anaemia is common. Anaemia in patients with lupus may be drug-induced or due to chronic disease, but it is sometimes due to haemolytic anaemia. In this case, Coombs' antibody, reticulocyte count and haptoglobins may need to be checked.
- Leukopenia and thrombocytopenia occur frequently but can also be due to immunosuppressive therapy.
- ESR is raised but CRP may be normal unless there is intercurrent infection or serositis.
- ANA: screening test with a sensitivity of 95% but not diagnostic in the absence of clinical features. It is a nonspecific antibody that is also present in many patients with systemic autoimmune conditions - eg, systemic sclerosis (scleroderma), polymyositis and primary Sjögren's syndrome. The titre does not alter significantly with disease activity.
- Anti-dsDNA: high specificity but sensitivity is only 70%. The level reflects disease activity. The value often varies with disease activity and sometimes guides changes in therapy. A rise in antibody titre may indicate that immunosuppression needs to be increased.
- Anti-Sm is the most specific antibody but sensitivity is only 30-40%.
- Anti-SSA (Ro) or Anti-SSB (La) are present in 15% of patients with SLE and other connective tissue diseases - eg, Sjögren's syndrome; also associated with neonatal lupus.
- Anti-ribosomal P are uncommon antibodies that may correlate with lupus cerebritis.
- Anti-RNP may indicate mixed connective tissue disease with overlap SLE, scleroderma, and myositis.
- Anti-histone: drug-induced lupus ANA antibodies are often this type.
- Antiphospholipid antibodies: anticardiolipin antibodies and lupus anticoagulant should be checked in lupus patients, as they are associated with APLS.
- Complement C3 and C4 levels are decreased and C3d (a degradation product) increased with increased disease activity.
- Other investigations will depend on system involvement - eg, MRI brain scan, echocardiogram, renal biopsy.
- Women with SLE are at greatly increased risk of premature atherosclerosis and the risk is independent of established cardiovascular risk factors. Monitoring for all cardiovascular risk factors is therefore essential.
- Overlap syndromes: some patients with 'lupus' do not have pure SLE as described, but have overlapping features with other connective-tissue diseases, such as scleroderma, polymyositis, rheumatoid arthritis and Sjögren's syndrome.
- They are prone to other autoimmune conditions such as thyroiditis. They also have a higher incidence of drug allergy and an increased risk of infection.
- Patients with SLE are also at increased risk of certain other comorbidities, including atherosclerosis, hypertension, dyslipidaemias, diabetes, osteoporosis, avascular necrosis and malignancies (especially non-Hodgkin's lymphoma).
- Patients often require considerable counselling about their individual prognosis and symptoms. Avoid sun exposure as much as possible and use sun screens.
- Identify and treat any underlying cause (eg, anaemia, depression) and encourage regular aerobic exercise.
- Joint and muscle pains, headaches, and musculoskeletal chest pains respond to simple analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) - the latter should be used with caution because of gastrointestinal, renal, and cardiovascular risks.
- When simple analgesia and NSAIDs are insufficient to control symptoms or disease, additional treatment is considered, depending on the individual systems involved:
- Corticosteroids: very effective but also implicated in the increased mortality in lupus, as a result of infection, cardiovascular disease and complications of fractures. High-dose prednisolone is reserved for life-threatening SLE.
- Useful for skin lesions, arthralgia, myalgia and malaise. Cutaneous manifestations may respond within days but, more often, clinical improvement takes 6-12 weeks of treatment.
- Hydroxychloroquine is generally very well tolerated but may cause irreversible ocular toxicity.
- Hydroxychloroquine remains first-line treatment for patients with mild SLE, especially for those with arthralgia, skin rashes, alopecia, and oral or genital ulceration.
- Cyclophosphamide is reserved for treatment of life-threatening disease, particularly lupus nephritis, vasculitis and cerebral disease.
- Mycophenolate mofetil:
- Mycophenolate mofetil is as effective as cyclophosphamide in inducing remission in lupus nephritis, but is safer with a lower risk of ovarian failure.
- Mycophenolate mofetil is more effective than azathioprine in maintenance therapy for preventing relapse with no increase in clinically important side-effects.
- Azathioprine is used as a steroid-sparing agent. As an alternative to cyclophosphamide, azathioprine is much safer but probably less effective, particularly in active nephritis. Azathioprine does predispose to infection but to a lesser extent than cyclophosphamide or corticosteroid therapy.
- Other immunosuppressive agents used in severe SLE include methotrexate and ciclosporin.
- Intravenous high-dose pooled gammaglobulin and granulocyte-colony stimulating factor have a role in autoimmune thrombocytopenia and neutropenia. Intravenous immunoglobulins are increasingly being used in the treatment of resistant lupus and also have a role in patients who have concomitant infection and active lupus, for whom immunosuppression treatment is often inappropriate.
- Belimumab (cytokine modulator) inhibits the activity of B-lymphocyte stimulator. Belimumab is licensed as adjunctive therapy in patients with active, autoantibody-positive SLE with a high degree of disease activity despite standard therapy.
- Other 'biological drugs' that have been used in the treatment of resistant SLE include TNF antagonists, rituximab, abatacept, tocilizumab and eculizumab.
- Patients who are seriously ill with life-threatening disease may undergo plasma exchange as a holding measure until the immunosuppressive therapy takes effect.
- Lupus patients should be offered the flu vaccination; they should not receive live vaccinations.
