Vasculitis

Vasculitis refers to inflammation of blood vessels.

Vasculitis is a very broad term that in its simplest form refers to inflammation of blood vessels. There are many different causes of vasculitis and they usually present in a myriad of ways. The exact cause of vasculitis is unknown and the underlying mechanisms leading to blood vessel inflammation vary between conditions (e.g. antibody-mediated, T-cell mediated).

There has been a lot of work on classifying vasculitides into different types. They are a very heterogenous group of conditions that can affect multiple organs and in some cases be life-threatening.

Several important terms are used when discussing vasculitides, which may include:

• Primary versus secondary
• Localised versus systemic
• Size of the vessels affected
• Classic features (e.g. ‘vasculitic rash’)

Primary versus secondary

Vasculitis can be broadly divided into primary or secondary:

• Primary: inflammation of blood vessels is the primary pathological process with no identifiable cause
• Secondary: inflammation of blood vessels is secondary to a connective tissue disease (e.g. rheumatoid), infection (e.g. hepatitis C) or exposure to a drug (e.g. penicillin)

Localised versus systemic

Blood vessel inflammation may affect multiple organs (i.e. systemic) or be restricted to a single organ (i.e. localised). When vasculitis is localised to single organ it is usually termed single-organ vasculitis (SOV).

SOV classically affects the skin, central nervous system or aorta:

• Skin: known by many names including hypersensitivity vasculitis, cutaneous small vessel vasculitis, or leukocytoclastic vasculitis (this latter name is actually a histopathological term)
• Central nervous system: referred to as primary central nervous system vasculitis
• Aorta: may cause an isolated aortitis

Overtime, SOV may develop into a more systemic vasculitis involving other organs.

Affected vessels

Any blood vessel may be affected in vasculitis. These include:

• Large vessels (e.g. aorta and major branches)
• Medium vessels (e.g. main visceral arteries and their branches)
• Small vessels (e.g. small arteries within an organ, arterioles, capillaries, and venules)

The size of the blood vessel involved forms part of the classification system for primary vasculitis syndromes (discussed further below).

Classic features

The clinical features of vasculitis depend on both the size of the vessels involved (e.g. large, medium or small) and the location of the vessels involved (e.g. kidney, skin or gut vessels). However, there are certain clinical features that are strongly suggestive of a vasculitic process. These features include:

• Palpable purpura: vasculitis classically causes ‘palpable purpura’ that is often referred to as a ‘vasculitic rash’. Purpura are small (3-10 mm) red/purplish skin lesions that are non-blanching (i.e. do not go pale when pressed) and occur due to damaged blood vessels. Suggest cutaneous involvement of vasculitis
• Constitutional symptoms: refers to features such as fever, weight loss, and fatigue. Non-specific and simply suggestive of a systemic process (e.g. infection, cancer, inflammatory disorder). Need to be considered in the context of other features
• Asymmetrical neuropathies: damage to the small blood vessels that supply peripheral nerves can lead to peripheral neuropathy with sensory and/or motor features. Typically cause mononeuritis multiplex or an asymmetrical polyneuropathy
• Unexplained bleeding: patients with unexplained haemoptysis or haematuria is suggestive of a vasculitic process affecting the small vessels of the pulmonary and renal vasculature. This may be seen with many small-vessel vasculitides

Classification of the vasculitides is based on the international Chapel Hill Consensus Conference nomenclature.

The international Chapel Hill Consensus Conference helps to classify all types of vasculitides into broad categories and provides useful definitions for each category.

• Large-vessel vasculitis (e.g. Takayasu arteritis, Giant cell arteritis)
• Medium-vessel vasculitis (e.g. Polyarteritis nodosa, Kawasaki disease)
• Small-vessel vasculitis (e.g. ANCA-associated vasculitis, Cryoglobulinaemic vasculitis)
• Variable vessel vasculitis (e.g. Behçet syndrome)
• Single-organ vasculitis (e.g. cutaneous small vessel vasculitis)
• Vasculitis associated with systemic disease (e.g. rheumatoid arthritis)
• Vasculitis associated with probable aetiology (e.g. hepatitis B)

The primary vasculitides are divided based on vessel size (large, medium, small) and the secondary vasculitides are divided into subgroups depending in the suspected aetiology (associated with systemic disease, associated with likely aetiology). SOV is divided into a separate category and for vasculitides that can affect any size vessel the term ‘variable vasculitis’ is used.

The exact cause of vasculitis remains unknown.

There are numerous theories as to why vasculitis develops, which are related to both environmental and genetic factors. However, the exact cause remains unknown. The principal problem is inflammation of blood vessels, which may manifest by several different mechanism that can include:

• Immune-complex formation (e.g. components of the immune system are deposited in vessels leading to damage)
• Antibody-mediated (e.g. antibodies such as ANCA are directed against specific antigens such as those found in neutrophils)
• Cell-mediated (e.g. activated T-cells lead to vascular injury through recruitment of other immune cells)

The exact pathological mechanisms are complex and related to the underlying disease process.

