Overview of the Research
Rheumatology research in Bradford was established in 1996 as a small two person team. Over the years modest expansion had taken place and our staff list now comprises seven. We carry out a mixture of portfolio non-commercial studies and commercial studies of new pharmaceuticals. However, although relatively small, we have a list of high impact factor publications, including the Lancet, and have developed a number of instruments for use in clinical rheumatology research in the field of psoriatic arthritis.
The Research Team
Current research profile
TUDOR (BTHFT 2031) (ADOPTED)
Recuited over 100 patients in this NIHR funded multicentre study of early identification of psoriatic arthritis in primary care in the UK.
MAXIMISE (BTHFT 2046)(ADOPTED)
Commercial study managing axial manifestations in psoriatic arthritis with secukinumab.
AMGEN MTX + ETANERCEPT v ETANERCEPT mono (BTHFT 1998 ) (ADOPTED )
Commercial strategy trial in psoriatic arthritis with a target of 3 patients. 5 screened,5 randomised. 3 ongoing, 1 withdrawn, 1completed
NOVARTIS CAIN457F2342 FUTURE 5 (BTHFT 1976) (ADOPTED)
A global study of secukinumab in psoriatic arthritis. 6 ongoing. 2 withdrawn patients.
NOVARTIS PsA(Secukinumab) (BTHFT 1363 & BTHFT 1629)( ADOPTED )
One patient ongoing and approaching final visit. Post trial medication requested.
LILLY BARICITINIB in RA JADY (BTHFT 1557) (ADOPTED UKCRN 2341)
2 patients now in extension study – drug is now licensed for use in NHS. Further extension in planning.
LILLY IXEKIZUMAB PsA (BTHFT 1479)(ADOPTED)
Four patients completed this pivotal study and publications underway.
PFIZER TOFACITINIB trial extension(BTHFT 1801)(ADOPTED)
Recruitment closed. Now in extension study. 9 screened, 4 ongoing, 5 withdrawn.
NOVARTIS F2308(BTHFT2068) (ADOPTED LCRN 5473)
Secukinumab in ankylosing spondylitis. Five patients randomised.
USEFUL. (UltraSound Evaluation For mUsculoskeletal Lupus). (ADOPTED)
Non-commercial study of imaging in systemic lupus erythematosus ….Dr Zayat. Is PI on this study.
This is a non-commercial strategy trial in psoriatic arthritis. Dr Helliwell is co-investigator in Leeds and Bradford is a PIC site for this study.
Factors contributing to the impact of calcinosis in connective tissue disease.
PIC site for Leeds 128 questionnaires posted. 13 returned, 2 declines.
ELI LILLY IXEKIZUMAB/ADALIM COMPARATOR (ADOPTED)
This is a commercial strategy trial – a head to head comparison of two biologics in psoriatic arthritis. Recruitment ongoing.
TRIALS CLOSED in last 12 months
ASAS-HI AS (ReDA 1879)(ADOPTED)Leeds MSK dept.14 recruited. Database locked
PROMPT PsA (ReDA 1788)(?ADOPTED) 16 pts
SCRAPS PsO (BTHFT 1788 )(ADOPTED) 24 pts recruited.
HISTORICAL RESEARCH AND IMPACT OF RESEARCH
Psoriatic Arthritis (PsA) was first defined by Moll and Wright, in Leeds, in 1973 but it has only been in the last decade that research into this condition has accelerated. This has come as a result of improved and more rapid diagnosis through new classification criteria, more accurate and sensitive outcome measures to chart the disease progress and response to therapy, and genetic studies which provide new insights into pathogenesis. Dr Helliwell has contributed to all these areas for 30 years, the original work being co-authored with Verna Wright, thus providing a link between new insights and the original concepts in this disease. Recent work has illustrated the diverse and heterogeneous nature of PsA and we have contributed to this area through re-definition of clinical subgroups. Genetic studies have highlighted novel pathways of importance in PsA and as a result, new treatment paradigms have been developed. These differ with respect to rheumatoid arthritis. It is not yet entirely clear that PsA fits the rheumatoid arthritis pattern of ‘treat early to remission’ to prevent damage and disability, and both International and National studies to address these issues have been led by Dr Helliwell. In summary these are the key areas of this research:
- Re-defined clinical subgroups and concept of spondyloarthropathy
- International study to develop new classification criteria for PsA based on rigorous methodology (CASPAR)
- Development of outcome measures for PsA (OMERACT initiative, enthesitis, dactylitis, minimal disease activity, true composite measures and psoriatic disease impact)
- Development and validation of tools for screening and identifying PsA in the community
- Identification of novel susceptibility loci by contribution to genome wide screening initiative (PAGE consortium)
- Development of treatment guidelines (both GRAPPA and EULAR)
- Research based evidence for new treatment paradigms (TICOPA, RETREAT)
Clinical sub-groups and concept of spondyloarthropathy
Dr Helliwell re-defined the original spondyloarthropathy concept of Moll and Wright in an article with Prof Wright published in 1987 [Helliwell and Wright 1987]. Essentially, evidence was presented that focussed on the primacy of axial involvement and the inevitable loss of both Whipple’s and Behcet’s disease from the original concept. We subsequently re-examined many of the cases originally described by Moll and Wright, performing isotope scans on many of the cases, and re-defining clinical sub-groups of PsA based on these results [Helliwell et al. 1991]. This led to lively debate in the rheumatology journals [Helliwell and Wright 1992] and a subsequent proposal that the argument be resolved by defining two sub-groups, those of axial and peripheral involvement [Taylor et al. 2005].
