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