Guidelines
BSR and BHPR guidelines for the management of adults with ANCA
associated vasculitis
C. Lapraik1, R. Watts2,3, P. Bacon4, D. Carruthers5, K. Chakravarty6, D. D’Cruz7, L. Guillevin8,
L. Harper9, D. Jayne10, R. Luqmani11, J. Mooney12, D. Scott1,2 on behalf of the BSR and
BHPR Standards, Guidelines and Audit Working Group
KEY WORDS: Vasculitis, Guideline, Management, Cyclophosphamide.
Section 1: Scope and purpose
1.1 Background to disease
The primary systemic vasculitides (PSV) are heterogeneous, multi-
system disorders characterized by inflammation and necrosis of
small and medium blood vessels. Their aetiology is unknown.
Three distinct clinico-pathological syndromes, often associated
with anti-neutrophil cytoplasmic antibodies (ANCA) [sometimes
called ANCA associated vasculitis (AAV)], have been identified
and collectively comprise the most common subgroup: Wegener’s
granulomatosis (WG), Churg–Strauss syndrome (CSS) and
microscopic polyangiitis (MPA). Other forms of systemic vascu-
litis (listed in Table 1) are usually ANCA negative, and are defined
by their clinico-pathological features.
There are no validated diagnostic criteria for primary systemic
vasculitis. However, the American College of Rheumatology
(ACR) devised classification criteria for different vasculitides
including WG, CSS and polyarteritis nodosa (PAN) but not
MPA, and the Chapel Hill consensus conference (CHCC)
recommended definitions for WG, CSS, PAN and MPA [1–4].
The CHCC definitions were not intended for classification or
diagnosis but provide a useful description of disease and include
some features that have been used for classification purposes.
Lanham et al. [5] reviewed CSS in 1984 and provided a slightly
different and mainly clinical orientated set of classification criteria
when compared with the ACR for CSS.
The ACR also provided classification criteria for giant cell
arteritis, Takayasu’s arteritis, classical polyarteritis nodosa and
Henoch–Scho¨nlein purpura. The treatment for these conditions is
outside the scope of this review which concentrates on the ANCA
associated vasculitides. However, there are patients with primary
and secondary vasculitis that are treated with cyclophosphamide,
and these guidelines can be used for such conditions although the
references to clinical studies for these conditions have not been
included in this document.
The classification of systemic vasculitis seen in Table 1 is the
most widely accepted classification system [6].
There are several measures of disease activity, severity
and damage such as the Birmingham Vasculitis Activity Score
(BVAS), Vasculitis Damage Index (VDI), the damage extent
index (DEI) and the five factor score. BVAS and VDI are
validated clinical tools that are most widely used as measures of
disease severity, activity and damage [7, 8]. It should be noted
that these do not incorporate ANCA as part of the assessment of
disease activity.
The use of cyclophosphamide and other immunosuppressive
agents has transformed the prognosis of many of the
systemic vasculitides. The natural history of untreated WG and
MPA is of a rapidly progressive, usually fatal disease. Walton
observed a mean survival of 5 months, with 82% of patients
dying within 1 yr and more than 90% dying within 2 yrs in
patients with WG [9]. The introduction of cyclophosphamide
combined with prednisolone resulted in a significant improvement
in mortality of WG with a 5-yr survival rate of 82%,
although there remains considerable morbidity associated with
both disease and treatment [10, 11]. The prognosis is worse
for elderly patients, those with renal disease (especially high
creatinine at presentation), pulmonary involvement, high
ESR and those with a high disease activity and damage
scores [12–17].
Diagnosis. In the early phases of the disease, the symptoms
can be non-specific and a high index of suspicion is required to
1Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich,
2School of Medicine Health Policy and Practice, University of East Anglia, Norwich,
3Department of Rheumatology, Ipswich Hospital NHS Trust, Ipswich, 4Department
of Rheumatology, University of Birmingham, 5Department of Rheumatology, City
Hospital Birmingham, 6Department of Rheumatology, Harrold Wood Hospital,
London, 7Department of Rheumatology, St Thomas’s Hospital, London,
8Department of Internal Medicine, University of Paris-Nord, Paris, 9Department
of Nephrology, Queen Elizabeth Hospital, Birmingham, 10Department of
Nephrology, Addenbrooke’s Hospital, Cambridge, 11Department of
Rheumatology, Nuffield Orthopaedic Centre and University of Oxford, Oxford
and 12School of Nursing and Midwifery, University of East Anglia, Norwich.
Submitted 3 November 2006; revised version accepted 24 April 2007.
Correspondence to: Dr Richard Watts, Consultant Rheumatologist,
Ipswich Hospital NHS Trust, Heath Road, Ipswich IP4 5PD, UK.
