Systemic vasculitides: anoverviewRachel B Jones

SYSTEMIC VASCULITIDESCaroline O S Savage

AbstractSystemic vasculitides comprise a collection of disorders characterized by

the presence of fibrinoid necrosis and inflammation of blood vessels. This

article provides an overview for small, medium and large vessel

vasculitides.

Keywords ANCA; anti-neutrophil cytoplasm antibodies; blood vessel

disorders; systemic vasculitis

Spectrum of vasculitis

There is no classification of vasculitis that is accepted without

dispute.1 One reason for this is the lack of an aetiological factor in

most types of vasculitis.

Vasculitic disorders can be divided into primary and sec-ondary, distinguishing vasculitides in which the vasculitic

process is the main focus of tissue injury (e.g. giant cell

arteritis, microscopic polyangiitis) from those deemed to be

associated with another underlying disease (e.g. systemic

lupus erythematosus, rheumatoid arthritis, malignancy).

Another division is between vasculitides associated withthe presence of anti-neutrophil cytoplasmic antibodies

(ANCA) and those in which ANCA are seldom detected.

The three ANCA-associated forms of vasculitis are gran-

ulomatosis with polyangiitis (GPA; previously known as

Wegeners granulomatosis), microscopic polyangiitis

(MPA) and eosinophilic granulomatosis with polyangiitis

(EGPA; previously known as ChurgeStrauss syndrome).

Closer to a system of classification is subdivision of theprimary systemic vasculitides according to the predomi-

nant size and type of the vessel affected and/or whether

there are associated granulomata (Table 1).

Despite the term systemic, vasculitis can be localized to a single

organ and does not invariably become systemic. This is illustrated

by so-called idiopathic rapidly progressive glomerulonephritis,

which is now recognized as a form of microscopic polyangiitis

limited to the kidney. A limited form of GPA affecting the head and

neck also occurs; this is usually granulomatous rather than vascu-

litic initially, but can develop into a systemic vasculitic disease.

Definitions

The primary systemic vasculitides are the most difficult to define

because of the lack of known aetiological factors in most cases

Rachel B Jones MD MRCP is a Consultant Nephrologist at Addenbrookes

Hospital, Cambridge, UK. Conflicts of interest: none declared.

Caroline O S Savage PhD FRCP FMedSci is an Honorary Consultant

Nephrologist, at the University of Birmingham, UK.MEDICINE 42:3 134and the overlap of clinical features between syndromes. Never-

theless, several syndromes have been recognized. In 1994, an

international consensus conference attempted to define the main

syndromes to facilitate international understanding and aware-

ness, and because of advances in understanding in 2012 the

definitions were updated.2

Relationship to age

Vasculitis can occur at any age, but the clinical syndromes with

which it is associated show age-specific differences:

Kawasakis disease is seen only in children HenocheSchonlein purpura occurs mainly in children, but

can present in adults

MPA and GPA are generally present in adults with a peakincidence in the 60e70-year age range

giant cell arteritis is predominantly a disease of peopleolder than 50 years.

Importance of diagnostic precision

Distinguishing subsets of vasculitis is justified because the

aetiological factors or pathogenic mechanisms are likely to differ,

the requirements for therapy differ, and prognosis varies

between different syndromes. Precision is also necessary for

therapeutic, epidemiological and national or international

studies.

Vasculitides are medical emergencies. Organ survival can be

threatened if a diagnosis is not made quickly and accurately,

enabling implementation of appropriate therapy. Blindness can

occur in an elderly patient in whom giant cell arteritis is missed,

cardiac infarction can occur in a child with Kawasakis disease,

and renal failure and life-threatening lung haemorrhage can

develop in an adult with MPA or GPA. If in doubt about a

diagnosis, consult an appropriate specialist.

New approaches to therapy

In recent years, understanding of how best to apply established

therapies has increased, and some new therapeutic agents have

been introduced.

In the ANCA-associated vasculitides, cyclophosphamide and

corticosteroids have been the main treatments for 30 years. The

majority of treatment trials have focused on ANCA-associated

vasculitis, grouping patients with GPA and MPA together. Re-

sults of trials have helped optimize and reduce the use of cyclo-

phosphamide and evaluate other immunosuppressive agents.3

The CYCAZAREM trial has indicated that shorter courses of

cyclophosphamide followed by azathioprine are as effective as 12

months of cyclophosphamide, so cyclophosphamide can now be

safely switched to azathioprine after 3e6 months.4 The CYCLOPS

trial demonstrated that intravenous cyclophosphamide is as good

as oral cyclophosphamide for remission induction with less cu-

mulative exposure.5 The MEPEX trial has shown that plasma ex-

change improves the likelihood of recovery of renal function,

compared to pulses of methylprednisolone, when used in

conjunction with cyclophosphamide and prednisolone in patients

presentingwith severe renal disease (defined as a serumcreatinine

>500 mmol/L)6 and the role of plasma exchange is now being

further evaluated in the ongoing PEXIVAS trial (NCT00987389). 2014 Published by Elsevier Ltd.

