Eular Vaskulitis Anca

Recommendation
Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209133 on 23 June 2016. Downloaded from http://ard.bmj.com/ on 30 April 2019 by guest. Protected by copyright.
EULAR/ERA-EDTA recommendations for the
management of ANCA-associated vasculitis
M Yates,1,2 R A Watts,2,3 I M Bajema,4 M C Cid,5 B Crestani,6 T Hauser,7
B Hellmich,8 J U Holle,9 M Laudien,10 M A Little,11 R A Luqmani,12 A Mahr,13
P A Merkel,14 J Mills,15 J Mooney,1 M Segelmark,16,17 V Tesar,18 K Westman,19
A Vaglio,20 N Yalçındağ,21 D R Jayne,22 C Mukhtyar1
Handling editor Tore K Kvien ABSTRACT BACKGROUND AND RATIONALE

▸ Additional material is In this article, the 2009 European League Against In 2009 the European League Against Rheumatism
published online only. To view Rheumatism (EULAR) recommendations for the (EULAR) published recommendations for managing
please visit the journal online management of antineutrophil cytoplasmic antibody primary small and medium vessel vasculitis which
(http://dx.doi.org/10.1136/
annrheumdis-2016-209133). (ANCA)-associated vasculitis (AAV) have been updated. included the management of AAV.10 The publica-
The 2009 recommendations were on the management tion of 1691 papers in the past 5 years on primary
For numbered affiliations see
of primary small and medium vessel vasculitis. The 2015 systemic vasculitis in internal medicine, rheumatol-
end of article.
update has been developed by an international task ogy and nephrology journals, as well as the licens-
Correspondence to force representing EULAR, the European Renal ing of rituximab for AAV, make this an opportune
Dr Chetan Mukhtyar, Association and the European Vasculitis Society (EUVAS). time to update the recommendations with an AAV
Department of Rheumatology, The recommendations are based upon evidence from focus. This update was made in conjunction with
Norfolk and Norwich University
Hospital, Norwich NR4 7UY systematic literature reviews, as well as expert opinion the European Renal Association—European Dialysis
UK; chetan.mukhtyar@nnuh. where appropriate. The evidence presented was and Transplant Association (ERA-EDTA).
nhs.uk discussed and summarised by the experts in the course This paper reassesses standard therapy, including
of a consensus-finding and voting process. Levels of the use of biological agents, the prognostic value
Received 5 January 2016
Revised 24 May 2016
evidence and grades of recommendations were derived of histopathology and management of long-term com-
Accepted 27 May 2016 and levels of agreement (strengths of recommendations) plications, integrating these into treatment algorithms.
Published Online First determined. In addition to the voting by the task force
23 June 2016 members, the relevance of the recommendations was METHODS
assessed by an online voting survey among members of The EULAR standardised operating procedure for
EUVAS. Fifteen recommendations were developed, the elaboration, evaluation, dissemination and
covering general aspects, such as attaining remission implementation of recommendations were fol-
and the need for shared decision making between lowed.11 The full details are available in the online
clinicians and patients. More specific items relate to supplementary material. The task force comprised
starting immunosuppressive therapy in combination with 21 members representing EULAR and ERA-EDTA:
glucocorticoids to induce remission, followed by a period a patient ( John Mills), a nurse ( Janice Mooney), a
of remission maintenance; for remission induction in life- pathologist (IMB), an otorhinolaryngologist (ML),
threatening or organ-threatening AAV, cyclophosphamide a pulmonologist (BC), an immunologist (TH), an
and rituximab are considered to have similar efficacy; ophthalmologist (NY), two general internists (AM,
plasma exchange which is recommended, where MCC), six renal physicians (MAL, MS, VT, KW, AV
licensed, in the setting of rapidly progressive renal failure and DRJ) and six rheumatologists (RAW, BH, JUH,
or severe diffuse pulmonary haemorrhage. These RAL, PAM and CM) with academic experience
recommendations are intended for use by healthcare and/or clinical expertise in the field of vasculitis.
professionals, doctors in specialist training, medical MY was the Clinical Fellow.
students, pharmaceutical industries and drug regulatory A Delphi exercise was conducted to identify items
organisations. needing update and new items. This instructed the
systematic literature review (SLR) strategy. The
manuscripts were formally scored using the Critical
Appraisal Skills Programme checklist (http://www.
INTRODUCTION casp-uk.net/). Details are available in the online
Granulomatosis with polyangiitis (GPA, Wegener’s supplement.
granulomatosis), microscopic polyangiitis (MPA)
and eosinophilic granulomatosis with polyangiitis STATEMENTS
(EGPA, Churg-Strauss syndrome) are termed The statements in this manuscript are termed
the antineutrophil cytoplasmic antibody (ANCA)- ‘recommendations’ as opposed to ‘guidelines’ or
associated vasculitides (AAVs).1 GPA, MPA and ‘points to consider’ because they offer guidance
EGPA have respective annual incidence rates of which needs to be tailored to meet individual
2.1–14.4, 2.4–10.1 and 0.5–3.7 per million in requirements (table 1). They are intended for use by
To cite: Yates M, Watts RA, Europe, and the prevalence of AAV is estimated at healthcare professionals, doctors in specialist train-
Bajema IM, et al. Ann to be 46–184 per million.2–8 The 5-year survival ing, medical students, pharmaceutical industries and
Rheum Dis 2016;75: rates for GPA, MPA and EGPA are estimated to be drug regulatory organisations. An algorithm has
1583–1594. 74–91%, 45–76% and 60–97%, respectively.9 been developed to reflect the statements (figure 1).
Yates M, et al. Ann Rheum Dis 2016;75:1583–1594. doi:10.1136/annrheumdis-2016-209133 1583
Recommendation
Table 1 Recommendation statements
Statement Level of evidence Grade of recommendation
1. We recommend that patients with AAV are managed in close collaboration with, or at, centres of expertise. 3 C
2. A positive biopsy is strongly supportive of a diagnosis of vasculitis and we recommend biopsies to assist in 3 C
establishing a new diagnosis and for further evaluation for patients suspected of having relapsing vasculitis.
3. For remission-induction of new-onset organ-threatening or life-threatening AAV we recommend treatment with a 1 for GPA/MPA, 3 for A for GPA/MPA, C for EGPA
combination of glucocorticoids and either cyclophosphamide OR rituximab. EGPA
4. For remission-induction of non-organ-threatening AAV we recommend treatment with a combination of 1B B for MTX, C for MMF
glucocorticoids and either methotrexate or mycophenolate mofetil*.
