Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a heterogeneous, inflammatory, multi-system 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
• More common in Chinese, Southeast Asian (1 in 1000) and Afro-Caribbean origin (1 in 500).
• Prevalence is least common in women of Northern European origin (prevalence 1 in 2800).

Risk factors

• Certain human leucocyte 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

• Remitting and relapsing illness
• Symptoms and signs are often non-specific,³ 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.⁴
• 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 and 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. 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 vasculitisor thrombosis associated with antiphospholipid syndrome.

Diagnosis

The American College of Rheumatology Classification system for SLE⁵ 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):

• Malar rash
• Discoid lupus
• Photosensitivity
• Oral or nasal ulcers
• Arthritis
• Serositis
• Renal involvement with blood or protein in urine
• Seizures or mental illness
• Haematological disorders
• Immunological disorders
• Positive LE test
• Anti-DNA antibody
• Anti-Smith antibody
• False positive test for syphilis
• A positive antinuclear antibody

Investigations

• When SLE is suspected, useful screening investigations are a full blood count, ESR or plasma viscosity and antinuclear factor
• Full blood count 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.
  • Leucopenia and thrombocytopenia occur frequently but can also be due toimmunosuppressive therapy
  • ESR is raised but CRP may be normal unless intercurrent infection or serositis.
• Autoantibodies: antinuclear antibody (ANA) is a non-specific antibody that is present in many patients with systemic autoimmune conditions, e.g. systemic sclerosis (scleroderma), polymyositis and primary Sjogren's syndrome. The titre does not alter significantly with disease activity.
• Anti-dsDNA antibodies are specific to lupus patients. 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.
• The extractable nuclear antibodies Ro, La, RNP and Sm are also often found in lupus patients
• Antiphospholipid antibodies: anti-cardiolipin antibodies and lupus anticoagulant should be checked in lupus patients as they are associated with antiphospholipid syndrome.
• Complement C3 and C4 levels are decreased and C3d (a degradation product) are 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 (Hughes') syndrome:
  • Occurs in 20-35 per cent of patients with lupus. It is characterised by presence of the lupus anticoagulant and/or antibodies to cardiolipin, and arterial/venous thrombosis, recurrent fetal loss and thrombocytopenia.
  • If antiphospholipid antibodies are detected, then treatment with low-dose aspirin should be considered in order to prevent thromboses
  • If they have already experienced a thrombosis then they should receive life-long anticoagulation with warfarin.
• 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 Sjogren's syndrome
• Prone to other autoimmune conditions such as thyroiditis. They also have a higher incidence of drug allergy and an increased risk of infection.

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 NSAIDs (NSAIDs 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-doseprednisolone is reserved for life-threatening 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 steroids⁶ or high dose monthly or quarterly intravenous pulse cyclophosphamide but recent studies have shown that short courses of low dose pulse cyclophosphamide followed by azathioprine is as effective and less toxic.²
    • Cyclophosphamide appears to be more effective in the treatment of neuropsychiatric involvement in SLE compared with methylprednisolone.⁷
  • Azathioprine is used as 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 anti-cardiolipin 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 retardation 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 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 is 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.

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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. Johnson AE, Gordon C, Hobbs FD, et al; Undiagnosed systemic lupus erythematosus in the community. Lancet. 1996 Feb 10;347(8998):367-9. [abstract]
4. 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]
5. American College of Rheumatology; Guidelines for referral and management of adults with systemic lupus erythematosus. 1999.
6. Flanc RS, Roberts MA, Strippoli GF, et al; Treatment for lupus nephritis. Cochrane Database Syst Rev. 2004;(1):CD002922. [abstract]
7. 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]