HC32: Vasculitis

Vasculitis

Vasculitis is a hypersensitivity reaction. It is a systemic disease. There is an inflamed blood vessel and fibrinoid necrosis caused by white blood cells that have been stimulated by ANCA. Every blood vessel can be damaged and eventually lead to death.

Peri-arteritis nodosa

In the 19^th century, many descriptions of similar patients appeared. The general name given to their symptoms was periarteritis/polyarteritis nodosa. There was an inflammation of the blood vessels → arteritis, which was arranged in a nodular fashion → nodosa. Both similarities and variations were noticed:

• Similarities
  • Illness of the vessels
  • Rapid course
  • Death
• Variations
  • Organ involvement
  • Differences in histology

This mainly occurred in combination with kidney disease and progressive muscle weakness. Several hypotheses on the etiology of vasculitis were made based on environmental factors, viruses and genetics.

Subtypes

Henoch Schonlein purpura:

Henoch Schonlein purpura is a subtype of vasculitis mainly affecting the skin and gut, but other organs may be affected as well. Patients are mainly children and elderly. The disease is characterized by:

• Abdominal pain
• Purpura on the legs
  • Purple point bleedings

Henoch Schonlein can also affect the kidneys → deposition of IgA in the glomeruli of the kidneys. It is possibly related to IgA nephropathy, which is the most common immune mediated disease in the western world. Therefore, IgA vasculitis is a suggested alternative name for Henoch Schonlein purpura. In other subtypes of vasculitis, no glomerular disposition is visible → the ANCA-test is negative.

Churg-Strauss syndrome:

In 1951, Jacob Churg and Lotte Strauss published on 13 patients with vasculitis who had prominent lung involvement and were previously known with asthma. This typical combination of the lung with eosinophilia became known the Churg-Strauss Syndrome.

Churg-Strauss syndrome is a vasculitis typically involving the lungs with an eosinophilic infiltrate, in patients previously known with asthma. Both asthma and in this case also vasculitis are strongly related to eosinophilic granulocytes. The disease is also known as EGPA (eosinophilic GPA).

Granulomatosis with polyangiitis:

Granulomatosis with polyangitis (GPA) is type of vasculitis that used to be known as Wegener’s granulomatosis. It is a combination of:

• Upper airway vasculitis
• Renal involvement
• Histologically proven presence of granulomas

Typical for people with GPA is the “saddle nose”. This is chronic and is caused by vasculitis destroying the cartilage in the nose → there is no tissue left in the middle of the nose. This may be associated with staphylococcus aureus infections.

Anti-neutrophilic cytoplasmatic auto-antibodies

In case of systemic ANCA-associated vasculitis, anti-neutrophilic cytoplasmic auto-antibodies (ANCA) are detected. These antibodies are a form of IgG and are directed against components in the primary granules of neutrophils, for example:

• Proteinase-3
• Myeloperoxidase
• Elastase
• Other components

ANCA-test:

The ANCA-test is used a lot for diagnostics. It is a type of indirect immunofluorescence:

1. Granulocytes (neutrophils) from healthy donors are put on a glass slide
2. Patient serum is put on the slide
3. ANCA directed towards neutrophils binds to the neutrophils
4. An anti-human-IgG antibody with a fluorescent signal is added → binds to the ANCA
5. A fluorescent signal is given

2 types of patterns can be distinguished:

• Cytoplasmatic pattern: closely associated with anti-Pr3 antibodies
• Perinuclear pattern: closely associated with anti-MPO antibodies

Tests can also be done using ELISA. The tests distinguish subtypes of vasculitis:

• GPA
  • Indirect immunofluorescence → cytoplasmic ANCA-pattern
  • ELISA → lots of anti-Pr3
• Churg-Strauss syndrome
  • Indirect immunofluorescence → perinuclear ANCA-pattern
  • ELISA → lots of anti-MPO
• Henoch-Schonlein purpura
  • Indirect immunofluorescence → rarely positive
  • ELISA → rarely positive

Mechanism:

It is unknown which exact mechanisms cause ANCA diseases, but there is a moderate relation between ANCA-titers and the severity of the disease. Vasculitis is caused as follows:

1. ANCA binds to neutrophils in the blood vessel
2. Neutrophilic granules are degranulated
3. The basal membrane is destroyed → inflammation
   • This is the first sign of necrotic lesions

Approximately 10% of patients with systemic vasculitis don’t have ANCAs.

Experiments with mice show that ANCAs indeed are pathogenic. Mouse MPO from a physiologic mouse was put into a healthy mouse → started making anti-MPO antibodies → ANCAs.

ANCA-associated vasculitis in the kidney

Histological images of ANCA-associated vasculitis in the kidney can be seen at the level of the glomerular capillary:

1. Breaks in the basement membrane lead to leakage of fibrin and cytokines in Bowman’s space
2. Epithelial cells lining Bowman’s capsule proliferate
3. Formation of crescents and cell necrosis takes place

Crescents are layers of epithelial cells surrounding part of a glomerulus. There are multiple stages of crescents in crescentic glomerulonephritis:

1. Cellular
2. Normal or advanced
3. Advanced
4. Fibrocellular
5. Fibrous

Damage to glomeruli can be repaired in case it isn’t too advanced. This can be done by inhibiting the proliferation of the basal membrane. Damage is irreversible once fibroblasts come in.

Classification flow-chart:

Not all glomeruli are equally affected, even though vasculitis is a systemic disease. For example, the infection can be focal → less than 50% of the glomeruli are affected. The cause of this is still unknown. Therefore, ANCA-associated vasculitis can be classified based on the involvement of the kidneys:

• Sclerotic class: >50% globally sclerotic glomeruli
• Focal class: >50% normal glomeruli
• Crescentic class: >50% cellular crescents
• Mixed class: everything occurs <50%

Organ involvement

Many organs may be damaged by vasculitis, but this can remain unknown because there aren’t any symptoms.