Small vessel vasculitides

What’s new?

C Etanercept is not useful in the treatment of ANCA-associated

vasculitis

C Pulsed cyclophosphamide is as effective as continuous oral

cyclophosphamide for induction of remission in systemic

vasculitis, and is associated with a marked reduction in

cumulative dose

C Rituximab, an anti-CD20 monoclonal antibody, is emerging as

an effective and well-tolerated induction therapy for systemic

vasculitis

C Induction therapy for severe systemic vasculitis (creatinine

>500 mmol/l) with plasma exchange is more effective than

pulsed high-dose methylprednisolone.

SYSTEMIC VASCULITIDES

Small vessel vasculitidesLorraine Harper

Mark A Little

AbstractSmall vessel vasculitis can be associated with immune complex deposi-

tion, as in HenocheSchonlein purpura or systemic lupus erythematosus,

or with minimal immune deposits, as in Wegener’s granulomatosis, micro-

scopic polyangiitis or renal-limited vasculitis. The latter conditions are

associated with circulating anti-neutrophil cytoplasm antibodies (ANCA)

and are the most common causes of rapidly progressive glomerulo-

nephritis. This review describes recent advances in the understanding

of the pathogenesis underlying these conditions and reviews common

presentations. Consideration is given to recent clinical trials in the

management of ANCA-associated vasculitides.

Keywords ANCA; anti-neutrophil cytoplasm antibodies; microscopic

polyangiitis; therapy; vasculitis; Wegener’s granulomatosis

Introduction

Primary small vessel vasculitis includes Wegener’s gran-

ulomatosis, microscopic polyangiitis (MPA) and ChurgeStrauss

syndrome, and is commonly associated with anti-neutrophil

cytoplasm antibodies (ANCA). Although uncommon, with an

incidence of 20/million population, prevalence now approaches

200/million because of improvements in treatment. These

diseases can occur at any age, including childhood, but are most

common in elderly patients (peak age 55e70 years); they

predominantly affect Caucasians, and occur equally in both

sexes. Management of these diseases is challenging. Rapid

diagnosis is essential to reduce the permanent scarring caused by

vasculitis and death from pulmonary haemorrhage. Considerable

delay in diagnosis can occur because of the multiple non-specific

manifestations associated with disease. Untreated, these condi-

tions are fatal, although the use of cyclophosphamide-based

regimens has improved 5-year survival to 80%.

HenocheSchonlein purpura is a related disorder that should

be differentiated from ANCA-associated vasculitis. It is charac-

terized by immunodeposition of immunoglobulin A (IgA). It is

the commonest vasculitis in children.

Secondary vasculitides include leucocytoclastic vasculitis,

rheumatoid vasculitis and systemic lupus erythematosus (SLE)

vasculitis.

Lorraine Harper PhD MRCP is a Senior Lecturer/Consultant Nephrologist

at the University of Birmingham and Queen Elizabeth Hospital

Birmingham, UK and is currently Secretary of the Renal Association.

Competing interests: none declared.

Mark A Little PhD MRCPI is a Senior Lecturer/Consultant Nephrologist at

University College London and Royal Free Hospital, London, UK.

Competing interests: none declared.

MEDICINE 38:2 84

Primary small vessel vasculitis

Aetiology and pathogenesis

The aetiology of primary small vessel vasculitis is unknown.

However, significant advances have been made in understanding

disease pathogenesis. The strong clinical association with ANCA

suggests an autoimmune disease and implies that these anti-

bodies are directly pathogenic.1 A report of the development of

ANCA-associated vasculitis in a neonate following maternal

transfer of anti-myeloperoxidase (MPO) ANCA adds weight to

the clinical evidence that ANCA are pathogenic. Animal models

also support this view.2,3 In one model, MPO knockout mice

were immunized with murine MPO. Anti-MPO antibodies, puri-

fied from the serum of immunized animals, were transferred to

wild-type mice that express MPO. The recipient mice developed

pauci-immune focal necrotizing crescentic nephritis, demon-

strating that anti-MPO antibodies alone were sufficient to cause

disease in this setting. A rat model shows development of typical

pauci-immune nephritis when rats develop ANCA following

immunization with human MPO. No good model of granulo-

matous inflammation exists, but passive transfer of anti-PR3

antibodies into a mouse exacerbates local cutaneous inflamma-

tion following tumour necrosis factor administration.4

ANCA activate cytokine-primed neutrophils and monocytes,

which express the target antigens PR3 and MPO on the cell

surface. Neutrophils respond by generating a respiratory burst,

degranulating, and secreting pro-inflammatory cytokines. Endo-

thelial cells are also important in localizing inflammation. These

cells are important for maintaining an anticoagulant and anti-

inflammatory environment. In response to cytokines, endothelial

cells take on an activated phenotype, with enhanced expression

of adhesion molecules that allow interaction with circulating

leukocytes, and release factors promoting thrombosis. ANCA

activation of neutrophils in this environment promotes stationary

adhesion to endothelial cells and transmigration, releasing

inflammatory factors in the wrong place and thereby promoting

endothelial damage.

