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HeikkiJulkunen

Systemic Lupus Erythematosus (Sle)

Essentials

  • Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects primarily women and is characterized by clinical diversity and a number of immunological abnormalities, notably the development of autoantibodies targeting the structures of the cell nucleus.
  • The prognosis of SLE has improved substantially during the recent decades as a result of active early diagnosis and intensified treatment of the underlying disease and its complications.
  • A patient with a mild or moderately severe SLE may have fever, fatigue, arthralgia and arthritis, myalgia, skin rashes, pleuritis, pericarditis or slight changes in the blood picture, which are treated with hydroxychloroquine, NSAIDs, glucocorticoids and methotrexate.
  • A severe form of the disease is characterized by glomerulonephritis, complications of the central nervous system, heart and lungs, severe changes in the blood picture and vasculitis of large vessels. In addition to high doses of glucocorticoids at the early stage, pharmacological treatment comprises hydroxychloroquine, azathioprine, cyclosporin, mycophenolate and cyclophosphamide.
  • Long-term use of glucocorticoids should be avoided or the dose should be as low as possible (dose of prednisone 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 disease itself, it is also essential to actively treat the associated diseases that negatively affect 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 estimated to be about 44 (ranging from 16 to 109) per 100 000 individuals and in women about 79 (29-196) per 100 000) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9933169/.
    • There is substantial regional variation, as well as variation between sex and age groups.
    • Epidemiological data are lacking for almost 80% of countries.
    • The number of patients with latent or incomplete disease is not known exactly.
  • 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 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 (incomplete)
    • mild
    • moderately severe
    • 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. Initial findings may also include changes in blood count (anaemia, leukopenia and thrombocytopenia) and nephritis (proteinuria and haematuria).
  • Joint and muscle symptoms
    • Arthralgia and joint swelling are present in almost all patients. Joint deformities are rare.
    • Myalgia is common, but myositis is rare.
  • Skin and mucosal symptoms
    • Common skin changes include malar rash (also called butterfly rash; picture ), photosensitivity, discoid lupus erythematosus (picture ) and alopecia (picture ). Less common findings are small vessel vasculitis (picture ) and subacute cutaneous lupus (the lesions are either annular or papular; picture ), leg ulcers and other complex rashes.
    • Mucous membrane ulcers are seen in about 20% of patients during the acute phase of the disease (picture ).
    • A mild form of Raynaud's phenomenon Raynaud's Phenomenon (RP) or White Finger Disease.
  • Kidney, lung and heart symptoms
    • 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 Pleural Effusions and Thoracentesis. Acute pneumonitis, diffuse alveolar haemorrhage and chronic interstitial lung disease are rare.
    • Pericarditis Pericarditis is somewhat less common than pleuritis. Other cardiac complications include endocarditis (Libman-Sacks), myocarditis and coronary heart disease Chronic Coronary Syndrome (Coronary Heart Disease). Hypertension is common particularly in nephritis.
  • Neurological symptoms
    • The most common neurological symptom is headache.
    • The risk of cerebral thrombosis and TIA Transient Ischaemic Attack (TIA) increases, particularly at a later age. In younger patients, such events are often associated with antiphospholipid antibodies.
    • The patient may have epileptic seizures which are either generalised or focal Diagnosis of Epilepsy: Definitions and Workup.
    • Inflammation of the cranial or peripheral nerves will develop in about 10% of patients.
  • Psychiatric symptoms
    • The most severe psychiatric symptoms are associated with highly active disease. These may include confusion, impaired level of consciousness, delusions, hallucinations, and distorted reality.
    • Mild disturbances of cognitive function (such as memory, learning, finding words) are common. Disturbances of mood are also common.
  • Lymph nodes may become enlarged, especially during an acute phase of the disease.
  • Gastrointestinal symptoms
  • Pregnancy complications are 2-3 times more common than in healthy women; see below, SLE and pregnancy here.

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 antibodies, anticardiolipin antibodies and anti-beta-2-glycoprotein I antibodies) in 20-40% of patients
  • In nephritis: proteinuria, microscopic haematuria, increased creatinine levels and decreased creatinine clearance

Diagnosis

  • If SLE is suspected within primary care, the suitable 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 the diagnosis and determination of treatment.
  • Sometimes, patients may develop acute disease with severe symptoms, and emergency assessment in specialized care may be needed.
  • Diagnosis is based on characteristic symptoms, clinical findings and the results of laboratory tests. Classification criteria from 2019 are available to aid diagnosis (table T1).

