Meeting Minutes. Getting a greater slice of the funding cake for spondyloarthropathy!

Transcription

1 Arthritis Research UK Spondyloarthopathy Clinical Study Group First Annual Study Day Theme: Stratified Medicine in Spondyloarthropathy Date: Wednesday 17 th 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 Reconciliation of respective classification criteria used in the field (e.g. axial spondyloarthropathy vs peripheral spondyloarthopathy vs psoriatic arthritis) 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) Targeting treatment to potentially discordant pathological mechanisms that may fluctuate according to stage of disease (synovitis vs enthesitis, bone erosion vs proliferation) Biomarkers less obvious than in other rheumatic diseases (e.g. lack of specific autoantibodies, imaging modalities need more validation) Getting a greater slice of the funding cake for spondyloarthropathy! 1

2 The definition, types and categories of biomarker were described. The categories include 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 To learn of forthcoming ARUK initiatives in funding for stratified medicine 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 2

3 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: ). 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 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 N- telopeptides (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. 3

4 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 % 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). 4

5 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 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. 5

6 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 Which patients with SPA are most likely to benefit from targeting IL-17 potentiated pathways? Evaluating the benefits of exercise and/or self-management/coping skills intervention using a stratified approach Dose-optimisation of anti-tnf therapy characterization of those patients in whom treatment can be tapered and/or withdrawn In patients with severe psoriasis can treatment (e.g. apremilast) alter preclinical indications of arthritis (e.g. ultrasound) 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 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 24 th. There is also the intention for the ARUK and Dutch Arthritis Charity Reumafonds to hold a one day combined meeting on spondyloarthropathy in November 6