Systemic lupus erythematosus (SLE) is a heterogeneous, inflammatory, multisystem autoimmune disease in which antinuclear antibodies occur (often years before clinical symptoms).¹ 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.

Epidemiology²

• Prevalence is 50-100 cases per 100,000.
• The peak age of onset is in the twenties or early thirties, but cases do occur in children and the elderly.
• Women are affected nine times more frequently than men.²
• It is more common in those of Chinese, Southeast Asian (1 in 1,000) and Afro-Caribbean origin (1 in 500).
• Prevalence is least common in women of Northern European origin (prevalence 1 in 2,800).

Risk factors

• Certain human leukocyte antigen DRB1 types are more common in lupus patients, e.g. 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, e.g. the Epstein-Barr virus, and some drugs
  Drugs known to cause drug-induced lupus include chlorpromazine, methyldopa, hydralazine, isoniazid, d-penicillamine and minocycline.

Presentation

• Systemic lupus erythematosus (SLE) is a remitting and relapsing illness.³
• Symptoms and signs are often nonspecific,⁴ e.g. 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.⁵
• 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.
• Arthralgia:
  • 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.
• Mucocutaneous:
  • 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 rash: 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.

Diagnosis

The American College of Rheumatology Classification system for systemic lupus erythematosus (SLE) suggests that a person may be classified as having lupus if 4 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):⁶

• Malar rash.
• Discoid lupus.
• Photosensitivity.
• Oral or nasopharyngeal ulcers.
• Non-erosive arthritis involving 2 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.

Investigations

• When systemic lupus erythematosus (SLE) is suspected, useful screening investigations are an FBC, ESR or plasma viscosity and antinuclear factor.
• 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.
• Autoantibodies:³
  • ANA: screening test with a sensitivity of 95% but not diagnostic in the absence of clinical features. Is a nonspecific antibody that is also present in many patients with systemic autoimmune conditions, e.g. systemic sclerosis (scleroderma), polymyositis and primary Sjögren's syndrome. The titre does not alter significantly with disease activity.
  • Anti-dsDNA: high specificity but sensitivity 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, e.g. 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 antiphospholipid syndrome (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, e.g. 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.

Associated diseases

• Antiphospholipid syndrome (APLS).
• Overlap syndromes: some patients with 'lupus' do not have pure systemic lupus erythematosus (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).⁷

Management

• 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 (e.g. 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 systemic lupus erythematosus (SLE).
  • Hydroxychloroquine:
    • 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.²
  • Cyclophosphamide:
    • Cyclophosphamide treatment is reserved for treatment of life-threatening disease, particularly lupus nephritis, vasculitis and cerebral disease.
    • The established treatment for lupus nephritis has been cyclophosphamide combined with steroids⁸ or high-dose monthly or quarterly intravenous pulse cyclophosphamide; however, recent studies have shown that short courses of low-dose pulse cyclophosphamide followed by azathioprine are as effective and less toxic.²
    • Cyclophosphamide appears to be more effective in the treatment of neuropsychiatric involvement in SLE compared with methylprednisolone.⁹
  • 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.
• 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.

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.²
  • 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 antiphospholipid syndrome (APLS) and a history of miscarriage.

Prognosis

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.²
• Patients who develop renal involvement, particularly focal and diffuse proliferative glomerulonephritis, have a poorer prognosis.
• Drug-induced lupus usually subsides when the responsible drug is discontinued.

Document references

1. D'Cruz DP, Khamashta MA, Hughes GR; Systemic lupus erythematosus. Lancet. 2007 Feb 17;369(9561):587-596. [abstract]
2. D'Cruz DP; Systemic lupus erythematosus. BMJ. 2006 Apr 15;332(7546):890-4.
3. Bartels CM et al; Systemic Lupus Erythematosus, eMedicine, Mar 2011
4. Johnson AE, Gordon C, Hobbs FD, et al; Undiagnosed systemic lupus erythematosus in the community. Lancet. 1996 Feb 10;347(8998):367-9. [abstract]
5. Cervera R, Khamashta MA, Font J, et al; Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore). 1993 Mar;72(2):113-24. [abstract]
6. Guidelines for referral and management of adults with systemic lupus erythematosus, American College of Rheumatology, 1999
7. Bertsias G, Ioannidis JP, Boletis J, et al; EULAR recommendations for the management of systemic lupus erythematosus. Report Ann Rheum Dis. 2008 Feb;67(2):195-205. Epub 2007 May 15. [abstract]
8. Flanc RS, Roberts MA, Strippoli GF, et al; Treatment for lupus nephritis. Cochrane Database Syst Rev. 2004;(1):CD002922. [abstract]
9. Trevisani VF, Castro AA, Neves Neto JF, et al; Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD002265. [abstract]

Acknowledgements