Arthritis Research UK Spondyloarthopathy Clinical Study Group
First Annual Study Day
Theme: Stratified Medicine in Spondyloarthropathy
Date: Wednesday 17th April 2013
Venue: Royal National Hospital for Rheumatic Diseases
Chairman: Professor Neil McHugh
Meeting Minutes
Attendees: Sangita Agarwal, Hussein Al-Mossawi, Jim Archer, Ramani Arumugam, Alex
Bennett, Paul Bowness, Sinead Brophy, Andrei Calin, Debbie Cook, Paul Creamer, Lisa
Dunkley, Hill Gaston, Sue Gurden, Claire Harris, Rhys Hayward, Philip Helliwell, Margaret
Hughes, Deepak Jadon, Edd James, Amjad Jilani, Gareth Jones, Lesley Kay, Andrew Keat,
Ellie Korendowych, Gary Macfarlane, Kirsten Mackay, Melanie Martin, Jane Martindale,
Alison Nightingale, Ejaz Pathan, Thalia Roussou, Matt Row, Laura Savage,
Marina Scolnik, Raj Sengupta, Stefan Siebert, Alan Silman, Sophia Steer, Amanda Thomas,
William Tillett, Vivienne Winrow
Apologies: Ade Adebajo, Zoe Ash, Dominique Baeten, David Chandler,
Sarah Cole, Christopher Edwards, Dirk Elewaut, Karl Gaffney, Pauline Ho, Adrian Jones,
Gabrielle Kingsley, Stuart Kyle, Dennis McGonagle, Ira Pande, Michelle Rutherford,
Jonathon Sherlock, Peter Taylor, Paul Wordsworth,
The morning session was chaired by Raj Sengupta who welcomed all attendees. It was
pleasing to note attendance at the meeting from a broad range of backgrounds and interests
(Rheumatologists 72%, Health Professionals 13%, Non-clinical Scientists 10% Patient
representatives 5%). All speakers were introduced with a brief bio-profile.
1. Neil McHugh outlined the aims of the workshop with some introductory slides.
One commonly used definition of stratified medicine is ‘The right therapy for the right
patient in the right dose at the right time’. Specific challenges for applying a stratified
medicine approach to spondyloarthropathy include
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Reconciliation of respective classification criteria used in the field (e.g. axial
spondyloarthropathy vs peripheral spondyloarthopathy vs psoriatic arthritis)
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Bringing together expertise in the fields of ankylosing spondylitis versus psoriatic
arthritis and the specialist networks in which they interact (e.g. ASAS vs GRAPPA etc)
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Targeting treatment to potentially discordant pathological mechanisms that may
fluctuate according to stage of disease (synovitis vs enthesitis, bone erosion vs
proliferation)
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Biomarkers less obvious than in other rheumatic diseases (e.g. lack of specific
autoantibodies, imaging modalities need more validation)
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Getting a greater slice of the funding cake for spondyloarthropathy!
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The definition, types and categories of biomarker were described. The categories include
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Prognostic biomarker
– a baseline patient or disease characteristic that categorises patients by
degree or risk for disease occurrence or progression
• informs about the natural history of the disorder in that particular
patient
Predictive biomarker
– a baseline characteristic that categorises patients by their likelihood for
response to a particular treatment
• may predict a favourable response or an unfavourable response
(adverse event)
Pharmacodynamic (or activity) biomarker
– a dynamic assessment that shows that a biological response has occurred in
a patient after having received a therapeutic intervention
Surrogate endpoint
– a biomarker intended to substitute for a clinical efficacy endpoint
– expected to predict clinical benefit (or harm, or lack of benefit or harm)
– a subset of pharmacodynamic biomarkers
The broad learning objectives and aims of the day were the following

To receive updates of the current state of knowledge of biomarkers in
spondyloarthopathy that may help inform a stratified medicine strategy
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To learn of forthcoming ARUK initiatives in funding for stratified medicine
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To identify and help prioritise the most important research questions that may
benefit from a stratified medicine approach
2. Laura Savage discussed biomarkers that may predict development of arthritis in
people with psoriasis
The importance of early diagnosis was highlighted as there is some evidence that early
diagnosis and treatment is associated with better outcome. As psoriasis precedes arthritis in
70% of cases, dermatologists are ideally placed to help identify early disease. Certain clinical
phenotypes of psoriasis (nail, scalp, gluteal cleft) may confer increased risk (Wilson FC, et al.