Activation of neutrophils and endothelial cells is important for

the early development of vasculitic lesions and progression is

accompanied by recruitment of T cells and monocytes. Several

studies have suggested that T cells can proliferate in response to

� 2009 Elsevier Ltd. All rights reserved.


MPO or PR3 exposure and that they remain activated despite

disease remission, suggesting that T cells contribute to the rela-

psingeremitting nature of ANCA-associated vasculitis.

Environmental and genetic factors also influence disease

pathogenesis. Autoimmune diseases are often associated with

major histocompatibility antigens but no consistent associations

are reported with primary small vessel vasculitis. There is an

association between deficiency of a1-antitrypsin (the main

inhibitor of PR3) and Wegener’s granulomatosis. Patients

carrying the main deficiency allele, PiZ, have more severe

disease and a poor prognosis. However, a1-antitrypsin deficiency

per se is not sufficient to induce vasculitis, suggesting that it acts

as a ‘second-hit’ amplifier of inflammation. Neutrophil surface

expression of PR3 is also genetically determined and individuals

expressing large amounts of PR3 on the neutrophil surface are

also more likely to develop disease.5 Patients with MPA and

Wegener’s granulomatosis are more likely to carry poly-

morphisms in CTLA4 and PTPN22 genes that are suggested to be

‘general’ susceptibility factors associated with autoimmune

disease.

ANCA-associated vasculitis can also be precipitated by expo-

sure to drugs, including propylthiouracil, minocycline and

penicillamine. Infectious agents have often been implicated as

initiators of vasculitis and nasal carriage of Staphylococcus

aureus has been associated with relapse in Wegener’s gran-

ulomatosis. Silica exposure, which can also result in granuloma

formation, is associated with an increased risk of ANCA-associ-

ated vasculitis.

Pathology

Small vessel ANCA-associated vasculitides are characterized by

inflammation and necrosis of capillaries, arterioles and venules,

but can also affect larger vessels. In the kidney, the process

primarily affects the glomeruli, leading to focal segmental

necrotizing glomerulonephritis with crescent formation but

without immunoglobulin deposition; this is termed ‘pauci-

immune glomerulonephritis’. There is often an associated inter-

stitial inflammation. Within the kidney, there are no absolute

differences in pathology between MPA and Wegener’s gran-

ulomatosis, although patients with microscopic polyangiitis tend

to have more chronic lesions. In the lung, the findings are usually

of capillaritis, often associated with lung haemorrhage.

Granulomatous lesions occur in Wegener’s granulomatosis

and ChurgeStrauss syndrome but not in MPA. In the lung, there

are often large, ill-defined collections of inflammatory cells near

affected vessels; these can present as cavitating nodules. In the

upper airways, this granulomatous reaction can present as

ulceration. Renal granulomata are probably whole necrotic

glomeruli.

Clinical features

Clinical differentiation between Wegener’s granulomatosis and

MPA is often difficult initially. However, this distinction is not

important clinically, because their treatment and prognosis are

similar. Systemic non-specific symptoms such as malaise, flu-like

symptoms and weight loss are common and can pre-date other

symptoms.6 The archetypal presentation of severe systemic

vasculitis is with a ‘‘pulmonaryerenal syndrome’’, i.e. the

combination of rapidly progressive organ dysfunction in both the

MEDICINE 38:2 85

lung and kidney. The differential diagnosis of this syndrome is

wide (Table 1), but should always have systemic vasculitis near

the top.

Clinical features of Wegener’s granulomatosis: limited disease

e respiratory tract symptoms are common and can be present in

90% of patients at the time of diagnosis. Upper respiratory tract

symptoms include sinusitis, epistaxis, otitis media and hoarse-

ness. Complications of granulomatous inflammation can cause

mucosal ulceration and nasal septal perforation with a saddle

nose. Subglottic stenosis occurs in up to 16% of adults and 48%

of children. It often becomes fixed and irreversible and can cause

life-threatening upper airways obstruction. This so-called limited

disease can have an indolent course for many years before

transforming into systemic disease.

Systemic Wegener’s granulomatosis is characterized by:

� upper respiratory tract involvement

� pulmonary disease

� renal involvement with glomerulonephritis

� ANCA directed against the neutrophil enzyme PR3.

Typically, there are granulomata and small vessel vasculitis.

Patients often present initially with limited upper airways disease

with granulomatous inflammation, though presentation with

a fulminating life-threatening illness is not uncommon.

Clinical features of MPA: MPA is characterized by rapidly

progressive glomerulonephritis, pulmonary disease (often tend-

ing towards a more fibrosing, restrictive lung disease pattern)

and ANCA directed against MPO. Although nasal and upper

airway symptoms can occur, granulomatous tissue destruction is

not seen.

Specific organ involvement in Wegener’s granulomatosis or

MPA: pulmonary involvement e pulmonary involvement is less

common at presentation (45e70%), but occurs in 85% of

patients with Wegener’s granulomatosis at some stage. Patients

can present with asymptomatic pulmonary infiltrates or cough,

haemoptysis, pleuritis or dyspnoea. Life-threatening alveolar

haemorrhage can occur and is associated with poor prognosis.

