Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune connective tissue disease characterised by multisystem inflammation resulting from the production of autoantibodies and immune complex deposition. SLE predominantly affects women of childbearing age and has a higher prevalence among individuals of African, Hispanic, and Asian descent. It has a staggering 9:1 prevalence in women compared to men (especially women in their reproductive years). Clinically, it is highly variable, with manifestations ranging from mild skin and joint involvement to severe organ damage affecting the kidneys, central nervous system, and cardiovascular system.

Pathophysiology

We are still not entirely sure of the exact cause of SLE. There are certainly multiple components at play in the aetiology of the disease.

Let’s take a look at some of the aetiological factors involved in the disease:

• Genetic factors - familial clusters emphasise a heritable component to the disease. There are associations with HLA class II alleles, particularly HLA-DR2, HLA-DR3 and HLA-B8. Additionally mutations in complement components have been implicated.
• Environmental factors
• Drugs - such as hydralazine, isoniazid, procainamide, minocycline.
• Ultraviolet exposure
• Infections - such as Epstein-Barr virus and parvovirus B19 may trigger SLE through molecular mimicry or immune activation.
• Hormonal factors - oestrogen is suggested to be involved as SLE is much more prevalent in women of reproductive age.
• Immune dysregulation - issues with apoptosis and clearance of apoptotic cells is seen within the disease.

SLE is a type 3 hypersensitivity reaction that has the following pathophysiology:

1. Loss of self-tolerance - the immune system recognises self-antigens as non-self which leads to autoantibody production (for example, against double-stranded DNA or histones which are found within the nucleus of the cell).
2. Immune complex formation - autoantibodies bind to the antigens which then form complexes that circulate in the blood.
3. Deposition of immune complexes - the complexes get deposited in tissues such as the skin, kidneys, joints, blood vessels etc.
4. Complement activation - the deposited immune complexes trigger the complement cascade which results in immune aggregation to the deposition site, inflammation and tissue injury.
5. Defective clearance of apoptotic cells - cells that undergo apoptosis are not effectively cleared, and this perpetuates the immune activation.
6. Immune hyperactivity - overproduction of autoantibodies from B-cells, and overproduction of type I interferons leads to a chronic and heightened inflammatory response that results in tissue damage which affects tissues and organs.

⚠️ Risk factors

• Female sex
• Young-middle age - 15 to 45 years old (women of reproductive age).
• Asian, African and Afro-Caribbean ethnicity
• Drugs - such as hydralazine, isoniazid, procainamide, minocycline, terbinafine, sulfasalzine, phenytoin and carbamazepine.
• Ultraviolet exposure
• Family history
• Smoking

😷 Presentation

SLE affects all parts of the body in an unspecific and unpredictable manner. The most characteristic feature of SLE is the photosensitive malar rash (butterfly rash) that spreads across the cheeks and spared the nasolabial folds. As it is photosensitive, it worsens with sunlight exposure.

Additional constitutional symptoms include:

• Fever
• Malaise
• Weight loss

Let’s take a look at some of the features in different systems in the body:

• Dermatological
• Discoidal rash - we shall discuss this in more detail below.
• Raynaud’s phenomenon
• Livedo reticularis
• Non-scarring alopecia
• Mouth ulcers
• Musculoskeletal
• Arthralgia
• Arthritis
• Morning stiffness
• Joint deformity - these are often reducible with passive movement (as opposed to those seen in rheumatoid arthritis which are not reducible). It is also known as Jaccoud’s arthropathy.
• Respiratory
• Pleuritis
• Alveolitis
• Bronchiolitis
• Pulmonary embolus - if the patient has secondary antiphospholipid syndrome.
• Cardiovascular
• Pericarditis
• Hypertension
• Libman-Sacks endocarditis
• Haematological
• Lymphadenopathy
• Splenomegaly
• Anaemia and/or leukopenia and/or thrombocytopenia
• Neropsychiatric
• Anxiety
• Depression
• Psychosis
• Seizures
• Neuropathy
• Headaches

😷

Discoid lupus erythematosus

Discoid lupus erythematosus is another form of lupus erythematosus that primarily affects the skin without systemic involvement.

