Update in ANCA Associated VasculitisRichard McCroryST5 Renal / Internal Medicine
Updates on...
● Classification Issues● Pathobiology● Treatment Induction / Maintenance
From invariably fatal, to a chronic relapsing / remitting condition..Cumulative survival from EUVAS
○ 1 year 88%, 5 year 78%○ 38% had a relapse
Death within the first year
● Infection (48%) and Active Disease (19%)
Death after 1 year
● Cardiovascular disease (26%), malignancy (22%), and infection (20%)
The Limburg Registry - 30 Years of Follow-Up (NDT, 2012)
Disease Activity - BVAS
Assessing the DamageHigher Vasculitis Damage Index
● older age at baseline● lower glomerular filtration rate● higher BVAS scores● increased cumulative glucocorticoid use● increasing number of relapses (Robson et al. Rheumatology 2014)
Patient Related Outcomes● Higher numbers of AAV patients report reduced QoL indicators c/w
general population (Basu et al . ADR 2014)● 25% report unemployment as a result of ill health related to AAV and
it’s treatment (Basu et al. Rheumatology 2014)
Histopathological Categorization and relation to Renal Survival
(Berden et al 2010)
Some consistency found in analysis of other ANCA cohorts(Tanna et al. NDT 2014Quintana et al. NDT 2014)
How do we fight (appropriately) for every nephron?!?!
“You can't compare an
apple to an orange. It
will cause a lot of self-
esteem issues”
Revising AAV Classification
Classification by Phenotype (Mahr et al. Ann Rheum Dis 2013)
● Renal AAV with PR3-ANCA ● Renal AAV without PR3-ANCA● Non-renal AAV● Cardiovascular AAV● Gastrointestinal AAV
Revising AAV ClassificationClassification by Genotype
Wellcome Trust Case Control Consortium (NEJM 2012)● MHC (Chr 6) / α1-Antitrypsin (SERPINA)(Chr 14) /
PRTN3 (Chr 19) associated with PR3● HLA-DQ associated with MPO
Something old, something new?
1995● Heterozygosity for PiZ allele of α1-antitrypsin
correlates with more disseminated c-ANCA disease at presentation
2011● Elevated levels of α1-AT polymers on
immunochemistry with carriage of the Z allele support a causal association with the Z allele but not the S allele.
Pathobiology - ANCA Antibodies
“The Forbidden Clones”● ~10% PR3-ANCA Antibody Positive without evidence of
Vasculitis (McAdoo et al 2012)● Low titre, low avidity for Neutrophils
BUT
● Generating ANCA Antibodies may be predictive of future ANCA disease (US Dept of Defence Serum Repository, Olson et al CJASN 2013)
Pathobiology- The Role of the Complement System
In Mice Models of MPO Vasculitis● C5 Knockout Mice - Prevents Crescent Formation● C4 Knockout Mice - No difference in Crescent Formation
In vivo evidence to support complement inhibition● CCX168 (oral C5 inhibitor) + CYC non-inferior to CYC +
Standard Prednisolone in ANCA flaresJayne et al ERA-EDTA 2014
From Jannette & Falk 2014
Induction TherapyRAVE & RITUXVAS● Similar remission rates for newly diagnosed patients between
rituximab(RTX)- and cyclophosphamide(CYC)-based regimens when combined with high-dose glucocorticoid
● RTX > CYC for relapsing disease● No difference in safety profiles (?effect of steroid)
How much induction RTX is needed?Single dose RTX achieving 3 month probability of CR 80%
Turner Stokes et al Rheumatology 2014
Am J Kidney Dis. 57(4):566-574. © 2011
PEXIVAS
Maintenance of RemissionWEGENT
● Methotrexate no different to Azathioprine
WGET● Enteracept no better than AZA with increased SAE’s
IMPROVE● MMF < AZA
MAINRITSAN - Using Rituximab for Maintaining Remission
ANCA Vasculitis reaching ESRD
ANZDATA Registry36,884 ESRD patients
● 228 Microscopic Polyangiitis (MPA)● 221 Granulomatosis with Polyangiitis (GPA)
Compared with other causes of ESRD, survival on dialysis comparable46 MPA patients (21%) and 47 GPA (20%) patients received 98 renal allografts.
Tang et al . CJASN 2013
MPA GPA non-AAV
10-yr graft survival 50% 62% 70%
10-yr patient survival 68% 85% 83%
The Great Unknowns
● Remission Maintenanceo Who needs it? And how much?
● How to maintain remission following rituximab?
● What’s the best agent for relapsing disease?● How to manage refractory disease?
Where Future Trials Lead us...
MAINRITSAN 2● Regular RTX vs. RTX “on demand”
RITAZAREM● RTX vs. Azathioprine for Relapsing Disease
Other Biologicals
ALEVIATE● Alemtuzumab in Refractory Disease
BREVAS - Belimumab● Monoclonal Antibody Against BAFF
Arthritis Care & ResearchVolume 62, Issue 8, pages 1166-1173, 16 MAR 2010 DOI: 10.1002/acr.20176http://onlinelibrary.wiley.com/doi/10.1002/acr.20176/full#fig2
Glucocorticoid Wiithdrawal: If or When?
The TAPIR TrialRecruiting patients with GPA via social media as well as by treatment centres.
Prednisolone 5mg vs. 0mg
6 month outcomes● Prednisone dose increase for
disease relapse● Time from randomisation to flare● Health related QoL● Adverse Events● Protocol Compliance
SummaryDefining & Standardising
● Disease phenotypes for future trial recruitment● Disease damage relating to Long Term (Patient Related) Outcomes
Pathobiology● Genetics informing disease phenotype & treatment response● Identifiying at risk individuals and new therapeutic targets
Clarifying Treatment Standards● “Off-drug” vs. “On-drug” Remission