Pulmonary disease is less common in MPA; approximately 30%

of patients develop pulmonary haemorrhage.


MPA: renal disease e renal disease can range from an active

urinary sediment (containing red cells and casts) to rapidly

progressive glomerulonephritis with severe damage. Renal

involvement in MPA is invariable. So-called idiopathic rapidly

progressive glomerulonephritis, without immune deposits and

with no systemic features of vasculitis, is now considered part of

the spectrum of microscopic polyangiitis. Renal involvement is

not a common presentation (18%) in patients with Wegener’s

granulomatosis, but up to 77% of patients will develop glomer-

ulonephritis at some point.


MPA: other organs e ocular involvement is common and can

present as conjunctivitis, scleritis or uveitis. In those with gran-

ulomatous inflammation, proptosis can occur and is commonly

associated with extensive sinus disease. Optic nerve vasculitis


Differential diagnosis of pulmonaryerenal syndrome

Disease Vasculitis Granulomata ANCA status Features

C Wegener’s granulomatosis Present Present PR3-ANCA See text

C Microscopic polyangiitis Present Absent MPO-ANCA Primary small vessel vasculitis is the most common cause of pulmonary

renal syndrome (>56% of cases)

C ChurgeStrauss syndrome Present Present MPO-ANCA (50%) See text

C Goodpasture’s disease Present Absent Seldom positive

(10e38%)

Linear IgG deposition on glomerular basement membrane

Antiglomerular basement membrane antibody positive

In patients with ANCA, treatment should be as for primary small

vessel vasculitis; prognosis may be better than in those with

antiglomerular basement membrane antibody alone

C Systemic lupus erythematosus Present Absent Seldom positive Antinuclear factor and anti-dsDNA positive

Low C3 and C4

C HenocheSchonlein purpura Present Absent Negative Lung involvement uncommon

IgA deposition in vessel walls and mesangium

C Behcet’s disease Present Absent Negative Diagnosed on clinical criteria

Associated with recurrent oral and genital ulceration, eye

lesions (including uveitis) and skin lesions; renal involvement

usually mild

C Infection Rarely present (e.g.

subacute bacterial

endocarditis)

Absent Negative Pneumonia may be associated with acute tubular necrosis

or interstitial nephritis (rarely)

Subacute bacterial endocarditis may be associated with ANCA-negative

pauci-immune glomerulonephritis

Post-streptococcal glomerulonephritis

Blood cultures, atypical serology and anti-streptolysin-O

titre should be undertaken

ANCA, anti-neutrophil cytoplasm antibodies; dsDNA, double-stranded DNA; IgG, immunoglobulin G; MPO, anti-myeloperoxidase.

Table 1

SYSTEM

ICVASCULIT

IDES

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�2009

Elsevie

rLtd

.All

rights

rese

rved.

Figure 1 Portable chest radiograph from a man with acute pulmonary

haemorrhage, showing bilateral interstitial shadowing.


and retinal artery thrombosis are rare but important complica-

tions. Loss of sight has been reported in 8% of patients. Myalgia

and arthralgia are common. Non-erosive arthritis occurs in up to

28% of patients. Skin disease can manifest as palpable purpura,

ulcers and subcutaneous nodules, and occurs in up to 50% of

patients. The heart (pericarditis, coronary arteritis), nervous

system (mononeuritis multiplex, peripheral neuropathy) and

gastrointestinal tract (haemorrhagic ulceration, bowel perfora-

tion) can also be involved.

Clinical features of ChurgeStrauss syndrome: this is charac-

terized by hypereosinophilia with tissue infiltration, formation of

granuloma and vasculitis. It is less common than Wegener’s

granulomatosis and MPA; the estimated incidence is 2.4/million.

Allergic rhinitis and/or asthma precede the development of

vasculitis, and are often associated with non-specific symptoms.

Asthma is often more severe in the weeks preceding vasculitis. A

rash and mononeuritis multiplex are common presenting

features. Pulmonary involvement includes dyspnoea, alveolar

haemorrhage or pleurisy and is associated with non-specific

pulmonary infiltrates on chest radiography. Cardiac involve-

ment, manifested as myocarditis with eosinophilic infiltration,

coronary artery vasculitis and myocardial infarction, carries

a poor prognosis and is often a late manifestation. Gastrointes-

tinal involvement can present in various ways with pain, diar-

rhoea and ascites. Renal involvement is not uncommon (up to

50%) but is usually mild.

Investigations

Routine laboratory investigations: common abnormalities

include leucocytosis, thrombocytosis (>400,000/mm3), normo-

chromic, normocytic anaemia and elevation of inflammatory

markers, including erythrocyte sedimentation rate (ESR) and C-

reactive protein (CRP). ChurgeStrauss syndrome is usually

associated with blood eosinophilia (>1.5 � 109/l) and elevated

IgE concentration.

Urinalysis: urinalysis is a sensitive marker of renal involvement.

An active urinary sediment with red blood cells and casts indicates

glomerular disease. Proteinuria is often present. Elevated urea and

creatinine concentrations are common, though active renal

disease can be present even if biochemical indices are normal.