5. For a major relapse of organ-threatening or life-threatening disease in AAV we recommend treatment as per new 1 for GPA/MPA, 3 for A for GPA/MPA, C for EGPA
disease with a combination of glucocorticoids and either cyclophosphamide OR rituximab. EGPA and CYC, 4 for and CYC, C for EGPA and
EGPA and RTX RTX
6. (i) Plasma exchange should be considered for patients with AAV and a serum creatine level of ≥500 mmol/L 1B B
(5.7 mg/dL) due to rapidly progressive glomerulonephritis in the setting of new or relapsing disease.
6. (ii) Plasma exchange can also be considered for the treatment of severe diffuse alveolar haemorrhage. 3 C
7. For remission-maintenance of AAV we recommend treatment with a combination of low-dose glucocorticoids and 1B for GPA/MPA A for GPA/MPA, C for EGPA
either azathioprine, rituximab, methotrexate or mycophenolate mofetil*. 3 for EGPA and AZA and AZA
8. We recommend that remission-maintenance therapy for AAV be continued for at least 24 months following 4 D
induction of sustained remission.
9. For patients with AAV refractory to remission-induction therapy we recommend switching from cyclophosphamide 3 C
to rituximab or from rituximab to cyclophosphamide. These patients should be managed in close conjunction
with, or referred to, an expert centre for further evaluation and potential enrolment in clinical trials.
10. We recommend that structured clinical assessment rather than ANCA testing should inform decisions on changes 4 D
in treatment for AAV.
11. We recommend the investigation of persistent unexplained haematuria in patients with prior exposure to 2B C
cyclophosphamide.
12. Hypoimmunoglobulinaemia has been noted after treatment with rituximab. We recommend testing of serum 3 C
immunoglobulin levels prior to each course of rituximab and in patients with recurrent infection.
13. We recommend periodic assessment of cardiovascular risk for patients with AAV. 2B B
14. We recommend that patients with AAV should be given a clear verbal explanation of the nature of their disease, 3 C
the treatment options, the side effects of treatment, and the short-term and long-term prognoses.
15. We recommend that following the remission-induction phase of treatment, patients with AAV be assessed for the 4 D
extent and ongoing impact of comorbidities associated with their diagnosis. Patients should then be advised
where they might find the necessary therapies or support for these conditions.
*The drugs are listed in order of the strength of vote (see text).
AAV, ANCA-associated vasculities; ANCA, antineutrophil cytoplasmic antibody; AZA, azathioprine; CYC, cyclophosphamide; EGPA, eosinophilic granulomatosis with polyangiitis; GPA,
granulomatosis with polyangiitis; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; MTX, methotrexate; RTX, rituximab.
AAV is a very variable disease group which is unpredictable in previously unaffected organ systems.25–27 Patients may
and potentially life-threatening. Treatment usually involves develop complications from the treatment many years after dis-
potent immunosuppressive drugs, often with risk of significant continuing treatment.28 29 Long-term follow-up and rapid access
side effects. Full drug-free remission can be achieved but relapse to specialist services are necessary for all patients with AAV. For
is common. In addition, AAV adversely affects quality of life these reasons patients with AAV should be managed in close
even in patients thought to have clinical remission.12 13 This collaboration with, or at, centres of expertise.30
may be an effect of the disease or its treatment. We recommend
the overarching principle of shared decision making between
the patient and their specialist. Statement 2
A positive biopsy is strongly supportive of a diagnosis of vascu-
litis and we recommend biopsies to assist in establishing a new
Statement 1 diagnosis and for further evaluation for patients suspected of
We recommend that patients with AAV are managed in close col- having relapsing vasculitis. Level of evidence 3; grade of recom-
laboration with, or at, centres of expertise. Level of evidence 3; mendation C; strength of vote 81%.
grade of recommendation C; strength of vote 100%. A positive biopsy for AAV is helpful when considering an initial
The rarity of AAV makes it difficult to maintain expertise in diagnosis or recurrent disease. Histopathological evidence of vas-
their management.2 14–16 Assessment of these patients requires culitis, such as pauci-immune glomerulonephritis or necrotising
expert guidance to differentiate activity from damage or infec- vasculitis in any organ, remains the gold standard for diagnostic
tion and to consider differential diagnoses. Patients may require purposes. The likely diagnostic yield varies and is dependent on
interventions by specialists with expertise in AAV, such as the organ targeted. In patients with GPA with renal involvement
immunological monitoring, use of rituximab in patients with the diagnostic yield from renal biopsy can be as high as 91.5%.31
refractory disease, specialised radiography, assessment of eye Otorhinolaryngological examination in patients with GPA often
involvement, injection of subglottic stenosis and renal transplant- reveals abnormal findings and biopsies of these areas may be posi-
ation.17–24 For patients with refractory disease, the best option tive for inflammatory changes in up to 68.4%.32 33 A large study
may be consideration of referral to centres participating in clin- of 60 nasal, 27 paranasal sinus, 17 laryngeal, 5 periorbital, 5 oral,
ical trials. AAV may relapse years after remission is achieved, even 4 middle ear, 3 mastoid, 2 external ear and 3 salivary gland
1584 Yates M, et al. Ann Rheum Dis 2016;75:1583–1594. doi:10.1136/annrheumdis-2016-209133
Recommendation
Figure 1 Algorithm to describe the management of new antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Dashed lines indicate
alternative or supplementary action to consider.
biopsies revealed that they often yield non-specific chronic inflam- about cumulative cyclophosphamide dosage, pulsed intravenous
mation and the more specific findings of granulomas and vasculitis regimens were designed and tested, the largest study being the
are seen less frequently than in other tissue biopsies.34 Lung biop- CYCLOPS (randomised trial of daily oral versus pulse
sies vary in their diagnostic sensitivity, with only 12% of trans- Cyclophosphamide as therapy for ANCA-associated Systemic
bronchial biopsies of alveolar tissue positive for GPA and 66.7% Vasculitis) trial.43 This trial was designed following a
for EGPA in one study.32 Open lung biopsies, although more meta-analysis of three studies involving 143 patients44–46 which
invasive, provide a much higher diagnostic yield.35 concluded that pulsed cyclophosphamide was more likely to
Percutaneous renal biopsy should be performed using achieve remission and was associated with fewer side effects than
ultrasound guidance where possible and has been shown to be oral cyclophosphamide.47 Long-term follow-up of the CYCLOPS
associated with a low risk of complications including haemor- cohort revealed that although the proportion of participants with
rhage.36 The risk of bleeding following percutaneous renal at least one relapse was higher in those individuals treated with
biopsy is higher in patients treated with plasma exchange pulsed cyclophosphamide, there were no differences in survival,
(PLEX).37 Generic factors associated with an increased risk of renal function at the end of the study or adverse events between
bleeding necessitating transfusion include old age, increased sys- the two arms.48 However, pulsed regimens are favoured due to
tolic blood pressure and worse renal function.38 the reduced total dose of cyclophosphamide overall and reduced
Existing classification systems need further validation but risk of bladder-related complications.
