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Table 1-1 2010 ACR/EULAR criteria for diagnosis of rheumatoid arthritis adapted
from (Aletaha et al. 2010) 33!
Table 1-2 Factors associated with poorer prognosis and disease in RA
(abbreviations can be found in text or Chapter 8.1 ‘Abbreviations
used‘) 35!
Table 1-3 NCEP ATP III characteristics of the metabolic syndrome (adapted from
(Grundy 2004) 38!
Table 1-4 Diagnostic criteria for the metabolic syndrome NCEP(Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults 2001), WHO (Nishida et al. 2010) 38!
Table 1-5 Summary of British Hypertension Society (BHS) and NICE hypertension
guideline targets 40!
Table 1-6 ACR response criteria (Felson et al. 1995) 44!
Table 1-7 EULAR response criteria (adapted from (Hyrich et al. 2006) 44!
Table 1-8 Variables assessed by the commonly used disease activity assessment
tools in RA (adapted from Fujiwara 2012) PhG-Physician global,
PG=Patient Global 45!
Table 1-9 Selected representative mean FACIT-F levels from selected published
significant biologic trials 50!
Table 1-10 Mode of action and administration of available biologic therapies
licensed to treat severe RA 56!
Table 1-11 Important considerations and cautions and with TNFi therapy 57!
Table 1-12 Proposed molecular mechanisms of disease resistance 61!
Table 1-13 Roles for microRNA in human development, physiology and tissue
repair 76!
Table 1-14 Selected microRNA-155 publications in RA 85!
Table 1-15 selected microRNA-146 publications in RA 88!
Table 1-16 selected microRNA-223 publications in RA 90!
Table 1-17 Additional selected relevant microRNA publications in RA 91!

Table 2-18 Inclusion and Exclusion criteria to biologic resistant study group 100!
Table 2-19 Inclusion and Exclusion criteria to the ORBIT study 102!
Table 2-20 Inclusion criteria to DMARD good responder study group 102!
Table 2-21 Assessments performed on biologic resistant study group 105!
Table 2-22 Questionnaires administered to biologic therapy study group 106!
Table 2-23 Patient related outcome measures used in biologic resistant group 106!
Table 2-24 ORBIT study assessments imported and examined for DMARD
resistant group 107!
Table 2-25 Proposed study numbers and study visit timetable 108!
Table 3-26 Total study recruitment numbers 113!
Table 3-27 Summary descriptive findings of biologic resistant group 116!
Table 3-28 Disease history, extra-articular manifestations and phenotype of
biologic resistant study group 117!
Table 3-29 Reasons for discontinuation of first biologic therapy 119!
!
!
KI!
Table 3-30 Current biologic therapy at baseline study visit and prior biologic
therapies of total group 121!
Table 3-31 Distribution of biologic treatments at study visits 123!
Table 3-32 Responsiveness of disease activity and disability (HAQ) in those
biologic resistant patients that had treatment escalation between
baseline and six-month study visit 124!
Table 3-33 CCP antibody status of biologic resistant study group 125!
Table 3-34 Rheumatoid factor status of biologic resistant study group 125!
Table 3-35 Combined autoantibody status of biologic resistant study group 126!
Table 3-36 Influence of autoantibody status and selected clinical variables 126!
Table 3-37 DAS28 ESR score of biologic resistant study group at all study visits 127!
Table 3-38 Combined assessments of disease activity at three study visits 130!
Table 3-39 DAS28 score component analysis between study visits 131!

Table 3-40 EQ-5D questionnaire results of biologic resistant group (%
experiencing problems) 132!
Table 3-41 EQ-5D pain VAS score at baseline and six months in biologic resistant
group 132!
Table 3-42 Disability (HAQ) at baseline and six months 133!
Table 3-43 Bivariate analysis of disability (HAQ) and clinical and biochemical
variables 135!
Table 3-44 Bivariate correlations between SF-36 components and HADS-
D/HADS-A scores 136!
Table 3-45 FACIT fatigue results at baseline and six month study visits 137!
Table 3-46 Correlation between fatigue and clinical, biochemical variables and
composite disease activity scores 137!
Table 3-47 Bivariate correlation between fatigue and mood 138!
Table 3-48 Selected clinical factors associated with severity of fatigue at baseline in
biologic resistant RA 141!
Table 3-49 Individual bivariate correlations between clinical, disease, patient
outcome measures and fatigue (FACIT-F) at baseline 142!
Table 3-50 selected publications where SF-36 data published (mean values) 143!
Table 3-51 Disability (HAQ) pre- and post-introduction of new biologic therapy 144!
Table 3-52 Influence of deprivation and clinical factors 146!
Table 3-53 Medical comorbidities in biologic resistant group 147!
Table 3-54 Number of cardiovascular (CV) risk factors at baseline visit in biologic
resistant study group 147!
Table 3-55 Lipid profile of biologic resistant study group (n=44) Normal range;
Greater Glasgow Biochemistry Laboratory 148!
Table 3-56 Blood pressure findings of biologic resistant group at baseline visit
(n=46) 148!
Table 3-57 Combined features of the MetS in the biologic resistant study group 150!
Table 3-58 Results of Rose angina question in biologic resistant study group 151!
Table 3-59 SCORE cardiovascular risk estimation of biologic resistant study group

