Clinical and epigenetic factors underlying treatment refractory Rheumatoid Arthritis

Baxter, Derek (2014) Clinical and epigenetic factors underlying treatment refractory Rheumatoid Arthritis. MD thesis, University of Glasgow.

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Abstract

Rheumatoid Arthritis (RA) is a chronic, progressive, multisystem inflammatory disorder for which there is, at present, no cure. It affects up to 1% of the population resulting in chronic pain, disability and, through loss of function, may lead to loss of employment. It is associated with major co-morbidities that account for premature mortality. There is now extensive published research that suggests early treatment with disease modifying drugs can retard joint damage and improve outcome. In a proportion, drug- free remission is possible. However, there remain both individuals with persistently active disease despite standard drug treatments and those with longstanding disease not exposed to effective early treatment that remain relatively unresponsive to therapy. There is a growing literature that epigenetic modifications may underpin, or at least accelerate the development of many autoimmune disorders. These include alterations in DNA methylation patterns, histone tail modifications, post-translational mRNA regulation by microRNA and combinations therein. Having established the human genome project and underlying human DNA sequence, the recognition of dynamic epigenetic regulation of the genome has added further complexity. Few data however are currently available in ‘real-world’ cohorts of patients. In order to explore the hypothesis that specific epigenetic changes may underpin differences in response to therapy, I first examined the characteristics of a cohort of fifty RA patients with longstanding and active disease (DAS28 >3.2) despite receipt of standard therapies (disease modifying drugs (DMARD) and biologic therapies. This included a detailed examination of clinical characteristics, immune profile, inflammatory markers and burden of co-morbid complications such as vascular disease and depression. Outcomes such as disability, quality of life assessments and fatigue were evaluated by means of previously validated questionnaires. These groups were assessed at baseline, three months and six months. I then measured one of the many epigenetic marks, namely microRNA, of this cohort. We analyzed the accessible profile of peripheral RA CD14+ cell microRNAs in treatment resistant RA patients, in healthy controls, DMARD inadequate responders and DMARD good responders in order to determine the presence of a microRNA profile indicative of biologic resistance. An analysis of the serum cytokine profile of the biologic resistant and DMARD resistant groups was also performed. Finally, to extend the analysis beyond conventional clinical and novel molecular biomarkers the influence of additional patient factors such as coping and illness perception were evaluated by questionnaire to determine subjective disease severity in discrete patient groups. Active inflammatory disease was present as judged by the DAS28 score and there was some improvements seen over the six-month assessment period reflecting treatment changes in all groups. Substantial disability and impaired quality of life was found particularly in the therapeutic resistant group but also in those with inadequate response to DMARD, and remained relatively unresponsive to treatment escalation. Clinical variables, deprivation, quality of life and fatigue were strongly correlated with mood suggesting close interactions and resultant increase in disease activity as measured by the DAS28. Multiple cardiovascular risk factors were determined and, having applied cardiovascular risk scoring systems, unmet treatment of modifiable risk was demonstrated. Exploratory analysis of candidate microRNA -34a, -27b and -125a showed no correlation with clinical or biochemical variables other than swollen joint counts but differential expression between study groups. Exploratory microarray profiling between the four study groups demonstrated a number of differentially regulated microRNA. Of these, a unique microRNA profile of the biologic resistant group was found. MicroRNA-423 and -1275 showed higher expression in the biologic resistant group and fell in parallel with the DAS28 reduction between study visits raising their potential utility as biomarkers. MicroRNA-3178 showed higher relative expression in the biologic resistant group. Cytokine profiles demonstrated significant differences vs healthy controls but biologic resistant, DMARD resistant and DMARD good responder groups were less distinct and individual cytokines failed to discriminate in these study groups. Cytokine profiling did not correlate with observed clinical variables, inflammatory markers nor central processes such as mood or fatigue. Finally, those coping strategies favoured were adaptive and problem based. These were unaffected by the high prevalence of mood disturbance. Conversely, illness perception was influenced by mood and both affected subjective disease assessments. The strong influence of mood and fatigue raise the hypothesis that blunted treatment response may be partially driven by these variables. Ultimately we seek to explain, identify and target those patients with aggressive disease as early intervention may prevent established disease and it's accompanying co-morbid conditions. Undoubtedly, a personalised assessment of disease variables and co-morbid conditions is necessary where treatment response is being evaluated. In such a way, significant cardiovascular morbidity and mortality may be prevented. The question of true biologic resistance remains open. Undoubtedly residual inflammation exists in longstanding RA but significant ‘disease activity’ may be explained at least in part by those subjective clinical variables influenced by both external and internal factors. The identification of a ‘biologic resistant’ microRNA profile could act both as a biomarker of treatment response in longstanding disease, superior to the DAS28 scoring system and, through target identification, better understanding of the regulation of the molecular pathways of inflammation operating in such patients. In this way novel pathways of treatment resistance may be exposed and novel treatment targets revealed. However, mood and thus illness perception also contribute to resistance to therapy and should be sought, characterized, and directly addressed to add to the global improvements in outcome that we seek in a holistic model of care in the rheumatic diseases.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Rheumatoid arthritis. microRNA, epigenetic, cardiovascular risk, cytokines, fatigue, depression, anxiety, biologic therapy
Subjects: R Medicine > R Medicine (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Funder's Name: UNSPECIFIED
Supervisor's Name: McInnes, Professor Iain and Porter, Dr Duncan
Date of Award: 2014
Depositing User: Dr Derek Baxter
Unique ID: glathesis:2014-5608
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 06 Nov 2014 14:40
Last Modified: 06 Nov 2014 14:53
URI: http://theses.gla.ac.uk/id/eprint/5608

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