Arth Rheumatism 2009;61(2):233-9). Screening questionnaires such as PEST, PACE and
ToPAS have been developed, are being refined, have been compared and were discussed.
The place of imaging including plain radiography, ultrasound, MRI and FDG-PET was briefly
reviewed with regard to sensitivity, accuracy and feasibility
Biomarkers that may confer a risk for the development of PsA were reviewed.
Genetic loci that have been implicated in both psoriasis and psoriatic arthritis include
PSORS1 (HLA-C), IL12B, IL23A, IL23R, TNIP1, IL2/IL21, LCE, TRAF31P2, ZNF313, FBXL19. Of
interest, these genes are involved in 3 broad immunological processes; antigen presentation,
T cell signaling and the NFkB pathway. There are 2 further gene loci that seem specifically
associated with PsA but not psoriasis; HLA-B27 and IL-13, whereas HLA-Cw6 is less enriched
in PsA than in psoriasis
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There is also interest in cellular markers on circulating osteoclast precursors (CD16 +
monocytes) that are upregulated in PsA. Christopher Ritchlin’s group have reported that
there is increased DC-STAMP expression on peripheral blood mononuclear cells in patients
with psoriasis who go on to develop PsA.
Biomarkers that help detect PsA in people with psoriasis were also reviewed
From a list of possible candidate soluble biomarkers Chandron et al reported that hs-CRP,
OPG, MMP-3 and CPII:C2C were independently associated with the presence of PsA
compared to psoriasis alone (Chandran V et al. Rheumatol 2010;49:1399-1405). The
properties and evidence for each of these four biomarkers was reviewed as was future
direction for research and emerging bioinformatic approaches
3. Deepak Jadon discussed biomarkers as predictors of disease activity and outcome in
PsA
Biomarkers can be utilized in PsA for the following purposes
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identify psoriasis patients with subclinical arthritis
predict prognosis
facilitate monitoring of
o disease activity
o treatment response
predict treatment response
CRP and ESR are useful markers of inflamed joints but are normal in 50% of patients with
active disease and are not specific to cartilage or bone destruction. Bone loss may be local or
systemic, and bone formation can be peripheral or axial. A table of serum bone resorption
biomarkers was demonstrated including structure and knowledge of function. These
included MMP-3, sclerostin, Dickoppf-1, RANKL, M-CSF, CTX-1, deoxypyridinoline, and NTx.
Bone formation biomarkers include osteoprotegrin, BMP (2,4,6), alkaline phosphatase,
osteocalcin and PIIINP. Cartilage degradation markers include COMP, C2C, C1-2C, and
CPII:C2C <1. Cartilage formation markers include CPII and CPII:C2C >1.
Deepak presented results of his systematic review to determine whether certain serum bone
and cartilage turnover markers are associated with PsA, PsA disease activity, severity or
clinical phenotype. Ten full papers met the specified criteria and results were presented. The
conclusions were that comparing PsA with healthy controls biomarkers associated with PsA
were MMP-3, DKK1, M-CSF, CTX1, CPII:C2C and TRAIL. Comparing PsA with psoriasis the
markers associated with PsA were MMP-3, DKK1, M-CSF, OPG and CPII:C2C. There was
some limited evidence for certain markers to be associated with clinical characteristics or
disease activity. RANKL and M-CSF may correlate with more severe radiological indices.
There was conflicting data regarding the MMP-3 levels predicting response to TNF inhibitor
therapy. The evidence for other serum biomarkers including hsCRP and IL-6 was reviewed.