changes like glomerular sclerosis have obvious adverse prognos- The grade of evidence for cyclophosphamide use in EGPA is
tic value for patients with AAV.39–41 lower than for GPA/MPA as no randomised controlled trials
(RCTs) for the treatment of EGPA have been published. One
Statement 3 study did compare cyclophosphamide doses: cyclophosphamide
For remission-induction of new-onset organ-threatening or life- (0.6 mg/m2) was used initially every 2 weeks for a month then
threatening AAV we recommend treatment with a combination every 4 weeks.49 The intervention arm was given six pulses in
of glucocorticoids and either cyclophosphamide OR rituximab. total, while the control arm received 12 pulses. Complete remis-
▸ Cyclophosphamide sion was achieved in both groups at a similar rate (21/23 in
– level of evidence 1A for GPA and MPA; grade of recom- intervention arm, 21/25 in control arm).
mendation A; strength of vote 100%. Antiemetic therapy should be routinely administered with
– level of evidence 3 for EGPA; grade of recommendation C; intravenous cyclophosphamide. Cyclophosphamide metabolites
strength of vote 88%. are toxic to the urothelium and can cause haemorrhagic cystitis
▸ Rituximab in the short term and malignancy in the long term.28 29 50
– level of evidence 1B for GPA and MPA; grade of recom- If clinically appropriate, patients should be encouraged to
mendation A; strength of vote 82%. drink plenty of fluids or given intravenous fluids on the day of
– level of evidence 3 for EGPA; grade of recommendation C; the infusion to dilute the metabolites in the urine. Patients
strength of vote 59%. receiving pulse cyclophosphamide may also be given oral or
Since the 1970s therapy consisting of a combination of gluco- intravenous 2-mercaptoethanesulfonate sodium (MESNA)
corticoids (1 mg/kg/day—maximum daily dose 80 mg) with which binds to acrolein, a toxic metabolite of cyclophospha-
cyclophosphamide (2 mg/kg/day—maximum 200 mg/day) has mide, rendering it non-toxic.26 MESNA also retards the degrad-
been used for remission induction in AAV.42 Due to concerns ation of 4-hydroxymetabolites, further reducing the toxic
Recommendation
acrolein products in the urine. MESNA may also be beneficial in
patients receiving continuous oral cyclophosphamide.25 26 51
Monitoring of patients receiving cyclophosphamide should
follow standard protocols.52 In both modalities of administration,
dose changes or discontinuation of cyclophosphamide may be
necessary in the event of an acute leucopenia or a gradual
fall over time. In the event of a stable leucopenia, it may be pos-
sible to maintain the immunosuppression with stringent blood
monitoring. We encourage prophylaxis against infection with
Pneumocystis jirovecii with trimethoprim/sulfamethoxazole (800/
160 mg on alternate days or 400/80 mg daily) in all patients being
treated with cyclophosphamide, where not contraindicated.53–55
The use of inhaled monthly pentamidine in the event of an Figure 2 Protocol target prednisolone dosages in the key induction
adverse reaction or contraindication to trimethoprim/sulfameth- trials of antineutrophil cytoplasmic antibody associated vasculitis.
oxazole may be useful but is not cost-effective and not routinely
indicated.53 Other alternatives include dapsone and atovaquone.
Rituximab in AAV has been tested in two RCTs (RAVE ▸ Methotrexate
(Rituximab for the Treatment of Wegener’s Granulomatosis and – Level of evidence 1B; grade of recommendation B;
Microscopic Polyangiitis) and RITUXVAS (an international, ran- strength of vote 77%.
domised, open label trial comparing a rituximab based regimen ▸ Mycophenolate mofetil
with a standard cyclophosphamide/azathioprine regimen in the – Level of evidence 1B; grade of recommendation C;
treatment of active, ‘generalised’ ANCA associated vascu- strength of vote 65%.
litis)).56 57 In both studies patients initially received high-dose The task force was keen to stress that the use of methotrexate
glucocorticoids with subsequent dose tapering. The rituximab or mycophenolate mofetil should not be used for remission
dose in both studies was 375 mg/m2 of body surface area, once induction in the following scenarios:
a week for four infusions. In both trials, rituximab was non- ▸ Meningeal involvement
inferior to cyclophosphamide and appeared more effective for ▸ Retro-orbital disease
relapsing disease in RAVE. Details of the clinical trials in this ▸ Cardiac involvement
section are available in the online supplement. ▸ Mesenteric involvement
The grade of evidence for the use of rituximab in patients ▸ Acute-onset mononeuritis multiplex
with EGPA is lower than for GPA/MPA. A retrospective analysis ▸ Pulmonary haemorrhage of any severity
of 41 patients with EGPA who received differing regimens of Methotrexate (20–25 mg/week, oral or parenteral) may be
rituximab found that 34% achieved complete remission at used as an alternative to cyclophosphamide in patients with
6 months and 49% at 12 months.58 less severe disease and in those with normal renal func-
Due to high cost, rituximab use is restricted in some countries tion.25 65 74–81 There have been trials using either methotrexate
and therefore involvement of expert centres is mandated. There or mycophenolate mofetil as the remission induction agent in
may be specific instances where rituximab is preferable to cyclo- patients with AAV.65 Oral methotrexate 20–25 mg/week was
phosphamide, for example, in patients who wish to preserve non-inferior to oral cyclophosphamide at 6 months but long-
their reproductive potential. Cyclophosphamide is associated term follow-up revealed that patients treated with methotrexate
with reduced ovarian reserve, ovarian failure and male infertil- had less effective disease control as compared with those treated
ity.59–63 The long-term effects of rituximab on fertility have not with cyclophosphamide.82 Methotrexate should therefore be
been studied but no such concerns have been reported. In considered only for non-organ-threatening disease. Examples
patients with severe disease, treatment should not be delayed include the following in the absence of renal involvement
but discussion of these issues should take place. ▸ Nasal and paranasal disease without bony involvement
The task force considered appropriate a target of between 7.5 (erosion) or cartilage collapse or olfactory dysfunction or
mg and 10 mg of prednisolone (or equivalent) after 3 months deafness
(12 weeks) of treatment. A review of the prednisolone protocol ▸ Skin involvement without ulceration
reduction regimens published for the key trials illustrated that ▸ Myositis (skeletal muscle only)
on average a dose of 10 mg was achieved after 19 weeks, and a ▸ Non-cavitating pulmonary nodules/infiltrate without
dose of 7.5 mg after 21 weeks (figure 2).43 49 56 57 64–68 haemoptysis
Therefore although a target prednisolone dose of 7.5–10mg is ▸ When cyclophosphamide or rituximab are not available or
desirable by 3 months, in practice it may be 5 months before contraindicated or patient choice
this is achieved. The induction trials involving methotrexate are generally
The AAVs have protean manifestations and the spectrum of larger and of higher evidence grade than those using mycophe-
disease ranges from the indolent to the life-threatening.69–73 nolate mofetil. To date, the two RCTs using mycophenolate
Although the evidence and thus the recommendations follow mofetil have been conducted primarily in patients with MPA (of
current classification systems, it is not our intention to maintain the 76 participants 75 had MPA).83 84 MPA often affects renal
this delineation in the long term and future evidence about out- function and in such situations methotrexate would not be indi-
comes of phenotypes may change current labels. cated. The trials did not include patients with lung haemorrhage
or central nervous system (CNS) involvement and therefore
Statement 4 mycophenolate mofetil should not be routinely preferred in life-
For remission-induction of non-organ-threatening AAV we rec- threatening situations.
