Establishing an evidence-based therapeutic approach to ANCA-associated vasculitis-Jayne
Submitting InstitutionUniversity of Cambridge
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Technology: Medical Biotechnology
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences
Summary of the impact
Jayne's team have co-ordinated a sequence of randomised clinical trials,
that have defined the standard of care for ANCA vasculitis treatment and
shaped national and international guideline statements, NHS national
commissioning guidance and an on-going NICE assessment. Together with Ken
Smith his group have pioneered the use of the B cell-depleting agent
rituximab, in vasculitis, contributing key evidence that led to its
licence approval (USA and EU) for this indication. Ken Smith's group
supported by Jayne's clinical team have discovered novel therapeutic
biomarkers, patented and being assessed in Phase II clinical studies, that
promise to deliver "personalised medicine" in this and related conditions.
These activities have harmonised the management of vasculitis, are
improving patient outcomes, and have provided a resource for on-going
scientific and clinical studies.
Over the last decade Professor Ken Smith, Chair of Medicine and Dr David
Jayne, University Reader in Vasculitis (both tenured appointments in the
Department of Medicine, respectively from 1996 and September 2013; Jayne
was previously Associate Lecturer through the office of the School of
Clinical Medicine from March 2013 and NHS Consultant, Renal Unit,
Addenbrooke's Hospital since 2001), have built up a translational
programme focussed on biomarker identification and delivering improved
therapy for Anti-neutrophil cytoplasmic antibody (ANCA) — associated
vasculitis (AAV). AAV is a severe systemic inflammatory condition, with 20
new cases per million in the UK each year. It commonly causes renal
failure or pulmonary haemorrhage and has a fatality rate of up to 30% at 5
years, while causing substantial long — term morbidity in survivors. David
Jayne co-ordinates an expanding international vasculitis network
supporting clinical trials and biomarker studies (1).
Bringing a novel therapeutic approach into the clinic: B cell
depletion in AAV
Rituximab is a depleting monoclonal antibody against the B cell-specific
surface antigen CD20, previously developed for the treatment of B cell
lymphoma. Following basic research in Cambridge defining the humoral
contribution to pathogenesis of AAV, Smith and Jayne commenced the first
pilot study of B cell depletion as a potential induction therapy in 2001.
This demonstrated a high remission rate for patients with disease
refractory to the standard of care and suggested rituximab might provide
an effective alternative to the relatively toxic cyclophosphamide and
inspired a subsequent international trial, RITUXVAS, led by Jayne (2). The
response permitted withdrawal of immunosuppressives and glucocorticoids,
improvement in quality of life, reduced hospitalisations and protection of
vital organ function.
Defining new biomarkers and targets for future therapy
Personalised therapy, that would allow those with mild disease to receive
reduced therapy, (with reduced toxicity), and those with an aggressive
disease course to benefit from intensified therapy (with increased
efficacy), is a major goal in AAV as in other autoimmune diseases. The
Smith group have identified polymorphisms underlying disease
susceptibility (3). Such an approach also requires prognostic biomarkers —
Smith and colleagues, using a transcriptomic approach studying pre-sorted
circulating leucocytes, have identified phenotypic differences in an
immune activation pathway of use both as a biomarker and for the study of
disease pathogenesis, this CD8-T cell transcriptional signature predicts
long-term prognosis in those presenting with AAV (4), and is likely to
have widespread application as it also effective in SLE, Crohn's Disease
and Inflammatory Bowel Disease (5).
An additional approach to define novel therapeutic pathways has involved
a genetic study of AAV. Building on a number of candidate gene studies
performed in Cambridge and elsewhere, the first Genome-Wide Association
Study of the disease performed in 2012 by a European Consortium led by Ken
Smith and funded by the British Heart Foundation and NIHR Cambridge
Biomedical Research Centre. This compared DNA samples 2,500 AAV patients
with those from healthy controls. This has demonstrated conclusively that
Wegener's Granulomatosis and Microscopic Polyangiitis are genetically
distinct diseases, raising the possibility that they may respond to
different therapeutic approaches rather than to the identical ones
currently used. It has also shown that the primary disease causing factor
and genetic abnormality in Wegener's Granulomatosis is the response to a
single autoantigen, as the MHC, alpha1-antitrypsin, and its substrate the
autoantigen proteinase 3, are all risk factors for disease. That a single
antigenic response lies at the core of disease susceptibility suggests
novel future approaches to therapy (6).