Classification of psoriatic arthritis
Dr Helliwell conceptualised (with Dr William Taylor), and was the Chief Investigator of the Classification of Psoriatic arthritis (CASPAR) study, published in 2006. Prior to this study, the Moll and Wright criteria predominated, but it was widely accepted that the Moll and Wright criteria did not fully reflect the clinical presentation, as the patients included under this rubric were becoming increasingly polyarticular and rheumatoid-like. Between 2001 and 2003 data were collected in a large international study in order to develop new classification criteria for psoriatic arthritis (ClAssification Study for Psoriatic Arthritis, CASPAR)[Taylor et al. 2006]. These criteria were the first validated criteria for PsA derived from patient data contributed by a global group of acknowledged experts in this field: Dr Helliwell coordinated this process and provided the conceptual framework, co-ordinated the group and analysed the results. These criteria have now been widely adopted by the international rheumatology community (over 500 citations in the peer-reviewed literature) since their publication in 2006. Further, the CASPAR criteria have been widely adopted for use in clinical trials and epidemiological studies. The CASPAR criteria have, for the first time, ensured uniformity in patient selection for both epidemiological and interventional studies and have permitted better comparison of clinical outcomes and risk factors, resulting in better patient care.
Outcome measures for rheumatology
Dr Helliwell has been prominent worldwide in the development of validated outcome measures for PsA, driven by the need to ensure that measures are sensitive and specific to the unique features of patients with psoriatic arthritis. This process has developed in parallel with activities within the umbrella of the international OMERACT (Outcome Measures in Rheumatology Clinical Trials) group and GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic arthritis), the latter representing psoriatic arthritis worldwide. Specifically we developed the only validated outcome measures for characteristic clinical features of PsA, namely enthesitis and dactylitis [Healy and Helliwell 2008;Healy and Helliwell 2007;Healy et al. 2008] and more recently examined the optimal joint count to ensure inclusivity in composite indices of disease activity [Coates et al. 2013a]. Dr Helliwell led the development of disease specific composite disease activity and responder indices in PsA, resulting in three candidate disease activity measures (psoriatic arthritis disease activity index, PASDAS; GRAPPA composite index, GRACE; composite psoriatic disease activity index, CPDAI) and one responder index (minimal disease activity, MDA) [Mumtaz et al. 2011; Helliwell et al. 2012;Coates et al. 2010]. Further development of cut-offs for response and very low disease activity have been developed for each of the disease activity indices [Helliwell et al. 2014]. Further validation of these indices demonstrates their importance as a target for treatment where achievement of MDA [Coates et al 2010b], or the low disease activity cut-offs of the PASDAS, GRACE and CPDAI [Helliwell et al 2014a, Helliwell et al. 2014b, Helliwell et al 2014c, Coates and Helliwell, 2015] result in better clinical and radiographic outcomes.
Dr Helliwell was on the steering committee of the EULAR group which, over the course of 18 months, developed a novel outcome measure to assess patient impact of psoriatic arthritis – the Psoriatic arthritis impact of disease (PSAID) tool. Specifically this patient completed questionnaire adds another dimension to outcome measurement in both the clinic and in clinical trials.
Development and validation of tools for screening and identifying psoriatic arthritis in the community It is believed that PsA should be diagnosed early and treated aggressively in order to prevent joint damage and functional disability. Most patients first present with psoriasis, developing PsA an average of 10 years later. The majority of patients with psoriasis are managed by either primary care physicians or by dermatologists, thus the challenge is to identify early those with musculoskeletal disease amongst the large number of psoriasis patients who do not have PsA and to refer to rheumatologists for appropriate treatment. Delay in diagnosis is unfortunately not uncommon with 27% of patients in one early PsA study having joint damage at presentation. In order to address this issue, we have been at the forefront in developing and validating screening tools for PsA, particularly in primary care and dermatology clinic settings. We developed the Psoriasis Epidemiology Screening Tool (PEST) [Ibrahim et al. 2009] which is simpler to administer, robust and superior to existing measures. The PEST is internationally accepted at the screening tool for psoriatic arthritis: it has been translated into 15 languages, and is the recommended screening tool by NICE, SIGN and CORRONA. In order to enhance the response to screening in primary care, we have developed an educational tool, a simple, cartoon based leaflet which can be distributed with other materials. Subsequent use of the educational material in a cluster randomised study indicated that it might enhance response to screening in certain populations [Coates et al. 2015b].
The adoption of screening tools in primary care and in dermatology clinics will lead to earlier diagnosis of PsA and, hopefully, better outcomes long term. In order to test this hypothesis we have been a successful co-applicant on a grant of over two million pounds awarded by the UK National Institute for Health Research. This program grant, led by Prof Neil McHugh in Bath, will examine the utility, in terms of health outcomes, of an enhanced screening program in primary care. The data collected in this study, due to complete in 2020, will also permit an examination of existing screening tools, and the comparative utility of composite outcome measures.
