Vasculitis
Causes of vasculitis
The term ‘vasculitis’ implies inflammation affecting predominantly the blood vessels. The effects of the process depend on the location of the inflammatory change and the size and type of the vessel involved. It is unclear why there is selectivity for vessels of a certain type, size, or location. Although at present vasculitis is divided into primary and secondary, it is likely that, with the passage of time, we shall identify environmental triggers for most of the so-called ‘primary vasculitides’.
Primary vasculitis
Many classifications have been proposed for primary vasculitis, but the most satisfactory is that based on the size of the vessel involved and on the presence or absence of granulomata (Table 13.1). However, there is considerable overlap in the size of vessels involved.
Secondary vasculitis
There are many causes of secondary vasculitis and the following is not an exhaustive list.
Infections: bacterial (streptococci, bacterial endocarditis), spirochetes (syphilis, Borrelia), fungal (histoplasma), mycobacterial, rickettsial, viral (EBV, HIV, VZV, CMV, hepatitis A, B, and C, influenza), with and without cryoglobulins.
Malignancy: hairy cell leukaemia, lymphoma, acute myeloid leukaemia, with and without cryofibrinogens.
Drugs: biologicals (serum sickness), oral contraceptive, sulphonamides, penicillins, thiazides, aspirin, illicit drugs (cocaine, amphetamines, LSD).
Secondary to other autoimmune diseases: primary biliary cirrhosis, Goodpasture’s syndrome, SLE, RhA, systemic sclerosis, Sjögren’s syndrome, polymyositis/dermatomyositis, hypocomplementaemic urticaria, relapsing polychondritis.
Secondary to inflammatory bowel disease: ulcerative colitis, Crohn’s disease; also intestinal bypass surgery.
Complement component deficiency; α1-anti-trypsin deficiency.
Mimics of vasculitis: cholesterol embolus, myxoma embolus, ergotism.
Table 13.1 Classification of primary vasculitis | ||||||||||||||||||||||||||||||||||||||||||||||||
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Diagnostic tests
Biopsy
The most important diagnostic test is often biopsy of the affected organ, which is particularly convenient if the skin is involved. Some vasculitides may mimic neoplasia, e.g. Wegener’s and lymphomatoid granulomatosis, and may therefore be difficult to distinguish on imaging.
Small biopsies are frequently non-diagnostic if vessels are not included.
Temporal artery biopsy is essential in giant cell arteritis.
Imaging
Imaging is an essential source of diagnostic information in cranial vasculitis (MRI is better than CT), unless invasive biopsy is considered justified.
Angiography is particularly helpful in identifying large- and mediumvessel disease. MR angiography is less invasive than conventional angiography.
Where there is suspected involvement of the coronary arteries, ECG, echocardiography, and coronary angiography will be required.
Immunological tests
Immunoglobulin measurements contribute very little to diagnosis, being on the whole non-specifically elevated.
Electrophoresis is necessary to identify paraproteins.
Consider the possibility of cryoglobulinaemia and cryofibrinogenaemia.
Complement measurements (including complement breakdown products or other tests of complement turnover) are essential, particularly in secondary vasculitis.
Role of anti-endothelial cell antibodies (AECA) is not determined as these antibodies do not seem to be disease-specific.
Acute-phase response
Acute-phase response is mostly high (except in the case of SLE, although the ESR is high, and scleroderma).
In some vasculitides, the caeruloplasmin is significantly elevated. This accounts for the greenish colour of serum from patients with active vasculitis.
Ferritin is high (>1000) in adult Still’s disease.
Complement levels will be elevated: both C3 and C4 are acute-phase proteins.
Serum electrophoresis will show reduced albumin (negative acutephase protein) and elevated α2 band (α2-macroglobulin).
Fibrinogen levels will also be elevated.
Regular monitoring of the acute-phase response provides useful information on the response of the disease to treatment.
Blood count
Full blood count will often show the anaemia of chronic disease, together with a thrombocytosis.
There is often a lymphopenia.
Henoch-Schönleín purpura (HSP)
Aetiology and immunopathogenesis (see Box 13.1)
HSP is a disease of the small blood vessels, characterized by palpable purpura and triggered by infections, drugs, foods, insect bites, and occasionally malignancy.
IgA-containing immune complexes can be detected in affected tissues, including glomeruli. These involve both IgA1 and IgA2, but contain mostly polymeric IgA.
IgA rheumatoid factors are also detectable and the levels are highest in the acute phase of the disease; IgA ANCA may occur in some patients (but not frequently enough to be diagnostically valuable).
Polyclonal increase in IgA.
