Systemic lupus erythematosus

What is systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease, involving complex pathogenetic mechanisms that can present at any age. It most commonly presents in women in the reproductive age group although SLE is increasingly recognised after the age of 40 particularly in Europeans.¹

The disease is prone to relapses and remissions, resulting in considerable morbidity due to flares of disease activity and accumulated damage, with an increased risk of premature death mostly due to infection or cardiovascular disease.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.

How common is systemic lupus erythematosus? (epidemiology)¹

• SLE affects nearly 1 in 1,000 of the population in the UK.

• The highest incidence rates are seen in those of African-Caribbean descent, 31.4/100,000/year compared to 6.7/100,000/year for those of white European descent. The mean age at diagnosis is 48.9 years but it is lower in those of African ancestry in the UK and North America.

• There is some evidence of increasing incidence of SLE.²

Risk factors

• Certain human leukocyte antigen DRB1 types are more common in patients with SLE - eg, DR3 and DR2.

• Patients who have a defective C4 complement gene (C4A null allele) also develop a lupus-like illness.

• Sunlight and ultraviolet light have been thought to be causative factors in development of SLE and of flares but this is not supported by the most recent study.³

• Viruses including the Epstein-Barr virus have also been thought to be causative but evidence is weak.²

• Cigarette smoking is a significant risk factor for development of SLE. ²

• Drugs known to cause drug-induced lupus include chlorpromazine, methyldopa, hydralazine, isoniazid, d-penicillamine and minocycline, but this is not a true systemic lupus erythematosus.²

Symptoms of systemic lupus erythematosus (presentation)

• SLE is a remitting and relapsing illness, with a variety of different presentations.⁴⁵

• More active disease is usually seen in patients of Afro-Caribbean heritage or those diagnosed younger.⁵

• More organ damage occurs in men and older patients.⁵

• 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 (keratoconjunctivitis sicca) and dry 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.

• 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:

    Lupus

    

    Doktorinternet, CC BY-SA 4.0, via Wikimedia Commons
    

  • 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:
    

    Discoid

    

    Leonard C. Sperling, M.D., COL, MC, USA, Department of Dermatology, Uniformed Services University, Public domain, via Wikimedia Commons

  • 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.

Classification of systemic lupus erythematosus⁶

The American College of Rheumatology Classification system for SLE suggests that a person may be classified as having SLE 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.

• Photosensitivity.

• 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.⁷

Diagnosing systemic lupus erythematosus (investigations)¹

SLE is a multisystem autoimmune disorder. The diagnosis requires a combination of clinical features and the presence of at least one relevant immunological abnormality. If there is a clinical suspicion of lupus, blood tests including serological markers should be checked.

• 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.

• Serology:

  • Antinuclear antibodies (ANAs) are present in about 95% of SLE patients. If the test is negative, there is a low clinical probability of the patient having SLE. A positive ANA occurs in approximately 5% of the adult population and alone has poor diagnostic value in the absence of clinical features of autoimmune rheumatic disease.

  • The presence of anti-dsDNA antibodies, low complement levels or anti-Smith (Sm) antibodies are highly predictive of a diagnosis of SLE in patients with relevant clinical features. Anti-Ro/La and anti-RNP antibodies are less specific markers of SLE as they are found in other autoimmune rheumatic disorders as well as SLE.

  • Antiphospholipid antibodies should be tested in all lupus patients at baseline, especially in those with an adverse pregnancy history or arterial/venous thrombotic events. Confirmatory tests for antiphospholipid syndrome are positive lupus anticoagulant, anti-cardiolipin antibodies (IgG, IgM) and/or anti-beta-2 glycoprotein-1 (IgG, IgM) on two occasions at least 12 weeks apart.

• 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.

Associated diseases

• APLS.

• 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).⁸

Managing systemic lupus erythematosus

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.

  • Hydroxychloroquine.

  • Cyclophosphamide is reserved for treatment of life-threatening disease, particularly lupus nephritis, vasculitis and cerebral disease.

  • Mycophenolate mofetil:⁹

    • Mycophenolate mofetil may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile.

    • Calcineurin combined with lower-dose mycophenolate mofetil may improve induction of disease remission compared with IV cyclophosphamide.

    • Azathioprine may increase disease relapse as maintenance therapy compared with mycophenolate mofetil.

  • 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.¹⁰

• Other 'biological drugs' that have been used in the treatment of resistant SLE include TNF antagonists, rituximab, abatacept, tocilizumab and eculizumab.¹¹

• 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.

