Patient reported outcomes in rheumatoid arthritis Data from the Oslo Rheumatoid Arthritis Register Thesis by Cathrine Austad 2017 Diakonhjemmet Hospital University of Oslo Department of Rheumatology Faculty of Medicine Oslo, Norway Oslo, Norway © Cathrine Austad, 2017 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8377-019-3 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo. Contents Acknowledgements ............................................................................................................. 3 Funding ................................................................................................................................ 5 Abbreviations ....................................................................................................................... 6 List of papers ....................................................................................................................... 7 1. Background ...................................................................................................................... 9 1.1 Introduction to rheumatoid arthritis ........................................................................... 9 1.1.1 Classification criteria .......................................................................................... 9 1.1.2 Epidemiology .................................................................................................... 11 1.1.3 Pathogenesis ..................................................................................................... 13 1.1.4 Risk factors for disease development and progression ..................................... 15 1.1.5 Pharmacological treatment ............................................................................... 18 1.1.6 Window of opportunity .................................................................................... 22 1.1.7 Treat to target .................................................................................................... 22 1.2 Patient reported outcomes and measures of health related quality of life ............... 23 1.2.1 Pain ................................................................................................................... 23 1.2.2 Patient reported health state .............................................................................. 24 1.2.3 Patient Reported Disease Acticity .................................................................... 26 1.2.4 Health utility ..................................................................................................... 27 1.2.5 Physical function .............................................................................................. 28 1.2.6 Rheumatoid Arthritis Impact of Disease (RAID) ............................................. 30 1.2.7 Sleep disturbance .............................................................................................. 30 1.2.8 Fatigue .............................................................................................................. 33 1.2.9 Gastrointestinal discomfort ............................................................................... 34 1.2.10 Coping and patient acceptable symptom state ................................................ 34 1.3 Measures of disease activity .................................................................................... 35 1.3.1 Single measures ................................................................................................ 35 1.3.2 Composite measures ......................................................................................... 36 1.4 Imaging of joint damage .......................................................................................... 36 2. General aim and specific research questions ................................................................. 37 2.1 General aim .............................................................................................................. 37 2.2 Specific research questions ...................................................................................... 37 3 Materials and methods .................................................................................................... 38 3.1 Study design ............................................................................................................ 38 3.2 Data collection ......................................................................................................... 39 3.2.1 Demographic and disease related variables ...................................................... 40 3.3 Data included in current thesis ................................................................................ 42 3.4 Statistics ................................................................................................................... 42 3.4.1 Descriptive and explorative analyses ................................................................ 42 3.4.2 Univariate and bivariate analyses ..................................................................... 43 3.4.3 Multivariate analyses ........................................................................................ 43 3.5 Legal and ethical aspects ......................................................................................... 44 4. Summaries of results ..................................................................................................... 45 4.1 Paper I ...................................................................................................................... 45 4.2 Paper II .................................................................................................................... 46 4.3 Paper III ................................................................................................................... 47 4.4 Paper IV ................................................................................................................... 48 5. General discussion ......................................................................................................... 49 5.1 Methodological aspects ........................................................................................... 50 1 5.1.1 Study design ..................................................................................................... 50 5.1.2 Representativity of study population ................................................................ 51 5.1.3 RA patients and population included in papers I-IV ........................................ 53 5.1.4 Patient-reported outcome measures .................................................................. 54 5.1.5 Changes in management of patients with rheumatoid arthritis ........................ 56 5.2. Discussion of main results ...................................................................................... 57 5.2.1 Development in the Oslo RA population over 15 years ................................... 57 5.2.2 Sleep disturbance in rheumatoid arthritis ......................................................... 60 5.2.3 Gastrointestinal discomfort, NSAIDs and self-reported disaeas activity ......... 65 5.2.4 Health information important to patients: The RAID score ............................. 67 6. Conclusions ................................................................................................................... 