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HeikkiJulkunen

Systemic Lupus Erythematosus (Sle)

Essentials

  • Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that primarily affects women and is characterized by clinical diversity and a complex set of immunological abnormalities, notably the development of autoantibodies targeted against the structures of the cell nucleus.
  • The prognosis of SLE has clearly improved during the recent decades as a result of active early diagnostics and improved treatment of the underlying disease and its complications.
  • A patient with a mild SLE most commonly presents with fatigue, joint and muscle symptoms, skin rashes, pleuritis and mild changes in the blood picture, and is treated with NSAIDs, prednisone, hydroxychloroquine and methotrexate.
  • A severe form of the disease is characterized by glomerulonephritis, complications of the central nervous system, heart and lungs, as well as severe changes in the blood picture. In addition to prednisone and hydroxychloroquine, pharmacological treatment comprises azathioprine, cyclosporin, mycophenolate, cyclophosphamide, and in special cases biological drugs.
  • Long-term use of prednisone should be avoided or the dose should be as small as possible (preferably < 7.5 mg/day).
  • All patients with SLE should use hydroxychloroquine, provided that they tolerate it (dose in long-term use < 5 mg/kg/day).
  • In addition to managing the basic disease, it is also essential to actively treat the associated diseases that negatively affect the prognosis and quality of life, such as infections, osteoporosis, diabetes and cardiovascular diseases, as well as their risk factors.

Epidemiology

  • The prevalence of SLE worldwide is 4-250 per 100 000 individuals. About 90% of the patients are female, and in just under 50% of cases the disease is diagnosed before the age of 30.
  • About 15% develop the disease in childhood, most commonly between the ages of 12 and 14 years.
  • The concordance rate in identical twins is 30-60% and in non-identical twins 2-5%.

Symptoms

  • The clinical presentation is highly variable. The initial symptoms may develop suddenly or slowly, clinical activity may be continuous or may fluctuate or the condition may subside altogether, any single organ may be affected and different organs may be affected by inflammatory processes exhibiting differing activity and severity.
  • Polymorphic symptoms and clinical signs cause diagnostic and therapeutic problems. They may derive from an activation of the underlying primary disease, chronic organ damage, adverse effects of drugs, infections or other illnesses that may or may not be associated with the primary disease.
  • The clinical disease can be classified into latent, mild, severe and inactive.
  • Typical initial symptoms include arthralgia, swelling of joints, myalgia, rashes, pleuritis, pericarditis and general symptoms, such as fever, fatigue and weight loss.
  • Arthralgia and swelling of the joints affect almost all patients. Joint deformities are rare.
  • Myalgia is common, but myositis is rare.
  • Common skin changes include malar rash (also called butterfly rash; picture 1), photosensitivity, discoid lupus erythematosus (picture 2) and alopecia (picture 3). More rare are small vessel vasculitis (picture 4) and subacute cutaneous lupus (the lesions are either annular or papular; picture 5), leg ulcers and other complex rashes.
  • Mucous membrane ulcers are seen in about 20% of patients during the acute phase of the disease (picture 6).
  • A mild form of Raynaud's phenomenon.
  • About 30-50% of patients will develop nephritis at some stage of their disease, the clinical presentation of which varies from mild proteinuria and haematuria to nephrotic syndrome and severe renal failure.
  • About 20-40% of patients develop pleuritis. Acute pneumonitis, diffuse alveolar haemorrhage and chronic interstitial lung disease are rare.
  • Pericarditis is somewhat less common than pleuritis. Other cardiac complications include endocarditis (Libman-Sacks), myocarditis and coronary heart disease. Hypertension is common particularly in nephritis. T-wave changes are usual in the ECG.
  • Neuropsychiatric symptoms affect about 30-40% of patients.
    • The most common neurological symptom is headache. The patient may have epileptic seizures which are either generalised or focal, and inflammation of the cranial or peripheral nerves will develop in about 10% of patients.
    • Psychiatric symptoms, such as confusion, delusions and impaired level of consciousness, are rare. Mild disturbances of cognitive function (memory, learning) are seen particularly during the active phase of the disease. Mood fluctuations are common.
  • Venous thrombosis develops in about 10% of SLE patients, and most of these cases are associated with antiphospholipid antibodies. The risk of cerebral thrombosis and TIA increases, particularly at a later age.
  • Lymph nodes may enlarge, especially during an acute phase of the disease.
  • Abdominal pains, nausea and increased aminotransferase levels are common gastrointestinal signs and symptoms. Ascites, lupoid hepatitis and pancreatitis are rare.
  • Pregnancy complications are 2-3 times more common than in healthy women; see below, SLE and pregnancy.