There are a few studies using urine biomarkers e.g. Type I collagen cross-linked Ntelopeptides (NTx) Deoxypyridinoline (DPD) and urine hydroxyproline
Genetic studies were briefly reviewed. Disease progression was more likely with HLA-B39,
HLA B27 (with DR7 absent), and disease progression less likely with HLA-DR7 and HLA-B22.
PsA patients with HLA-Cw6 and DR7 may have a less severe disease course.
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Reasons for disparity between studies were highlighted. Research priorities include carefully
performed longitudinal studies on well characterized clinical cohorts with standardized
sampling using a panel of biomarkers
4. Alex Bennett discussed the role of imaging in determining disease activity and
predicting outcome in ankylosing spondylitis
It is now well recognized that the diagnosis of AS based on the Modified New York Criteria
that requires radiologic presence of sacroiliitis is too insensitive in targeting early disease.
The ASAS criteria for axial spondyloarthopathy does not mandate the presence of x-ray
abnormalities, and so allows for pre-radiographic diagnosis of axial spondyloarthropathy.
However it is worth noting that the imaging arm of the criteria alone that includes MRI
remains relatively insensitive. Also the definition of active MRI sacroiliitis is still relatively
subjective.
The assessment of disease activity in AS remains a challenge. There is heavy reliance on
patients reported outcome measures such as the BASDAI. The ASDAS includes a
measurement of CRP, but the acute phase response may often be normal. Therefore MRI
imaging should have a major role in providing an objective measure of disease activity.
However MRI has shown poor correlation with other outcome measures as well as with
histopathology and findings may fluctuate considerably. There have been several scoring
methods proposed (Leeds, SPAARC, Berlin, Aarhus) that were briefly described, together
with issues that need resolving. Further work should be directed at increasing sensitivity of
MRI and improving, accuracy of lesion measurement using 3-D measurement of volume of
lesion and an added 4th dimension of intensity
Axial spondyloarthopathy may be regarded as a spectrum from inflammatory back pain,
non-radiographic axial SPA, radiographic sacroiliitis to syndesmophytosis. However
progression, if at all, along this pathway is highly variable. Longitudinal studies recording the
progression from non-radiographic axial SPA to AS have used variable methodology and
definitions. In all between 36-59 % of patients may have progress over a 10 year period.
Results from the GErman SPondyloarthritis Inception Cohort (GESPIC) suggest
syndesmophytes, increased acute phase reactants and smoking are risk factors for
progression. Other studies have suggested HLA-B27, male gender, buttock pain and other
baseline imaging factors. Data from Maksymowych et al suggests that fat and inflammation
on baseline MRI are both associated with development of syndesmophytes, but fat is the
strongest predictor.
5. Ejaz Pathan reviewed laboratory markers of response to therapy in AS
The various players involved in the pathology at the enthesis in AS may include TNF
(inflammation), Cathepsin K, MMP1 (erosion) and BMP and Wnt pathways (syndesmophyte
formation) (Tam L-S, Nature Rev Rheum 2010). An expanded list of candidate markers of
inflammation include acute phase reactants (ESR, CRP, IgA), lymphocyte subsets, cytokines
(TNF, IL-17, IL-23), chemokines and growth factors (VEGF, E-Selectin). Markers of tissue
destruction include MMPs (MMP3), markers of osteoclastogenesis (RANKL, TRAP5B),
markers of cartilage breakdown (YKL-40, CTX-II) and markers of bone loss (CTX-I). Markers of
bone formation include wnt inhibitors (Dkk-1), BMP antagonists (sclerostin), and markers of
osteoblastic activity (osteocalcin, bone alkaline phosphatase and OPG).