Complement C3 and C4 are normal but C3d is increased, indicating an increase in complement turnover. Properdin levels are decreased while C1q levels are normal, suggesting alternate pathway activation. Properdin and C3 deposits can be detected in affected kidneys. There is an increased incidence of HSP in patients with C2 and C4 deficiency.
Clinical presentation
Mainly disease of small children, with a peak age at onset of around 3 years, although it can occur at any age and does occur in adults, in whom it is possibly more chronic.
Male predominance.
Often a history of a preceding upper respiratory tract infection.
Typical clinical feature is palpable purpura especially at sites of pressure (socks). These occur in crops, often with an urticarial component, and may become confluent. There is gastrointestinal involvement, often with GI haemorrhage and associated with colic, vomiting, and intussusception (3%).
Renal disease with nephritis occurs in 50%, although in most cases this recovers spontaneously and does not lead to long-term renal damage. It may recur in transplanted kidneys in the small proportion who have progressive renal damage (4-14%). Renal disease may be more common in adult forms.
Testicular involvement, pulmonary haemorrhage, pancreatitis, and CNS involvement are all very rare complications.
Myocardial involvement occurs in adults but rarely in children.
Fever in 45-75% and often a migratory arthralgia.
Attacks may recur every few weeks to months and are thought to be triggered by b-haemolytic streptococci.
Diagnosis (see Box 13.2)
Diagnosis is based on the signs and symptoms. If there is doubt, biopsy will assist.
In practice, only complement C3, C4 and total immunoglobulins will be measured.
Raised IgA in only 50%.
Assays for IgA immune complexes and IgA rheumatoid factors are not routinely available.
Treatment
Treatment is not generally required as HSP is a self-limiting disease.
Aspirin should be avoided as it will exacerbate the bowel bleeding.
Steroids reduce symptoms but do not shorten the illness; they may reduce the risk of developing nephritis.
Factor XIII, which is required for healing of the bowel wall, has been used experimentally by infusion to reduce GI haemorrhage.
No conclusive evidence to support the use of plasmapheresis or cytotoxics, although the latter would be used if there was major glomerular involvement with significant proteinuria.
IgA nephropathy (Berger’s disease)
IgA nephropathy (Berger’s disease) is probably closely related to HSP, and may be HSP with renal disease but no rash as the glomerular lesion is identical (IgA deposition, with C3).
Male preponderance.
Often a history of a preceding upper respiratory tract infection.
Unlike HSP, it may be familial but no specific genes identified.
Bowel involvement and arthralgia may occur.
Associated with IgA immune complexes and IgA RhF.
Haemophilus parainfluenzae membrane antigens have been detected in the kidney, and it is thought that this may be the candidate triggering antigen.
Persistent polyclonal elevation of IgA present.
Relapses and remissions are common, but long-term prognosis is good.
Can recur in transplanted kidney.
Buerger’s disease (thromboangiitis obliterans)
Affects predominantly small- and medium-sized arteries and veins.
Occurs mainly in male smokers >30 years of age (<5% of patients are non-smokers).
Presents as a migratory thrombophlebitis with claudication in the lower limbs, and less commonly in the upper limbs.
Raynaud’s phenomenon is common.
Ischaemic features will arise with peripheral gangrene.
Systemic features are usually absent.
No acute-phase response.
Histology shows infiltration of blood vessels by neutrophils early, and mononuclear cells later. Eventually fibrosis of the vessel supervenes.
Active inflammatory lesions improve when smoking ceases, suggesting a direct toxic effect, although fibrotic lesions will not improve.
Diagnosis is on the history backed up by angiography.
The most important therapeutic intervention is cessation of smoking.
Aspirin, vasodilators, and anticoagulants are of no proven value, although infusions of epoprostenol may help.
Amputation may be required.
Hypersensitivity (‘allergic’) vasculitis
This is a generic term, which is less used now, for small-vessel cutaneous vasculitis.
It is not a discrete disease and may be caused by:
drugs, infections
cryoglobulins
inflammatory bowel disease
HSP.
Typical features are:
purpura
urticaria
ulceration
bullae
systemic features (fever, arthralgia, myalgia).
Drugs causing small vessel vasculitis include:
hydralazine, propylthiouracil, allopurinol, thiazides, sulphonamides, phenytoin, gold, penicillin
some drugs (hydralazine, propylthiouracil) also trigger the appearance of anti-MPO ANCA.
Microscopic polyarteritis (MPA)
Aetiology and immunopathogenesis
Clinical features
Illness is often of relatively sudden onset with a short prodrome of fever, malaise, and myalgia/arthralgia, followed by onset of glomerulonephritis with hypertension and renal insufficiency.
There may be pulmonary haemorrhage mimicking Goodpasture’s syndrome. This has a high (75%) mortality.