Laboratory findings

  • ESR is moderately elevated, but CRP level is often normal
  • Mild to moderate anaemia of chronic disease. Haemolytic anaemia is rare
  • Leucocytopenia (lymphocytopenia in particular) and mild thrombocytopenia
  • An immunofluorescent assay for antinuclear antibodies is positive in over 95% of patients.
  • About 50-60% of patients have antibodies to native DNA.
  • A more detailed analysis of antinuclear antibodies (extractable nuclear antigens) may reveal anti-Sm (10%), anti-SS-A (30%) and anti-RNP (30%) antibodies.
  • Polyclonal hypergammaglobulinaemia
  • Complement deficiency (C3 and C4) in about 60% of patients
  • Antiphospholipid antibodies (lupus anticoagulant antibody, anticardiolipin antibody and anti-beta-2-glycoprotein I antibody) in 20-40% of patients
  • In nephritis: proteinuria, microscopic haematuria, increased creatinine levels and decreased creatinine clearance
  • Creatine kinase (myositis), TSH, free T4 (hypothyroidism), 25-OH vitamin D (prevention of osteoporosis)

Diagnosis

  • If SLE is suspected within primary care, the applicable initial investigations include ESR, CRP, basic blood count with platelet count, anti-nuclear antibodies and chemical urinalysis.
  • A patient with suspected SLE should be referred to specialized care for the confirmation of diagnosis and determination of treatment.
  • Diagnosis is based on characteristic symptoms, clinical findings and the results of laboratory tests. Classification criteria from 2012 are available to aid diagnosis (table T1).
  • In practice, the diagnosis of SLE cannot be made in the absence of autoantibodies.

Classification criteria for SLE 2012 6

Criteria
The patient is classified as having SLE if
  • 4 criteria out of the 17 are fulfilled and at least one the 4 criteria is clinical and one immunological or
  • the patient has biopsy-proven nephritis compatible with SLE and with ANA or anti-dsDNA antibodies.

Source: Petri M, Orbai AM, Alarcón GS ym. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64(8):2677-86.
Clinical criteria
1. Acute cutaneous lupus
2. Chronic cutaneous lupus
3. Alopecia (nonscarring)
4. Oral or nasal ulcers
5. Synovitis involving two or more joints
6. Serositis (pleuritis or pericarditis)
7. Nephritis (proteinuria > 500 mg/24 h or red blood cell casts)
8. Neurological findings (seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, or acute confusional state)
9. Haemolytic anaemia
10. Leucopenia (< 4 × 10 9 /l) at least once or lymphopenia (< 1 × 109 /l) at least once
11. Thrombocytopenia (< 100 × 109 /l) at least once
Immunological criteria
12. Anti-dsDNA antibodies
13. Anti-Sm antibodies
14. Antiphospholipid antibodies (false-positive RPR, lupus anticoagulant, anticardiolipin [medium or high titer] or anti-beta-2-glycoprotein I)
15.Low complement (C3, C4 or CH50)
16. Direct Coombs test in the absence of hemolytic anemia
17. ANA

Treatment Hydroxychloroquine in the Treatment of Systemic Lupus Erythematosus, Dehydroepiandrosterone (Dhea) for Systemic Lupus Erythematosus (Sle), Treatment of Lupus Nephritis, Drugs for Discoid Lupus Erythematosus, Cyclophosphamide Versus Methylprednisolone for Treating Neuropsychiatric Involvement in Sle, Belimumab for Systemic Lupus Erythematosus