ommend treatment with a combination of glucocorticoids and Details of the clinical trials discussed in this statement are
either methotrexate or mycophenolate mofetil. available in the online supplement.
Recommendation
Statement 5 composite end point of end stage renal disease (ESRD) or death
For a major relapse of organ-threatening or life-threatening in patients with renal vasculitis.92
disease in AAV we recommend treatment as per new disease However most trials of PLEX did not restrict use to individuals
with a combination of glucocorticoids and either cyclophospha- with a serum creatine >500 mmol/L (5.7 mg/dL). One RCT with
mide OR rituximab. long-term follow-up tested whether PLEX may benefit indivi-
▸ Rituximab duals with a serum creatine of <500 mmol/L (5.7 mg/dL):93 after
– level of evidence 1B for GPA and MPA; grade of recom- 1 month, none of the PLEX participants required haemodialysis
mendation A; strength of vote 94%. (HD) or had worsening renal function compared with six with
– level of evidence 4 for EGPA; grade of recommendation declining renal function and five on HD in the reference group
D; strength of vote 100% (p<0.05).93 Despite the improvements in renal function, there
▸ Cyclophosphamide were no differences in all-cause mortality between the PLEX and
– level of evidence 1A for GPA and MPA; grade of recom- reference groups after 5 years of follow-up.93 PEXIVAS (Plasma
mendation A; strength of vote 88%. Exchange and Glucocorticoids for Treatment of Anti-Neutrophil
– level of evidence 3 for EGPA; grade of recommendation C; Cytoplasm Antibody (ANCA) - Associated Vasculitis) is a global
strength of vote 88%. trial that is currently recruiting patients with moderate renal
Most trials published on remission induction in AAV make no impairment (estimated glomerular filtration rate (eGFR)<50 mL/
distinction between those participants treated for a new or min) and aims to provide definitive answers regarding the use of
relapsing presentation of their disease. It is for these reasons PLEX in AAV.90
that the trial evidence for new or relapsing disease is often from Further details about the clinical trials and the PEXIVAS
the same studies. However, some studies have distinguished protocol are available in the online supplement.
between those participants with new and relapsing disease and There is also potential benefit for PLEX in patients with AAV
have stratified by this factor when randomising patients. who are also anti-glomerular basement membrane (GBM) anti-
The largest RCT to investigate the use of rituximab for remis- body positive, particularly those in whom there is linear staining
sion induction in AAV (RAVE) stratified participants by new or of IgG on the glomerular basement membrane, and PLEX
relapsing disease: those with relapsing disease treated with ritux- should be performed early in such patients to improve
imab were more likely to be in disease remission at the 6-month outcome.89 94
and 12 month time points but not the 18 month follow-up
visit.57
The cumulative dose of cyclophosphamide is related to tox- Statement 7
icity and is a particular concern with prolonged oral dosing, For remission maintenance of AAV we recommend treatment
where cumulative doses are higher.85 For this reason the task with a combination of low-dose glucocorticoids and either
force has favoured a greater strength of recommendation for azathioprine, rituximab, methotrexate or mycophenolate
rituximab over cyclophosphamide for relapsing disease. mofetil.
The treatment of non-severe relapses in AAV with a tempor- GPA/MPA
ary increase in the glucocorticoid dose restores disease remission ▸ Azathioprine
in most patients but recurrent relapses within a relatively short – Level of evidence 1B for GPA and MPA; grade of recom-
time period remain common.86 Given these data, alternative mendation A; strength of vote 94%.
approaches to the treatment of non-severe relapses must be con- ▸ Rituximab
sidered, especially if relapses are frequent. We therefore recom- – Level of evidence 1B for GPA and MPA; grade of recom-
mend treatment with intensification or modification of the mendation A; strength of vote 59%.
immunosuppressive remission maintenance regimen. The details ▸ Methotrexate
of the data are available in the online supplement. – Level of evidence 1B for GPA and MPA; grade of recom-
mendation A; strength of vote 53%
▸ Mycophenolate mofetil
Statement 6 – Level of evidence 1B for GPA and MPA; grade of recom-
Plasma exchange should be considered for patients with AAV mendation A; strength of vote 53%
and a serum creatine level of >500 mmol/L (5.7 mg/dL) due to EGPA
rapidly progressive glomerulonephritis in the setting of new or ▸ Azathioprine
relapsing disease. Level of evidence 1B; grade of recommenda- – Level of evidence 3 for EGPA; grade of recommendation
tion B; strength of vote 77%. C; strength of vote 77%.
Plasma exchange can also be considered for the treatment of Long-term therapy with cyclophosphamide has been used to
severe diffuse alveolar haemorrhage. Level of evidence 3; grade maintain remission in patients with AAV.25 However the toxicity
of recommendation C; strength of vote 88%. of long-term cyclophosphamide makes it an unattractive
PLEX use is usually reserved for patients with either option.28 50 29 Azathioprine (2 mg/kg/day) is safer than oral
severe renal impairment or those with diffuse alveolar haemor- cyclophosphamide but as effective at 18 months in preventing
rhage.87–89 The largest trial published to date is MEPEX which relapse.67 95 Methotrexate (20–25 mg/kg/week) has been effect-
recruited those individuals with either a serum creatine ively used for maintenance therapy after induction of remission
>500 mmol/L (5.7 mg/dL) or those requiring dialysis.68 with cyclophosphamide (if the serum creatine is <130 mmol/L
Long-term follow-up and analysis of this trial have also been pub- or 1.5 mg/dL).96 97 Leflunomide (20–30 mg/day) may be more
lished.90 PLEX appeared to be of value in preventing end-stage effective than methotrexate in remission maintenance but
renal disease or death at 3 months,68 but long-term follow-up is associated with more adverse effects.98 Therefore leflunomide
revealed no statistically significant benefit for the PLEX group.91 is considered for second line treatment in cases of intolerance
A prior meta-analysis had concluded that PLEX may decrease the to azathioprine, methotrexate, mycophenolate mofetil or

Recommendation
rituximab. Early cessation of therapy is associated with an lack of data for this area. It should be noted that there was a
increased risk of relapse.65 trend to increase the duration of therapy in patients who are
The MAINRITSAN (Efficacy Study of Two Treatments in the PR3-ANCA positive and this was reflected with median of the
Remission of Vasculitis) trial compared low-dose rituximab in vote for 36 months of maintenance therapy in this particular
GPA/MPA (at a fixed 500 mg dose) to tapering dose of scenario.