69 6.1 Answers to research questions ................................................................................. 69 6.2 Clinical implications ................................................................................................ 70 7. References ..................................................................................................................... 71 8. Papers I - IV ................................................................................................................... 87 2 Acknowledgements The work included in this thesis would not have been possible without the contribution of a large number of people to whom I am sincerely grateful. First of all I would like to thank my main supervisor, professor Till Uhlig, who has generously shared his expertise in epidemiological research and followed my work every step of the way. He has spent hours reading manuscripts and abstracts and given important feedback to my work. His detailed knowledge of the Oslo rheumatoid arthritis register has been invaluable, and I am forever grateful for all input he has given, in particular towards the final steps of my PhD. I would also like to thank my co-supervisor professor Tore K. Kvien who recruited me as a research fellow when I was a medical student in 2004. As I gradually became more involved in different projects, my own interest in medical research grew up to the point where I became PhD student. He has shared his extensive knowledge and enthusiasm for research, and I am grateful the time you have set aside in your busy schedule to give me constructive input and thorough review of all my work. My “statistical mentor” and co-author Inge C. Olsen has been a source of inspiration and support for most of my time as a PhD student. His excellent input with statistical analyses or other aspects of academic writing is greatly appreciated. I would also like to thank Turid Heiberg who generously invited me to join one of her projects in validating the rheumatoid arthritis impact of disease (RAID) questionnaire in Norwegian. The data-collection for ORAR was performed over many years and would not have been possible without the work of secretaries and study personnel who organised all aspects of data collection and organisation. I would also like to thank all patients who kindly took part in our study. Without their time and effort none of these studies would have been possible. I would like to thank Diakonhjemmet Hospital for providing excellent institutional support and the South Eastern Regional Health Authority for financial support. 3 To all past and present PhD students and postgraduate researchers in the ”Villa” I owe a great deal. You have all contributed to making my time as a PhD student unforgettable. I value your academic input and support as well as the friendly working environment with extended lunches and non-academic discussions. In particular I treasure the close friendship I have with Anna-Birgitte Aga and other gardening-enthusiasts like myself. I will never forget the bulging tomato-crop we grew on the upstairs porch in the Villa during one of the summers. Before my PhD was finished I started working as a rheumatologist in Drammen. The enthusiasm and eagerness to teach all the consultants had was invaluable when I was trying to find my way through the myriad of complicated rheumatological diseases. In particular I would like to thank Åse Lexberg and Yngvill Bragnes who were head of department and my personal supervisor respectively. During the last few months Kjetil Bergsmark at Diakonhjemmet has been a supportive boss while I worked full-time in the clinic and finished the PhD. Finally I would like to thank my family and friends for their endless love and care. My parents have always been there to support me, and my daughter Nora who has given me endless pleasure for the last 11 years. No matter how tired I have been, somehow she always manages to make my day and bring a smile to my face. 4 Funding Institutional support has generously been provided by the administration of Diakonhjemmet Hospital AS. Financial support was received with gratitude from the Norwegian South Eastern Regional Health Authority (“Helse Sør-Øst”). Additional financial support for data collection in the Oslo Rheumatoid Arthritis Register was received from the Norwegian Rheumatism Association and Grete Harbitz legacy. 5 Abbreviations ACPA Anti-citrullinated protein antibody ACR American College of Rheumatology AIMS Arthritis impact measurement scales (also AIMS 2) Anti-CCP Antibodies to cyclic citrullinated peptide CDAI Clinical disease activity index CI Confidence interval COX Isoenzyme cyclo-oxygenase, isoforms I and II (COX-I and COX-II) Coxib Cox-2 inhibitor CRP C-reactive protein DAS Disease activity score (also DAS-28, based on 28 joint counts) DMARD Disease modifying antirheumatic drug bDMARD Biologic DMARD, also biologic originator (boDMARD) and biosimilars (bsDMARD) sDMARD Synthetic DMARD, also conventional synthetic (csDMARD) and targeted synthetic (tsDMARD) EULAR European league against rheumatism ESR Erythrocyte sedimentation rate GI Gastrointestinal HAQ Health assessment questionnaire HLA Human leukocyte antigen HRQoL Health related quality of life MCS Mental component summary from SF-36 MCID Minimal clinically important difference MCII Minimal clinically important improvement MDHAQ Multi dimensional health assessment questionnaire MHAQ Modified health assessment questionnaire MOS SF-36 Medical outcomes study 36-item short form MOS sleep Medical outcomes study sleep questionnaire MRI Magnetic resonance imaging NSAIDs Non-steroidal anti-inflammatory drugs NRS Numeric rating scale OMERACT Outcome measures in rheumatology OR Odds ratio ORAR Oslo Rheumatoid Arthritis Register PASS Patient acceptable symptom state PCS Physical component summary from SF-36 PROM Patient reported outcome measure PtGA Patient global assessment of disease RA Rheumatoid arthritis RADAI Rheumatoid arthritis disease activity index RAI Rheumatoid attitude index RAID Rheumatoid arthritis impact of disease RF Rheumatoid factor SD Sleep disturbance SDAI Simple disease activity index SES Self-efficacy scales SF6D Short form 6 Dimensions Disability Index (derived from SF-36) SPSS Statistical package for the social sciences TNF Tumor necrosis factor VAS Visual analogue scale 15D 15 Dimensional questionnaire 6 List of papers I. Austad C, Kvien TK, Olsen IC, Uhlig T. Health status has improved more in women than in men with rheumatoid arthritis from 1994 to 2009: results from the Oslo rheumatoid arthritis register. Ann Rheum Dis 2015;74(1):148-55. II. Austad C, Kvien TK, Olsen IC, Uhlig T. Sleep disturbances in patients with rheumatoid arthritis are related to fatigue, disease activity and other patient reported outcomes. Scand J Rheumatol 2016; online first june 2016: 1-9 III. Austad C, Kvien TK, Uhlig T. Abdominal discomfort in patients with rheumatoid arthritis is associated with physical and mental function, self- reported disease activity, and use of anti-inflammatory medication. Scand J Rheumatol 2013;42(4):333-5. IV. Heiberg T, Austad C, Kvien TK, Uhlig T. Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to other patient-reported outcomes in a register of patients with rheumatoid arthritis. Ann Rheum Dis 2011;70(6):1080-2. 7 8