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Several studies were reviewed that include data on biomarkers in AS with findings as follows
 Correlation of baseline ASDAS with CRP, IL-6, VEGF, MMP-3 (Pedersen ARD 2011)
 MRI inflammation on SI joints associated with CTX II and radiographic progression
associated with decreased inflammation (CRP, IL-6) Pedersen Arthritis Rheum 2011)
 BASDAI associated with panel of MMP-8, MMP-9, HGF, CXCL8 (Mattey ART 2012)
 Circulating vimentin fragments associated with disease progression (Bay-Jensen
Arthritis Rheum 2013)
 Other relevant studies are Wagner ARD 2012, Taylan BMC Musculoskeltal Disorders
2012, and findings from a small study of apremilast
The conclusions were that a laboratory marker of disease activity remains elusive and that
laboratory markers that correlate to disease activity may not necessarily correlate to
imaging biomarkers and vice versa. There was still a need to study biomarkers in an early
cohort and assess changes with flares as well as correlation to imaging over time, study
differences in biomarkers depending on disease burden (progressors versus nonprogressors) and to study differences in biomarkers in different treatment groups
6. Alan Silman provided an overview of the ARUK initiative within stratified medicine.
Some points to note are as follows
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The area of spondyloarthropathy gets £4.4 million grant income from ARUK at
present (£2.6 M basic science and £1.8 M clinical research) which is less that 5% of
total ARUK grant support, and so may be under-represented
Stratified Medicine is not limited to ‘medicine’ but may encompass other
interventions
Pharma companies are not so much interested in new ‘blockbuster’ drugs as
targeting or repurposing what is currently available with new ‘diagnostics’
There are differences in ‘personalized’ medicine from ‘stratified’ medicine that at
least in part may relate to psychology, diet, environment, individual beliefs
Stratified medicine may include use of a novel diagnostic to stratify for an existing
therapy or a novel therapy for an existing diagnostic, or co-development of a novel
diagnostic/therapy
Other concepts include avoidance of side effects and health economic gains
Research on biomarkers may include a single biomarker informing several
treatments or a multiple biomarkers informing a single treatment. However
biomarker funded work would be directed as using biomarkers to improve
effectiveness of treatment rather than biomarker discovery or biomarkers as
predictors of outcome
Carefully controlled observational studies may still be fundable but need to have
vigorous methodology
7. The afternoon session was divided into 4 workshops chaired by Andrew Keat, Gary
Macfarlane, Jon Packham and Philip Helliwell
The groups were given one hour to discuss and identify the most important research
questions that require a stratified medicine approach for funding within
spondyloarthropathy and provide at least 3 key priorities. A secondary aim was to identify
any major barriers, limitations, reservations about taking such an approach.
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Each group fed back via a reporter to the main meeting and following further wider
participation then there was a panel discussion with the Chairs asked to provide their most
preferred research questions
The following are the areas that had common interest, in most cases were rated as
important by most groups, although for some a clear method for stratification needs further
work. They are not necessarily listed here in order of priority, and further consultation likely
to be conducted through an online survey with other stakeholders including patient
participation is anticipated at a later date. It is of interest to note that most of the areas
were common to both AS and PsA
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Which patients with SPA are most likely to benefit from targeting IL-17 potentiated
pathways?
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Evaluating the benefits of exercise and/or self-management/coping skills
intervention using a stratified approach
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Dose-optimisation of anti-TNF therapy – characterization of those patients in whom
treatment can be tapered and/or withdrawn
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In patients with severe psoriasis can treatment (e.g. apremilast) alter preclinical
indications of arthritis (e.g. ultrasound)
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In light of the paucity of evidence for robust biomarkers there was a strong feeling
for the need of an observational study of an early inception cohort of patients with
spondyloathropathy including measurement of candidate biomarkers
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How can imaging modalities be best utilized to identify patients requiring a stratified
approach to treatment?
Finally the meeting was closed with information that findings from the workshop would
provide the basis for feeding into an ARUK meeting on stratified medicine being held on July
24th. There is also the intention for the ARUK and Dutch Arthritis Charity Reumafonds to hold
a one day combined meeting on spondyloarthropathy in November
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