(n=40) 152!
Table 3-60 Overall HADS questionnaire results biologic resistant group 154!
Table 3-61 Overall HADS anxiety and depression scores at baseline study visit 154!
!
!
KL!
Table 3-62 Proportion of biologic resistant group with ‘possible’ and ‘probable’
mood disturbance at baseline and six months 154!
Table 3-63 Correlation between fatigue and mood 156!
Table 3-64 Correlation between mood and disability (HAQ) 159!
Table 3-65 Correlation between mood (HADS score) and SF-36 physical and
mental component scores 160!
Table 3-66 Correlation between mood and clinical variables/inflammatory indices 160!
Table 3-67 Demographics and disease characteristics of DMARD resistant group at
baseline 163!
Table 3-68 Autoantibody status of DMARD resistant study patients 163!
Table 3-69 Disease activity of DMARD resistant study patients at baseline 164!
Table 3-70 DMARD resistant patients; treatment between study visits with overall
EULAR response at time of sample collection 167!
Table 3-71 Medical comorbidity in DMARD resistant study patients 167!
Table 3-72 Demographics and disease characteristics of DMARD good responder
study patients 168!
Table 3-73 Numbers of medical comorbidities in DMARD good responder study
group 168!
Table 3-74 Clinical assessments, inflammatory markers and composite disease
activity scores of DMARD good responder study group 169!
Table 3-75 Autoantibody status of the DMARD good responder study patients 169!
Table 3-76 Summary descriptive findings of the healthy control study group 170!
Table 3-77 Summary of clinical and biochemical results between study and control
groups (* statistically significant p<0.01) differences between

groups) 171!
Table 4-78 Clinical variables between groups in microRNA-34a experiment 185!
Table 4-79 Correlations between copy number of microRNA-34a (relative to let-
7a) and clinical/biochemical variables 190!
Table 4-80 Clinical variables between groups in microRNA-27b experiment 192!
Table 4-81 Correlations between relative expression of microRNA-27b and
clinical/biochemical variables 196!
Table 4-82 Clinical variables between groups in microRNA-125a experiment 198!
Table 4-83 Correlations between relative expression of microRNA-125b and
clinical/biochemical variables (where significance assumed if
p<0.05) 202!
Table 4-84 Differential expression of microRNA between groups and statistical
evaluation 207!
Table 4-85 Clinical variables between patients studied for microRNA-423, -574, -
1275 and -3178 qPCR 208!
Table 4-86 Correlation between microRNA-423, -1275, -1275 and -3178 213!
Table 4-87 Patient numbers studied at the three study visits 217!
Table 5-88 Selected cytokines grouped by postulated function (adapted from
(Boissier 2011) 236!
Table 5-89 Cytokines studied in biologic and DMARD resistant study groups, brief
function and role 240!
Table 5-90 Paired sample t-test results (p value) between baseline and three months
and three month and six month study visits for all cytokine analytes 289!
!
!
KU!
Table 5-91 Selected cytokines and inflammatory markers examined by
autoantibody status 290!
Table 5-92 Correlation between selected cytokines and mood (HADS) and fatigue 291!
Table 6-93 Coping and illness perception questionnaires administered, data