ANCA: ANCA are a very useful marker for diagnosis. Please see

section on auto-antibodies for a full description. Wegener’s

granulomatosis is associated with ANCA directed against PR3

(PR3-ANCA) and MPO-ANCA are found in microscopic poly-

angiitis (70%, although PR3-ANCA can also occur). Of patients

with ChurgeStrauss syndrome, 50% are positive for MPO-

ANCA, usually in the setting of vasculitic disease. However, the

positive predictive value of a positive test for ANCA is very

dependent on the clinical situation.

Chest radiography: pulmonary haemorrhage is the most serious

form of lung involvement and is seen as diffuse pulmonary

shadowing (Figure 1) associated with a low haemoglobin, low

arterial pO2 and raised corrected transfer factor. In Wegener’s

granulomatosis, chest radiography commonly shows pulmonary

nodules that often cavitate. Other radiographic features include

MEDICINE 38:2 87

reticulonodular shadowing, pneumonic changes, collapse and

pleural involvement with effusions.

Tissue biopsy: tissue biopsy confirms disease. The kidney is

usually the best site for diagnosis. Renal biopsy is characterized

by necrotizing small vessel vasculitis, with fibrinoid necrosis and

pauci-immune crescent formation. In Wegener’s granulomatosis,

nasopharyngeal or transbronchial biopsy often shows non-

specific inflammation. Lung biopsy generally requires an open

procedure, and special stains and cultures should be undertaken

to exclude the presence of infections that can produce gran-

ulomata, vasculitis and necrosis.

Management

Vasculitis must be recognized and treated early before perma-

nent scarring occurs; left untreated, these conditions have

a mortality of 80% at 2 years. Treatment must be tailored to the

stage and severity of disease (Table 2), to balance the dangers of

disease damage against those of treatment-related toxicity.

Opportunistic infections are common, and prophylactic anti-

fungal agents and Pneumocystis carinii prophylaxis (e.g. alter-

nate-day co-trimoxazole) are useful.

Bone protection with bisphosphonates (in those with an

estimated glomerular filtration rate (eGFR) >30 ml/min) or

calcium and vitamin D supplements should be considered, and

those at high risk of reduced mineral density should be screened

with bone densitometry. Adverse effects of cyclophosphamide

(e.g. haemorrhagic cystitis, bladder cancer, lymphoma, bone

marrow suppression, infertility) are related to the cumulative

dose. Patients of child-bearing age should be counselled about

the risks of infertility and gamete storage should be offered.

Patients taking long-term azathioprine should be examined

regularly for cutaneous malignancies.

Acute disease e induction therapy: in general, initial treatment

should include cyclophosphamide and high-dose corticosteroids, the

dosages of which are reduced as inflammation resolves.7 Remission

is achieved in approximately 90% of patients by 6 months. Results of

a recent large multi-centre trial of 150 patients, comparing pulsed

cyclophosphamide every 2-3 weeks with standard continuous oral

cyclophosphamide, concluded that the two regimens are equally

effective but that the pulsed regimen had a lower cumulative dose of

cyclophosphamide, suggesting that this is a safer way to administer


Management of primary small vessel vasculitis

Induction therapy C Continued for 3 months following remission

C Prednisolone, 1 mg/kg, maximum dose 80 mg; rapid reduction in corticosteroid dose e 50%

over 2 weeks and to a dose of 0.25 mg/kg at week 8

C Pulsed cyclophosphamide e 10 pulses over 25 weeks, 15 mg/kg i.v.; dose reductions must be

made for age and raised creatinine

C Continuous cyclophosphamide can also be given, 2 mg/kg/day p.o., maximum dose 200 mg;

age >60 years reduce by 25%, age >70 years reduce by 50%

C WBC count must be checked between day 10 and day 14 following pulse; if <3 � 109/l,

a suitable dose reduction must be made for the next pulse

Adjuvant therapy for life-threatening disease C Life-threatening disease includes creatinine >500 mmol/l and/or pulmonary haemorrhage

C Plasma exchange should be strongly considered

Maintenance therapy C Prednisolone, 5e10 mg/day

C Azathioprine, 1.5 mg/kg/day, maximum dose 200 mg

C Methotrexate 20e25 mg/week (contraindicated in patients with creatinine >170 mmol/l)

C Alternatives to azathioprine include mycophenolate mofetil, 1 g 12-hourly

C Consider addition of co-trimoxazole

Relapse therapy C Major relapse e return to initial induction therapy

C Minor relapse e increase corticosteroid dose

Rescue therapy for relapsing and refractory

disease

C Standard induction therapy fails to induce remission in 10% of patients; patients who

frequently relapse necessitating recurrent use of cyclophosphamide are also a difficult group

C Newer therapies that may prove beneficial include B cell depletion with rituximab, polyclonal

anti-thymocyte globulin, deoxyspergualin and other newer immunosuppressant drugs that have

shown promise in organ transplantation

WBC, white blood cell.

