Next Lesson - Immunological Therapies
Core
Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that can manifest in multiple different ways depending on the organs affected. In SLE, autoantibodies (antibodies that attack the body's own tissues) that target a variety of autoantigens (the body's own molecules) are produced, forming immune complexes (clumps of antibody stuck to antigen) that deposit in different areas of the body. This results in inflammation and damage to the tissues containing these autoantigens.
The incidence of SLE (the number of new diagnoses) is about 400,000 people each year worldwide, or about 5 per 100,000 people per year. The prevalence (the number of people living with SLE at any given time) is about 3.41 million people around the world, or about 44 per 100,000 people (source). In the UK, nearly 1 in 1,000 people have SLE (source).
Women are more likely to have SLE than men, with women making up approximately 3 million of those currently diagnosed with SLE (about 3.04 million women and 0.36 million men). This shows that SLE affects women much more often than men, at a ratio of about 8:1.
SLE is thought to have a strong genetic component, as a family history of the disease among first-degree relatives (parents, siblings and children) or second-degree relatives (grandparents, aunts and uncles) is a significant risk factor for developing it.
SLE can present in many ways and can affect many body systems, so a thorough examination is important in a patient with suspected SLE. A systematic approach helps, such as the 'glove and sweater' approach. This begins with an examination of the hands, arms, trunk, chest, and face.
In the hands, it is important to look for Raynaud’s phenomenon (a condition affecting the small blood vessels in the hands, particularly when exposed to cold), synovitis (inflammation of the joint lining) and skin rash. Further along the arms, patients can present with proximal muscle weakness (weakness of the muscles nearest the trunk, such as the upper arms, due to myositis, which is inflammation of the muscle, or to steroid treatment, which can damage muscle), rashes or painful, sometimes swollen, joints. In the trunk, SLE can present with truncal rash or signs of pericarditis (inflammation of the sac around the heart) or pleuritic rub (a scratchy sound from inflamed linings of the lung, heard through a stethoscope) upon auscultation. Finally, in the face, SLE can cause alopecia (hair loss), facial rashes (malar, the butterfly rash across the cheeks, or discoid, coin-shaped scaly patches), and mouth ulcers.
A serious complication of SLE is lupus nephritis (inflammation of the kidneys caused by SLE), which develops in about one in three people with SLE in the UK. It occurs when the immune complexes formed from the SLE autoantibodies develop in the kidneys and damage them. It is often silent and is picked up when a urine test shows protein (proteinuria) or blood (haematuria), or when the blood pressure, urea or creatinine is raised. Some people have a nephritic picture (signs of inflamed kidneys, such as hypertension and renal impairment). Significant proteinuria can lead to oedema and foamy urine. Lupus nephritis is treated with immunosuppressive drugs (drugs that dampen the immune system) alongside glucocorticoids (steroids), but the damage may be irreversible and the presence of lupus nephritis is associated with a worse prognosis. In one UK cohort, about one in five people with lupus nephritis developed end-stage renal disease (kidney failure, needing dialysis, a machine that filters the blood) within 10 years.
Routine investigations to take when there is suspicion of SLE are urinalysis (a urine dipstick test for protein and blood, to look for kidney involvement), full blood count, urea & electrolytes, liver function, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). CRP and ESR are blood markers of inflammation. In SLE the ESR is raised but the CRP may be normal unless there is infection or serositis (inflammation of the lining of the lungs or heart). These tests also check for contraindications to treatment and for levels of systemic inflammation.
Specific blood tests related to SLE include the following (source):
Anti-nuclear Antibodies (ANA) - it is the most sensitive test for SLE, which makes it a good screening test rather than a diagnostic one, as it is present in about 95% of patients with SLE. However, it can also be present in patients with other connective tissue disorders. This means that ANA is sensitive (a negative ANA makes SLE unlikely) but not specific, as a positive ANA can occur in many other conditions and even in healthy individuals.
Anti-dsDNA Antibodies (anti-dsDNA, antibodies against double-stranded DNA) - positive anti-dsDNA antibodies are highly predictive of SLE in patients with symptoms.
Anti-Sm (Smith) antibodies are relatively specific for SLE but are absent in many affected patients, so a negative result does not exclude it. Do not confuse them with anti-smooth-muscle antibodies, which are found in autoimmune hepatitis (inflammation of the liver caused by the immune system) and are not a specific SLE marker.
Anti-Ro and La Antibodies (also called anti-SSA and anti-SSB) - these are not specific for SLE as they are found in other autoimmune rheumatic diseases (diseases of the joints and connective tissue) such as Sjogren’s syndrome (dry eyes and dry mouth), rheumatoid arthritis, or systemic sclerosis (tightening and hardening of the skin). They matter in pregnancy: women with anti-Ro and anti-La antibodies need fetal screening for congenital complete heart block (a fault in the electrical signal between the upper and lower chambers of the baby's heart).
Complement Factors - complement is a group of blood proteins that help antibodies to destroy their targets. C3 and C4 complement factors tend to be low in patients with SLE, because they are used up when immune complexes form.