captured and scoring method 300!
Table 6-94 Theoretical dimension grouping to describe coping strategies 301!
Table 6-95 Dimensions examined by the Brief IPQ questionnaire (based on B-IPQ
questionnaire, Appendix 7) 301!
Table 6-96 Study group (n=30) demographics, previous treatments, HADS score
and immunology 302!
Table 6-97 Disease activity component scores, composite disease activity, disability
and fatigue of resistant RA group 304!
Table 6-98 Influence of mood and clinical variables 304!
Table 6-99 Cronbach’s internal consistency score by coping domain (Brief COPE
questionnaire) 305!
Table 6-100 Most frequently and least commonly used coping strategies in study
group 305!
Table 6-101 Cronbach’s ICC results and mean coping domain score (n=30) 306!
Table 6-102 Brief-COPE questionnaire results by coping strategy and effect of
mood 307!
Table 6-103 Illness perception item scoring (Brief IPQ scoring results) 308!
Table 6-104 Illness perception and the effect of depression, anxiety and disability 308!
Table 6-105 Bivariate associations of clinical, disease activity, patient outcome
measures and illness perception with anxiety, depression and fatigue 309!
Table 6-106 ‘Enter’ method multiple regression model of fatigue 310!
Table 6-107 Forward stepwise regression model for fatigue 311!
Table 6-108 ‘Enter’ method multiple regression model of anxiety 311!
Table 6-109 Forward stepwise regression model for anxiety 311!
Table 6-110 ‘Enter’ method multiple regression model of depression 312!
Table 6-111 Forward stepwise regression model for depression 312!
Table 6-112 Influence of deprivation and coping strategy and with illness
perception responses 313!
Table 7-113 Effect of depression and BMI/selected inflammatory markers 321!
!

! !
!
!
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7+/#8!*5!9)0:'# 2 !
!
Figure 3-1 Biologic resistant study group recruitment consort diagram 115!
Figure 3-2 Carstairs deprivation categories, biologic resistant RA group at baseline
assessment 116!
Figure 3-3 Mean body mass index biologic resistant study group 118!
Figure 3-4 Median waist:hip ratio of biologic resistant study group 119!
Figure 3-5 Biologic therapy use between study visits 122!
Figure 3-6 ‘box and whisker’ plot of DAS28 ESR biologic resistant study group
between study visits 128!
Figure 3-7 Representation of DAS28 ESR of biologic resistant study group change
by patient between visits 129
Figure 3-8 ‘Box and whisker’ plots of EQ-5D VAS pain score baseline and six
months 133
Figure 3-9 ‘Box and whisker’ plots of HAQ at baseline and six months……… …….134
Figure 3-10 Baseline and six-month SF36 questionnaire domain and summary
scores…………………………………… …………………………….136
Figure 3-12 Scatterplot of anxiety and fatigue in biologic resistant study group at
baseline study visit 138!
Figure 3-13 Scatterplot of depression and fatigue in biologic resistant study group
at baseline study visit 139!
Figure 3-14 Scatterplot of disease activity and fatigue in biologic resistant study
group at baseline study visit 140!
Figure 3-15 Quantification of CV risk as assessed by Framingham risk calculator 152!
Figure 3-16 Scatterplot of disease duration and HADS-A (anxiety) at baseline 155!
Figure 3-17 Scatterplot of disease duration and HADS-D (depression) at baseline 156!

Figure 3-18 Scatterplot of fatigue and depression at baseline 157!
Figure 3-19 Figure scatterplot of fatigue and anxiety at baseline 157!
Figure 3-20 Scatterplot of fatigue and anxiety at six months 158!
Figure 3-21 Scatterplot of fatigue and depression at six-month visit 159!
Figure 3-22 Representative changes in CRP between study visits of DMARD
resistant study patients 165!
Figure 3-23 Representative changes in ESR between study visits of DMARD
resistant study patients 165!
Figure 3-24 Representative changes in DAS-28 ESR between study visits of
DMARD resistant study patients 166!
Figure 3-25 DAS28 ESR median values between study groups 172!
Figure 3-26 Tender joint count box and whisker plots 173!
Figure 3-27 Swollen joint count box and whisker plots between study groups 174!
Figure 4-28 Representation of principles microRNA methodology (adapted from
(Recchiuti et al. 2011) 179!
Figure 4-29 Flowchart of microRNA extraction and kits used 181!
Figure 4-30 Cell purity and RNA integrity of samples undergoing analysis 184!
Figure 4-31 Joint counts between study groups in microRNA-34a analysis group 186!
Figure 4-32 Inflammatory markers between study groups in microRNA-34a
analysis group 187!
!
!
K\!
Figure 4-33 DAS28 scores between study groups in microRNA-34a analysis group 188!
Figure 4-34 MicroRNA-34a between study groups at baseline visit 189!
Figure 4-35 MicroRNA-34a copy number between study groups at baseline visit 189!
Figure 4-36 Scatterplot of log microRNA-34a and swollen joint count (all groups
combined) 190!
Figure 4-37 Joint counts between study groups in microRNA-27b analysis group 192!
Figure 4-38 Inflammatory markers between study groups in microRNA-27b

