Biomarkers of response to therapy in Ankylosing Spondylitis

Ankylosing Spondylitis (AS) is a chronic inflammatory disorder of the spine which leads to progressive spinal fusion and deformity. With improvements in MRI, this condition is now being recognized earlier. The treatment of this condition so far is limited to physiotherapy, NSAIDs and anti-TNF therapy. The assessment of response to therapy is largely subjective using clinical outcome measures such as the Bath Ankylosing Spondylitis disease activity index (BASDAI). This thesis describes the search for an objective measure of response to therapy in AS. It does so by studying two separate patient cohorts- one receiving anti-TNF therapy and the other receiving a novel oral phosphodiesterase-4 inhibitor, apremilast, in a clinical trial setting. In addition to various clinical outcome measures and laboratory biomarkers, it also explores novel volumetric analysis of bone oedema lesions on MRI and its correlation to clinical indices. The results of this study indicate that apremilast improves clinical indices of response in AS and also modulates bone biomarkers. However, it may do so differently to anti-TNF agents with plasma sclerostin and RANKL: OPG possibly playing important roles in its mechanism of action. This study highlights the fact that different laboratory biomarkers may be modulated differently by different drugs. The novel volumetric analysis developed using Dynamika software showed promise with good correlation to established methods of scoring scans such as Berlin scoring. In particular, a novel biomarker, the product of the volume of the lesion and its intensity correlated well with changes in BASDAI in the anti-TNF cohort. However, there are a number of issues, notably inter-observer variability as well as time required to carry out the analysis, that need to be resolved. This could be done by developing automated regions of interest using this software on the basis of intensity of the lesions, hence providing an objective measure of response to therapy in AS.Open Acces

The link between ankylosing spondylitis and oral health conditions : two nested case-control studies using data of the UK Biobank

This research has been conducted using the UK Biobank Resource under Application Number 26307. The authors declare that they have no competing interests. HMA received funding from the Higher Committee for Education Development in Iraq (HCED-Iraq) to undertake her PhD. The authors are grateful to Professor Gary Macfarlane (Epidemiology Group, University of Aberdeen) for his valuable comments and suggestions on the analysis and the draft of manuscript.Peer reviewedPublisher PD

Oral Health and Risk of Arthritis in the Scottish Population:Results from the Scottish Health Survey

We acknowledge the ScotCen Social Research, Scottish Government and the UK Data Archive for providing these data for research purposes. They bear no responsibility for any further analysis or interpretation. Hadeel Mohammed Abbood received funding from the Higher Committee for Education Development in Iraq (HCED-Iraq) to undertake her PhD. Hadeel Mohammed Abbood is grateful to Ms Shifa Sarica (Epidemiology Group, University of Aberdeen, UK) for help with manuscript editing. The authors declare no conflicts of interest related to this study. Although all efforts are made to ensure the quality of the materials, neither the original data creators, depositors, the funders of neither the data collections, nor the UK Data Archive bear any responsibility for the accuracy or comprehensiveness of these materials.Peer reviewedPublisher PD

Generating EQ-5D-5L health utility scores from BASDAI and BASFAI : A mapping study in patients with axial spondyloarthritis using longitudinal UK registry data

Acknowledgments: We are grateful to the staff of the British Society for Rheumatology Biologics Register in Axial Spondyloarthritis. Claudia Zabke, Maureen Heddle, Nafeesa Nazlee and Barry Morris, and to the recruiting staff at the clinical centres, details of which are available at: https://www.abdn.ac.uk/iahs/research/epidemiology/spondyloarthritis.php#panel1011 Funding/Support: The British Society for Rheumatology Biologics Register in Ankylosing. Spondylitis (BSRBR-AS) is funded by the British Society for Rheumatology (BSR), which in turn has received funding from the manufacturers of the biologic therapies included in the study (Abbvie, Pfizer and UCB). Pharmaceutical companies providing funds to BSR do not have a role in the oversight of the study, but they do receive advance notice of publications on which they can comment. They do not have access to the data collected but can request analyses of the data, for which additional funds are provided.Peer reviewedPostprin

Predicting response to anti-TNFα therapy among patients with axial spondyloarthritis (axSpA) : results from BSRBR-AS

We are grateful to the staff of the British Society for Rheumatology Biologics Register in Axial Spondyloarthritis register and to the recruiting staff at the clinical centres, details of which are available at: https://www.abdn.ac.uk/iahs/research/epidemiology/spondyloarthritis.php#panel1011. We are grateful to Jonathan Lock for commenting on the manuscript. Funding: This work was supported by the British Society for Rheumatology (BSR) who have funded the BSRBR-AS. The BSR received funding for this from Pfizer, AbbVie and UCB. These companies receive advance copies of manuscripts for comments but have no input in to the topics for analysis in the register nor the work involved in undertaking analysis. Analysis of data was supported by the Versus Arthritis/Medical Research Council Centre for Musculoskeletal Health and Work [grant number 20665].Peer reviewe