The major consequence of acute or chronic inflammation in blood vessels is that it interrupts blood flow to vital organs. This disruption occurs due to bleeding from damage of the vascular structures or from occlusion as a result of the inflammatory process. In either case, there is ischaemia, tissue damage and ultimately organ dysfunction. This organ dysfunction may occur acutely and can be life-threatening (e.g. gut ischaemia, acute kidney injury).

Giant cell arteritis is a classic cause of large vessel vasculitis.

The two major causes of large vessel vasculitis include:

• Giant cell arteritis
• Takayasu arteritis

Giant cell arteritis

Giant cell arteritis (GCA), also known as temporal arteritis, is a large vessel vasculitis that predominantly affects the aorta and its branches. It typically occurs in older adults and has a predilection for the branches of the carotid artery. It is characterised by a unilateral headache, scalp pain, and visual loss due to involvement of the ophthalmic artery. It is considered a medical emergency because without prompt recognition and treatment it can lead to permanent visual loss.

For more information see our Giant cell arteritis note.

Takayasu arteritis

Takayasu arteritis is a rare type of vasculitis that predominantly affects woman (>80%) and is mainly seen in patients of Asian ethnicity. It predominantly affects the aorta and its major branches leading to features of arterial insufficiency (e.g. weak or absent distal pulses, limb claudication). Diagnosis is usually made on imaging.

Kawasaki disease is a medium vessel vasculitis predominantly found in children.

The two major causes of medium vessel vasculitis include:

• Polyarteritis nodosa
• Kawasaki disease

Polyarteritis nodosa

Polyarteritis nodosa (PAN) is a rare medium vessel vasculitis that may also affect the small vessels in some cases. It can affect virtually any organ and is slightly more common in males with a peak incidence in the sixth decade of life. The majority of cases are idiopathic but it can be associated with underlying hepatitis B or C infection. PAN characteristically affects the skin (e.g. purpura), kidneys (e.g. acute kidney injury, hypertension), nervous system (e.g. peripheral neuropathy) and causes abdominal pain (due to mesenteric arteritis). On imaging, typical findings in PAN are multiple aneurysms and irregular constrictions of arterial vessels.

Kawasaki disease

This is the most common form of vasculitis in children and leads to widespread involvement of medium-sized vessels. It is typically a self-limiting disease that is diagnosed based on characteristic criteria of fever for ≥ 5 days alongside 4/5 of the following features:

• Bilateral conjunctivitis
• Oral mucous membrane changes (e.g. strawberry tongue)
• Peripheral extremity changes (erythema, oedema and/or periungual desquamation of the hands/feet)
• Polymorphous rash
• Cervical lymphadenopathy

Other features can be present and long-term children may develop cardiovascular complications including coronary artery aneurysms, heart failure, arrhythmias and peripheral arterial disease.

The small vessel vasculitides can be divided based on their association with the autoantibody ANCA.

Vasculitis of the small vessels typically causes inflammation of the small arteries of organs, arterioles, capillaries and venules. They are classically caused by immune-complexes or the autoantibody antineutrophil cytoplasmic antibody (ANCA).

ANCA-associated vasculitis (AAV)

AAV is an umbrella term for three conditions:

• Microscopic polyangiitis (MPA)
• Granulomatosis with polyangiitis (GPA): previously known as Wegener’s granulomatosis
• Eosinophilic granulomatosis with polyangiitis (EGPA): previously known as Churg-Strauss syndrome

These conditions are small vessel vasculitides characterised by a positive ANCA that can affect arterioles, capillaries and venules. While MPA and GPA are similar conditions, EGPA has a different predilection of organ involvement (predominantly ENT, pulmonary and cutaneous involvement) and also affects medium-sized vessels. In AAV, ANCA autoantibodies have characteristic staining patterns and associate with two antigen targets known as myeloperoxidase (MPO) and proteinase 3 (PR3).

For more information see our separate notes (links above)

Immune-complex small vessel vasculitis

This refers to small vessel inflammation caused be deposition of immunoglobulins and/or complement. The renal glomeruli are frequently involved in these types of vasculitis. There are four principal causes:

• Anti-glomerular basement membrane disease
• Cryoglobulinaemic vasculitis (characterised by cryoglobulins, which are serum immunoglobulins and/or complement proteins that precipitate in the cold (<37º) and dissolve upon rewarming)
• Henoch-Schönlein purpura (i.e. IgA vasculitis)
• Hypocomplementemic urticarial vasculitis

Vasculitis may be associated with an underlying autoimmune disorder, infection or culprit drug.