Extra-renal complications include:
weight loss
mononeuritis multiplex
cutaneous vasculitis
episcleritis
rarely, coronary artery involvement
lung and upper airway involvement does not occur.
Diagnosis (see Box 13.3)
Renal biopsies show a necrotizing glomerulonephritis without evidence of granulomata.
Renal lesions are similar to those found in Wegener’s granulomatosis.
There is a paucity of immunoglobulin and complement in the biopsy (pauci-immune GN).
Granulomata are not found in biopsies.
Angiography of the mesenteric vessels does not show microaneurysms, thus distinguishing MPA from polyarteritis nodosa (PAN).
P-ANCA, with anti-myeloperoxidase specificity on ELISA, can be detected in the serum of 75% of patients; a few patients have C-ANCA with proteinase 3 specificity; some patients may also have anti-GBM antibodies.
C3, C4 will be normal or high.
Normochromic normocytic anaemia is to be expected.
Creatinine will be elevated.
Microscopic haemturia is constant and there will be proteinuria (>3g/24 hours).
Other reported abnormalities include eosinophilia (14%).
Treatment
Treatment is with high-dose (usually pulsed intravenous) steroids and cyclophosphamide (pulse IV or continuous oral).
There may be an acute role for plasmapheresis in preserving renal function.
Rituximab may be an effective alternative to cyclophosphamide
Azathioprine or methotrexate may be used as maintenance therapy once remission has been obtained.
Pneumocystis prophylaxis is required.
Primary angiitis of the CNS (PACNS)
Aetiology and clinical features
Primary cerebral vasculitis is very difficult to diagnose ante-mortem without recourse to biopsy, which has significant hazards.
Diagnosis of exclusion in patients with an acquired neurological deficit.
Similar features have been found following the use of cocaine, amphetamines, and phenylpropanolamine, in ergotism, and with phaeochromocytomas, suggesting a vasospastic origin.
An association with viral (herpesviruses) and mycoplasma infections has also been postulated; turkeys infected with Mycoplasma gallisepticum develop a very similar illness.
The disease is rare, and is primarily of small arteries of the cortex and meninges.
Presents in older patients with headache, disturbance of higher mental function, and stroke. Males are more commonly affected.
A more benign variant has also been described (benign angiitis of the CNS (BACNS)), which is found more commonly in females.
Systemic symptoms are absent (if they are present, it is likely that there is a systemic vasculitis with cerebral involvement).
Diagnosis (see Box 13.4)
Histology shows that most cases have a granulomatous infiltrate around the blood vessels (granulomatous angiitis of the CNS (GACNS)).
CSF may be normal or show elevated protein and cell count.
MRI scanning and angiography may be required to establish the extent of the disease.
Box 13.4 Testing for PACNS
Behçet’s disease
This is a multisystem vasculitis which, unusually, involves veins as well as arteries. Agreed international criteria for diagnosis are as follows.
Recurrent oral ulceration with at least two of the following:
recurrent genital ulceration
eye lesions
skin lesions
pathergy (sterile pustule formation at sites of skin trauma, e.g. needle puncture sites).
Aetiology and immunopathogenesis
Histology shows transmural vascular inflammation with arterial and venous involvement.
The disease is common in eastern Mediterranean countries where there is a strong association with HLA-B5 (B51) and also an increase in DR2, DR7, and DR52.
Sporadic cases occur, and these do not have the same MHC associations.
Polymorphisms have been identified in ICAM-1, VEGF, and the FMF gene (MEFV), among others. The significance is unknown.
The cause of the disease is unknown.
An abnormal response to antigens from Streptococcus mutans and possibly Helicobacter pylori antigens has been postulated.
Immunological features include the following:
Excessive response of polymorphs to fMLP.
IgA antibodies to the 65kDa heat shock protein of bacteria.
Detectable anti-endothelial cell antibodies (these are non-specific).
Reduced mannose-binding lectin levels are associated with more severe disease.
Autoantibodies have been identified to a range of antigens, including anti-Saccharomyces cerevisiae (ASCA), as in inflammatory bowel disease, retinal-S antigen, other retinal antigens, and antikinectin. None are specifically diagnostic.
Clinical features and presentation
The disease is characterized by recurrent orogenital ulceration, similar to aphthous ulceration but deeper, which may heal with scarring.
Erythema nodosum may occur.
Eye disease is often present, including:
anterior and posterior uveitis
hypopyon
retinal vasculitis
optic atrophy.
Vascular features include:
thrombophlebitis
deep vein thrombosis (DVT)
arteritis (large vessel).
Arthralgia/arthritis which is often asymmetric and typically affects large joints, especially the knees.
CNS disease is due to vasculitis and typically causes pontine lesions.
Other CNS complications include:
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