Classification criteria for SLE 2019 6

Background
  1. Patient with antinuclear antibodies (above the laboratory reference range in Hep2 test or equivalent); this is the "entry criterion".
  2. Finding not explained by other disease.
  3. Within each domain, only one criterion will be counted toward the total score. The highest score within the same domain will be counted.
  4. There must be scores from at least one clinical domain.
  5. SLE diagnosis requires ≥ 10 points from the additive criterias below.
DomainCriterionScore
Clinical domains and criteriaConstitutionalFever2 p
HaematologicalLeukopenia3 p
Thrombocytopenia4 p
Autoimmune haemolysis4 p
NeuropsychiatricDelirium2 p
Psychosis3 p
Seizure5 p
MucocutaneousNon-scarring alopecia2 p
Oral ulcers2 p
Subacute cutaneous or discoid lupus4 p
Acute cutaneous lupus6 p
SerosalPleural or pericardial effusion5 p
Acute pericarditis6 p
JointArthritis in ≥ 2 joints OR
Tenderness of ≥ 2 joints and morning stiffness of ≥ 30 min		6 p
RenalProteinuria > 0.5g/24h4 p
Class II or V lupus nephritis8 p
Class III or IV lupus nephritis10 p
Immunology domains and criteriaAntiphospholipid antibodiesAnticardiolipin antibodies OR
Anti-beta-2-glycoprotein-1 antibodies OR
Lupus anticoagulant		2 p
Complement proteinsLow C3 or C43 p
Low C3 and C44 p
Highly specific antibodiesAnti-dsDNA antibodies or anti-Sm (Smith) antibodies6 p

Treatment Treatment of Lupus Nephritis, Drugs for Discoid Lupus Erythematosus, Cyclophosphamide Versus Methylprednisolone for Treating Neuropsychiatric Involvement in Sle, Belimumab for Systemic Lupus Erythematosus

  • The aim of treatment is to eliminate symptoms, suppress an active disease phase, prevent exacerbations, minimise adverse drug 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, injuries, stress, many drugs, such as sulfa products) should be avoided.
  • It is important to differentiate an infection from disease activity.
    • In active SLE, CRP is low or only moderately elevated.
  • Cardiovascular diseases and their risk factors should be actively treated (blood pressure, diabetes, lipid values, smoking, weight control, physical exercise).
  • Prevention and treatment of osteoporosis is important, particularly in elderly patients with multiple comorbidities, in severe SLE and when using glucocorticoids.
  • Antiphospholipid antibodies and pregnancy 1; see below here
  • All patients with SLE should use hydroxychloroquine.
    • It prevents exacerbation phases, vascular occlusions and infections, lowers lipid levels and improves life expectancy.
    • At a maintenance treatment dosage of < 5 mg/kg/day more severe adverse effects (retinopathy, carditis) are very rare.
  • Long-term use of glucocorticoids has a cumulative impact on permanent organ damage.
    • Their use for maintenance treatment should be avoided or the dose should be as low as possible (dose of prednisone preferably < 7.5 mg/day).
  • Biological drugs (belimumab, rituximab) may be considered in special cases, if the conventional drugs are not effective or suitable.

Treatment according to severity of disease

  • In latent or incomplete disease the patient has some clinical symptoms, signs or abnormal laboratory test results suggestive of SLE, but a definite diagnosis cannot be made.
    • Treatment is symptomatic, and only infrequent check-ups are needed.
  • In mild SLE, there may be fever, fatigue, arthralgia and joint swelling, myalgia, rashes and changes in the blood picture.
    • The primary medication is hydroxychloroquine monotherapy (at doses of 5-7 mg/kg/day).
    • NSAIDs can be used for symptomatic treatment.
  • In moderately severe SLE, the patient may have high fever, active arthritis, pleuritis, pericarditis and difficult skin symptoms.
    • In addition to hydroxychloroquine, a glucocorticoid needs to be given in most cases, at least for the initial symptoms.
    • Methotrexate can be used for the treatment of skin and joint symptoms, in particular (at doses of 10-25 mg per week p.o. or s.c.).
  • Patients with severe SLE may have nephritis, pneumonitis, carditis, CNS symptoms, severe changes in the blood picture and large vessel vasculitis.
    • In the beginning of treatment, high glucocorticoid doses are needed, combined immediately or later with strong immunosuppressive medication.
  • In inactive SLE the patient shows no symptoms, signs or laboratory values suggestive of active disease and uses no medication (in 15-20% of diagnosed cases the disease becomes inactive).

