LUPUS: A GP Guide to Diagnosis
Vasculitis means inflammation of blood vessels. Direct inflammatory changes within the wall of a blood vessel (i.e. vasculitis) frequently causes necrosis to the vessel wall, hence the term often used 'necrotizing vasculitis'.
Vasculitis can either be primary (e.g. polyarteritis nodosa, Wegener's granulomatosis) occurring in the absence of a recognised cause or associated disease or secondary to an established disease (e.g. rheumatoid arthritis or systemic lupus erythematosus) or secondary to infection such as hepatitis B, C or HIV.
The consequence of vasculitis depends on the size, site and number of blood vessels involved. The spectrum of involvement ranges from relatively mild disease affecting small vessels or isolated to a single organ, to rapidly life threatening multi-system disease. When muscular arteries are involved they can develop focal or segmental lesions. Focal lesions indicate only part of the wall is involved which may become weak, leading to aneurysm formation followed by rupture. Segmental lesions indicate that the whole circumference of the vessel is involved and is more common and will lead to narrowing or occlusion with distal infarction. Haemorrhage into, or infarction of, vital internal organs are, thus, the most serious complications of vasculitis. Prior to the introduction of cyclophosphamide the mortality of the primary vasculitides, particularly Wegener's granulomatosis and polyarteritis nodosa, was over 80% by one year. Improved treatment has dramatically improved the survival but there is still significant morbidity from the disease (and/or its treatment).
An understanding of the different types of vasculitis is helped by understanding classification.
A number of different classification systems have been used, a favoured system being Table 1 based on the dominant vessels involved and dividing diseases into primary and secondary vasculitis. Lupus is, obviously, included as one of the secondary vasculitides and most commonly is associated with small vessel vasculitis but can involve small vessels and medium arteries when the consequences are much more serious (see below). The importance of this classification is that the different groups require different types of treatment and this is shown in Table 2. Thus, patients with giant cell arteritis, which is the most common vasculitis seen in general practice, are usually treated with high dose corticosteroids and rarely with any other drugs, apart from those patients who have problems coming off their steroids. Patients with classical polyarteritis nodosa which is incredibly rare (see below) may be treated with steroids and/or cyclophosphamide but can respond to anti-viral therapy and plasma exchange. It is the group of diseases which overlap between medium arteries and small vessels, including severe lupus vasculitis, that are the most serious and life-threatening diseases and these often require high dose steroids with cyclophosphamide which can be very effective in controlling them. In contrast, pure small vessel disease involving the skin usually responds to relatively low doses of corticosteroids.
The vasculitides are relatively rare and the most common seen in the UK are giant cell arteritis with an incidence of approximately 1 patient per 10.000 over the age of 50 per year and cutaneous vasculitis with an incidence of approximately 30/million/year. Taking all the other systemic vasculitides together, their incidence is probably in the region of 40/million/year and specifically looking at lupus associated with severe systemic vasculitis, the incidence is probably less than 5 per million of the general population per year. This means that a practice of approximately 10,000 will see one or two patients with giant cell arteritis each year, probably one patient with Wegener's every 10 years and one with severe lupus vasculitis every 10-20 years. The consequence of giant cell arteritis with potential blindness is well known but it is important to recognise the other vasculitides because they are now treatable/curable diseases, having previously had median survival of less than 6 months before the introduction of drugs such as cyclophosphamide.
The clinical presentation of vasculitis varies dependent on the underlying disease. The most important organ involved in primary systemic vasculitis is the kidney. Any patient with suspected vasculitis should have labstix testing of the urine and in the presence of systemic illness haematuria and proteinuria are an important and serious prognostic sign. In those circumstances the differential diagnosis would include infection such as bacterial endocarditis, malignancy, connective tissue disease with or without vasculitis such as lupus and systemic vasculitis, particularly Wegener's granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis.
The most common clinical feature of vasculitis is a skin rash. Particularly common is a nonthrombocytopaenic purpuric rash often affecting the lower limbs. This is a classical presentation of Henoch-Schönlein purpura which is much more common in children than in adults but is also a feature of all the other primary vasculitides involving small vessels. Other clinical features depend on the organs involved. In Wegener's granulomatosis there is frequently ENT involvement with nasal crusting and recurrent nosebleeds which can precede the onset of vasculitis by months or years. Similarly, in Churg-Strauss syndrome the early features are those of adult or late onset asthma which can also precede systemic vasculitis by months or years. Asthma associated with a particularly high eosinophil count and the development of a rash should always alert the doctor to consider systemic vasculitis and, again, if this is unrecognised and untreated, it can be fatal due to kidney and also (in Churg-Strauss) heart involvement.
