3 TESLA MAGNETIC RESONANCE IMAGING AND COMPUTERISED IMAGE ANALYSIS IN THE EVALUATION OF RHEUMATOID HAND JOINTS Dr. Anshul Rastogi CID: 502666 Thesis submitted for MD (Res) degree Supervisors: Professor Peter Taylor and Professor Joseph Hajnal Kennedy Institute of Rheumatology Imperial College London 30th November 2015 1 This thesis consists of my work except where indicated in the text. All collaborative work is acknowledged where it is described in the thesis. The work was undertaken at Kennedy Institute of Rheumatology, Imperial College London and Robert Steiner MRI Unit, Hammersmith Hospital. Preliminary work and development of the patient positioning device was done in collaboration with project physicist, Lada V Krasnosselskaia and supervisor Professor Joseph V Hajnal. Initial image analysis work was carried out in collaboration with staff at IXICO, Ltd, London, primarily Kelvin Leung and Christopher Foley. Algorithms for image analysis conducted at Robert Steiner MRI Unit, were written by physicist, Rita Nunes, under supervision of Professor Joseph V Hajnal. Digital radiograph analysis using dxr-online TM was performed by SECTRA, Sweden. Industry Collaborations were with IXICO Ltd, UK; SECTRA, Sweden; and Image Analysis, UK. Funding was provided by GlaxoSmithKline, UK. 2 Copyright Declaration: The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the license terms of this work. 3 Summary The work presented in this thesis was aimed at evaluating computerised analysis tools for Magnetic Resonance Imaging (MRI) and radiographic rheumatoid arthritis (RA) disease activity measures longitudinally over time, while imaging at short and long time intervals on a high field strength (3 Tesla) MRI. The work has been presented as preliminary and main studies. The preliminary work was about development of a patient positioning device ‘the bridge’ for wrist imaging, which was subsequently used in a yearlong longitudinal study of RA patients. While imaging patients hand and wrist, the bridge positioning device allowed patients, in a supine position, to position their hands over their abdomen with comfort and good quality reproducible image capture. The main study was a longitudinal observational study of RA patients on routine treatment and healthy subjects using 3T wrist MRI, hand and feet radiographs and analysis using exploratory and new computerised methods in various pilot sub-studies. Techniques that were assessed during pilot work included bone segmentation methods both manual and semi-automatic, with a view to speed up analysis, quantify volume and change in bone shape over time. The registration and transformation technique allowed visual evaluation of small changes over time. The pilot work using computerised digital X-ray radiogrammetric analysis identified correlations between early metacarpal rate of bone mineral density loss with bone marrow oedema change at 1 year, which is a known predictor of future erosions and generated hypothesis that this may represent an earlier disease activity measure. The pilot work using computerised dynamic contrast enhanced MRI (DCE-RIM ) analysis highlighted that the dynamic parameters obtained correlate well with semiquantitative synovitis scores, and allow for robust and 4 sensitive analysis. The reliability of these measures paves way for utilization of this technique in assessment of therapeutic interventions and for remission targets. Abstract Objective: To explore development and testing of a new patient positioning device during wrist MRI. To evaluate rheumatoid arthritis (RA) wrist 3T MRI with computerised image analysis tools including bone segmentation techniques, semiquantitative scoring and dynamic contrast enhanced (DCE-MRI) for synovitis measures, with similar assessments on healthy subjects. To examine the relationship between X-ray/MRI disease activity measures and bone mineral density loss using computerised digital X-ray radiogammetry (DXR). Methods: Preliminary study was about development and evaluation of a new patient positioning device for wrist imaging and its evaluation against current standard positions. In the main longitudinal MRI study, 13 RA and 10 healthy subjects (HV) were recruited with 10 RA and 7 HV completing the study. Hand/wrist MRI and radiographs were performed over a year and assessed using semi-quantitative scoring and exploratory computerised image analysis tools, which included pilot work on bone segmentation techniques, including manual and semi-automated methods; bone mineral density loss assessment using DXR- online and its comparison with MRI disease activity measures; and dynamic contrast enhanced MRI (DCE-MRI) analysis using Dynamika software. Result: A developed bridge patient positioning device allowed for comfortable, good quality and reproducible imaging as compared to standard positions (Bridge vs hand by the side vs hand above head position: comfort score (out of 10) (mean±std) – 7.3±0.7 vs 7.1±0.8 vs 6.1±1.6, and image quality (Signal to noise/contrast to noise ratio) – 6.1±1.7/3.1±0.5 vs 5 5.3±1.5/2.6±0.5 vs 7.7±1.1/4±0.5), with subsequent use in a longitudinal study (Comfort score: RA/HV:9.1/8.1). The semi-automated bone segmentation method was much quicker than manual technique (10/8 vs 165/132 minutes for two readers), with good inter and intra-observer similarity for manual method and in between the two methods, though the semi-automated method failed in an advanced RA patient. The manual segmentation using SliceOmatic software was also time consuming - 3256 minutes for 2196 slices, but with image registration and transformation a visual analysis of future images was possible. In the main longitudinal study, there were stable moderate DAS 28 disease activity scores (Day 1 – 3.9 and week 52 – 4.0). MRI disease activity measures showed good correlation. Bone marrow oedema (BME) correlated with erosions, and automated early 3 month rate of metacarpal digital x-ray radiogrammetric bone mineral density loss (RC-BMD) correlated with 1 year wrist BME change (p=0.035). No significant change was seen for MRI, radiographic or any disease activity measure over the year, though there was small increase in MRI erosion: 2.4 (1.6%), BME: 0.4 (0.8%) and radiographic: 1.8 (0.4%) mean scores. In HV, no radiographic erosions were seen, but MRI showed erosion-like changes, low grade BME and low-moderate synovial enhancement. It was also demonstrated that dynamic contrast enhancement does occur in healthy volunteers, and the inherent variability of perfusion measures obtained with the quantitative DCE- MRI method was small both in HV and stable RA patients on routine treatment. Conclusion: A new MRI wrist patient positioning device was developed, tested and successfully used in a longitudinal study. New and exploratory computerised image analysis techniques in RA, including bone segmentation, DXR and DCE-MRI have a potential role in longitudinal RA clinical trials. 6 Table of Contents Summary……………………………………………………………………………………………………………………………..4 Abstract……………………………………………………………………………………………………………………………….5 Table of Figures…………………………………………………………………………………………………………………..15 List of Tables……………………………………………………………………………………………………………………….18 List of Abbreviations…………………………………………………………………………………………………………...20 1 INTRODUCTION ................................................................................................................ 23 1.1 Background: ............................................................................................................. 24 1.2 Pathophysiology of RA Joint Damage: ..................................................................... 25 1.3 Disease Activity in clinical practice: ......................................................................... 28 1.3.1 DAS 28: ............................................................................................................... 29 1.3.2 Joint Damage: .................................................................................................... 29 1.3.2.1 Joint damage and function: ........................................................................ 29 1.3.2.2 Challenges in clinically assessing joint damage: ......................................... 30 1.3.2.3 Early treatment strategies and joint damage: ............................................ 31 1.3.3 Osteoporosis in RA: ............................................................................................ 32 1.3.3.1 Osteoporosis and fracture risk: .................................................................. 34 1.3.3.2 Osteoporosis and functional impairment: ................................................. 34 1.3.3.3 Measuring bone mass: ............................................................................... 35 1.4 Imaging: .................................................................................................................... 35 1.4.1 Conventional Radiography: ................................................................................ 36 1.4.1.1 Role of X-ray in RA diagnosis: ..................................................................... 37 1.4.1.2 X-ray in established RA ..............................................................................