azathioprine for remission maintenance after induction with
pulsed cyclophosphamide.99 At month 28, major relapses had Statement 9
occurred: 17 in the azathioprine group and 3 in the rituximab For patients with AAV refractory to remission-induction therapy
group. Renal relapses occurred in 8/17 major relapses in the we recommend switching from cyclophosphamide to rituximab
azathioprine group and 0/3 in the rituximab group.99 or from rituximab to cyclophosphamide. These patients should
Azathioprine is preferred over mycophenolate mofetil for be managed in close conjunction with, or referred to, an expert
remission maintenance, because of the results from the centre for further evaluation and potential enrolment in clinical
IMPROVE (Mycophenolate Mofetil Versus Azathioprine for trials. Level of evidence 3; grade of recommendation C;
Maintenance Therapy in ANCA Associated Systemic Vasculitis) strength of vote 71%.
trial.100 In both groups the remission maintenance agent was Refractory disease is defined by EULAR as:111
reduced at two time points (after 12 months and 18 months) ▸ Unchanged or increased disease activity in acute AAV after
and withdrawn after 42 months.100 Relapses were noted in 42 4 weeks of treatment with standard therapy in acute AAV, or
participants treated with mycophenolate mofetil and in 30 parti- ▸ Lack of response, defined as <50% reduction in the disease
cipants in the azathioprine group ( p<0.01). activity score (eg, Birmingham Vasculitis Activity Score
The addition of trimethoprim/sulfamethoxazole (800/160 mg (BVAS) or BVAS/wegener’s granulomatosis (WG)), after
twice daily) to standard remission maintenance can reduce the 6 weeks of treatment, or
risk of relapse in GPA.101 Although trimethoprim/sulfamethoxa- ▸ Chronic, persistent disease defined as presence of at least one
zole has been used as the sole remission maintenance agent in major or three minor items on the disease activity score after
half the patients of one RCT, trimethoprim/sulfamethoxazole >12 weeks of treatment.
monotherapy may not be effective for maintenance of remis- It is important to consider why a particular patient may have
sion.101 102 In patients with nasal disease, treatment with topical refractory disease and what is driving the conclusion that they
antibiotics such as mupirocin may be considered in the presence have refractory disease. Items to consider are:
of chronic carriage of nasal Staphylococcus aureus.103 ▸ Re-evaluate the primary diagnosis; are they truly refractory—
do they have AAV?
Statement 8 ▸ Has the treatment regimen been optimised, that is, have
We recommend that remission-maintenance therapy for AAV be target dosages for therapy been reached?
continued for at least 24 months following induction of sus- ▸ Is this active disease or could it be damage?
tained remission. Level of evidence 4; grade of recommendation ▸ Is the present disease due to AAV or could it be due to an
D; strength of vote 75% for myeloperoxidase (MPO) persistent infection or other comorbidity or possible malignancy?
disease, 62% for MPO negative disease, 100% for PR3 persist- Rituximab has proven useful in patients with refractory
ent disease and 92% for PR3 negative disease. disease, particularly those previously treated with cyclophospha-
No published RCTs have directly compared duration of main- mide. Patients with refractory renal disease have the greatest
tenance therapy regimens. Early cessation of therapy is asso- chance of improvement, while those with retro-orbital disease
ciated with an increased risk of relapse.65 104 Most of the data pose a particular challenge.58 73 112 113 Based on the results of
regarding relapse risk are derived from a combination of obser- an additional analysis of the WEGENT (Comparison of
vational cohort data and long-term follow-up from clinical Methotrexate or Azathioprine as Maintenance Therapy for
trials. There are however important differences in the make-up ANCA-Associated Vasculitides) trial, as a potential strategy the
of the participants from these sources, with many more patients task force suggested a switch from pulsed to oral cyclophospha-
with GPA likely to be present in observational cohort studies.105 mide when rituximab is unavailable, under the guidance of an
In general, attempts at reduction of glucocorticoids should expert centre.114
be made prior to tapering of the immunosuppressive agent. In the follow-up of patients enrolled into the RAVE trial who
A meta-analysis of 13 studies (8 RCTs and 5 observational failed to achieve the primary end point, treatment with blinded
studies with 983 participants) examining the effect of duration cross-over or according to best medical judgement by the trial
of glucocorticoids on relapse rate concluded that continuing glu- physician lead to disease control in the majority.115 Rituximab
cocorticoids is associated with fewer relapses.106 The pooled may be better than cyclophosphamide for those participants
total estimate for the proportion of patients suffering with a who are PR3-ANCA positive.115
relapse recruited to RCTs was 36% (95% CI 25% to 47%) but For patients who fail to achieve remission and have persistent
only 14% for those studies which continued glucocorticoids. In low activity, adjunctive therapy with intravenous immunoglobu-
patients with AAV with renal involvement, worse prognosis is lin (IVIG) may help patients achieve remission.116–118 Prior to
associated with those who have MPO-ANCA, even after adjust- therapy, serum immunoglobulin levels must be measured because
ment for baseline factors such as age, sex and serum creatine.107 patients with selective IgA deficiency may develop an anaphyl-
Furthermore, patients with MPO-ANCA have more severe tubu- actic reaction on receiving IVIG or a pre-existing hyperglobuli-
lointerstitial inflammation and both CD3(+) T cell tubulitis and naemia may become aggravated leading to a hyperviscosity state.
tubular atrophy are independently associated with eGFR at 12 Further details of the data discussed in this statement are
months.108 In addition, kidney biopsies displaying sclerosis are available in the online supplement.
