Outcomes of Periodontal Treatment in Patients with Rheumatoid Arthritis (OPERA): Quantitative and Qualitative Results of a Pilot Randomized Controlled Trial By Stefan Teodor Serban A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Dentistry Institute of Clinical Sciences University of Birmingham December 2016 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Outcomes of Periodontal Treatment in Patients with Rheumatoid Arthritis (OPERA) was a pilot randomized controlled trial (RCT) that aimed to assess the feasibility for a larger, multi-center RCT which would investigate the efficiency of non-surgical periodontal treatment in reducing disease activity levels in patients with rheumatoid arthritis (RA). The OPERA trial used a mixed methods approach. The quantitative approach delivered pilot data regarding the clinical outcomes of the intervention, whilst the role of qualitative data was to provide a better insight into the experiences and values of the patients that would encourage their participation in the larger, definitive study. The findings of this trial highlighted the specific issues of the patient population, the logistic challenges and provided some possible solutions to facilitate patient participation. I Acknowledgements Clinical research is teamwork and this PhD project would not have been possible without the fantastic people that helped me get through the 3 years journey that has led to this thesis. I would like to express my gratitude for the continuous guidance, patience and mentorship provided by my supervisors: Prof. Dietrich, Prof. Chapple, Dr. de Pablo and Dr. Hill. For the friendship, help and shoulders to cry on provided by Patricia, Kaushik, Danielle, Praveen, Helen and Vahid. For all the support I received from the research and clinical staff from the Rheumatology Departments of Queen Elizabeth Hospital Birmingham, City Hospital and Heartlands Hospital – with special thanks to Prof. Raza and Dr. Filer. And to all my lovely patients that offered their time and effort to successfully implement the OPERA trial. II Table of Contents Abstract ................................................................................................................... I Acknowledgements ............................................................................................... II Table of Contents .................................................................................................. III Index of Tables .................................................................................................... XIV Index of Figures ..................................................................................................... 1 List of abbreviations .............................................................................................. 2 1 Introduction ...................................................................................................... 4 1.1 Outcomes of Periodontal Treatment in Patients with Rheumatoid Arthritis – The OPERA Study: ........................................................................... 4 1.2 Historical background ............................................................................... 6 1.3 Focal infection theory ............................................................................... 6 1.4 Oral vs systemic conditions ..................................................................... 7 1.5 Chronic periodontitis .............................................................................. 10 1.6 Case definitions and heterogeneity of the literature ............................ 10 1.6.1 The WHO definition ............................................................................. 11 1.6.2 The EFP definition ............................................................................... 11 1.6.3 The CDC/AAP definition ...................................................................... 12 1.6.4 The Joint EU/USA recommendation ................................................... 14 1.6.5 Aggregate measures of periodontal inflammatory burden .................. 15 III 1.7 Epidemiology and burden of periodontal disease in Europe .............. 16 1.8 Periodontal care in the NHS ................................................................... 17 1.9 Dysbiosis and host-mediated tissue damage ....................................... 18 1.10 Human impact (DALY, QUALY, Economic burden, QoL, mortality) . 19 1.11 Epidemiology and burden of rheumatoid arthritis ............................. 20 1.12 Etiology and pathogenesis ................................................................... 21 1.13 Progression ............................................................................................ 21 1.14 Biological models to explain the associations between periodontitis and RA ............................................................................................................... 22 1.15 Epidemiological associations between periodontitis and RA ........... 24 1.16 Brief introduction to qualitative research methodology .................... 25 1.17 The nature of qualitative research ....................................................... 25 1.17.1 Grounded theory research ................................................................ 28 1.17.2 Qualitative vs. quantitative research ................................................. 29 1.17.2.1 Rigorousness of the qualitative versus the quantitative research methodologies ............................................................................................. 30 1.17.2.2 Credibility .................................................................................... 31 1.17.2.3 Dependability .............................................................................. 31 1.17.2.4 Transferability ............................................................................. 31 1.17.2.5 Confirmability .............................................................................. 32 1.18 NICE Guidelines ..................................................................................... 32 1.19 Sampling in qualitative research .......................................................... 32 1.19.1 Sample size ....................................................................................... 35 IV 1.19.2 Saturation .......................................................................................... 35 1.20 Strengths and weaknesses of using mixed research methodology . 36 2 Aims and Objectives ...................................................................................... 38 3 Rationale for carrying out the study ............................................................. 40 4 Methodology ................................................................................................... 42 4.1 Overview ................................................................................................... 42 4.2 Study oversight ........................................................................................ 43 4.3 Study population ..................................................................................... 43 4.4 Recruitment procedures ......................................................................... 44 4.5 Inclusion criteria ...................................................................................... 47 4.6 Exclusion criteria ..................................................................................... 48 4.7 Clinical assessments .............................................................................. 50 4.7.1 General examination ........................................................................... 50 4.7.2 Rheumatologic examination ................................................................ 50 4.7.3 Disease Activity Score (DAS28) .......................................................... 51 4.7.4 Periodontal examination ..................................................................... 52 4.8 Patient reported outcomes ..................................................................... 53 4.8.1 Euro-Quol; ........................................................................................... 54 4.8.2 Patient Health Questionnaire (PHQ-9); ............................................... 54 4.8.3 Oral Health Impact Profile (OHIP) ....................................................... 54 4.9 Data management .................................................................................... 54 4.10 Data monitoring ..................................................................................... 55 V 4.11 Biological samples collection .............................................................. 56 4.11.1 Venous blood sampling and processing ........................................... 56 4.11.2 GCF sampling ................................................................................... 56 4.11.3 Saliva sampling