Neuropsychiatric SLE¹²

• 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.¹³

• Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic cardiovascular disease.

British Society for Rheumatology recommendations¹

Management of mild SLE

• Treatments for mild non-organ threatening disease include the disease modifying drugs hydroxychloroquine and methotrexate, and short courses of NSAIDs for symptomatic control. These drugs allow for the avoidance of or dose reduction of corticosteroids.

• Prednisolone at a low dose of up to 7.5 mg/day or less may be required for maintenance therapy. Topical preparations may be used for cutaneous manifestations and intra-articular injections for arthritis.

• High factor UVA and UVB sunscreen are important in the management and prevention of UV radiation-induced skin lesions. Patients must also be advised about sun avoidance and the use of protective clothing.

Management of moderate SLE

• The management of moderate SLE involves higher doses of prednisolone (up to 0.5 mg/kg/day), or the use of intramuscular or intravenous doses of methylprednisolone.

• Immunosuppressive agents are required often to control active disease and are steroid-sparing agents. They can also reduce the risk of long-term damage.

• Methotrexate, azathioprine, mycophenolate mofetil, ciclosporin and other calcineurin inhibitors should be considered in cases of arthritis, cutaneous disease, serositis, vasculitis, or cytopenias if hydroxychloroquine is insufficient.

• For refractory cases, belimumab or rituximab may be considered.

Management of severe SLE

• Patients who present with severe SLE including renal and neuropsychiatric manifestations need thorough investigation to exclude other aetiologies including infection.

• Treatment is dependent on the underlying aetiology (inflammatory and/or thrombotic) and patients should be treated accordingly with immunosuppression and/or anticoagulation.

• Immunosuppressive regimens for severe active SLE involve IV methylprednisolone or high-dose oral prednisolone (up to 1 mg/kg/day) to induce remission either on their own or more often as part of a treatment protocol with another immunosuppressive drug.

• Mycophenolate mofetil or cyclophosphamide are used for most cases of lupus nephritis and for refractory severe non-renal disease.

• Biologic therapies belimumab or rituximab may be considered, on a case-by-case basis, where patients have failed other immunosuppressive drugs due to inefficacy or intolerance.

• Intravenous immunoglobulin and plasmapheresis may be considered in patients with refractory cytopenias, thrombotic thrombocytopenic purpura, rapidly deteriorating acute confusional state and the catastrophic variant of antiphospholipid syndrome.

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, previously the advice was to avoid pregnancy but recent treatment has made pregnancy safer, particularly with a good fetal medicine team involved. Active disease increases the risks of poor outcomes for the mother and baby.¹⁴

  • All patients should stay on hydroxychloroquine during pregnancy and breastfeeding unless contraindicated.

  • There is a higher risk of pre-eclampsia and those at particular risk should start aspirin in the first trimester.

  • Sulfasalazine, and the immunosuppressive agents cyclosporine, azathioprine, and tacrolimus are compatible with pregnancy and safe whilst breastfeeding.

  • Rituximab, belimumab and other biologic agents can continue through conception and are safe whilst breastfeeding.

  • Cyclophosphamide, leflunomide, methotrexate, mycophenolate mofetil, and voclosporin should be stopped prior to pregnancy and avoided in lactating women.

  • Steroids can be used for flares as long as they are given at the lowest possible dose for the shortest possible time.

  • Women with anti-Ro and anti-La antibodies will need fetal screening for the development of congenital complete heart block.

  • Complications include recurrent early loss of pregnancy, pre-eclampsia, intrauterine growth restriction and preterm delivery. Pregnancies in women with SLE are more than twice as likely to end in a pregnancy loss than in women without SLE.

  • 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.

Prognosis¹

Although SLE survival has improved over the last 40 years, people with SLE still die years younger than average in the UK.¹⁵

• The death rate for SLE patients is 1.86% per year.

• The standardised mortality rate for SLE patients is 2.6 times the rate of patients without SLE.

• About one third of SLE patients develop lupus nephritis in the UK. Patients of African ancestry tend to present young with lupus nephritis in the UK, as in the USA and elsewhere, and are at considerable risk of developing end-stage renal disease (ESRD) and of dying prematurely.

• In one UK cohort, ESRD occurred in 20% of lupus nephritis patients within 10 years of diagnosis and the mean age at death in lupus nephritis patients was 40.3 years with an average of 7.5 years between development of lupus nephritis and death.

• The commonest causes of death in the UK are cardiovascular events.