Systemic vasculitis complicating lupus will often present with severe skin rashes which may be necrotic leading to gangrene. Deteriorating renal function is also important and in a patient with lupus with new proteinuria or haematuria a renal biopsy and formal assessment by specialists is essential and urgent. Cerebral symptoms in lupus can also be a consequence of vasculitis as can neuropathy. Peripheral nerve symptoms can be difficult to detect but sudden onset of numbness or weakness in a patient who is generally unwell should suggest the possibility of vasculitis and is more common in patients with Churg-Strauss syndrome and lupus than in the other vasculitides.
As indicated above, the single most important investigation in a patient with suspected vasculitis is urine testing. In a systemically unwell person the presence of blood and protein in the urine indicates the necessity for urgent referral and probably urgent treatment. Other investigations that can be helpful include a routine blood count and ESR. Anaemia of chronic disease develops quite rapidly in many vasculitides and is mostly associated with a high acute phase response as shown by a high ESR and/or CRP. Basic tests for renal and liver function are important to detect deteriorating renal function and mild derangement of liver enzymes is common in all inflammatory diseases including vasculitis, however, very high levels might indicate an associated hepatitis, such as hepatitis B or C infection.
Immunological tests are helpful. A low level of complement (C3 and C4) is often a feature of secondary vasculitis due to rheumatoid arthritis, lupus, Sjögren's syndrome or infection, but is very rarely seen in patients with primary vasculitis. High levels of the appropriate antibodies are seen, for example DNA binding and Sm antibodies, in lupus vasculitis and rheumatoid factor in rheumatoid vasculitis. The primary vasculitides - Wegener's granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis are associated with a relatively new antibody known as ANCA (antineutrophil cytoplasmic antibody). Recent studies have shown that the specificity of this antibody can also help differentiate disease in that when the antibody acts against proteinase 3 it is strongly associated with Wegener's granulomatosis but ANCA with specificity against other enzymes, particularly myeloperoxidase, is often found in Churg-Strauss syndrome and microscopic polyangiitis.
Investigations otherwise depend on the organ involved. The presence of haematuria and proteinuria indicates necessity for 24 hour urine protein and creatine clearance, haemoptysis which is common in Wegener's requires a chest X-ray and nasal crusting or nasal discharge or bleeding indicates a necessity for ENT referral and sinus X-rays. Polyarteritis nodosa is sometimes diagnosed on angiography but this, obviously, requires specialist referral and in-hospital investigation.
Temporal artery biopsy is often advocated by hospital based clinicians but is not always necessary or appropriate. Certainly, in any case where the diagnosis is in doubt, it is useful to order a temporal artery biopsy as a positive biopsy indicates the necessity for long-term treatment with steroids, also, despite literature suggesting that a temporal artery biopsy is of little help after a week's steroid treatment, this is not strictly true. Patients who have had temporal arteritis and been treated for weeks or months can have changes detectable on temporal artery biopsy showing old arteritis and this can be helpful in confirming the diagnosis and also the need for continued steroid treatment.
The introduction of cyclophosphamide has had the most dramatic effect on the treatment of the severe systemic vasculitides and has improved survival to 80 - 90% at 5 years. Cyclophosphamide may be given continuously in tablet form but is associated with a risk of cystitis and even bladder cancer and some groups now give cyclophosphamide intravenously intermittently with probably equal efficacy and fewer long-term side effects. These patients need careful monitoring and after discharge from hospital their care needs to be shared in terms of drug treatment and monitoring over a period of years between the hospital and general practitioner.
Recent advances in the understanding of the vasculitides have led to a dramatic improvement in outcome, increased recognition of the different types of vasculitis and an apparent increase in their incidence. Although rare they are important because they are treatable and should and can be recognised and referred appropriately from primary care.
Table 1. Classification of systemic vasculitis.
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Table 2. Relationship between vessel size and response to treatment.
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Prof. David G.I. Scott
Department of Rheumatology
Norfolk & Norwich Health Care NHS Trust
Brunswick Road
Norwich
Norfolk, NR1 3SR