- Glucocorticoids and immunosuppressive therapy are indicated when neuropsychiatric SLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis or acute confusional state) and in the presence of generalised lupus activity.
- There is very low-quality evidence that cyclophosphamide is more effective in reducing symptoms of neuropsychiatric involvement in SLE compared with methylprednisolone.
- Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic cardiovascular disease.
Contraception, fertility and pregnancy
- Oestrogen hormones can exacerbate lupus but the lowest-dose oestrogen oral contraceptive pill can be prescribed cautiously, providing there is no history of migraine, hypertension or thrombosis and providing anticardiolipin antibodies are negative. However, there is an increased risk of thrombosis.
- Fertility is normal and pregnancy is safe in mild or stable lupus. In severe lupus, pregnancy should be delayed until the disease is better controlled:
- Morbidity in pregnancy is common, especially if the woman has antiphospholipid antibodies.
- Complications include recurrent early loss of pregnancy, pre-eclampsia, intrauterine growth restriction and preterm delivery. Women are at increased risk of thrombosis, especially in the puerperium.
- The risks of pregnancy are greatly increased in the presence of lupus nephritis, hypertension and active disease, especially at the time of conception.
- Pre-existing renal disease may worsen in pregnancy and hypertension may be difficult to control.
- Low molecular weight heparin and low-dose aspirin are now the treatment of choice for women with APLS and a history of miscarriage.
The prognosis has improved with earlier recognition and improved management. The five-year survival rate is over 90%.
- Morbidity and mortality are usually higher in patients with extensive multisystem disease and multiple autoantibodies.
- Patients who develop renal involvement, particularly focal and diffuse proliferative glomerulonephritis, have a poorer prognosis.
- Although there tends to be less lupus nephritis in the elderly with late-onset SLE, more disease activity and damage may be present.
- Drug-induced lupus usually subsides when the responsible drug is discontinued.
Further reading and references
Management of medium to high-dose glucocorticoid therapy in rheumatic diseases; EULAR recommendations (July 2013)
Ocular Toxicity and Hydroxychloroquine: Guidelines for Screening; Royal College of Ophthalmologists and British Association of Dermatologists (2009)
Belimumab for treating active autoantibody-positive systemic lupus erythematosus; NICE Technology Appraisal Guidance, June 2016
D'Cruz DP, Khamashta MA, Hughes GR; Systemic lupus erythematosus. Lancet. 2007 Feb 17369(9561):587-596.
Gordon C, Amissah-Arthur MB, Gayed M, et al; The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology (Oxford). 2017 Oct 6. doi: 10.1093/rheumatology/kex286.
Somers EC, Thomas SL, Smeeth L, et al; Incidence of systemic lupus erythematosus in the United Kingdom, 1990-1999. Arthritis Rheum. 2007 May 1557(4):612-8.
D'Cruz DP; Systemic lupus erythematosus. BMJ. 2006 Apr 15332(7546):890-4.
Campar A, Farinha F, Vasconcelos C; Refractory disease in systemic lupus erythematosus. Autoimmun Rev. 2011 Sep10(11):685-92. doi: 10.1016/j.autrev.2011.04.027. Epub
Cervera R, Doria A, Amoura Z, et al; Patterns of systemic lupus erythematosus expression in Europe. Autoimmun Rev. 2014 Jun13(6):621-9. doi: 10.1016/j.autrev.2013.11.007. Epub 2014 Jan 10.
Anic F, Zuvic-Butorac M, Stimac D, et al; New classification criteria for systemic lupus erythematosus correlate with disease activity. Croat Med J. 2014 Oct55(5):514-9.
Ines L, Silva C, Galindo M, et al; Classification of Systemic lupus erythematosus: Systemic Lupus International Collaborating Clinics versus American College of Rheumatology criteria. Arthritis Care Res (Hoboken). 2015 Jan 7. doi: 10.1002/acr.22539.
Bertsias G, Ioannidis JP, Boletis J, et al; EULAR recommendations for the management of systemic lupus erythematosus. Report Ann Rheum Dis. 2008 Feb67(2):195-205. Epub 2007 May 15.
Henderson L, Masson P, Craig JC, et al; Treatment for lupus nephritis. Cochrane Database Syst Rev. 2012 Dec 1212:CD002922. doi: 10.1002/14651858.CD002922.pub3.
British National Formulary; 68th Edition (Sep 2014) British Medical Association and Royal Pharmaceutical Society of Great Britain, London
Belmont HM; Treatment of systemic lupus erythematosus - 2013 update. Bull Hosp Jt Dis (2013). 201371(3):208-13.
Bertsias GK, Ioannidis JP, Aringer M, et al; EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis. 2010 Dec69(12):2074-82. doi: 10.1136/ard.2010.130476. Epub 2010 Aug 19.
Fernandes Moca Trevisani V, Castro AA, Ferreira Neves Neto J, et al; Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database Syst Rev. 2013 Feb 282:CD002265. doi: 10.1002/14651858.CD002265.pub3.
Mackillop LH, Germain SJ, Nelson-Piercy C; Systemic lupus erythematosus. BMJ. 2007 Nov 3335(7626):933-6.
Lalani S, Pope J, de Leon F, et al; Clinical features and prognosis of late-onset systemic lupus erythematosus: J Rheumatol. 2010 Jan37(1):38-44. Epub 2009 Dec 15.