  • Treatment aims to eliminate symptoms, control an active disease phase, prevent exacerbations, minimise drug adverse effects as well as to improve the quality of life and prognosis.
  • Due to the polymorphic nature of the disease treatment is always individual.
  • External factors that exacerbate SLE (e.g. sunlight) should be avoided.
  • In latent or incomplete disease the patient has some clinical symptoms, signs or abnormal laboratory test results suggestive of SLE, but definite diagnosis cannot be made. Treatment is symptomatic, and only infrequent check-ups are needed.
  • Mild SLE is characterised by joint symptoms, rashes, pleuritis/pericarditis, general symptoms and minor changes in the blood picture.
  • In pleuritis and pericarditis, treatment is started with a higher dose of glucocorticoids (prednisone 20-40 mg/day)
  • Anaemia of chronic disease will be reversed as the underlying condition is managed with drug treatment, and mild blood cell changes do not require medication.
  • Severe SLE is characterised by nephritis, pneumonitis, carditis, major CNS symptoms and changes in the blood picture.
    • The choices for drug therapy include
      • glucocorticoids, high-dose if indicated, the initial dose in severe disease at least 40-60 mg prednisone/day, in some cases mega doses intravenously
      • azathioprine1-2.5 mg/kg/day (mild/moderate SLE, mild nephritis, maintenance therapy, a glucocorticoid-sparing agent)
      • cyclosporine 2-4 mg/kg/day (mild/moderate SLE, cytopenias, membranous glomerulonephritis)
      • mycophenolate 1 500-3 000 mg/day (drug of choice in severe focal or diffuse glomerulonephritis, maintenance therapy, a glucocorticoid-sparing agent)
      • cyclophosphamide 1-2 mg/kg/day or intravenously according to various regimens (severe focal or diffuse glomerulonephritis, other severe and life threatening complications)
  • Hydroxychloroquine for all patients, including those with severe SLE. Prevents exacerbation phases, vascular occlusions and infections, lowers lipid levels and improves life expectancy. As maintenance treatment dosage < 5 mg/kg/day, whereby more severe adverse effects are very rare (retinopathy, carditis).
  • Biological drugs (rituximab, belimumab) may be considered in severe SLE, if the conventional drugs are not effective or suitable.
  • Long-term use of glucocorticoids has a cumulative impact on permanent organ damage (dose recommendation: prednison 0-5 mg/day). Treting exacerbation phases with a short glucocorticoid pulse therapy is more effective and less toxic than increasing the long-term dose.
  • In inactive SLE the patient shows no symptoms, signs or laboratory values suggestive of an active disease and uses no medication (in 15-20% of diagnosed cases the disease becomes inactive).
  • It is important to differentiate an infection from disease activity. In active SLE, CRP is low or only moderately elevated.
  • Treatment of cardiovascular risk factors (blood pressure, diabetes, lipid values, smoking, weight control, physical exercise)
  • Prevention and treatment of osteoporosis, particularly in elderly patients with multiple comorbidities, in severe SLE and when using glucocorticoids
  • Antiphospholipid antibodies: see below here

Follow-up

  • Treatment and follow-up are usually carried out in specialist care.
  • Mild SLE may be monitored and treated in the primary health care
  • Follow-up visits every 3-12 months
    • Key symptoms and a targeted physical examination, home monitoring of blood pressure
    • ESR, CRP, basic blood count with platelet count, chemical urinalysis
    • Patients with known nephritis should also have the following tests: creatinine, estimated glomerular filtration rate (eGFR, calculator Gfr Calculator), 24-hour urine collection for protein or urine albumin/creatinine ratio, anti-DNA (native) antibodies and complement C3 and C4 levels.
  • Laboratory tests should be carried out more frequently in patients receiving immunosuppressive therapy (see Rheumatoid Arthritis for laboratory tests during drug treatment of rheumatoid arthritis).
  • In high risk patients fasting blood glucose or haemoglobin A1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and bone density measurements should be carried out occasionally.

Antiphospholipid antibodies

  • The diagnostic criteria of antiphospholipid antibody syndrome include at least one clinical finding and one out of three laboratory test values listed below.
    • Clinical findings
      • Arterial or venous thrombosis
      • At least 3 early miscarriages (< 10 weeks)
      • Preterm delivery (< 34 weeks) associated with pre-eclampsia or placental insufficiency
      • Inexplicable foetal death (> 10 weeks)
    • Laboratory tests (determined twice at an interval of 3 months)
      • Lupus anticoagulant
      • High/medium level of anti-beta-2-glycoprotein I antibodies
      • High/medium level of anticardiolipin antibodies
  • Primary antiphospholipid antibody syndrome: the patient is otherwise asymptomatic (50% of the patients)
  • Secondary antiphospholipid antibody syndrome: the patient has an underlying disease, usually SLE
  • A high risk patient: general risk factors that increase predisposition to thrombosis (overweight, smoking, hyperlipidaemia) and other diseases (diabetes, infections, hypertension, fatty liver, SLE, inflammatory bowel diseases), positive for lupus anticoagulant, antibody levels repeatedly high measured with several methods (so-called triple positivity)
  • Treatment of arterial thrombosis Antiplatelet and Anticoagulant Agents for Secondary Prevention of Stroke and other Thromboembolic Events in People with Antiphospholipid Syndrome
    • Prophylaxis in a high risk patient, if considered necessary, with aspirin (100-250 mg once daily)
    • Thrombolytic therapy, if deemed necessary. Initially low molecular weight heparin (LMWH) and aspirin or clopidogrel. Later warfarin (INR 2.0-3.0) with or without aspirin, in most cases as a permanent treatment. Used at least when there are other risk factors and antibody levels are repeatedly high measured with several methods.
  • Treatment of venous thrombosis
    • Initially LMWH. Later, heparin or warfarin (INR 2.0-3.0), in most cases permanently already after the first thrombosis. See treatment of arterial thrombosis.
  • If in repeated tests only low levels of anti-beta-2-glycoprotein I antibodies or of anticardiolipin antibodies are detected, or if antiphospholipid antibodies are detected only once, a thrombosis is treated as in the general population.
  • Active management of cardiovascular and other thrombotic risk factors. Statins may reduce also the risk of venous thrombosis. Hydroxychloroquine for all patients with SLE.
  • Not enough experience is available regarding the use of direct oral anticoagulants (DOACs).
  • Prophylactic therapy with heparin in situations that predispose to thrombosis (immobilization)