Connective tissue diseases are commonly associated with vasculitis and can include rheumatoid arthritis, systemic lupus erythematosus, relapsing polychondritis, or sarcoidosis. Treatment is usually targeted at both the underlying disease and the vasculitis with immunosuppressive therapies.

Infections linked with the development of vasculitis may include hepatitis B/C and syphilis. Many drugs can lead to a cutaneous small vessel vasculitis from a type of hypersensitivity reaction (type III) with formation of immune complexes. Common culprit medications include penicillins, cephalosporins, sulfonamides, phenytoin and allopurinol. Rarely, other organs may be involved. Some drugs can even cause an ANCA-associated vasculitis pattern.

In clinical practice, diagnosis of vasculitis can be difficult because of the non-specific presentation.

Vasculitis can present with many non-specific features such as fever, malaise and weight loss. This leads to the investigation of more common diagnoses such as infection or cancer before the diagnosis becomes more apparent or is searched for.

A specific diagnosis of vasculitis is usually reached by a diagnostic criteria depending on the underlying cause. These criteria usually involve a combination of clinical, laboratory, imaging and/or biopsy results.

Clinical features supportive of vasculitis

Certain clinical features may be non-specific in vasculitis (e.g. fever) whereas others are highly suspicious (e.g. palpable purpura). The features supportive of vasculitis include:

• Fever of unknown origin (i.e. infection has been excluded)
• Weight loss
• Weakness, general malaise
• Arthralgia
• Myopathy
• Palpable purpura: raised red/purplish lesions, which are non-blanching and non-painful
• Mononeuritis multiplex: simultaneous or sequential involvement of ≥2 separate nerves
• Unexplained haemoptysis/haematuria

Laboratory findings in vasculitis

Patients with suspected vasculitis usually undergo a ‘vasculitis screen’, which refers to a series of investigations to search for the possible underlying cause of vasculitis. This includes assessing for non-specific markers of an inflammatory process (e.g. CRP, ESR, complement), specific tests for primary vasculitides (e.g. ANCA) and specific tests for secondary vasculitides (e.g. Anti-CCP for rheumatoid).

Typical vasculitis screen

• Urinalysis (assess for haematuria)
• Full blood count
• Urea & electrolytes
• Liver function tests
• C-reactive protein / ESR
• Complement (C3/C4)
• Coagulation
• Anti-nuclear antibodies (ANA)
• Extractable nuclear antibodies (ENA)
• Specific autoantibodies: ANCA, Anti-dsDNA, Anti-CCP, Anti-GBM
• Serum cryoglobulins
• Viral hepatitis serology

Non-specific features suggestive of vasculitis include low complement levels, raised inflammatory markers, anaemia and/or evidence of organ dysfunction (e.g. acute kidney injury). More specific features include autoantibodies (e.g. positive ANCA or cryoglobulin).

Other investigations in vasculitis

Depending on the type of vasculitis, suspected aetiology and clinical presentation a variety of other investigations can be requested including imaging and some highly specialist tests.

• Chest x-ray: requested in patients with pulmonary symptoms
• CT chest: particularly important if haemoptysis is present
• Renal ultrasound: in the presence of acute kidney injury
• Nerve conduction studies/Electromyography: if peripheral neuropathy develops
• Neuroimaging +/- lumbar puncture: if neurological involvement

Vascular imaging

A variety of imaging modalities can be used to detect vascular involvement. This is mainly important for large and medium size vessel vasculitis. Options include MR angiograms, CT angiograms, vascular ultrasound and even positron emission tomography. Rarely, direct angiography may be used via the interventional radiologists to assess for structural vascular abnormalities.

Biopsies

Biopsies may be required depending on the presentation. Examples of when biopsies are used to confirm the diagnosis of vasculitis include:

• Skin biopsy: cutaneous vasculitis
• Renal biopsy: Small-vessel vasculitis involving the kidneys (e.g. ANCA-associated vasculitis)
• Temporal artery biopsy: Giant cell arteritis

The treatment of vasculitis typically involves the use of immunosuppressive drugs at high doses.

Immunosuppressive therapies are the principal agents used in the treatment of vasculitis but the choice, dose, route and frequency is guided by the underlying cause and extent of organ involvement. An in-depth analysis of the management of vasculitis is far beyond the scope of these notes.

Corticosteroids (e.g. prednisolone) form the standard medical therapy that are often given at high doses. In severe cases, intravenous methylprednisolone may be required (e.g. GCA with sight-threatening presentation). In small vessel vasculitides, corticosteroids may need to be combined with other immunosuppressive agents such as cyclophosphamide to prevent serious end-organ damage. If end-organ damage does occur, treatment needs to be directed towards this as well (e.g. dialysis in severe acute kidney injury). It is important to think about steroid-related side-effects that are commonly seen in this patient group due to the requirement of often long and protracted courses of steroids. Remember, topics such as steroid side-effects are far more commonly tested at undergraduate level than individual treatment regimens for different vasculitides.