associated with worse outcomes in AAV.109 However patients
with PR3-ANCA and those with cardiovascular or lung involve- Statement 10
ment are more likely to relapse.72 110 The resultant grade for We recommend that structured clinical assessment rather than
the strength of recommendation of the task force reflects the ANCA testing should inform decisions on changes in treatment
Recommendation
for AAV. Level of evidence 4; grade of recommendation D; cumulative dose of the drugs used. Cyclophosphamide treat-
strength of vote 100%. ment results in a decrease in immunoglobulin (Ig) levels and
The role of ANCA testing as a means of predicting future subsequent rituximab treatment in patients resulted in a further
relapse is controversial and evolving.119–122 ANCA testing decline in Ig levels.24 Surveying patients with AAV is warranted
should be performed at accredited labs which take part in post cyclophosphamide and rituximab treatment for serum
quality assurance testing programmes.123 124 A negative ANCA immunoglobulin concentrations and persisting hypoimmunoglo-
does not rule out AAV in the appropriate clinical context of bulinaemia.24 In patients who develop this complication,
active disease.125 126 involvement of a clinical immunologist is recommended. Not all
Some studies have shown that patients in whom the ANCA patients who develop hypoimmunoglobulinaemia have infec-
titres either persist, rise fourfold or become positive have a tious complications.135
higher incidence of relapse, while other studies did not confirm Patients with AAV should be immunised against infectious
this association.95 121 120 We believe that these factors should disease according to local policy. It should be noted that influ-
not lead to a change in therapy but more frequent clinical enza vaccination does not appear to be associated with relapse
assessment should be considered. in patients with AAV.136 137 In addition patients with GPA show
Multiorgan involvement is common in AAV therefore a struc- an adequate immune response to influenza vaccination.138
tured clinical assessment should be conducted in all patients. Vaccination against herpes zoster (follow local guidelines
This examination may be facilitated by the use of clinical tools because this is a live vaccine which may be contraindicated in
such as BVAS and the Vasculitis Damage Index.127–130 BVAS immunosuppressed patients), pneumococcus and influenza
(V.3) was modified in 2008.127 Other validated tools include should be considered in patients with AAV. However one should
BVAS/WG, the Disease Extent Index and the Five Factor take into account the patients’ need for treatment of their AAV
Score.131 132 These tools have a high degree of correlation and and of likely treatment choice for both induction and mainten-
are reliable.133 Training and certification in using these tools is ance therapy. Live attenuated vaccines should be avoided when-
recommended for clinicians caring for patients with AAV. ever possible. We refer readers to the EULAR recommendation
A structured examination of the patient should be carried out for vaccination in adult patients with autoimmune inflammatory
at each clinic visit to detect new organ involvement, which may rheumatic diseases.139
develop at any time in the disease course.134 Urinalysis should Further discussion is available in the online supplement.
be performed on each patient at each visit to screen for infec-
tion, renal relapse or response, as well as bladder complica- Statement 13
tions.28 50 29 During follow-up, inflammatory markers and renal We recommend periodic assessment of cardiovascular risk for
function should be measured periodically (every 1–3 months) to patients with AAV. Level of evidence 2B; grade of recommenda-
monitor disease status. A full blood count and liver function tion B; strength of vote 53%.
should be performed at similar intervals to screen for drug tox- Patients with AAV are at risk of complications, both from their
icity.52 67 An acute fall in white cell count or a progressive disease and its treatment.134 In AAV, renal, otolaryngological
leucopenia may require reduction or discontinuation of and treatment-related complications (cardiovascular disease, dia-
immunosuppressive drugs. Similarly, declining renal function betes, osteoporosis and malignancy) and damage increase over
may necessitate dose adjustment or alteration of immunosup- time. Around a third of patients have ≥five items of damage at a
pressive agents. Patients should have periodic assessment of mean of 7 years post diagnosis. At long-term follow-up, the
their blood glucose while on glucocorticoid therapy.10 most commonly reported items of treatment-related complica-
tions or damage were hypertension (41.5%; 95% CI 35.6% to
Statement 11 47.4%), osteoporosis (14.1%; 9.9% to 18.2%), malignancy
We recommend the investigation of persistent unexplained (12.6%; 8.6% to 16.6%) and diabetes (10.4%; 6.7% to
haematuria in patients with prior exposure to cyclophospha- 14.0%). Given that hypertension and diabetes are well known
mide. Level of evidence 2B; grade of recommendation C; cardiovascular risk factors it is perhaps unsurprising that
strength of vote 100%. patients with AAV are at an increased risk for cardiovascular
The use of cyclophosphamide is strongly associated with the disease. However, the risk of cardiovascular disease appears to
risk of bladder cancer.28 29 50 The use of MESNA as an uropro- be greater than can be explained through traditional cardiovas-
tective agent lowers the risk of haemorrhagic cystitis but there is cular risk factors alone. A comparison of 535 participants with
no clear evidence that it protects against bladder cancer.85 5-year follow-up from four European Vasculitis Society (EUVAS)
Transitional cell cancer can occur within months of commence- trials revealed that within 5 years of diagnosis, 14% of patients
ment of cyclophosphamide or many years after its discontinu- with GPA or MPA will have a cardiovascular event.140 This
ation.28 Tobacco smokers are particularly susceptible and may study also showed that independent determinants of cardiovas-
develop the cancer at lower doses and earlier than non-smokers.28 cular outcome were: older age (OR 1.45, 95% CI 1.11 to 1.90),
All patients should have periodic urinalysis for the duration of diastolic hypertension (OR 1.97, 95% CI 0.98 to 3.95) and
their follow-up. In the presence of haematuria confirmed on PR3-ANCA (OR 0.39, 95% CI 0.20 to 0.74).140 Annual review
urine microscopy, an urgent urology opinion must be sought. of traditional Framingham risk factors is appropriate.
Patients with AAV are at risk of long-term kidney damage.
Statement 12 Guidelines exist on the management of chronic kidney disease
Hypoimmunoglobulinaemia has been noted after treatment (CKD) such as Kidney Disease: Improving Global Outcomes
with rituximab. We recommend testing of serum immunoglobu- (KDIGO) (http://www.kdigo.org/clinical_practice_guidelines/
lin levels prior to each course of rituximab and in patients with pdf/CKD/KDIGO_2012_CKD_GL.pdf ).
recurrent infection. Level of evidence 3; grade of recommenda-
tion C; strength of vote 65%. Statement 14
Hypoimmunoglobulinaemia is associated with repeated use of We recommend that patients with AAV should be given a clear
cyclophosphamide and rituximab and is dependent on the verbal explanation of the nature of their disease, the treatment
Recommendation
options, the side effects of treatment, and the short-term and
long-term prognoses. Level of evidence 3; grade of recommen- Box 1 Research agenda
dation C; strength of vote 88%.