References to the research
1. Hiemstra TF, Walsh M, Mahr A, Savage CO, de Groot K, Harper L, Hauser
T, Neumann I, Tesar V, Wissing KM, Pagnoux C, Schmitt W, Jayne DR;
European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs.
azathioprine for remission maintenance in antineutrophil cytoplasmic
antibody-associated vasculitis: a randomized controlled trial. JAMA.
2. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage
CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K,
Jayne DR; European Vasculitis Study Group. "Rituximab versus
cyclophosphamide in ANCA-associated renal vasculitis." N Engl J Med.
3. Willcocks LC, Lyons PA, Clatworthy MR, Robinson JI, Yang W, Newland
SA, Plagnol V, McGovern NN, Condliffe AM, Chilvers ER, Adu D, Jolly EC,
Watts R, Lau YL, Morgan AW, Nash G, Smith KGC. Copy number of FCGR3B,
which is associated with systemic lupus erythematosus, correlates with
protein expression and immune complex uptake. J Exp Med.
4. McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DRW, Willcocks LC,
Koukoulaki M, Hatton A, MacAry PA, Brazma A, Chaudhry AN and Smith KGC. "A
CD8 memory T cell transcription signature predicts prognosis in autoimmune
diseases." Nature Medicine, 2010;16:586-589.
5. Lee JC, Lyons PA, McKinney EF, Carr EJ, Bredin F, Rickman HR,
Ratlamwala H, Hatton A, Rayner TF, Parkes M, Smith KGC. "Gene expression
profiling in CD8 T-cells predicts disease course in Crohn's disease and
ulcerative colitis." Journal of Clinical Investigation,
6. Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DRW, Baslund
B, Brenchley P, Bruchfeld A, Chaudhry AN, Cohen Tervaert JW, Deloukas P,
Feighery C, Gross WL, Guillevin L,Gunnarsson I, Harper L, Hrušková Z,
Little MA, Martorana D, Neumann T, Ohlsson S, Padmanabhan S, Pusey CD,
Salama AD, Sanders J-S F, Savage CO, Segelmark M, Stegeman CA, Tesař V,
Vaglio A, Wieczorek S, Wilde B, Zwerina J, Rees AJ, Clayton DG and Smith
KGC. "Genetically Distinct Subsets within ANCA-Associated
Vasculitis" New England Journal of Medicine, 2012;367:214-223.
Details of the impact
A. Clinical studies and Guidelines
Jayne has co-ordinated the European vasculitis network since 2001 and
founded the European Vasculitis Society (EUVAS) in 2011. EUVAS has taken a
strategic and collaborative approach to the development of an evidence
base to drive therapeutic advances in vasculitis Studies via the EUVAS
collaboration led by Jayne have informed changes in the classification of
disease, the 2012 Chapel Hill consensus statement, on clinical (1),
epidemiological (2), histological (3) and genetic (4) grounds, allowing
recommendations to be made to enhance clinical trial design and have
provided a framework for personalised medicine in vasculitis (1).
Such trials have improved patient outcomes by optimising the balance of
current therapies between efficacy and toxicity. They have also stratified
treatment according to severity and resulted in the publication of 5
consensus treatment recommendations, between 2006 and 2012, sponsored by
the European League against Rheumatism (EULAR) and the British Society of
Rheumatology, now used widely through Europe (5-8). Uptake of EUVAS
methodology and guidance has extended beyond the EU, with collaborative
studies in USA, Canada, Japan and Australia. NICE is conducting its first
Health Technology Appraisal (HTA) in vasculitis this year based, in part,
on work from this group.
The RITUXVAS trial (NCT 00748644, Jayne was PI) and other studies
contributed to the licensing of Rituximab for ANCA associated vasculitis
by the FDA in 2011 and EMA in 2013, and used in consultation in a NICE HTA
`Further Appraisal Consultation Document' (released September 2013) (9,
10). On-going studies by Jayne's group are defining pharmacogenomic
markers to guide dosing and patient stratification, which it is hoped will
provide long-term control of disease with a reduction in morbidity and
mortality and improve the cost-effectiveness and safety of this therapy.