Treatment of organ-specific manifestations

  • Medication for nephritis should be chosen depending on how active and chronic the inflammation is based on the biopsy specimen and on the patient's overall situation.
  • Severe pulmonary manifestations of SLE include acute or chronic pneumonitis, pulmonary haemorrhage, and increased pulmonary artery pressure.
  • Severe CNS manifestations
    • These require treatment with high doses of glucocorticoids and with cytostatic agents.
    • Drugs preventing seizures and vascular occlusion should be used as necessary, in some cases also psychotropic drugs for symptomatic treatment.
  • For myocarditis and endocarditis (Libman-Sacks), treatment of underlying disease activity
    • Valvular disease should be treated symptomatically.
  • Severe blood count changes (haemolytic anaemia and severe thrombocytopenia)
  • Large vessel vasculitis
    • A rare complication of SLE
    • Requires very active immunosuppressive medication.

Follow-up

  • Treatment and follow-up of active or severe disease are carried out in specialized care, usually at the outpatient clinic for rheumatology, but also at the outpatient nephrology clinic. Cooperation between several specialties (such as respiratory diseases, dermatology, neurology) may be required during the course of the disease.
  • 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 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 at-risk patients, fasting blood glucose or haemoglobin A1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, bone density measurements, 25-OH vitamin D should be tested less frequently.

Antiphospholipid antibody syndrome

  • Antibodies against phospholipids on the cell membrane increase the risk of venous and arterial thrombosis and pregnancy-related complications.
  • The prevalence of antiphospholipid antibodies in the general population is 1-5% but only a small share of these develop the antiphospholipid antibody syndrome (APS).
  • The diagnostic criteria of APS include at least one clinical finding and one out of three laboratory test values listed below.
    • Clinical findings
      • Arterial or venous thrombosis (excluding superficial venous thrombosis)
      • At least 3 early miscarriages (< 10 weeks)
      • Unexplained foetal death (> 10 weeks)
      • Preterm delivery (< 34 weeks) associated with pre-eclampsia or placental insufficiency
    • 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: a patient positive for lupus anticoagulant, repeatedly high antibody levels measured with several methods (so-called triple positivity), risk factors that increase general predisposition to thrombosis (overweight, smoking, hyperlipidaemia) and other diseases (diabetes, infections, hypertension, fatty liver, SLE, inflammatory bowel diseases)
  • In addition to using antithrombotic medication, it is important to assess and treat risk factors increasing the patient's general susceptibility to thrombosis.
  • 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, as considered necessary, with aspirin (100 mg once daily)
    • At the acute phase, thrombolytic therapy, as deemed necessary, and low molecular weight heparin (LMWH). Later warfarin (INR 2-3) with aspirin or clopidogrel, and minimization of further risk factors.
    • Permanent anticoagulant therapy is recommended for high risk patients after arterial thrombosis.
  • Treatment of venous thrombosis
    • Initially LMWH, later warfarin (INR 2.0-3.0)..
    • Permanent treatment is needed in most cases, at least if the thrombosis occurred without a predisposing factor and the risk of recurrence is estimated to be high (high risk patient). Temporary treatment can be considered if a transient factor (such as immobilization, healed cancer) contributed to the development of venous thrombosis.
    • Prophylactic therapy with LMWH in situations that predispose to venous thrombosis
  • If repeated tests detect only low levels of anti-beta-2-glycoprotein I antibodies or of anticardiolipin antibodies, or if antiphospholipid antibodies are detected only once, a thrombosis should be treated as in the general population.
  • Hydroxychloroquine for all patients with SLE.
  • Not enough experience is available regarding the use of direct oral anticoagulants (DOACs).
  • For the treatment of obstetric complications, see below, SLE and pregnancy.

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
  • Patients planning pregnancy should be referred to the care of a rheumatologist/obstetrician.
  • 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%.
  • Use of hydroxychloroquine throughout pregnancy and breastfeeding is recommended. The drug prevents exacerbations of SLE and may reduce the incidence of premature labour and low infant birth weight, 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
    • Primary prevention is normally not used because only some of the patients with antiphospholipid antibodies develop pregnancy complications. Aspirin (100 mg once daily) may be considered in high risk patients (such as triple positive patients or those with SLE nephritis) before the first pregnancy already.
    • Patients with antiphospholipid antibody syndrome and a history of pregnancy complications should be given aspirin (100 mg once daily) before pregnancy and LMWH in prophylactic or increased prophylactic doses when pregnancy is confirmed.
    • Thrombosis in patient history: aspirin (100 mg once daily) before pregnancy + LMWH with therapeutic dosage when pregnancy is detected
    • After pregnancy LMWH with prophylactic or therapeutic dosage 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

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