E-mail: Richard.watts@ipswichhospital.nhs.uk
Rheumatology 2007;46:1–11 doi:10.1093/rheumatology/kem146b
1
� The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
achieve an early diagnosis. Symptoms that should prompt
consideration of a diagnosis of vasculitis are unexplained systemic
disturbance, arthritis or arthralgia, polymyalgia, episcleritis,
neuropathy, microscopic haematuria, pulmonary infiltrates or
nodules and maturity onset asthma.
Once major organ involvement occurs the diagnosis usually
becomes clear. Unfortunately, the presence of more advanced
disease at diagnosis limits the potential benefit of therapy.
Detailed clinical and laboratory assessments are very important
to provide a full picture of the disease and assist in identifying the
specific type of vasculitis in the majority of cases. Laboratory and
imaging studies are essential in helping to confirm a clinical
diagnosis but are of limited value in the absence of clinical signs
when considering a diagnosis of systemic vasculitis and its
differential diagnosis [18].
Differential diagnosis. Vasculitic syndromes are considered
in the differential diagnosis of patients with multi system illness or
pyrexia of unknown origin. However, there are a number of
specific conditions that can mimic vasculitis, including infections,
non-infectious inflammatory diseases, malignancy, drugs and
factitious illnesses. Disorders such as atrial myxoma, cholesterol
emboli and catastrophic anti-phospholipid syndrome may also
mimic vasculitic disorders. Vasculitis occurs commonly in
the context of other autoimmune connective tissue diseases
such as systemic lupus erythematosus (SLE) and rheumatoid
arthritis (RA) [19, 20].
Investigations. Investigations are aimed at confirming the
diagnosis, excluding secondary causes of vasculitis, assessing
organ involvement and disease severity. Acute phase reactants
such as CRP and ESR are typically elevated in the acute phases of
most vasculitides. Urinalysis should be performed as soon as a
diagnosis of vasculitis is suspected because renal involvement in
particular may progress silently. Full blood count (FBC) should
be measured, looking particularly for eosinophilia. It is essential
to investigate critical organ function including renal, cardiac and
pulmonary assessments, with appropriate organ-specific tests
(creatinine clearance, echo-cardiography, pulmonary function
tests, etc).
Autoantibodies including ANCA are useful in the appropriate
clinical setting. It is important to recognize that a negative ANCA
does not exclude vasculitis and a positive ANCA does not
necessarily prove vasculitis [18]. ANCA specificity is also
important, with the presence of PR3 ANCA being strongly
suggestive of a diagnosis of WG [21]. MPO ANCA is less specific,
but also is most frequently associated with MPA and CSS. Thirty
percentage of cases with CSS or localized WG may be ANCA
negative.
Other useful tests include ANA (to exclude SLE, although it
can be difficult to interpret the presence of pANCA in the
presence of ANA), rheumatoid factor, complement levels (may be
raised as part of an acute phase response but lowered in immune
complex mediated essential mixed cryoglobulinaemia, bacterial
infections and SLE), cardiolipin antibodies and lupus anti-
coagulant for anti-phospholipid syndrome and cryoglobulins.
Cryoglobulinaemia may occur in isolation or in association with
other connective tissue diseases. In essential mixed cryoglobulin-
aemia associated with small vessel vasculitis, the cryoglobulins
may be associated with internal organ damage and may require
aggressive therapy.
Infection should be excluded by blood culture and appropriate
serology (including parvovirus, Hepatitis B, Hepatitis C and HIV)
because the treatment for PSV involves intense immunosuppres-
sion. A tissue diagnosis should be obtained wherever possible. The
choice of biopsy site is dependant on the clinical features, but skin
and renal are often helpful for diagnosis. It is important to
recognize that very early in the disease process, the classical
histological features of vasculitis may be absent. For example,
in one series of patients with WG with classical disease only 50%
had classical granuloma on histology. Upper airway biopsy
frequently shows changes compatible with the diagnosis but
rarely classical granulomatous vasculitis. The treatment should
not be delayed solely to get a biopsy if there are strong clinical
grounds to make a diagnosis of vasculitis.
Imaging investigations including angiography should be care-
fully considered in appropriate cases. The role of MRA/MRI and
PET are particularly valuable in assessing large vessel vasculitis
such as giant cell arteritis, but they have limited availability.
Coeliac axis angiography should be considered in situations where
PAN is strongly suspected, such as patients with severe abdominal
pain, frank haematuria and HBV infection.
1.2 Need for guideline
The primary systemic vasculitides are more common than was
previously realized with an incidence of 20/million and peak age of
onset 60–70 yrs [22]. Treatment has evolved over the last 20–30 yrs
and a number of new treatments are now available. Therefore, it
seems appropriate to review the current treatments and to
highlight where there is an evidence base for treatment protocols
and where treatment is based on individual preference.