Establishing an evidence base for conventional therapy of AAV
David Jayne has extended the EUVAS group to include vasculitis networks in
Japan, North America, Australia and New Zealand permitting large scale
clinical trials and parallel biomarker and epidemiologic studies. The
Cambridge team has lead an international consortium since 2001, that
firstly developed and validated clinical assessment tools and a
methodology for performing large scale interventional clinical trials,
then co-ordinated eleven randomised controlled trials that now define the
standard of care in ANCA vasculitis (6,7). The team are leading on a study
examining the applicability of plasma exchange (funded by government
agencies in the UK, USA, Canada, Australia and Japan; PEXIVAS NCT00987389,
Jayne is PI, commenced 2010). They have also shown the efficacy of
maintenance therapy in preventing relapse in AAV, and are leading an
international trial RITAZAREM (NCT01697267, Jayne is PI, commenced April
2013), contributing to a stratification approach for individual patient
B. Novel Therapeutics; B cell depletion with Rituximab in vasculitis
The outcome of the initial use of rituximab in vasculitis in Cambridge has
been the completion of two phase 3 studies of its use as induction
therapy, one was Jayne-led, which were published together in the New
England Journal of Medicine. The introduction of rituximab since 2005 for
ANCA associated vasculitis has been hailed by patient groups and the
medical press alike (9, 10), and resulting in immediate widespread changes
to clinical practice.
C. Personalised Medicine in vasculitis
Prognostic biomarker discovery by the Cambridge group has led to great
interest in the clinical and scientific community, successful patent
protection (11), and the development of on-going clinical studies prior to
commercialisation. These biomarkers are now undergoing clinical validation
for their utility in patient stratification and personalised medicine
(12). Validation of this biomarker in a prospective study in AAV (ARC
grant funded) and Crohn's Disease (Wellcome Trust Translational Award
funded) is about to commence led by the Smith team.
Sources to corroborate the impact
A. Clinical studies via the EUVAS collaboration
- Hellmich B, Flossmann O, Gross WL et al. EULAR recommendations for
conducting clinical studies and/or clinical trials in systemic
vasculitis: focus on anti-neutrophil cytoplasm antibody- associated
vasculitis. Ann Rheum Dis. 2007;66:605-617.
- Watts RA, Scott DG, Jayne DR et al. Renal vasculitis in Japan and the
UK--are there differences in epidemiology and clinical phenotype?
Nephrol Dial Transplant. 2008;23:3928-3931.
- Berden AE, Ferrario F, Hagen EC et al. Histopathologic Classification
of ANCA-Associated Glomerulonephritis. J Am Soc Nephrol. 2010
- Lyons PA, Rayner TF, Trivedi S et al. Genetically distinct subsets
within ANCA-Associated Vasculitis. N Engl J Med. 2012;367: 214-223.
- Lapraik C, Watts R, Bacon P et al. BSR and BHPR guidelines for the
management of adults with ANCA associated vasculitis. Rheumatology
- Mukhtyar C, Guillevin L, Cid MC et al. EULAR Recommendations for the
management of primary small and medium vessel vasculitis. Ann Rheum Dis.
- Mukhtyar C, Guillevin L, Cid MC et al. EULAR Recommendations for the
management of large vessel vasculitis. Ann Rheum Dis. 2009;68:318-323.
- Guerry MJ, D'Cruz D, Brogan P, et al. Recommendations for the use of
rituximab in ANCA vasculitis. Rheumatology 2012 Apr;51(4):634-43.
B. B cell depletion with Rituximab in vasculitis
- Patient Organisations such as the Vasculitis Foundatiion
C. Personalised Medicine in vasculitis
- US Provisional patent application number 61/145,824 — priority date:
20 January 2009. Title: Methods for classifying subjects (1). US
Provisional patent application number 61/145,831 - priority date 20
January 2009. Title: Methods for classifying subjects (2)
- McKinney EF, Lyons PA, Carr EJ et al. "A CD8 memory T cell
transcription signature predicts prognosis in autoimmune diseases."
Nature Medicine, 2010;16:586-591.