Update on Patterns of Study in ANCA Associated Vasculitis presented at regional Northern Ireland Nephrology Meeting with Dr David Jayne as guest speaker..

1. Update in ANCA
Associated Vasculitis
Richard McCrory
ST5 Renal / Internal Medicine

2. Updates on...
● Classification Issues
● Pathobiology
● Treatment Induction / Maintenance

3. 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%)

4. The Limburg Registry - 30 Years of
Follow-Up (NDT, 2012)

5. Disease Activity - BVAS

6. Assessing the Damage
Higher 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)

7. Histopathological Categorization and relation to
Renal Survival
(Berden et al 2010)
Some consistency found in
analysis of other ANCA
cohorts
(Tanna et al. NDT 2014
Quintana et al. NDT 2014)

8. How do we fight (appropriately) for
every nephron?!?!

9. “You can't compare an
apple to an orange. It
will cause a lot of self-esteem
issues”

10. 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

12. Revising AAV Classification
Classification 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

13. 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.

14. 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)

15. 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 flares
Jayne et al ERA-EDTA 2014

16. From
Jannette &
Falk 2014

18. Induction Therapy
RAVE & 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

19. Am J Kidney Dis. 57(4):566-574. © 2011

20. PEXIVAS

21. Maintenance of Remission
WEGENT
● Methotrexate no different to Azathioprine
WGET
● Enteracept no better than AZA with increased SAE’s
IMPROVE
● MMF < AZA

22. MAINRITSAN - Using Rituximab for
Maintaining Remission

23. ANCA Vasculitis reaching ESRD
ANZDATA Registry
36,884 ESRD patients
● 228 Microscopic Polyangiitis (MPA)
● 221 Granulomatosis with Polyangiitis (GPA)
Compared with other causes of ESRD, survival on dialysis comparable
46 MPA patients (21%) and 47 GPA (20%) patients received 98 renal
allografts.
MPA GPA non-AAV
10-yr graft survival 50% 62% 70%
10-yr patient survival 68% 85% 83%
Tang et al . CJASN 2013

24. The Great Unknowns
● Remission Maintenance
o 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?

25. Where Future Trials Lead us...
MAINRITSAN 2
● Regular RTX vs. RTX “on demand”
RITAZAREM
● RTX vs. Azathioprine for Relapsing Disease

26. Other Biologicals
ALEVIATE
● Alemtuzumab in Refractory Disease
BREVAS - Belimumab
● Monoclonal Antibody Against BAFF

27. Glucocorticoid Wiithdrawal: If or When?
Arthritis Care & ResearchVolume 62, Issue 8, pages 1166-1173, 16 MAR 2010 10.1002/acr.20176http://onlinelibrary.wiley.com/doi/10.1002/acr.20176/full#fig2

28. The TAPIR Trial
Recruiting 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

29. Summary
Defining & 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