It is a generally accepted principle in medical practice that
▸ Diagnostic and classification criteria for ANCA-associated
patients who are well informed and educated about their illness
vasculitis (AAV).
and understand it have better outcomes. An evaluation of
▸ Identification of biomarkers for AAV.
patient education has taken place using an inpatient education
▸ Adjunctive plasma exchange–indications for use including
programme in a tertiary referral centre, although this was not a
serum creatinine cut-off.
RCT.141 Patients should be encouraged to share responsibility
▸ Adequately powered clinical trials of novel biological agents
for dealing with their illness.141
for the treatment of refractory AAV.
AAV can be a bewildering and confusing illness for patients
▸ Adequately powered randomised controlled trials in
who can be very fearful when receiving a diagnosis of such an
eosinophilic granulomatosis with polyangiitis.
uncommon disease. Like all rare diseases there is little common
▸ Long-term outcome studies in AAV.
experience and understanding of vasculitis so there are no
readily available sources of information. Patients with rare dis-
eases often feel isolated and alone.142
The internet can now provide access to reliable and from supporting some of the statements with stronger grades.
up-to-date information and advice, and to patient support The project has also led the committee to propose a research
groups which provide the reassurance of peer support and the agenda for AAV (see box 1). These recommendations have been
ability to share knowledge and experience. The internet can multidisciplinary with inputs from rheumatologists, internists,
also provide incorrect, unproven and even dangerous informa- renal physicians and also from a clinical immunologist, an oto-
tion. It is often the least articulate and least confident who are rhinolaryngologist, a chest physician, an ophthalmologist, a vas-
most vulnerable and need support. culitis nurse and a patient with vasculitis. In addition to these
AAV is characteristically a relapsing disease. Each relapse may recommendations, we have also produced advice on AAV involv-
result in further morbidity so early prediction or recognition of ing the eye and the nose (online supplement) and a lay summary
relapse is essential. A patient who understands and is educated for patients and relatives (online supplement).
about the disease is frequently better able to recognise the early The previous recommendations were published in 2009 and
signs and symptoms of relapse. importantly had a wider remit, covering small and medium
vessel vasculitis and not just AAV.10 Readers are encouraged to
Statement 15 refer to them for treatment decisions on: mixed essential cryo-
We recommend that following the remission-induction phase of globulinaemic vasculitis (non-viral), the use of antiviral therapy
treatment, patients with AAV be assessed for the extent and for the treatment of hepatitis C associated cryoglobulinaemic
ongoing impact of comorbidities associated with their diagnosis. vasculitis and antiviral therapy, PLEX and glucocorticoids for
Patients should then be advised where they might find the hepatitis B-associated polyarteritis nodosa (PAN). Ultimately the
necessary therapies or support for these conditions. Level of evi- treatment aim of viral-associated cryoglobulinaemic vasculitis
dence 4; grade of recommendation D; strength of vote 100%. should be to treat the underlying viral disease according to
AAV is a systemic disease with the potential to affect almost current best management strategies.
any organ.143 Patients may be left with permanent damage to The current recommendations provide a framework of prac-
kidneys, lungs and respiratory tract, heart, peripheral and tice which have updated the previous recommendations and
central nervous system, total or partial loss of sight or should apply to the majority of patients with AAV. Although
hearing.144 145 Patients may lose digits or limbs or be left with once again 15 statements have been formulated; some have
facial disfigurement (like a saddle-nose) or severe skin scar- been changed and some have been combined: for example there
ring.27 Severe fatigue, muscle weakness and chronic pain are fre- is no longer a separation of glucocorticoids as they are used in
quent direct consequences of AAV.146 147 Side effects of conjunction with other immunosuppressive agents. For remis-
treatment can be serious, even life-threatening.148 sion maintenance the voting of the task force reveals that
The consequences of AAV may have a serious impact on edu- azathioprine is the preferred option over other immunosuppres-
cation, employment prospects and job retention.149 Personal sive agents. In specific situations, where a less aggressive induc-
and social relationships may be seriously disrupted, sometimes tion regimen has to be preferred—methotrexate or
resulting in the total breakdown of family bonds. These factors mycophenolate mofetil may be recommended. The task force
may contribute to depression as a secondary consequence of appreciates that the induction trials involving methotrexate are
AAV.150 151 larger and of higher evidence grade than those using mycophe-
AAV is a controllable but currently incurable lifelong illness. nolate mofetil. We have been explicit in the limited scenarios
Treating clinicians need to be aware that AAV often has long- where methotrexate or mycophenolate mofetil may be justified.
term lifestyle consequences. A ‘holistic’ approach to treatment Each statement should be an opportunity for auditing clinical
and ongoing care should be adopted. practice (an audit tool has been produced—see online supple-
ment). In addition these current recommendations have pro-
DISCUSSION duced algorithms which provide clear and concise information
Implementation of these recommendations for the management of AAV (see figure 1).
The recommendations have been based on an extensive litera- These recommendations have also been voted on by the
ture search. In the absence of evidence, statements have been EUVAS membership the results of which are available as a sup-
based on the opinion and practice of experts from 12 countries plementary online file (see online supplement). The results of
(Czech Republic, France, Germany, Ireland, Italy, Netherlands, the EUVAS vote are largely in agreement with the strength of
Spain, Sweden, Switzerland, Turkey, UK and USA). The applica- recommendation vote by the task force. There are differences
tion of internationally accepted grading criteria prevents us particularly when there are a number of options available and
Recommendation
the resultant vote may represent the diversity of the EUVAS 6 Gibelin A, Maldini C, Mahr A. Epidemiology and etiology of wegener
membership. Importantly task force members who are also granulomatosis, microscopic polyangiitis, churg-strauss syndrome and goodpasture
syndrome: vasculitides with frequent lung involvement. Semin Respir Crit Care
members of EUVAS did not vote in the EUVAS survey. Med 2011;32:264–73.
Recommendations for clinical management need periodic updat- 7 Mahr A, Guillevin L, Poissonnet M, et al. Prevalences of polyarteritis nodosa,
ing and because of the many advances and ongoing research in microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome
this field, this group recommends an update of these recommen- in a French urban multiethnic population in 2000: a capture-recapture estimate.
Arthritis Rheum 2004;51:92–9.
dations should be conducted in 3 years.
8 Ormerod AS, Cook MC. Epidemiology of primary systemic vasculitis in The
Australian Capital Territory and south-eastern New South Wales. Intern Med J
Author affiliations 2008;38:816–23.