Table 2


this agent.8 There remains uncertainty whether reducing the cumu-

lative dose of cyclophosphamide increases the risk of long-term

relapse. In those with severe disease (creatinine >500 mmol/l or

pulmonary haemorrhage) plasma exchange should be added to the

standard induction regimen.9 There is currently no evidence to

support theuseofplasmaexchangeandmethylprednisolone together

and in combination may increase the risk of infection. In those

without critical organ involvement or extensive disease, metho-

trexate may be used instead of cyclophosphamide for induction

therapy but this is associatedwithan increased relapse rate.10 Clinical

trials are in progress to assess the use of mycophenolate mofetil and

anti-CD20 antibodies (rituximab) as alternatives to cyclophospha-

mide induction regimens.

Maintenance of remission: following induction of remission,

azathioprine should be substituted for cyclophosphamide.

In a large randomized controlled trial following induction

therapy, azathioprine substitution was as effective as cyclo-

phosphamide continued for a year in maintaining disease

remission.7 Long-term azathioprine is associated with fewer

adverse events than cyclophosphamide. In those with normal

renal function methotrexate may be used. Alternative agents

include mycophenolate mofetil or leflunomide. The results of

a large randomized controlled trial comparing mycophenolate

mofetil with azathioprine for maintenance of remission will be

available at the end of 2009. In a small study for maintenance of

remission in 54 patients, leflunomide use was associated with

less relapse but greater toxicity than methotrexate.

MEDICINE 38:2 88

Management of resistant disease: standard induction therapy

fails to induce remission in approximately 10% of patients. A

further group of difficult patients comprises those who relapse

frequently, necessitating recurrent use of cyclophosphamide.

Rituximab, a CD20 B cell-depleting antibody, has been

reported to induce disease remission in several reports in

those with refractory disease. Disease can recur with B cell

repletion and some subsets of disease may be less responsive

(e.g. chronic granulomatous disease). Rituximab was licensed

for treatment of non-Hodgkin lymphoma and has a good

safety and tolerability profile. It has shown promise in many

autoimmune diseases and two randomized controlled studies

in patients with new-onset ANCA-vasculitis will report in

2010. The use of anti-TNFa therapy in systemic vasculitis,

although supported by initial uncontrolled studies, has fallen

from favour following publication of a negative randomized

controlled trial of etanercept in resistant Wegener’s gran-

ulomatosis.11 Subjects in this trial had relapsing granuloma-

tous disease and use of this agent is not recommended in this

setting.

Other therapies in small series have also suggested benefit in

refractory patients. Anti-thymocyte globulin (a T cell-depleting

polyclonal antibody directed against surface antigens of activated

T cells) and deoxyspergualin (an immunosuppressant success-

fully used in renal allograft rejection) have both shown benefit in

patients with vasculitis, including those with granulomatous

disease. Adverse effects are not uncommon with these treat-

ments and they should not be used routinely.



Management of ChurgeStrauss syndrome: corticosteroids are

the mainstay of treatment in ChurgeStrauss syndrome.

However, cyclophosphamide should be added in those with

severe disease. Disease severity can be assessed using the five

factor score (1 point for each: creatinine >140 mmol/l, protein-

uria >1 g, severe GI involvement, cardiomyopathy and central

nervous system (CNS) signs). Cyclophosphamide improves

survival in those with a five factor score of more than 2.12

Monitoring during treatment: regular white blood cell (WBC)

monitoring is essential. Patients should undergo blood tests twice

weekly in the first month, on alternate weeks in the second

month and monthly thereafter. If the WBC count falls below 4 �109/l, cyclophosphamide or azathioprine should be discontinued

and re-started at a lower dose once the count has recovered. An

urgent WBC count should be performed in patients with signs of

infection. Allopurinol (a xanthine oxidase inhibitor) is contra-

indicated in those taking azathioprine, because of the high risk of

bone marrow suppression.

Relapse

It is unclear for how long maintenance immunosuppressive

therapy should be continued; most physicians recommend at

least 2 years. Relapse (50% by 5 years) can occur at any time,

and patients should be reviewed regularly (3-monthly) to detect

early signs of disease recurrence and drug toxicity. Relapse

occurs more commonly in Wegener’s granulomatosis and in

those who remain ANCA positive. ANCA testing should be per-

formed at each review. Indicators of relapse include:

� recurrence of symptoms (these may differ from the original

presentation)

� rising inflammatory markers (CRP, ESR)

� recurrence of or rising ANCA titre (patients who remain

ANCA positive may be at greater risk of relapse)

� reappearance of haematuria and/or granular casts in urine

� increased serum creatinine.

Treatment depends on the severity of the relapse. Following

a major relapse, induction therapy as described above should be

re-started, whereas a minor relapse can be managed by

increasing corticosteroid dosage. Escalation of therapy should

not be based solely on a rising ANCA titre. Whereas the titre

generally correlates with clinical activity, the positive predictive

value of an increasing titre varies (20e80%), depending on the

study.

Prognosis

Figure 2 This purpuric rash has coalesced to form necrotic patches. The

differential diagnosis includes primary small vessel vasculitis and

HenocheSchonlein purpura. The rash associated with HenocheSchonlein

purpura usually involves the buttocks and extensor aspects of the lower

limbs. It usually resolves within 1 month, but fresh crops often appear.