Genetic Predictors of PsA susceptibility and phenotypic features
Dr Helliwell was a founding member of the Psoriatic Arthritis Genetics in Europe (PAGE) consortium, established in 2005. The aim of this consortium is to undertake studies to investigate the genetic basis of psoriatic arthritis primarily in terms of susceptibility but also outcome, where data allows, in a European population. A large cohort of over 2000 patients (including over 200 from Bradford) has been collected and a number of publications have already resulted from the work of this consortium including the publication of the first Genome-Wide Association Study (GWAS) in PsA. The most important finding from this GWAS is that of a new association of TRAF3IP2 in psoriatic arthritis [Huffmeier et al. 2010]. TRAF3IP2 codes for an adaptor protein known as ACT-1 which is a key component of the IL-17 pathway.
Additional loci have also been identified from this cohort. Given the excessive vascular tortuosity on the synovial surface in psoriatic arthritis we investigated the role of vascular endothelial factor, and other genes [Bowes et al. 2012]. We have replicated the association of PTPN22 coding SNP rs2476601 with PsA risk (with a genome-wide level of significance) but, additionally, using previous published case-control datasets on psoriasis, demonstrated that rs2476601 is not associated with psoriasis risk [Bowes et al. 2015].
Dr Helliwell has also led an exome sequencing study to investigate the extreme phenotype of arthritis mutilans. These data are currently undergoing a complex analysis and several possible candidate genes are under investigation – this is a collaboration with Prof Jonathan Barker of Guys and St Thomas’.
Identification of novel biomarkers of treatment response and severity
Together with OMERACT, GRAPPA is planning to conduct a study examining biomarkers of radiographic progression in PsA, an international initiative led by Oliver FitzGerald (Dublin) with Dr Helliwell on the Steering Committee. The protocol is complete and the co-ordinating centre has been selected (University of Toronto, Canada). This study, while not yet fully funded, is currently undergoing some pilot data collection. This data will be derived from the samples collected in the Tight Control in Psoriatic arthritis (TICOPA) study and in a new intervention study just started in Leeds (led by Dr Helena Marzo-Ortega).
Development of treatment guidelines (both GRAPPA and EULAR)
Dr Helliwell has had a pivotal involvement, by membership of the steering committee, in the development of the two sets of major international treatment guidelines, recently revised, for psoriatic arthritis. For both editions of the GRAPPA guidelines, a systematic literature review was performed for each of five areas: peripheral arthritis, skin, axial disease, dactylitis and enthesitis. This was then brought together in a document which was discussed and voted on by the whole GRAPPA membership [Ritchlin et al. 2008]. For the revision of these guidelines a more strict examination of the literature and evidence was undertaken, while maintaining the division of recommendations into five domains: joints, enthesitis, dactylitis, spine, and skin/nails. In the revised guidelines we have followed the GRADE system for evaluating evidence and also formulated a series of PICO (population, intervention, comparator, outcomes) questions. These recommendations have been presented at both EULAR and ACR in 2015[ Coates et al. 2015c].
The EULAR guidelines followed a slightly different process, relying on discussion and consensus among a small group of rheumatologists, but supported by a further systematic literature review. This resulted in 10 recommendations for treatment [Gossec et al. 2012]. These recommendations have also been revised and re-submitted in 2015 [Gossec et al 2015]. We have contributed significantly to the evidence base for these recommendations (see next section).
Research based evidence for new treatment paradigms (TICOPA and RETREAT)
With new developments in understanding the pathophysiology of PsA, novel treatment regimens have been developed by the applicant. The TICOPA (Tight control in psoriatic arthritis) trial is the first strategy trial in psoriatic arthritis and a pivotal study, funded by a large grant from Arthritis Research UK (Helliwell, Chief Investigator). The study aims answered several questions on the treatment of early psoriatic arthritis. The main question was: can an intensive, treat to target algorithm, result in better clinical and radiographic outcomes in early psoriatic arthritis? Secondary outcomes included the differential response to treatment based on different clinical phenotypes (oligoarthritis, polyarthritis, enthesitis and axial), the relationship between ultrasound imaging and clinical assessments [Freeston et al. 2012; Freeston et al. 2014], and the efficacy of other measures of disease activity. We were able to demonstrate improved clinical outcomes with an intensive, tight control strategy although radiographic outcomes did not differ between the two treatment groups (very little damage was seen in either group at baseline or follow-up). The study was recently published in the Lancet [Coates et al 2013c; Coates et al. 2015d]. A follow up randomised controlled study commenced September 2012 in which treatment was withdrawn in people in low disease activity (RETREAT: REmoving TREATment in low disease activity in psoriatic arthritis). This pilot and feasibility study, also funded by Arthritis Research UK, completed in 2014. The study demonstrated a high relapse rate (66%) over a three month period and it was concluded that going forward to a full trial, using the same design, was neither ethical nor feasible [Moverley et al. 2013; Moverley et al. 2015].