SLE and pregnancy Prevention of Recurrent Miscarriage for Women with Antiphospholipid Antibody or Lupus Anticoagulant, Oral Contraceptives in Women with Systemic Lupus Erythematosus

  • The risk of complications (miscarriage, preterm delivery, pre eclampsia, low birth weight) is about 2-3 times that of healthy women.
    • Associated with active disease, nephritis and elevated antiphospholipid antibody levels
  • The prognosis for pregnancy is good if SLE has been quiescent for 6 months before conception, the dose of glucocorticoids is less than 10 mg of prednisone, blood pressure is well managed, eGFR is > 60 ml/min, proteinuria is < 1 g/day and antiphospholipid antibodies are negative or low.
  • If the anti-SS-A/SS-B antibodies are elevated, the child's risk of congenital atrioventricular block in the first pregnancy is about 1-2%.
  • Patients planning pregnancy should be referred to the care of a rheumatologist/obstetrician.
  • It is recommended to use hydroxychloroquine throughout the periods of pregnancy and breastfeeding. The drug prevents exacerbations of SLE and may reduce the incidence of premature labours and low birth weight of the infant, complications related to antiphospholipid antibodies and the fetus' risk of atrioventricular heart block.
  • The pregnancy should be monitored at a prenatal clinic in primary care and at a secondary or tertiary level hospital.
  • SLE, antiphospholipid antibodies and pregnancy
    • First pregnancy or earlier at least one normal pregnancy: careful follow-up of pregnancy + aspirin (100 mg/day) before pregnancy, or no medicationat all
    • Recurrent early miscarriages (< 10 weeks) in patient history without thrombosis: aspirin (100 mg/day) before pregnancy + low molecular weight heparin (LMWH) with prophylactic dosage when pregnancy is detected, or no LMWH
    • Foetal death, pre-eclampsia or placental insufficiency in patient history: aspirin (100 mg/day) before pregnancy + LMWH with prophylactic or therapeutic dosage when pregnancy is detected
    • Thrombosis in patient history: aspirin (100 mg/day) before pregnancy + LMWH with therapeutic dosage when pregnancy is detected
    • After pregnancy LMWH with prophylactic or therapeutic dose (with or without aspirin) for a period of at least 6 weeks.
  • Combined oral contraceptives and hormone replacement therapy are contraindicated if the patient has a severe and active disease or antiphospholipid antibodies.

References

  • Petri M, Orbai AM, Alarcón GS et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64(8):2677-86. [PubMed]
  • Bertsias G, Ioannidis JP, Boletis J et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008;67(2):195-205. [PubMed]
  • Espinosa G, Cervera R. Current treatment of antiphospholipid syndrome: lights and shadows. Nat Rev Rheumatol 2015;11(10):586-96. [PubMed]
  • Andreoli L, Bertsias GK, Agmon-Levin N et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017;76(3):476-485. [PubMed]
  • Bertsias GK, Tektonidou M, Amoura Z et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71(11):1771-82. [PubMed]
  • Andreoli L, Crisafulli F, Tincani A. Pregnancy and reproductive aspects of systemic lupus erythematosus. Curr Opin Rheumatol 2017;29(5):473-479. [PubMed]
  • Gordon C, Amissah-Arthur MB, Gayed M ym. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology (Oxford) 2018;57(1):e1-e45. [PubMed]
  • Ugarte A, Danza A, Ruiz-Irastorza G. Glucocorticoids and antimalarials in systemic lupus erythematosus: an update and future directions. Curr Opin Rheumatol 2018;30(5):482-489. [PubMed]

Evidence Summaries ⬆