Survival is currently 70e80% at 5 years. Early death is usually

a consequence of opportunistic infection. Poor prognostic indi-

cators include greater age, pulmonary haemorrhage and severe

renal disease. End-stage renal disease occurs in 20e25% of

patients. With improved survival, long-term damage from

disease and drug toxicity are major problems.

HenocheSchonlein purpura

HenocheSchonlein purpura is a systemic vasculitis characterized

by IgA deposition. It is most common in children, often occurring

before the age of 5 years, though it can occur at any age. The

aetiology is unknown, but the condition commonly follows an

upper respiratory infection.

MEDICINE 38:2 89

It is characterized by:

� rash, usually affecting the buttocks and lower limbs (100%)

(Figure 2)

� arthralgia (75%)

� gastrointestinal involvement, with abdominal pain and

bloody diarrhoea (30e40%)

� glomerulonephritis (50%),oftenmoreseverewith increasingage.

Other organs, including the CNS (seizures) and lung

(pulmonary haemorrhage), can also be involved.

Diagnosis

This is based on clinical symptoms and confirmed by tissue

biopsy. Skin biopsy reveals leucocytoclastic vasculitis with IgA

deposition in the blood vessels or dermo-epidermal junction.

Renal histology can vary from mild mesangial proliferation to

focal segmental necrotizing glomerulonephritis, but always

shows IgA deposition in the mesangium. Renal biopsy should be

performed in patients with proteinuria and haematuria, because

the severity of renal involvement (particularly the number of

crescents) is important for prognosis.

Management

HenocheSchonlein purpura is usually self-limiting and requires

only symptomatic relief. Immunosuppressants should be

considered in patients with renal involvement, particularly those

with severe disease. Uncontrolled studies have suggested benefit

in patients with poor prognostic indicators, though no random-

ized controlled studies have been performed.

Prognosis

In most patients, the prognosis is excellent. In those with renal

involvement, however, damage may persist and progress

without signs of active disease. The course of the renal lesion is

often worse in older patients. Relapses are common, particularly

in patients with nephritis.

Secondary vasculitides

Leucocytoclastic cutaneous vasculitis

Leucocytoclastic vasculitis is also known as cutaneous vasculitis

or hypersensitivity vasculitis, and is often part of a systemic



disorder (Table 3). Most cases are caused by exposure to drugs,

such as penicillin, cephalosporins, sulphonamides (including

most loop and thiazide-type diuretics), phenytoin and allopu-

rinol. Lesions are manifested as palpable purpura and atypical

urticarial lesions. Livedo reticularis, ulcerations and necrosis also

occur.

Pathology: leucocytoclastic vasculitis is characterized by fibri-

noid necrosis of the vessel walls with infiltration of neutrophils,

some of which are disrupted, resulting in the presence of nuclear

debris within the tissue. With repair mechanisms, a mononuclear

infiltrate can develop and become evident when biopsies are

taken late.

Investigations: patients who present with leucocytoclastic

vasculitis should be investigated to find a cause and to assess the

presence and severity of systemic disease. The diagnosis is often

suggested by the clinical findings and the history of an offending

drug or infection, and will influence other investigations. Patients

in whom there is no obvious cause should be screened for

systemic disease (Table 4).

Management: management depends on the presence or absence

of systemic involvement and whether a secondary cause is

identified. Symptomatic relief alone is often adequate in patients

with isolated cutaneous involvement, though injury to other

organs may mandate immunosuppression. The need for treat-

ment should be weighed against the toxicity of immunosup-

pressive therapies. Antihistamines and colchicine have also been

effective.

Rheumatoid vasculitis

Rheumatoid vasculitis is a small vessel vasculitis, though

medium-sized vessels can also be involved. It typically presents

in patients with severe destructive rheumatoid arthritis (RA) and

rheumatoid nodules, and is associated with high rheumatoid

factor levels. Clinically evident vasculitis occurs in 2e5% of

patients; subclinical disease is more common.

Clinical features: cutaneous disease, manifested as purpura, is

the most common symptom of rheumatoid vasculitis. Vasculitic

Systemic disease associated with leucocytoclasticvasculitis

C Other vasculitic syndromes e Wegener’s granulomatosis,

microscopic polyangiitis, HenocheSchonlein purpura

C Autoimmune rheumatic disorders e rheumatoid arthritis, systemic

lupus erythematosus, dermatomyositis

C Infections e hepatitis B and C (often from cryoglobulins), HIV,

streptococci, subacute bacterial endocarditis

C Dysproteinaemia e cryoglobulinaemia, Waldenstrom’s

macroglobulinaemia

C Others e inflammatory bowel disease, neoplasia, a1-antitrypsin

deficiency

Table 3

MEDICINE 38:2 90

ulceration and, less commonly, pyoderma gangrenosum can

occur. Isolated nail-fold infarcts are not predictive of rheumatoid

vasculitis. Peripheral neuropathy is common; 40% of patients

have sensory neuropathy, and mononeuritis multiplex can also

be present. CNS involvement occurs rarely. Eye disease mani-

fests as necrotizing scleritis, which can result in scleral ulcera-

tion. These patients often require surgical intervention in

addition to cytotoxic therapy. Necrotizing scleritis must be

distinguished from other ocular conditions, such as non-necro-

tizing scleritis and episcleritis or keratoconjunctivitis sicca,

which are not as threatening to the eye and do not indicate the

presence of vasculitis.

