Medicine – Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune connective tissue disease characterised by the production of numerous autoantibodies and the formation of immune complexes. These immune abnormalities can produce inflammation and tissue damage in almost any organ system. The clinical presentation is therefore highly variable, ranging from relatively mild skin and joint manifestations to severe renal, neurological, cardiovascular, or haematological disease. SLE typically follows a course of flares and remissions, with periods of increased disease activity alternating with periods of relative stability.

American College of Rheumatology Revised Criteria for SLE

The 1982 revised American College of Rheumatology (ACR) criteria were historically used to classify SLE. According to these criteria, the presence of four or more of eleven criteria, occurring either simultaneously or at different times, strongly supported classification as SLE. These criteria have subsequently been replaced by newer classification systems, but the original ACR criteria remain useful for understanding the major manifestations of the disease.

1. Malar Rash

The malar or butterfly rash is an erythematous eruption occurring over the cheeks and bridge of the nose. It typically follows the shape of a butterfly and often spares the nasolabial folds. Exposure to sunlight may trigger or worsen the rash because photosensitivity is common in SLE.

2. Discoid Rash

A discoid rash consists of raised, well-defined erythematous plaques with adherent scaling. As the lesions heal, they may leave scarring, pigmentary changes, and areas of skin atrophy. When lesions involve the scalp, permanent scarring alopecia may occur.

3. Photosensitivity

Photosensitivity refers to an abnormal skin reaction following exposure to ultraviolet radiation. Sunlight may provoke or worsen lupus rashes and can sometimes contribute to a more general disease flare. Patients are therefore usually advised to minimise excessive ultraviolet exposure and use appropriate sun protection.

4. Oral Ulcers

Patients may develop recurrent oral or nasopharyngeal ulcers, which are often painless. Ulcers may occur on the palate, buccal mucosa, or other mucosal surfaces and can appear during periods of active disease.

5. Arthritis

Arthritis is one of the most common manifestations of SLE. It is usually a non-erosive inflammatory arthritis affecting two or more peripheral joints. Patients commonly experience joint pain, swelling, tenderness, and morning stiffness, particularly involving the small joints of the hands, wrists, and knees.

6. Serositis

Inflammation of serosal membranes may produce pleuritis or pericarditis. Pleuritis commonly causes sharp chest pain that becomes worse with deep inspiration, while pericarditis may produce central or positional chest pain. Pleural or pericardial effusions may also develop.

7. Renal Disease

Renal involvement is an important cause of morbidity in SLE. Under the older ACR criteria, renal disease was demonstrated by persistent proteinuria greater than 0.5 g per day or the presence of cellular casts. Lupus nephritis can vary considerably in severity, ranging from mild urinary abnormalities to rapidly progressive renal dysfunction.

8. Neurological Disorder

Neurological involvement under the traditional criteria included seizures or psychosis when these could not be explained by medications, metabolic abnormalities, or another identifiable cause. SLE can also produce many other neurological and psychiatric manifestations.

9. Haematological Disorder

Several blood abnormalities may occur as a consequence of autoimmune destruction or bone marrow effects. These include haemolytic anaemia, leukopenia, lymphopenia, and thrombocytopenia. The abnormalities may occur individually or in combination and can fluctuate with disease activity.

10. Immunological Disorder

The older ACR immunological criterion included characteristic autoimmune laboratory abnormalities such as anti-double-stranded DNA (anti-dsDNA) antibodies, anti-Smith (anti-Sm) antibodies, and antiphospholipid antibodies. Historically, LE cells and a false-positive serological test for syphilis, such as VDRL, were also included.

11. Antinuclear Antibody

A positive antinuclear antibody (ANA) test is highly sensitive for SLE and is present in the great majority of patients. However, ANA is not specific for lupus and may occur in several other autoimmune diseases and even in some healthy individuals.

Clinical Features of SLE

1. Mucocutaneous Manifestations

Mucocutaneous abnormalities are very common, traditionally reported in approximately 81% of patients. Characteristic skin manifestations include malar, discoid, and photosensitive rashes. Alopecia may occur and can be diffuse or associated with discoid lesions.

Patients may also develop oral, nasal, or genital ulcers. Vascular manifestations include Raynaud’s phenomenon, which has historically been reported in approximately half of patients, as well as livedo reticularis and cutaneous vasculitis. Features of Sjögren’s syndrome, particularly dry eyes and dry mouth, may coexist in some patients.