Presentation

• Discoid skin lesions - often in sun-exposed areas such as the face and scalp. The lesions are erythematous and scaly. They are most commonly found on the face, scalp, neck and ears.
• Atrophic scarring

🔍 Investigations

The diagnosis of SLE involves a combination of clinical features along with laboratory investigations:

• FBC - may show signs of anaemia of chronic disease, leukopenia, and thrombocytopenia.
• CRP and ESR - these inflammatory markers are raised with systemic inflammation.
• C3 and C4 levels - as these soluble proteins are used up with complement activation, they are decreased with active SLE.
• Urinalysis - to assess for lupus nephritis (showing an increased urine:creatinine ratio, proteinuria and haematuria).
• Renal biopsy - to assess for lupus nephritis.
• Antibody testing - discussed below.

It is important to follow up the patient with regular assessments of the serological parameters (every 3-4 months at least or more in more active disease).

💯 Criteria

The European Alliance of Associations for Rheumatology and the American College of Rheumatology (EULAR/ACR) criteria from 2019 is used in aiding the diagnosis. There are 2 sections to the criteria - entry criterion and weighted domains:

1. Entry Criterion - positive ANA is required to consider SLE. If ANA is negative, SLE is unlikely.
2. Weighted domains - the criteria use a point system across 7 domains, with each feature assigned specific points based on its association with SLE. A total score of ≥10 points confirms SLE, provided the entry criterion is met.
1. Constitutional - fever >38.3°C with no other cause: 2 points
2. Haematologic - leukopenia, thrombocytopenia, or hemolytic anemia: 4–8 points
3. Neuropsychiatric - seizures, psychosis, or delirium: 2–5 points
4. Mucocutaneous - non-scarring alopecia, oral ulcers, acute cutaneous lupus (e.g., malar rash), or subacute cutaneous lupus: 2–6 points
5. Serosal - pleuritis or pericarditis: 5–6 points
6. Musculoskeletal - synovitis in ≥2 joints or tenderness with morning stiffness: 6 points
7. Immunologic - anti-dsDNA, anti-Smith antibodies, low complement levels, or antiphospholipid antibodies: 2–6 points
8. Renal - proteinuria or biopsy-confirmed lupus nephritis: 4–10 points

🧰 Management

🚨 Complications

• Lupus nephritis
• Interstitial lung disease
• Pleural effusion
• Pulmonary hypertension
• Myocarditis
• Cardiac failure
• Neurpsychiatric lupus
• Antiphospholipid syndrome

Lupus nephritis

The most common cause of death with patients suffering from SLE. It is a severe manifestation that leads to end-stage renal failure.

It may stay asymptomatic for a while before presenting as nephritic or nephrotic syndrome.

🔢 Classification

The International Society of Nephrology and the Renal Pathology Society have created a classification for lupus nephritis based on the histopathologic features:

1. Class I: Minimal mesangial lupus nephritis
2. Class II: Mesangial proliferative lupus nephritis
3. Class III: Focal lupus nephritis
4. Class IV: Diffuse lupus nephritis - this is the most common form and most severe form.
5. Class V: Lupus membranous nephropathy
6. Class VI: Advanced sclerosing lupus nephritis

😷 Presentation

These are the features of SLE. Renal involvement may present as either nephritic or nephrotic syndrome as mentioned previously.

• Rash
• Photosensitivity
• Arthritis
• Serositis

🔍 Investigations

It is a clinical diagnosis.

Renal biopsy may show different features depending on the class that is present. Class IV, which is most common, may show up as a “wire-loop appearance” with thickening of glomerular capillaries and immune complex deposition.

🧰 Management

• SLE patients need to undergo regular monitoring for renal disease. This is done through BP monitoring, and assessing for proteinuria and haematuria on urinalysis.

1. ACEI/ARB + BP management is the mainstay of management.
2. Class III and IV - BP management + immunosuppression (glucocorticoids + mycophenolate or cyclophosphamide)
1. This is followed up with mycophenolate therapy.