This site is intended for healthcare professionals as a useful source of information on the diagnosis, treatment and support of patients with lupus and related connective tissue diseases.

Introduction

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 which may be followed by rupture. Segmental lesions indicate that the whole circumference of the vessel is involved and is more common and this will lead to narrowing or occlusion with distal infarction. Haemorrhage into, or infarction of, vital internal organs are 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).

Classification

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 shown in 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. 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. Patients with classical polyarteritis nodosa which is rare (see below) may be treated with steroids and/or cyclophosphamide but can also 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 lifethreatening and these usually require treatment with high dose steroids and cyclophosphamide. In contrast, pure small vessel disease which most commonly involves the skin usually responds to relatively low doses of corticosteroids.

Epidemiology

The vasculitides are relatively rare, the most common being 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 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.

Clinical features

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 the 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 nose bleeds 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 a nephrologist is essential and urgent. Cerebral symptoms in lupus can also be a consequence of vasculitis as can peripheral 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 commoner in patients with Churg-Strauss syndrome and lupus than in the other vasculitides.

Investigations

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 most are 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. 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 requires specialist referral and in-hospital investigation.

In patients with suspected giant cell arteritis, temporal artery biopsy is often advocated but not always necessary. In any case where the diagnosis is in doubt it is useful to obtain a temporal artery biopsy because a positive biopsy indicates the necessity for long-term treatment with steroids.

Treatment

The introduction of cyclophosphamide has had the most dramatic effect on the treatment of the severe systemic vasculitides and has improved survival to between 80 and 90% at 5 years. Cyclophosphamide may be given continuously in tablet form but is associated with a significant risk of cystitis and some increased risk of late bladder cancer. For some years many patients have been given cyclophosphamide in pulsed form, usually intravenously, and a recent study from Europe has shown that this way of giving cyclophosphamide is equally efficaceous but associated with significantly less side effects. Patients requiring cyclophosphamide need to be monitored carefully, and patients with vasculitis need long-term follow up shared between general practitioner and the hospital because of the risk of relapse and toxicity from their treatment. The role of other immunosuppressive and biologic drugs has been highlighted in the last few years with mycophenolate mofetil proving to be particularly useful for lupus nephritis. This drug may also have a role as an alternative to cyclophosphamide in patients with vasculitis but studies for this are ongoing. There is also a lot of interest in the biologic treatment of vasculitis, particularly rituximab which has been used in many cases of severe relapsing Wegener’s granulomatosis and is now a significant advance in treatment of severe lupus, and may be an appropriate treatment to consider where cyclophosphamide causes problems in severe vasculitis complicating lupus.

Conclusion

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.

Dominant vessels involved

Large arteries



Medium arteries


Small vessels and medium arteries




Small vessels (leukocytociastic)
Primary

Giant cell arteritis
Takayasu arteritis
Isolated CNS angiitis

Classical PAN
Kawasaki disease

Wegener's granulomatosis*
Churg-Strauss syndrome*
Microscopic polyangiitis*


Henoch-Schönlein-purpura
Essential mixed cryoglobulinaemia
Cutaneous leukocytociastic angiitis
Secondary

Aortitis associated with RA
Infection (e.g syphilis)


Infection (e.g.hepatitis B)


Vasculitis secondary to RA and SLE
Sjögren's syndrome
Drugs
Infection (e.g. HIV)

Drugs†
Infection (e.g. hepatitis B and C)

PAN = Polyarteritis nodosa; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus.
* Diseases most commonly associated with ANCA (anti-myeloperoxidase and anti-proteinase 3 anti-bodies), which have a significant risk of renal involvement and which are most responsive to immunosuppression with cyclophosphamide.
† For example, sulphonamides, penicillins, thiazide diuretics and many others.
Reproduced from Scott and Watts (1994, British Journal of Rheumatology 33: 897-898)

Table 2. Relationship between vessel size and response to treatment.



Dominant vessels involved

Large arteries

Medium arteries

Small vessels and medium arteries

Small vessels



Corticosteroids alone

+++

+

+

+
Cyclophosphamide

+ Corticosteroids

-

++

+++

-



Others

+

++*

-

++
* Includes plasmapheresis, anti-viral therapy for hepatitis B-associated vasculitis and intravenous immunoglobulin for Kawasaki disease.
+++ most responsive
++ moderately responsive
+ some response
- not frequently used.
Reproduced from Scott and Watts (1994, British Journal of Rheumatology 33: 897-898)

Prof David G I Scott
Department of Rheumatology
Norfolk & Norwich University Hospital
Colney Lane
Norwich NR4 7UY