analysis group 193!
Figure 4-39 DAS28 between study groups in microRNA-27b analysis group 194!
Figure 4-40 MicroRNA-27b relative expression levels between study groups at
baseline 195!
Figure 4-41 Relative expression of microRNA-27b between study groups at
baseline 195!
Figure 4-42 Scatterplot of relative expression levels of microRNA-27b and swollen
joint group 197!
Figure 4-43 Joint counts between study groups in microRNA-125a analysis group 198!
Figure 4-44 Inflammatory markers between study groups in microRNA-125a
analysis group 199!
Figure 4-45 DAS28 between study groups in microRNA-125a analysis group 200!
Figure 4-46 Relative expression levels of microRNA-125a between study groups at
baseline 201!
Figure 4-47 Relative expression levels of microRNA-125a between study groups at
baseline visit 201!
Figure 4-49 Scatterplot of relative expression of microRNA-125a at baseline and
tender joint count 204!
Figure 4-50 Differentially expressed microRNA between study groups 206!
Figure 4-51 Relative expression levels of microRNA-423 between study groups at
baseline study visit (where *=p<0.05 and **=p<0.01) 209!
Figure 4-52 Relative expression levels of microRNA-1275 between study groups at
baseline study visit (where *=p<0.05 and **=p<0.01) 210!
Figure 4-53 Relative expression levels of microRNA-574 between study groups at
baseline study visit (where *=p<0.05 and **=p<0.01) 211!
Figure 4-54 Relative expression levels of microRNA-3178 between study groups at
baseline study visit (where *=p<0.05 and **=p<0.01) 212!
Figure 4-55 Scatterplot of relative expression of microRNA-423 and -1275 213!
Figure 4-56 Scatterplot of relative expression of microRNA-423 and -574 214!
Figure 4-57 Scatterplot of relative expression of microRNA-574 and -1275 215!

Figure 4-58 Scatterplot of relative expression of microRNA-423 and ESR at
baseline 216!
Figure 4-59 Scatterplot of relative expression of microRNA-1275 and ESR at
baseline 217!
Figure 4-60 Relative expression of microRNA-423 at baseline, three and six month
study visits 218!
Figure 4-61 Relative expression of microRNA-423 at baseline, three and six month
study visits 219!
Figure 4-62 DAS change between baseline and six months of biologic resistant
study group (n=40) 220!
!
!
K]!
Figure 4-63 Reduction in DAS28 ESR between study visits of biologic resistant
group 221!
Figure 4-64 Reduction in joint counts between study visits of biologic resistant
group 222!
Figure 4-65 Reduction in inflammatory markers between study visits of biologic
resistant group 223!
Figure 4-66 Scatterplot of change in DAS28 ESR from baseline study visit to six-
month study visit against relative expression of microRNA-423 224!
Figure 4-67 Scatterplot of change in DAS28 ESR from baseline study visit to six-
month study visit against relative expression of microRNA-1275 225!
Figure 4-68 Scatterplot of MMP-12 at baseline visit and relative expression of
microRNA-423 226!
Figure 4-69 Scatterplot of RANKL at baseline visit and relative expression of
microRNA-423 227!
Figure 4-70 MicroRNA-34a- relative higher expression in Biologic IR group vs
other group 228!
Figure 4-71 MicroRNA-27b- relative reduced expression levels in inflamed groups 229!