1
Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, 9 Mukhtyar C, Flossmann O, Hellmich B, et al. Outcomes from studies of
UK antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the
2
Norwich Medical School, University of East Anglia, Norwich, UK European League Against Rheumatism systemic vasculitis task force. Ann Rheum
3
Department of Rheumatology, Ipswich Hospital NHS Trust, Ipswich, Suffolk, UK Dis 2008;67:1004–10.
4
Department of Pathology, Leiden University Medical Center, Leiden, The 10 Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management
Netherlands of primary small and medium vessel vasculitis. Ann Rheum Dis 2009;68:310–7.
5
Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, 11 Dougados M, Betteridge N, Burmester GR, et al. EULAR standardised operating
University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer procedures for the elaboration, evaluation, dissemination, and implementation of
(IDIBAPS), Barcelona, Spain recommendations endorsed by the EULAR standing committees. Ann Rheum Dis
6
Assistance Publique-Hôpitaux de Paris, Department of Pulmonology, Bichat-Claude 2004;63:1172–6.
Bernard University Hospital, Paris, France 12 Boomsma MM, Bijl M, Stegeman CA, et al. Patients’ perceptions of the effects of
7
Immunologie-Zentrum Zürich, Zürich, Switzerland systemic lupus erythematosus on health, function, income, and interpersonal
8
Vaskulits-Zentrum Süd, Klinik für Innere Medizin, Rheumatologie und Immunologie, relationships: a comparison with Wegener’s granulomatosis. Arthritis Rheum
Kreiskliniken Esslingen, Kirchheim-Teck, Germany 2002;47:196–201.
9
Rheumazentrum Schleswig-Holstein Mitte, Neumünster, Germany 13 Koutantji M, Harrold E, Lane SE, et al. Investigation of quality of life, mood, pain,
10
Department of Otorhinolaryngology, Head and Neck Surgery, University of Kiel, disability, and disease status in primary systemic vasculitis. Arthritis Rheum
Kiel, Germany 2003;49:826–37.
11
Trinity Health Kidney Centre, Tallaght Hospital, Dublin, Ireland 14 Anderson K, Klassen J, Stewart SA, et al. Does geographic location affect
12
Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, incidence of ANCA-associated renal vasculitis in northern Saskatchewan, Canada?
Botnar Research Centre, University of Oxford, Oxford, United Kingdom Rheumatology 2013;52:1840–4.
13
Department of Internal Medicine, Hôpital Saint-Louis, Université Paris 7 René 15 Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis:
Diderot, Paris, France Clinical and laboratory findings in eighty-five patients. Arthritis Rheum
14
Division of Rheumatology and the Department of Biostatistics and Epidemiology, 1999;42:421–30.
University of Pennsylvania, Philadelphia, Pennsylvania, USA 16 Carruthers DM, Watts RA, Symmons DPM, et al. Wegener’s granulomatosis—
15
Vasculitis UK, West Bank House, Winster, Matlock, UK increased incidence or increased recognition? Br J Rheumatol 1996;35:142–5.
16
Department of Medical and Health Sciences, Linköping University, Linköping, 17 Hoffman GS, Thomas-Golbanov CK, Chan J, et al. Treatment of subglottic stenosis,
Sweden due to Wegener’s granulomatosis, with intralesional corticosteroids and dilation.
17
Department of Nephrology, Linköping University, Linköping, Sweden J Rheumatol 2003;30:1017–21.
18
Department of Nephrology, 1st School of Medicine, Charles University, Prague, 18 Langford CA, Sneller MC, Hallahan CW, et al. Clinical features and therapeutic
Czech Republic management of subglottic stenosis in patients with Wegener’s granulomatosis.
19
Department of Nephrology, Lund University, Skåne University Hospital, Lund and Arthritis Rheum 1996;39:1754–60.
Malmö, Sweden 19 Elmedhem A, Adu D, Savage COS. Relapse rate and outcome of ANCA-associated
20
Nephrology Unit, University Hospital of Parma, Parma, Italy small vessel vasculitis after transplantation. Nephrol Dial Transplant
21
Department of Ophthalmology, School of Medicine, Ankara University, Ankara, 2003;18:1001–4.
Turkey 20 Rahmattulla C, de Lind van Wijngaarden RA, Berden AE, et al. Renal function and
22
Lupus and Vasculitis Unit, Addenbrooke’s Hospital, Cambridge, UK ear, nose, throat involvement in anti-neutrophil cytoplasmic antibody-associated
vasculitis: prospective data from the European Vasculitis Society clinical trials.
Acknowledgements The authors thank Ms Karly Graham for proof reading. Rheumatology (Oxford) 2015;54:899–907.
Contributors All authors formed part of the task force that appraised the evidence 21 Homma S, Suzuki A, Sato K. Pulmonary involvement in ANCA-associated
and made recommendations for the management of ANCA-associated vasculitis. All vasculitis from the view of the pulmonologist. Clin Exp Nephrol 2013;17:
authors have contributed to editing of drafts of the main document and associated 667–71.
supplementary materials. 22 Le Berre L, Dufay A, Cantarovich D, et al. Early and irreversible recurrence
MPO-ANCA-positive glomerulonephritis after renal transplantation. Clin Nephrol
Funding This work was supported by and commissioned by the European League 2015;83:357–62.
Against Rheumatism (EULAR) and the European Renal Association—European 23 Schokkenbroek AA, Franssen CF, Dikkers FG. Dilatation tracheoscopy for laryngeal
Dialysis and Transplant Association (ERA-EDTA). and tracheal stenosis in patients with Wegener’s granulomatosis. Eur Arch
Competing interests DRJ has received research grants and consulting fees from Otorhinolaryngol 2008;265:549–55.
Roche/Genentech. 24 Venhoff N, Effelsberg NM, Salzer U, et al. Impact of rituximab on immunoglobulin
concentrations and B cell numbers after cyclophosphamide treatment in patients
Provenance and peer review Not commissioned; externally peer reviewed. with ANCA-associated vasculitides. PLoS ONE 2012;7:e37626.
25 Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of
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Handling editor Tore K Kvien ABSTRACT BACKGROUND AND RATIONALE

Yates M, et al. Ann Rheum Dis 2016;75:1583–1594. doi:10.1136/annrheumdis-2016-209133 1587

Yates M, et al. Ann Rheum Dis 2016;75:1583–1594. doi:10.1136/annrheumdis-2016-209133 1591

1592 Yates M, et al. Ann Rheum Dis 2016;75:1583–1594. doi:10.1136/annrheumdis-2016-209133

Yates M, et al. Ann Rheum Dis 2016;75:1583–1594. doi:10.1136/annrheumdis-2016-209133 1593

1594 Yates M, et al. Ann Rheum Dis 2016;75:1583–1594. doi:10.1136/annrheumdis-2016-209133

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