Definitions for the vasculitides adopted by the 2012 International Chapel Hill Consensus Conference on theNomenclature of Vasculitis

Large vessel vasculitis (LVV)

C Giant cell arteritis (GCA) Granulomatous arteritis of the aorta and its

major branches, with a predilection for

carotid, vertebral and temporal arteries

Usually occurs >50 years of age

Often associated with polymyalgia rheumatica

C Takayasus arteritis (TAK) Granulomatous arteritis of the aorta and its

major branches

Usually occurs

d b

ia a

r ar

ies

pa

t ar

mbo

ane

pa

rte

ries

an

r v

syst

SYSTEMIC VASCULITIDESTable 1 (continued )

C Hypocomplementaemic urticarial vasculitis

(HUV) (anti-C1q vasculitis)

Vasculitis accompanie

hypocomplementaem

(capillaries, venules o

with anti-C1q antibod

Variable vessel vasculitis (VVV)C Behcets disease (BD) Vasculitis occurring in

disease that can affec

vessel vasculitis, thro

arteritis, and arterial

C Cogans syndrome (CS) Vasculitis occurring in

syndrome, including a

medium, or large arte

aneurysms, and aortic

Single organ vasculitis (SOV) Vasculitis in arteries o

single organ withoutThe NORAM trial showed that methotrexate was as effective as

cyclophosphamide for induction of remission in patientswith GPA

in whom there was no major renal involvement.7 The WEGENT

trial showed that methotrexate was as good as azathioprine for

remission maintenance (for patients without severe renal dis-

ease).8 The RAVE and RITUXVAS trials found rituximab-based

regimens to have similar efficacy to cyclophosphamide for se-

vere active vasculitis.9,10 Ongoing trials are evaluating the role of

repeat rituximab dosing as a remission maintenance strategy.

Anti-tumour necrosis factor-a (anti-TNFa) therapies, gave initial

promising results in pilot studies, but the efficacy of etanercept

was not confirmed in a randomized controlled trial of GPA.11

Ongoing studies are evaluating newer agents, including abata-

cept, belimumab (anti-B lymphocyte stimulator) and an anti-

complement therapy (C5a receptor antagonist).

In hepatitis B-associated polyarteritis nodosa, use of the anti-

viral agent, lamivudine, aids viral clearance, attainment of which

greatly reduces the risk of relapse.12

In large vessel vasculitis, the anti-TNFa therapy, infliximab,

has shown promise for Takayasus arteritis, and in uncontrolled

studies the anti IL-6 therapy, tocilizumab, has shown promise for

Examples include, cutane

vasculitis, testicular arter

system vasculitis

Vasculitis associated with systemic disease Vasculitis that is associat

secondary to (caused by)

Vasculitis associated with probable aetiology Vasculitis that is associat

specific aetiology

Large arteries are the aorta and the largest branches directed towards major body

Medium-sized arteries are the main visceral arteries (e.g. renal, hepatic, coronary, m

Small arteries are distal arterial radicals that connect with arterioles.

Note that some small and large vessel vasculitides can involve medium-sized arteries

than arteries.

IgA, immunoglobulin A.

Table 1

MEDICINE 42:3 136y urticaria and

ffecting small vessels

terioles), associated

Glomerulonephritis, arthritis, obstructive

pulmonary disease and ocular inflammation

common

tients with Behcets

teries or veins. Small

angiitis, thrombosis,

urysms may occur

Behcets disease is characterized by recurrent

oral and/or genital aphthous ulcers

accompanied by cutaneous, ocular, articular,

gastrointestinal, and/or central nervous

system inflammatory lesions

tients with Cogans

ritis (affecting small,

), aortitis, aortic

d mitral valvulitis

Cogans syndrome is characterized by ocular

inflammatory lesions, including interstitial

keratitis, uveitis, and episcleritis, and inner

ear disease, including sensorineural hearing

loss and vestibular dysfunction

eins of any size in a

emic features

Vasculitis distribution may be unifocal or

multifocal (diffuse) within an organgiant cell arteritis and is under investigation in randomized

trials. A

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2014 Published by Elsevier Ltd.

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Practice points

C Vasculitis can present to various specialists; diagnosis is easy

if the possibility is included in the differential diagnosis in

relevant clinical situations (e.g. febrile children, pyrexia of

unknown origin)

C Vasculitis of any type should always be regarded as a medical

emergency e early treatment reduces organ damage and fail-

ure, and can save lives

SYSTEMIC VASCULITIDESMEDICINE 42:3 137 2014 Published by Elsevier Ltd.

Systemic vasculitides: an overviewSpectrum of vasculitisDefinitionsRelationship to ageImportance of diagnostic precisionNew approaches to therapyReferences