Figure 4-72 MicroRNA-125a- relative reduced expression levels in biologic IR
group vs DMARD responder and inadequate responder 229!
Figure 4-73 MicroRNA-423 and -1275; higher relative expression in biologic
resistant vs DMARD resistant and healthy controls 230!
Figure 4-74 MicroRNA-3178; higher relative expression in biologic resistant group
vs all control groups 231!
Figure 5-75 G-CSF by study group (where *=p<0.05 and **=p<0.01) 241!
Figure 5-76 IFNa by study group (where *=p<0.05 and **=p<0.01) 242!
Figure 5-77 IL-1 beta by study group (where *=p<0.05 and **=p<0.01) 243!
Figure 5-78 IL-2r by study group (where *=p<0.05 and **=p<0.01) 244!
Figure 5-79 IL-5 by study group (where *=p<0.05 and **=p<0.01) 245!
Figure 5-80 IL-6 by study group (where *=p<0.05 and **=p<0.01) 246!
Figure 5-81 IL-7 by study group (where *=p<0.05 and **=p<0.01) 247!
Figure 5-82 IL-12 by study group (where *=p<0.05 and **=p<0.01) 248!
Figure 5-83 IL-15 by study group (where *=p<0.05 and **=p<0.01) 249!
Figure 5-84 IL-17 by study group (where *=p<0.05 and **=p<0.01) 250!
Figure 5-85 TNFa by study group (where *=p<0.05 and **=p<0.01) 251!
Figure 5-86 IL-21 by study group (where *=p<0.05 and **=p<0.01) 252!
Figure 5-87 IL-23 by study group (where *=p<0.05 and **=p<0.01) 253!
Figure 5-88 IFN gamma by study group (where *=p<0.05 and **=p<0.01) 254!
Figure 5-89 GM-CSF beta by study group (where *=p<0.05 and **=p<0.01) 255!
Figure 5-90 IL-1ra by study group (where *=p<0.05 and **=p<0.01) 256!
Figure 91 IL-10 by study group (where *=p<0.05 and **=p<0.01) 257!
Figure 92 IL-4 by study group (where *=p<0.05 and **=p<0.01) 258!
Figure 5-93 IL-13 by study group (where *=p<0.05 and **=p<0.01) 259!
Figure 5-94 IL-2 by study group (where *=p<0.05 and **=p<0.01) 260!
Figure 5-95 OPG by study group (where *=p<0.05 and **=p<0.01) 261!
Figure 5-96 RANKL by study group (where *=p<0.05 and **=p<0.01) 262!
Figure 5-97 MMP-13 by study group (where *=p<0.05 and **=p<0.01) 263!
Figure 5-98 MMP-3 by study group (where *=p<0.05 and **=p<0.01) 264!

!
!
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Figure 99 MMP-12 by study group (where *=p<0.05 and **=p<0.01) 265!
Figure 5-100 IL-8 by study group (where *=p<0.05 and **=p<0.01) 266!
Figure 5-101 IP-10 by study group (where *=p<0.05 and **=p<0.01) 267!
Figure 5-102 MCP-1 by study group (where *=p<0.05 and **=p<0.01) 268!
Figure 5-103 MIG by study group (where *=p<0.05 and **=p<0.01) 269!
Figure 5-104 MIP1 alpha by study group (where *=p<0.05 and **=p<0.01) 270!
Figure 5-105 RANTES by study group (where *=p<0.05 and **=p<0.01) 271!
Figure 5-106 CXCL11 by study group (where *=p<0.05 and **=p<0.01) 272!
Figure 5-107 EOTAXIN by study group (where *=p<0.05 and **=p<0.01) 273!
Figure 5-108 MIP-1 beta by study group (where *=p<0.05 and **=p<0.01) 274!
Figure 5-109 VEGFb by study group (where *=p<0.05 and **=p<0.01) 275!
Figure 5-110 EGF by study group (where *=p<0.05 and **=p<0.01 276!
Figure 5-111 FGF by study group (where *=p<0.05 and **=p<0.01) 277!
Figure 5-112 HGF by study group (where *=p<0.05 and **=p<0.01) 278!
Figure 5-113 HGF in biologic and DMARD resistant study groups at baseline, three
and six-month study visit 280!
Figure 5-114 RANTES in biologic and DMARD resistant study groups at baseline,
three and six-month study visit 281!
Figure 5-115 EOTAXIN in biologic and DMARD resistant study groups at
baseline, three and six-month study visit 282!
Figure 5-116 MIP1 alpha in biologic and DMARD resistant study groups at
baseline, three and six-month study visit 283!
Figure 5-117 MCP-1 in biologic and DMARD resistant study groups at baseline,
three and six-month study visit 284!
Figure 5-118 IL-5 in biologic and DMARD resistant study groups at baseline, three
and six-month study visit 285!
Figure 5-119 TNF alpha in biologic and DMARD resistant study groups at

baseline, three and six-month study visit 286!
Figure 5-120 MIG in biologic and DMARD resistant study groups at baseline, three
and six-month study visit 287!
Figure 5-121 OPG in biologic and DMARD resistant study groups at baseline, three
and six-month study visit 288!
Figure 6-122 Deprivation categories of study group 303!
Figure 7-123 Representation of the factors that contribute to resistance to treatment
in this study 322!
Figure 7-124 Representation of the variables that could be used to determine
disease severity 323!
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