Antiphospholipid Antibodies - anti-cardiolipin, lupus anticoagulant and anti-beta 2 glycoprotein: these should be tested in all patients with suspected SLE as they are used as indicators for increased risk of clotting complications such as strokes, transient ischaemic attack (TIA, a short-lived stroke-like episode), clots in the veins (deep vein thrombosis and pulmonary embolism), or miscarriage. Despite its name, lupus anticoagulant increases the risk of clots. A positive result is confirmed by repeating the test at least 12 weeks later. In one recent cohort of people with newly diagnosed SLE, antibody levels did not correlate with disease activity scores. Finding these antibodies can still allow prevention of the above complications with treatment.
Most patients will have a positive ANA result, but this on its own is not enough to diagnose SLE. Usually, a combination of symptoms consistent with SLE and specific antibody or complement results is used to make an accurate diagnosis. Inflammatory markers such as ESR and CRP are not specific to SLE, so they cannot make the diagnosis on their own. Some of these values can help determine the severity of the disease or are related to specific subtypes of the diseases affecting specific organs more than others.
SOAP BRAIN MD is a historical mnemonic for the 11 items in the 1997 ACR classification criteria, which require at least 4 items. It is not a mnemonic for the newer weighted criteria and does not establish a clinical diagnosis. The 2019 EULAR/ACR classification criteria (from EULAR, the European Alliance of Associations for Rheumatology, formerly the European League Against Rheumatism, and the American College of Rheumatology, ACR) require ANA positivity at least once (a titre, meaning the antibody is still detected when the blood is diluted to 1:80 or more, on HEp-2 cells, a laboratory cell line, or an equivalent test), at least one clinical criterion, and ≥10 weighted points. Count a feature only when SLE is the most likely explanation, and count only the highest-weighted item within each domain (a group of related features, such as skin or kidney). Clinical diagnosis remains a judgement about the patient and competing causes. The historical mnemonic stands for the following:
- Serositis (inflammation of the lining of the lungs, pleuritis, or of the heart, pericarditis)
- Oral ulcers
- Arthritis (joint inflammation without bone erosion, in two or more peripheral joints, which are the joints of the limbs; joint pain alone, called arthralgia, does not count)
- Photosensitivity (a skin rash after exposure to sunlight)
- Blood (abnormal results on a full blood count, FBC: haemolytic anaemia, which is anaemia caused by red blood cells being destroyed early; leukopenia, a low white blood cell count; lymphopenia, a low lymphocyte count; or thrombocytopenia, a low platelet count)
- Renal abnormalities (persistent proteinuria, which is protein in the urine, as in lupus nephritis, or cellular casts, which are clumps of cells in the urine)
- ANA (anti-nuclear antibody) positive
- Immunological abnormalities (anti-dsDNA, anti-Sm or antiphospholipid antibodies; low C3 or C4 is part of the newer criteria, not the 1997 list)
- Neurological abnormalities (seizures or psychosis, which is a loss of touch with reality, with delusions or hallucinations)
- Malar Rash - also known as the butterfly rash, this is a red rash across the bridge of the nose and the cheeks
- Discoid Rash - round, coin-shaped lesions that mostly develop on the scalp or face. They are often scaly and red
Image - Malar rash. It is characteristically across the bridge of the nose and the cheeks
Creative commons source by Doktorinternet [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
Management will be tailored to the presentation and systems affected in each patient.
Conservative management involves lifestyle modifications such as the regular use of high-factor sunscreen (at least factor 50) and a hat, to protect the skin from further damage resulting from photosensitivity (a rash or other reaction to sunlight). Stopping smoking is also important, as smoking makes lupus worse.
In terms of pharmacological management, hydroxychloroquine is the disease-modifying anti-rheumatic drug (DMARD) of choice, and is recommended for all people with SLE unless contraindicated (not safe for that person). If it is not enough, an immunosuppressive drug (a drug that dampens the immune system) such as azathioprine, methotrexate or mycophenolate can be added, which also allows the steroid dose to be reduced. DMARDs reduce the disease activity and improve patient outcome. Hydroxychloroquine can damage the retina (the light-sensitive layer at the back of the eye), so the target dose is 5 mg/kg/day and the eyes are checked every year after 5 years of treatment. Mycophenolate, methotrexate and cyclophosphamide can harm an unborn baby, so they must be stopped before pregnancy, and women who could become pregnant need effective contraception. Hydroxychloroquine and azathioprine are compatible with pregnancy. For cutaneous (skin) flare-ups, topical corticosteroids (steroid creams and ointments) can be used. The least potent effective preparation should be chosen, for example hydrocortisone, and potent preparations should generally be avoided on the face and skin folds. The most potent preparations are reserved for stubborn lesions such as chronic discoid lupus. In severe flare-ups, high-dose glucocorticoids (steroids; intravenous methylprednisolone or high-dose prednisolone tablets) are used, usually together with another immunosuppressive drug such as intravenous cyclophosphamide or mycophenolate mofetil, depending on organ involvement. Cyclophosphamide is reserved for life-threatening disease, particularly lupus nephritis. Biologic drugs (medicines made from living cells), such as belimumab or rituximab, may be considered when other drugs have failed or caused side effects.
Everyone with SLE needs regular checks, such as blood tests for anaemia and urine tests for kidney problems, and patients with moderate to severe forms of the disease should be monitored regularly at a specialist clinic. Finally, SLE is a chronic disease and can affect patients psychologically. This should be explored in a holistic manner (looking at the whole person) and support provided when necessary.
Edited by: Dr. Maddie Swannack
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
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