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Oxford SPR club

Oxford SPR club

Mark Little

on 9 February 2017

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Transcript of Oxford SPR club

A model of anti-PR3 antibody associated vasculitis
Close to the human
Other autoimmune diseases?
Dissection of pathogenesis and assessment of novel biomarkers
15 per million/year
250/million prevalence
Granulomatosis with polyangiitis -

Anti-Proteinase 3 antibodies
Microscopic polyangiitis -
Anti-Myeloperoxidase antibodies
There is a genetic contribution to ANCA associated vasculitis pathogenesis
GPA and MPA are genetically distinct
This divergence associates very strongly with ANCA specificity
Strongly suggests that the immune response to the autoantigen PR3 is of central importance
Unravelling Vasculitis
C5a antagonism
Huugen et al, Kid Int (2007) 71, 646
Longitudinal clinical data capture via UKVAS eCRF
Sample processing, archiving and storage at TCD biobank - fully resourced for 5 years
Multi-disciplinary clinic at Tallaght
Local data capture and sample processing in CRC
Rules of engagement
Thank you for
your attention

“Burden of Therapy”
Cyclophosphamide-induced leukopenia, WCC=1.8
Mild steroid-induced diabetes (non-insulin requiring)
Admitted with pneumonia, treated with IV antibiotics
= 7
Probability of death as a direct consequence of therapy within the subsequent 100 days:
: 0.7%
: 8%
: 28%
Little et al, Ann Rheum Dis. 2010 Jun;69(6):1036
Genetic predisposition to ANCA associated vasculitis
Modelling of ANCA associated vasculitis
Minimising adverse events
Study of ANCA vasculitis, a rare disease
Little et al, PLoS One. 2012;7(1):e28626. Epub Jan 2012
An in silico thought experiment
The hump in dose with moderately severe kidney failure is mirrored by a hump in adverse events, reinforcing the notion that we don't know how to dose cyclophosphamide
Joseph Walshe
Peter Conlon

Peter Lavin
Catherine Wall
George Mellotte
Jeremy Duffield

Hamad Al Nuaimi
Bahjat Al Ani
Caroline Savage
Lorraine Harper

Rhian Daniel
Alan Salama

Ken Smith
Paul Lyons
University of Washington, Seattle
University of Birmingham
European Vasculitis Genetics Consortium
Mr MC, a 51yo carpenter
Presented with right sided knee pain
Had 2 episodes of sinusitis over past 4 months
Treated with penicillin - hives and migratory arthritis
Initial investigations:
Urinalysis normal
WCC 12,000 per cu mm
Underwent surgical exploration of the knee
Loose meniscus and inflamed synovium
Pain continued in the knee
At 2nd op, actinomyces was grown from joint fluid
6 months later...
Presented with migratory arthritis, fever, left sided proptosis and epistaxis
Urinalysis: some red cells
X-ray: pansinusitis and new right basal infiltrates
Lupus erythematosus suspected, but no LE cells
Treated with ACTH, with improvement in joint symptoms
Developed frank haematuria and exophthalmous worsened
Globulin level 3.6g per cent
Widespread petechial rash (normal clotting mechanism)
Blood urea nitrogen rose to 200mg pre cent
MC died on 30th June 1952
“disseminated necrotising arteritis” seen in Wegener’s granulomatosis may be due to an immunological reaction against an “antigen circulating in the blood stream”

Kahn RL. Tissue immunity; its possible relationship to midline facial granulomatous ulceration. Med Bull (Ann Arbor) 1954;20(8):209-18.
N Engl J Med. 2012;367:214
No immune system of their own
1 year mortality 11%
Mr MC, with globulin level of 3.6g per cent
We often see hypogammaglobulinemia
Continued refining of existing therapy through networked investigation
Focus on biomarker development: urinary metabolomics and exosomes
Further stratification of ANCA vasculitis along aetological lines

o k
n c
Passive transfer of PR3 ANCA
Vitamin R
UKVAS: a registry and biobank for study of systemic vasculitis in Ireland and the UK
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