HC33: Systemic Lupus Erythematosus

Clinical image

Systemic lupus erythematosus (SLE) is the prototype of a multisystem disease of auto-immune origin. It is a type III hypersensitivity reaction characterized by a broad spectrum of autoantibodies and butterfly rash (erythematosus). The clinical course is extremely variable → there are remissions and relapses.

SLE affects many different organs:

• Skin
• Kidneys
• Joints
• Heart
• Serosal membranes

Epidemiology:

The disease is fairly common in certain populations → in Asia, 1 in 2500 persons are affected. There is a strong female preponderance. Peculiarly, in areas where the disease is more common, the symptoms are less severe → the disease only manifests in 1 organ. In areas where the disease is rare, the symptoms are more severe → more organs are involved.

Lupus nephritis

Up to 60% of patients with SLE develop lupus nephritis. Lupus nephritis has a considerable morbidity and poor survival. The histopathological findings in lupus nephritis vary considerably → classification of lupus nephritis is essential for treatment decisions.

Diagnostics

There is a mnemonic to diagnose SLE → the symptoms together form “SOAP BRAIN MD”. SLE can be diagnosed when 4 of these symptoms are present during any amount of time:

• Serositis
  • For example pleuritis
  • Many organs have a thin layer of serosa → can be inflamed
• Oral ulci
• Arthritis
• Photosensitivity
  • Can cause rash after exposure to the sun
• Blood changes
  • Of any kind
• Renal involvement
  • Of any kind → nephrotic or nephritic syndrome
• ANA (anti-nuclear antibodies)
• Immunological changes
  • Low C3 levels
    • Caused by high activity of the complement system in this disease
• Neurological signs
  • Neuro-lupus and the fog
    • A vasculitis-like lesion is visible in the brain
    • Fog: patients feel like they’re in a surrealistic surrounding
• Malar rash
  • Butterfly rash
• Discoid rash
  • Rash on body parts other than the face

Serology

The is a wide spectrum of autoantibodies in SLE → there are antibodies against:

• Cytoplasmic components
• Surface antigens of blood cells
• Proteins in complex with phospholipids
• Nuclear components
  • Antibodies to DNA
  • Antibodies to histones
  • Antibodies to nonhistone proteins
  • Antibodies to nucleolar antigens

Etiology

It is peculiar that there can be antibodies against components of a cell. There are many hypotheses on etiological factors:

• Modification of a self-antigen
  • By a virus or drug
• Polyclonal B- or T-cell activation
  • Genetically determined
  • May be triggered by:
    • Viruses
    • Drugs
    • Bacteria
• Defective thymus
• Dysregulated apoptosis and/or clearance of apoptotic cells
• Chimerism

Apoptotic cells:

Apoptotic cells are present in the tissue. SLE causes the production of anti-nuclear antibodies (ANAs), which can be detected by indirect immunofluorescence. ANAs presumably destroy parts of the nucleus → cause apoptosis. This is called nuclear dust.

There is a hypothesis that because of a macrophage dysfunction, there is a defective clearance of nuclear antigens from apoptotic cells. The delayed removal of apoptotic cells may give rise to the formation of auto-antibodies such as ANAs.

Testing:

The immunofluorescence test for ANA is positive in almost every patient with SLE → the sensitivity is high. However, patients with other autoimmune diseases may also score positive → not very specific. Immunofluorescence patterns do not correspond uniquely to a specific antibody → after a positive result of the ANA-test, it needs to be determined whether the patient has antibodies to dsDNA.

Patterns of injury in lupus nephritis

Glomerular injuries, and also the clinical symptoms, are determined by immune complex localization. There are 3 patterns of injury:

• Mesangial injury → lupus I and II
  • Asymptomatic proteinuria
  • Microscopic hematuria
• Endocapillary injury → lupus III and IV
  • Hematuria
  • Loss of GFR
  • Proteinuria
  • Inflammatory lesions
• Epithelial injury → lupus V
  • Nephrotic range proteinuria
  • Non-inflammatory lesions

All 3 can be combined → for instance, a patient can have lupus III + V.

Classification of lupus nephritis

Lupus nephritis can have so many different faces that an international classification system is necessary for clinicians and pathologists to know what they are talking about:

• Lupus nephritis class I
  • Normal histology → no lesions at all
  • Full house immunofluorescence
• Lupus nephritis class II
  • Mesangial changes
  • Full house immunofluorescence
  • Deposits in the mesangium
• Lupus nephritis class III
  • Proliferative lesions in <50% of glomeruli
  • Full house immunofluorescence → subendothelial deposits
• Lupus nephritis class IV
  • Proliferative lesions in >50% of glomeruli
  • Full house immunofluorescence → subendothelial deposits
• Lupus nephritis class V
  • Subepithelial deposits
  • Membranous pattern of spikes
  • Full house immunofluorescence
• Lupus nephritis class VI
  • Global glomerulosclerosis in >90% of glomeruli
    • End stage renal failure
  • Full house immunofluorescence

Full house means that all 5 major immunofluorescent stains (IgM, IgG, IgA, C3 and C1q) on a renal biopsy are positive.

Therapy:

Therapy depends on the given class. The histopathology cannot be deducted from the clinical symptoms → in time, class changes may occur. The histopathological “damage index” correlates with the patient’s renal prognosis.

Anti-phospholipid antibodies

Anti-phospholipid antibodies are often present in lupus patients. Patients with these antibodies have an increased risk of blood clots and an increased risk of miscarriages. Thrombogenic events can occur.