1.3 Objective of guideline
The aim of this document is to provide guidelines for the
management of adults with primary systemic vasculitis/ANCA
associated vasculitis, especially the induction and maintenance of
remission. The guidelines concentrate particularly on the indica-
tions for using cyclophosphamide and the different therapeutic
regimens available.
1.4 Target audience
The target audience includes rheumatologists, general physicians
and specialists who may come across vasculitis in the course of
their work. We are also aiming guidance towards specialist
registrars in training, nurse practitioners dealing with vasculitis
and the information will also be of value to primary care physicians
to increase their understanding of these unusual conditions.
It is important, however, to recognize that these diseases are
relatively rare and it is recommended that a referral to a
consultant with a specialist interest in vasculitis is made in most
cases. Centres without consultants with a specialist interest in
vasculitis should contact expert centres and be in close liaison for
detailed advice.
TABLE 1. Classification of systemic vasculitis
Dominant vessel Primary Secondary
Large arteries Giant cell arteritis Aortitis associated
Takayasu’s arteritis with RA, infection
(e.g. syphilis,TB)
Medium arteries Classical PAN Hepatitis B
Kawasaki disease associated PAN
Small vessels and
medium arteries
Wegener’s
granulomatosisa
Vasculitis secondary to
rheumatoid arthritis,
systemic lupus
erythematosus,
Churg–Strauss
syndromea
Microscopic
polyangiitisa
Sjo¨grens syndrome,
drugs, infection
(e.g. HIV)
Small vessels Henoch–Scho¨nlein
purpura
Drugs, hepatitis
C-associated
infectionCryoglobulinaemia
cutaneous
leucocytoclastic
angiitis
aDiseases most commonly associated with ANCA and a significant risk of renal involvement,
and most responsive to immunosuppression with cyclophosphamide.
2 C. Lapraik et al.
1.5 The areas the guideline does not cover
The guidelines do not cover the management of other systemic
vasculitides, for example giant cell arteritis, Takayasu’s arteritis,
cutaneous vasculitis, classical PAN, cryoglobulinaemic vasculitis,
Henoch–Scho¨nlein purpura.
Section 2: Stakeholder involvement
2.1 Names and roles of members of multidisciplinary team
Coordination team
Chair. Professor David GI Scott, Consultant
Rheumatologist, Norfolk and Norwich University Hospital;
Honorary Professor, University of East Anglia School of
Medicine, Health Policy and Practice.
Members. Dr Richard Watts, Consultant Rheumatologist,
Ipswich Hospital, Senior Lecturer University of East Anglia
School of Medicine, Health Policy and Practice.
Dr Chloe Lapraik, Rheumatology Research Fellow, Norfolk
and Norwich University Hospital.
Working group members/advisors. Professor Paul Bacon,
Emeritus Professor, Birmingham.
Dr David Carruthers, Consultant Rheumatologist, City
Hospital Birmingham.
Professor Kuntal Chakravarty, Consultant Rheumatologist,
Harrold Wood Hospital.
Dr David D’Cruz, Consultant Rheumatologist, St Thomas’s
Hospital.
Professor Loic Guillevin, Professor of Medicine, Hospital
Avicenne, University of Paris-Nord.
Dr Lorraine Harper, Senior Lecturer in Nephrology,
Birmingham.
Dr David Jayne, Consultant Nephrologist, Addenbrooke’s
Hospital, Cambridge.
Dr Raashid Luqmani, Consultant Rheumatologist, Nuffield
Orthopaedic Centre, Oxford.
Allied health care professional representative. Mrs. Janice
Mooney, Nurse Lecturer, School of Nursing and Midwifery,
University of East Anglia.
2.2 Names and affiliations of users on the working party
The draft guidelines were reviewed by Mrs Judy Bilner (patient).
2.3 Involvement and affiliations of other people or
organizations including user representative organization and
pharmaceutical companies in the development of the
guideline
The Stuart Strange Trust is a registered charity that offers support
to family friends and sufferers of vasculitis. The guidelines have
been reviewed by Paul Pegg, the general secretary for the Trust,
who has given his approval and support on behalf of the Stuart
Strange Trust.
Section 3: Rigour of development
3.1 Statement of scope of literature search and strategy
employed
The general search strategy was to look for all evidence synthesis
in the Cochrane library and Medline (Ovid). The MEDLINE
database was also searched for randomized controlled trials and
non-randomized trials. The reference lists of identified papers and
previous reviews were also searched.