Renal disease in RA is often associated with nephrotic

syndrome caused by membranous nephropathy following gold or

penicillamine therapy or amyloid deposition. About one-quarter

of patients with rheumatoid vasculitis have renal involvement;

focal segmental necrotizing glomerulonephritis without immu-

noglobulin deposition has most often been reported. Presentation

is with microscopic haematuria, proteinuria and renal

impairment.

Diagnosis and investigations: rheumatoid vasculitis should be

suspected in any patient with a long history of RA or juvenile

arthritis who develops new extra-articular or constitutional

symptoms such as weight loss, fever and/or lethargy. Tissue

biopsy of the affected organ should be undertaken whenever

possible because of the poor prognosis of untreated systemic

vasculitis and toxicity of treatment.

Laboratory findings include raised inflammatory markers

(CRP and ESR) and high concentrations of IgM and IgG rheu-

matoid factor, although these are not good markers of clinical

activity. Antinuclear antibody is present in most cases of rheu-

matoid vasculitis. Atypical ANCA (commonly against lactoferrin)

may be present, but it is unclear whether they are involved in the

pathogenesis.

Management: isolated skin vasculitis may be treated with

corticosteroids. Biopsy-proven systemic vasculitis must be

treated aggressively. Regimens similar to those for primary

Patient evaluation in leucocytoclastic vasculitis

C History e drugs, infection, previous history of systemic disease,

systemic symptoms

C Examination e physical examination, urinalysis

C Skin biopsy e light microscopy, immunofluorescence for IgA

C Laboratory tests e full blood count, urea and electrolytes,

inflammatory markers (C-reactive protein and ESR), autoantibody

screen (antinuclear antibodies, dsDNA, ANCA, rheumatoid factor,

complement), hepatitis B and C, cryoglobulins and protein

electrophoresis, blood cultures

ANCA, anti-neutrophil cytoplasm antibodies; dsDNA, double-stranded DNA;

ESR, erythrocyte sedimentation rate; IgA, immunoglobulin A.

Table 4


Systemic lupus erythematosus and vasculitis e organ involvement

Skin

C Purpuric lesions, digital pulp infarcts, livedo reticularis; may be associated with Raynaud’s syndrome

C Note that patients with SLE are at increased risk of drug allergies; development of new rashes should raise the possibility of drug reactions

CNS

C True CNS vasculitis occurs in <10% of patients; symptoms range from mild cognitive dysfunction to psychosis, seizures and ischaemia

C MRI is often unhelpful; it may reveal periventricular white matter lesions but is not diagnostic

Cardiovascular systemC Extramural arteries may be involved, resulting in myocardial infarction (rare)

C Coronary artery disease is common as a result of accelerated atherosclerosis

Mesenteric vasculitis

C With or without infarction: a serious complication

C Presents with acute abdomen, fever and vomiting; may have an insidious onset

C High mortality

C Often associated with renal disease and other internal organ vasculitis

Kidney

C Focal segmental necrotizing glomerulonephritis with fibrinoid necrosis (rare)

C Distinguished from primary systemic vasculitis by deposition of immunoglobulin and complement

CNS, central nervous system; MRI, magnetic resonance imaging; SLE, systemic lupus erythematosus.

Table 5


systemic vasculitis should be used. Relapses occur in up to 25%

of patients.

SLE and vasculitis

Vasculitis is uncommon in patients with SLE, occurring in

approximately 10% of patients.

Clinical features (Table 5): cutaneous vasculitis is the most

common feature (90% of those with vasculitis). Other organ

involvement is uncommon. Many patients have constitutional

symptoms and other features of active SLE when they develop

vasculitis. Those patients with vasculitis are more likely to have

livedo reticularis, have higher scores of disease activity and have

anti-La/SS-B antibodies.13 The CNS is commonly affected in

patients with SLE, but true CNS vasculitis is uncommon.

Microvascular capillaritis can occur in the kidneys, leading to

abnormal urinalysis and rapidly deteriorating renal function, and

less commonly in the lungs, where it can manifest as pulmonary

haemorrhage.

Investigations: vasculitis occurs most often in patients with

active disease. Complement concentrations are often low and

double-stranded DNA (dsDNA) antibody titres high. ESR is

usually elevated, often in the context of a normal CRP level.

Antiphospholipid antibodies may be present. Regular urinalysis

is essential. The threshold for renal biopsy should be low in any

patient with cutaneous vasculitis.

Management: vasculitis in SLE requires early and aggressive

treatment with corticosteroids and cyclophosphamide. Intrave-

nous pulse cyclophosphamide may be less toxic than daily oral

therapy. Anticoagulation should be considered if anti-

phospholipid antibodies are present or the patient has neuro-

logical vasculitis. A

MEDICINE 38:2 91

REFERENCES

1 Morgan MD, Harper L, Williams J, Savage C. Anti-neutrophil cyto-

plasm-associated glomerulonephritis. J Am Soc Nephrol 2006; 17:

1224e34.

