Author: Mihir D Wechalekar
Wechalekar, Mihir D, 2015 Optimising Remission and Treatment Outcomes in Rheumatoid Arthritis, Flinders University, School of Medicine
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Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disorder affecting 1-2% of the population. Despite the advent of newer therapies, in combination with a treat-to-target approach, sustained remission remains elusive for a significant proportion of patients. This thesis explores measures to improve outcomes in early RA, a time when therapies are most likely to achieve sustained remission. The first section evaluates commonly used disease activity (DA) measures that omit assessment of the foot and ankle, a frequent site of joint involvement. Our initial cross-sectional and subsequent longitudinal studies demonstrate that when DA measures using 28 joint counts are used to define remission, a substantial proportion of patients have ongoing foot synovitis which predicts relapse, radiographic progression and worse long-term functional outcomes. We next addressed whether contemporary treat-to-target combination DMARD therapy in early RA translates into personal and societal benefits in terms of preserved work outcomes. Our findings revealed that good EULAR responders were more likely to be working at 10 years compared to those with moderate/no EULAR response. This difference was present from 2 years following diagnosis and became more pronounced over the next 8 years. Dissociation between radiographic progression and apparent remission can lead to unexpected treatment failures and in this section, we explored whether inclusion of bone biomarkers could improve assessment of treatment response. We found a significant reduction of RANKL following treatment, a slight increase in osteoprotegerin but no significant changes in the other bone biomarkers assessed. The RA synovium reflects the underlying cytokine milieu in each individual and in the final section of this thesis we detail our ongoing research exploring the clinical utility of arthroscopic biopsy in early RA. We initially discuss a proof-of-concept study followed by the currently ongoing ARBITRATE (Arthroscopic Synovial Biopsy Directed Targeted Therapy vs. Conventional Therapy in RA) study, an open label randomised parallel design treatment trial designed to address whether targeted therapy can improve disease outcome. We conclude with a critical review of the findings from this thesis and future research directions.
Keywords: rheumatoid arthritis, remission, treatment outcomes
Subject: Medicine thesis
Thesis type: Doctor of Philosophy
School: School of Medicine
Supervisor: Professor Malcolm D Smith