Impact of biological therapy on work outcomes in patients with axial spondyloarthritis : results from the British Society for Rheumatology Biologics Register (BSRBR-AS) and meta-analysis

Funding The BSRBR-AS is funded by the British Society for Rheumatology who have received funding for this from Pfizer, AbbVie and UCB. These companies receive advance copies of manuscripts for comments. This work was conducted within the Arthritis Research UK/Medical Research Council Centre for Musculoskeletal Work and Health (Grant No: 20665) Acknowledgements We are grateful to the staff of the British Society for Rheumatology Biologics Register in Axial Spondyloarthritis register who are currently Claudia Zabke, Maureen Heddle, Nafeesa Nazlee and Barry Morris, and to the recruiting staff at the clinical centres, details of which are available at: https://www.abdn.ac.uk/iahs/research/epidemiology/spondyloarthritis.php#panel1011. We would like to thank Dr Atul Deodhar, Benjamin Hsu and Chenglong Han for providing additional data relating to one of the studies, to allow it be included in the meta-analysis.Peer reviewedPublisher PD

Generating EQ-5D-5L health utility scores from BASDAI and BASFI : a mapping study in patients with axial spondyloarthritis using longitudinal UK registry data

Acknowledgements We are grateful to the staff of the British Society for Rheumatology Biologics Register in Axial Spondyloarthritis. Claudia Zabke, Maureen Heddle, Nafeesa Nazlee and Barry Morris, and to the recruiting staff at the clinical centres, details of which are available at: https://www.abdn.ac.uk/iahs/research/epidemiology/spondyloarthritis.php#panel1011. Funding The British Society for Rheumatology Biologics Register in Ankylosing. Spondylitis (BSRBR-AS) is funded by the British Society for Rheumatology (BSR), which in turn has received funding from the manufacturers of the biologic therapies included in the study (Abbvie, Pfizer and UCB). Pharmaceutical companies providing funds to BSR do not have a role in the oversight of the study, but they do receive advance notice of publications on which they can comment. They do not have access to the data collected but can request analyses of the data, for which additional funds are provided.Peer reviewedPublisher PD

Generating EQ-5D-5L health utility scores from BASDAI and BASFI:a mapping study in patients with axial spondyloarthritis using longitudinal UK registry data

BACKGROUND: Preference-based health-state utility values (HSUVs), such as the EuroQol five-dimensional questionnaire (EQ-5D-5L), are needed to calculate quality-adjusted life-years (QALYs) for cost-effectiveness analyses. However, these are rarely used in clinical trials of interventions in axial spondyloarthritis (axSpA). In these cases, mapping can be used to predict HSUVs. OBJECTIVE: To develop mapping algorithms to estimate EQ-5D-5L HSUVs from the Bath Ankylosing Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI). METHODS: Data from the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS) provided 5122 observations with complete BASDAI, BASFI, and EQ-5D-5L responses covering the full range of disease severity. We compared direct mapping using adjusted limited dependent variable mixture models (ALDVMMs) and optional inclusion of the gap between full health and the next feasible value with indirect response mapping using ordered probit (OPROBIT) and generalised ordered probit (GOPROBIT) models. Explanatory variables included BASDAI, BASFI, and age. Metrics to assess model goodness-of-fit and performance/accuracy included Akaike and Bayesian information criteria (AIC/BIC), mean absolute error (MAE) and root mean square error (RMSE), plotting predictive vs. observed estimates across the range of BASDAI/BASFI and comparing simulated data with the original data set for the preferred/best model. RESULTS: Overall, the ALDVMM models that did not formally include the gap between full health and the next feasible value outperformed those that did. The four-component mixture models (with squared terms included) performed better than the three-component models. Response mapping using GOPROBIT (no squared terms included) or OPROBIT (with squared terms included) offered the next best performing models after the three-component ALDVMM (with squared terms). Simulated data of the preferred model (ALDVMM with four-components) did not significantly underestimate uncertainty across most of the range of EQ-5D-5L values, however the proportion of data at full health was underrepresented, likely due in part to model fitting on a small number of observations at this point in the actual data (4%). CONCLUSIONS: The mapping algorithms developed in this study enabled the generation of EQ-5D-5L utilities from BASDAI/BASFI. The indirect mapping equations reported for the EQ-5D-5L facilitate the calculation of the EQ-5D-5L utility scores using other UK and country-specific value sets. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10198-022-01429-x

Co-Occurrence and Characteristics of Patients With Axial Spondyloarthritis Who Meet Criteria for Fibromyalgia : Results From a UK National Register

The British Society for Rheumatology (BSR) Biologics Register in Ankylosing Spondylitis is funded by the BSR and they have receive funds for this from Pfizer, AbbVie and UCB. These companies receive advance copies of manuscripts and can provide comments but have no input into determining the topics for analysis, publication and no input into the work involved in this analysis. This analysis is part-funded by Arthritis Research UK (Grant No: 21378)Peer reviewedPublisher PD