preventing psoriatic arthritis: targeting interventions in ... · psoriasis • psoriasis precedes...
TRANSCRIPT
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Preventing psoriatic arthritis: targeting
interventions in high risk groups
John Bowes
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Psoriatic Arthritis
• Arthritis associated with psoriasis
• Prevalence of PsA in patients with
psoriasis ~30% (UK)
• Heterogeneous disease
– peripheral arthritis
– axial disease (sacroiliitis)
– dactylitis
– enthesitis
– nails
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Impact on Quality of Life
Psoriasis
• Psoriasis precedes PsA
• Physical and psychological
burden
Arthritis and enthesitis
↑ disability
↓ physical and social function
↓ work productivity
Comorbidities
• Increased prevalence
•CVD, metabolic syndrome,
obesity, depression ....
• higher than psoriasis alone
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Predicting PsA
No PsA diagnosis
PsA diagnosis
Joint lesions
• Typically psoriasis precedes
PsA
• Represent a high risk group
- Prevalence of PsA ~30%
- Joint lesions ~50%
• Scenario for disease prediction
• Mitigate impact of PsA
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Predicting PsA
• Common complex disease
1. Genetic risk factors 2. Environment risk factors 3. G+E = liability
• Impact: need to identify PsA-specific risk factors
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Aim:
Identify risk factors that can help differentiate PsA
from cutaneous-only psoriasis
Benefits:
Improved diagnosis
Delay in diagnosis → worse outcome
Preventing disease
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Discovery
Identification of
risk factors
Genetic/Env.
Prediction
Can these risk
factors identify
high risk
groups?
Prevention
Need strategy
or intervention
options
Pathway to prevention
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Prevention
Need strategy
or intervention
options
Discovery
Identification of
risk factors
Genetic/Env.
Prediction
Can these risk
factors identify
high risk
groups?
Pathway to prevention
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Major Histocompatibility Complex
Importance
Major genetic risk factor
Enriched for immune genes
HLA – antigen presentation
Challenges
Highly polymorphic
Highly correlated variants
Study design is essential
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Discovery: genetic study
1. Recruitment
2. Collect genetic
information
3. Compare
Frequencies
4. Genetic basis
for disease
Cases Controls
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PsA
HLA-C
HLA-B
HLA-A
MHC fine mapping
Forward
stepwise
logistic
regression
• Comparison to controls
is problematic
• All our patients also
have psoriasis
• Challenging to identify
PsA-specific effects
• MHC – identical to PsC
• Any potential PsA
signal is lost
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Cross-phenotype analysis
Modified study design: integrate
psoriasis genotype data
Access to psoriasis cohort
Collaborate King’s College
London - Catherine Smith
- Jonathan Barker
- Richard Warren
- Christopher Griffiths
Data from the BSTOP study
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Cross-phenotype analysis
Direct comparison
No effect from known psoriasis risk
variants
HLA-B*27
Antigen presentation to cytotoxic T-
cells
Resolve association to amino acid 97
Floor of the peptide binding groove
Alter peptide specificity
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Prevention
Need strategy
or intervention
options
Discovery
Identification of
risk factors
Genetic/Env.
Prediction
Can these risk
factors identify
high risk
groups?
Pathway to prevention
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Disease risk prediction
Can PsA-specific variants predict disease?
Machine learning
Variable selection
Predictive modelling
Recruited post-
doctoral research
associate
Building collaborations
with the School of
Computer science
Work funded by
Arthritis Research UK
project grant
Which variants are
good classifiers?
Differentiate PsA from
PsC
Method: mutual
information
Important to address
confounding
Test the ability of
variables to predict
disease
Multiple methods:
- bagged trees
- random forests
- KNNC
validate in
independent data
- UK Biobank
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Disease risk prediction
Application to MHC data: 2 digit HLA alleles
HLA-B*27 20 features
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Disease risk prediction
Overfitting:
Independent
validation is
essential
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PREVENT PsA
Genetics
Clinical
Lifestyle
Variable selection and
prediction modelling
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2000
Psoriasis
Patients
Baseline Time point 1 Time point 2 Time point 3
Incident cases of PsA
Aim: Clinical benefit of screening and early diagnosis
DNA genetics + clinical data
Extend PROMPT to include genetics
longitudinal
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Discovery
Identification of
risk factors
Genetic/Env.
Prediction
Can these risk
factors identify
high risk
groups?
Pathway to prevention
Prevention
Need strategy
or intervention
options
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Implementation
Options for preventative strategies:
1.
2.
Early referral to rheumatologist
Preventative treatment
a. Statins
b. Methotrexate
c. Single low-dose biologic
- Rituximab
- Abatacept
RA
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Summary
• We are identifying PsA-specific risk factors
• Showing promise in prediction models
• Moving research towards a clinical setting
• Combining genetic and clinical data
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Prevention projects
High risk groups
Early intervention
or preventative
treatment
Prevent: disease
Increased prevalence
in IA
Understand this
relationship
Prevent: morbidity
Prevent PsA Comorbidities Uveitis JIA
Common in JIA
Can lead to blindness
Prevent: burden of
screening – reduce
intervention
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Current work: data integration
Variable selection
and prediction modelling
Genetics
Clinical
Lifestyle
Multiple data types Data integration Multiple time points
Time point 1 Time point 2
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Manchester: Professor Anne Barton (PI)
Dr Farideh Jalali
Australia: Prof. Matthew Brown (The
University of Queensland)
Dr. Marie Feletar (Monash University)
PAGE Collaborators: Prof. Neil McHugh (University of Bath) Prof. Ann Morgan (University of Leeds) Prof. Andre Reis (Erlangen University) Prof. Oliver FitzGerald (University College Dublin) Prof. Emiliano Giardina (University of Rome) Dr. Philip Helliwell (Leeds University) Dr. Gerd-Marie Alenius (University Hospital, Umea) Prof. Harald Burkhardt (Goethe University)
Acknowledgements
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