2 Xiao H, Heeringa P, Liu Z, et al. The role of neutrophils in the

induction of glomerulonephritis by anti-myeloperoxidase antibodies.

Am J Pathol 2005; 167: 39e45.

3 Little MA, Smyth CL, Yadav R, et al. Antineutrophil cytoplasm anti-

bodies directed against myeloperoxidase augment leukocytemicro-

vascular interactions in vivo. Blood 2005; 106: 2050e8.

4 Pfister H, Ollert M, Frohlich LF, et al. Antineutrophil cytoplasmic

autoantibodies against the murine homolog of proteinase 3

(Wegener autoantigen) are pathogenic in vivo. Blood 2004; 104:

1411e18.

5 Jagiello P, Gross WL, Epplen JT. Complex genetics of Wegener gran-

ulomatosis. Autoimmun Rev 2005; 4: 42e7.

6 Savage CO. ANCA-associated renal vasculitis. Kidney Int 2001; 60:

1614e27.

7 Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of

maintenance therapy for vasculitis associated with anti-

neutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:

36e44.

8 de Groot K, Harper L, Jayne D, et al. Pulse versus daily oral cyclo-

phosphamide for induction of remission in antineutrophil cyto-

plasmic antibody-associated vasculitis: a randomized trial. Ann

Intern Med 2009; 150: 670e80.

9 Jayne DRW, Gaskin G, Rasmussen N, et al. Randomised trial of plasma

exchange versus methyl prednisolone for severe renal vasculitis.

N Engl J Med 2007; 18: 2180e8.

10 De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial

of cyclophosphamide versus methotrexate for induction of

remission in early systemic antineutrophil cytoplasmic

antibody-associated vasculitis. Arthritis Rheum 2005; 52:

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Practice points

C Perform an ANCA test (as part of a full autoantibody screen) in

any patient with an undiagnosed multi-system illness, partic-

ularly when there is involvement of the upper respiratory tract,

lungs or kidneys

C A negative ANCA test does not exclude primary small vessel

vasculitis

C Manage the patient with systemic vasculitis with help from

a specialist centre; careful monitoring of clinical and labora-

tory markers of disease activity guides treatment and allows

early detection of relapse

C Any vasculitic rash should be taken seriously and efforts made

to find a cause; a systemic cause should be considered if there

is no obvious drug or infectious cause

C The threshold for renal investigation, including biopsy, should

be low in patients with cutaneous vasculitis

C Necrotizing scleritis in RA must be detected early and differ-

entiated from other eye lesions to preserve sight

C Vasculitis is uncommon in patients with SLE or RA, but should

be considered with active disease and atypical symptoms


11 Etanercept plus standard therapy for Wegener’s granulomatosis.

N Engl J Med 2005; 352: 351e61.

12 Guillevin L, Cohen P, Mahr A, et al. Treatment of polyarteritis nodosa

and microscopic polyangiitis with poor prognosis factors:

a prospective trial comparing glucocorticoids and six or twelve

cyclophosphamide pulses in sixty-five patients. Arthritis Rheum

2003; 49: 93e100.

13 Ramos-Casals M, Nardi N, Lagrutta M, et al. Vasculitis in systemic

lupus erythematosus: prevalence and clinical characteristics in 670

patients. Medicine (Baltimore) 2006; 85: 95e104.

FURTHER READING

Adu D, Tse WY. Rheumatoid arthritis, mixed connective tissue disease and

polymyositis. In: Adu A, Emery P, Madaio M, eds. Rheumatology and

the kidney. Oxford: Oxford University Press, 2001: 293e304.

(This chapter focuses on rheumatoid vasculitis)

Ball E, Knight J, Bridges Jr SL, eds. Vasculitis. Oxford: Oxford University Press,

2001.

(A comprehensive overview of many forms of vasculitis, including

Wegener’s granulomatosis and HenocheSchonlein nephritis)

Buhaescu I, Covic A, Levy J. Systemic vasculitis: still a challenging disease.

Am J Kidney Dis 2005; 46: 173e85.

(A recent review of treatment, well referenced for further reading)

Danning CL, Illei GG, Boumpas DT. Vasculitis associated with primary

rheumatologic diseases. Curr Opin Rheumatol 1998; 10: 58e65.

(A good overview of vascultis in RA and SLE)

D’Cruz D. Vasculitis in systemic lupus erythematosus. Lupus 1998; 7:

270e4.

(Includes additional information on treatment and pathogenesis)

MEDICINE 38:2 92

Levy J, Pusey CD. Systemic vasculitis. In: Davison AM, Cameron JS,

Grunfeld J-P, Kerr DS, Ritz E, Winearls CG, eds. Oxford textbook of

clinical nephrology. Oxford: Oxford University Press, 2005:

559e78.

(A review of renal involvement in primary small vessel vasculitis)


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Small vessel vasculitides