2. Musculoskeletal Manifestations

Musculoskeletal symptoms are among the most frequent manifestations of SLE and occur in the majority of patients. Arthritis is typically non-erosive and may be migratory. Persistent ligament and tendon laxity can occasionally produce reversible joint deformities known as Jaccoud arthropathy, despite the absence of the typical erosions seen in rheumatoid arthritis.

Patients may also experience myalgia, while inflammatory myositis can occasionally cause objective muscle weakness and elevated muscle enzymes. Joint and muscle symptoms can contribute substantially to pain and functional impairment even when other organs are unaffected.

3. Renal Manifestations

Renal involvement, particularly lupus nephritis, is one of the most clinically significant complications of SLE. Immune-complex deposition within the glomeruli can produce various patterns of glomerulonephritis, resulting in haematuria, proteinuria, cellular casts, and impaired renal function.

More severe disease may produce nephrotic syndrome and hypertension. Progressive renal injury can eventually result in chronic kidney disease and, in a minority of patients, end-stage renal failure. Early recognition and appropriate treatment of lupus nephritis are therefore essential.

4. Respiratory Manifestations

Pulmonary involvement may include pleurisy, often accompanied by pleural effusion. Patients can also develop inflammatory lung disease such as pneumonitis, although infection must always be considered in an immunosuppressed patient with new respiratory symptoms.

Other complications include pulmonary hypertension and the uncommon shrinking lung syndrome, which is characterised by unexplained reduction in lung volumes and respiratory symptoms without extensive pulmonary fibrosis.

5. Cardiovascular Manifestations

Pericarditis is one of the most frequent cardiac manifestations of SLE. Inflammation may also involve the myocardium, resulting in myocarditis or cardiomyopathy, which can impair cardiac function.

Another characteristic cardiac abnormality is Libman–Sacks endocarditis, a form of sterile non-bacterial endocarditis involving the heart valves. Patients with SLE also have an increased long-term risk of cardiovascular disease, including accelerated atherosclerosis.

6. Central and Peripheral Nervous System Manifestations

SLE can affect both the central and peripheral nervous systems. Neurological manifestations may include headaches or migraine, seizures, chorea, and psychiatric disturbances such as psychosis. The mechanisms are varied and may involve autoantibodies, inflammation, vascular injury, or thrombosis.

Cerebrovascular events such as stroke may occur, particularly in patients with associated antiphospholipid antibodies. Peripheral nervous system involvement may produce disorders such as mononeuritis multiplex, in which multiple individual peripheral nerves become affected.

7. Haematological Manifestations

Haematological abnormalities are common and include leukopenia, neutropenia, lymphopenia, and thrombocytopenia. Autoimmune haemolytic anaemia may also develop because antibodies are directed against circulating red blood cells.

Some patients develop lymphadenopathy or splenomegaly, particularly during active systemic disease. SLE is also strongly associated with antiphospholipid antibodies and antiphospholipid syndrome, which can cause recurrent arterial or venous thrombosis and pregnancy complications.

8. Gastrointestinal and Hepatic Manifestations

Gastrointestinal involvement may result from inflammation or vascular disease. Mesenteric vasculitis can compromise intestinal blood flow and produce abdominal pain, gastrointestinal bleeding, or more severe bowel complications.

Liver abnormalities may also occur. Although older descriptions include chronic active hepatitis, abnormal liver function in a patient with SLE requires consideration of several possibilities, including medication toxicity, infection, fatty liver disease, vascular complications, and overlapping autoimmune liver disease.

Typical Investigation Results in SLE

1. Anaemia

Patients with active SLE commonly develop normocytic, normochromic anaemia, particularly as a manifestation of chronic inflammation. Other causes include renal impairment, iron deficiency, medication effects, and autoimmune haemolysis.

2. Leukopenia and Lymphopenia

Leukopenia and lymphopenia are common haematological abnormalities and may reflect active autoimmune disease. Their severity can also be influenced by immunosuppressive treatment or infection.

3. Raised ESR

The erythrocyte sedimentation rate (ESR) is frequently elevated during active SLE because of increased circulating inflammatory and immunological proteins. ESR is nonspecific but can contribute to the assessment of inflammatory activity.

4. C-Reactive Protein

An interesting laboratory pattern in SLE is that the C-reactive protein (CRP) may remain relatively normal despite active disease. A substantial CRP elevation should raise particular concern for infection, although CRP can also increase with significant serositis or synovitis.

5. Positive ANA

Approximately 95% or more of patients with SLE have a positive ANA, making it a highly sensitive screening marker. However, because ANA positivity occurs in numerous other conditions, it cannot establish the diagnosis by itself.