3.2 Statement of extent of Cochrane, Nice, RCP, SIGN
guidelines
To date, no Cochrane reviews have been published and there are
few formal meta-analyses. There are no NICE, RCP, SIGN
guidelines for the treatment of primary systemic vasculitis.
3.3 Statement of any limits of search
The search was conducted in November 2005. No time or
language limits were placed on the search.
3.4 Statement of when guideline will be updated
The guideline will be updated every 3 yrs following publication.
Section 4: The guideline itself
There are no clear cut diagnostic criteria for systemic vasculitis.
It is common to apply classification criteria as surrogates
for diagnosis, but we recognize the limitations of this approach.
For the purpose of these guidelines, we have proposed
the following statements to allow us to identify patients
who have a diagnosis of vasculitis for the purpose of eligibility
for treatment.
4.1 Eligibility criteria
Eligibility for treatment depends on the assumption that a definite
diagnosis of vasculitis has already been made. The following
criteria must be fulfilled prior to a diagnosis of vasculitis:
A. Symptoms and signs characteristic of systemic vasculitis.
B. At least one of the following:
1. Histological evidence of vasculitis and/or granuloma
formation,
2. Positive serology for ANCA (either cANCA/PR3 or
pANCA/MPO),
3. Specific indirect evidence of vasculitis (from angiography,
MRI, CT imaging, neurophysiologyy).
yNeurophysiology must show mononeuritis multiplex or
mononeuropathy
C. No other diagnosis to account for symptoms or signs.
4.2 Exclusion criteria
For a diagnosis of primary systemic vasculitis, it is important to
consider other causes of systemic illness as outlined below, which
must be excluded as far as possible:
1. Malignancy,
2. Systemic infection—especially bacterial endocarditis,
3. Drugs—known to be associated with vasculitis (e.g.
propylthiouracil, allopurinol, hydralazine and cocaine),
4. Secondary forms of vasculitis associated with primary
connective tissue disease such as rheumatoid arthritis or
systemic lupus erythematosus.
5. Other vasculitides including Behc¸et’s disease, Takayasu’s
arteritis, giant cell arteritis, Kawasaki’s disease,
Cryoglobulinaemia, Henoch Scho¨nlein Purpura (must have
a biopsy demonstrating IgA deposits).
6. Vasculitis mimics, for example anti-phospholipid syndrome,
cholesterol embolism, calciphylaxis and atrial myxoma.
4.3 Remission induction treatment
Treatment for vasculitis requires induction of remission
followed by maintenance. Treatment regimens for each phase of
disease are different and are outlined subsequently. The categor-
ization used here follows that adopted by the European Vasculitis
Study Group (EUVAS) for clinical trials.
Guidelines for the management of adults with AAV 3
Treatment is tailored according to severity and extent of
disease. The level of immunosuppression should reflect the
severity of vasculitis. Table 2 shows categorization of disease
severity. Limited WG as used in the US literature most closely
overlaps with the early systemic/localized group.
4.3a Recommendation for patients with generalized
disease/threatened organ involvement. Initial treatment of
patients with primary systemic vasculitis with generalized/threa-
tened vital organ loss should include cyclophosphamide.
Cyclophosphamide may be given orally or intravenously (daily
oral 2mg/kg or IV pulses at 2- or 3- week intervals at a dose of
15mg/kg) (Table 3) (A).
Cyclophosphamide dose should be tapered to maintain total
white cell count above 4� 109/l and neutrophils >2.0� 109 to
reduce risk of infection (B). Cyclophosphamide dosage should be
reduced for age (B) and renal function (C).
Current clinical practice with these protocols for remission
induction are associated with an expected remission rate of �80%
at 3 months and 90% at 6 months [24].
Dose reductions
Dose reductions for continuous low dose oral
cyclophosphamide: For oral administration, if age >60 years
the dose of cyclophosphamide should be reduced by 25%. If the
age is >75 years the dose should be reduced by 50% to avoid
neutropenia [25] (B).
Reductions for pulsed cyclophosphamide, see Table 3.
Remission induction
Continuous low dose oral cyclophosphamide
regimen: Continuous low dose cyclophosphamide 2mg/kg/day
should be given for 3 months. The maximum dosage of
continuous low dose oral cyclophosphamide is 200mg/day.
If remission is not achieved by 3 months, continue 2mg/kg/day,
until remission is achieved then reduce cyclophosphamide to
1.5mg/kg/day. The total duration of treatment with cyclopho-
sphamide should not usually exceed 6 months [24].
Current clinical practice considers a transfer to maintenance
therapy at 3 months or within 3 and 6 months if remission is
delayed (A).
Continuous low dose oral cyclophosphamide
monitoring: Check full blood count (FBC), weekly for the first
month, 2 weekly for the second and third month and then
monthly thereafter. If w