6. Anti-dsDNA Antibodies

Anti-dsDNA antibodies are considerably more specific for SLE than ANA. Their concentrations may fluctuate with disease activity in some patients and are particularly useful when evaluating lupus nephritis.

7. Raised Immunoglobulins

Patients may demonstrate polyclonal hypergammaglobulinaemia, reflecting chronic activation of B lymphocytes and increased antibody production.

8. Low Complement Levels

During active immune-complex disease, complement components are consumed, producing reduced serum C3 and C4 concentrations. Falling complement levels, particularly when accompanied by rising anti-dsDNA titres, may indicate increasing disease activity in some patients.

9. Antiphospholipid Antibodies

Antiphospholipid antibodies occur in a substantial proportion of patients with SLE, historically quoted at around 30–40%. Persistent clinically significant antibodies may increase the risk of arterial or venous thrombosis and adverse pregnancy outcomes.

10. Coombs-Positive Haemolytic Anaemia

Some patients develop autoimmune haemolytic anaemia, in which antibodies bind to red blood cells and accelerate their destruction. The direct antiglobulin (Coombs) test may consequently be positive.

Causes of a Positive ANA

A positive ANA is not unique to SLE. It is frequently found in SLE, but may also occur in Sjögren’s syndrome, polymyositis or dermatomyositis, rheumatoid arthritis, systemic sclerosis, mixed connective tissue disease, and autoimmune hepatitis. ANA positivity can also occur in healthy individuals, particularly at low titres, so the result must always be interpreted in the appropriate clinical context.

Treatment of SLE

1. Sun Protection

Because ultraviolet radiation can provoke cutaneous lesions and potentially trigger disease activity, patients with photosensitivity should use broad-spectrum sunscreen, protective clothing, and appropriate avoidance of excessive sunlight.

2. NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) may provide symptomatic relief for selected patients with musculoskeletal pain or mild inflammatory manifestations. Their use must take into account gastrointestinal, cardiovascular, and renal risks, particularly when lupus nephritis is present.

3. Hydroxychloroquine

Hydroxychloroquine is a central treatment for most patients with SLE unless contraindicated. It is particularly helpful for skin manifestations, arthritis, and constitutional symptoms and also reduces the risk of disease flares. Long-term treatment requires appropriate ophthalmological monitoring because of the risk of retinal toxicity.

4. Corticosteroids

Corticosteroids are used to rapidly suppress inflammation during significant disease flares. The required dose depends on the severity and organs involved. Severe organ-threatening disease may require high-dose or intravenous corticosteroids, whereas lower doses may be used for shorter periods when necessary. Modern management aims to minimise prolonged corticosteroid exposure because of its substantial long-term adverse effects.

5. Immunosuppressive and Immunomodulatory Therapy

More severe disease may require additional immunosuppressive or immunomodulatory drugs. Depending on the manifestation, these may include azathioprine, methotrexate, mycophenolate, cyclophosphamide, or biologic therapies. Severe lupus nephritis and other organ-threatening manifestations generally require more intensive treatment than uncomplicated skin or joint disease.

6. Plasma Exchange

Plasma exchange is not routine treatment for SLE, but it may occasionally be considered in selected severe complications or overlapping conditions where rapid removal of pathogenic circulating factors is thought to be beneficial.

7. Anticoagulation

Patients with SLE who develop antiphospholipid syndrome with recurrent or significant thrombosis may require long-term anticoagulant therapy. Management depends on whether thrombosis is venous or arterial and the patient’s individual risk of recurrence and bleeding.

8. Treatment of Raynaud’s Phenomenon

Raynaud’s phenomenon can initially be managed by maintaining warmth and avoiding smoking and other vasoconstrictive factors. Persistent symptoms may require vasodilator therapy, particularly calcium channel blockers. More severe digital ischaemia may require additional vasodilator treatments such as prostacyclin analogues.

9. Antihypertensive Treatment

Hypertension should be identified and treated carefully, particularly in patients with renal involvement. Effective blood-pressure control helps reduce cardiovascular risk and may slow further renal damage.

Important Note on Classification

The 1982 ACR criteria described above are historical classification criteria rather than the current standard. Modern practice commonly uses the 2019 EULAR/ACR classification criteria, in which a positive ANA is an entry requirement followed by weighted clinical and immunological criteria. Nevertheless, the older eleven-point ACR framework remains useful for learning the classic multisystem manifestations of SLE.