| dc.description.abstract | Rheumatoid Arthritis (RA) is a chronic auto-immune disease that causes in
ammation in the
joints. Left uncontrolled, this prolonged in
ammation can lead to pain and structural damage,
resulting in erosions to the bones and total breakdown of the surrounding cartilage. Structural
joint damage, measured by plain radiographs, is an important outcome measure of RA. It provides
an objective marker of disease activity to assess any improvements or failures of treatments
in controlling for the disease. Increased long-term joint damage has been linked with increased
functional disability and decreased quality of life for RA patients. While a range of studies have
looked at radiographic outcomes from observational data, they tend to be restricted to historical
cohorts, with little long-term data on how radiographic progression may have changed in line
with changes in clinical management. Additionally, these studies have not used the appropriate
statistical methods to account for non-normal data distributions and within-patient variation
over time.
As a result, the main aim of this thesis is to investigate the long-term progression of structural
joint damage in patients with early RA. The speci c objectives were to; (1) investigate the
current evidence base to identify common methods in measuring and analysing radiographic
outcomes, (2) assess what statistical methods are most appropriate in modelling long-term radiographic
data, (3) use these models to understand the natural progression of radiographic
damage using data from two UK inception cohorts, and nally, (4) expand these models to
investigate the long-term relationship of radiographic damage with two important clinical outcomes;
disease activity and functional disability. The analysis is based on longitudinal data from
two UK prospective, multi-centre, early RA observational cohorts. These cohorts represent two
distinct eras in the management and treatment of RA, making them invaluable for investigating
how key RA outcomes have progressed in clinical practice over time.
Using multi-level count models, precise rates of radiographic progression for both cohorts are
presented. The models look at how seropositive RA and increased disease activity are related to
increased radiographic progression, and what impact this has on functional disability. The results
show that rates of radiological damage have declined dramatically in recent years. Possible
attributable factors to these declines include both milder disease and more e ective treatment
strategies.
Analysis of the earlier cohort (1986-2001) shows how seropositive RA and increased disease
activity lead to clinically meaningful increases in radiological damage. Conversely, their impact
on patients in the more recent cohort (2002-2011) suggest that their e ect on radiographic
progression is reduced, where increases in radiological damage were not larger than clinically
meaningful thresholds. This has large implications on the debate around the use of biologic
therapies in patients with less severe RA. However more data is sorely needed, particularly
long-term radiographic data from those patients on biologics treatments, before any de nitive
conclusions can be made.
The possible impact of these declines on functional disability appears to be relatively small. The
analysis shows that radiographic damage is more strongly associated with functional disability
in later disease, but there is little evidence to indicate that declines in radiographic damage has
lead to large improvements in long-term functional disability. These ndings are explored within
the framework of a dual-pathway model, which suggests that functional disability is caused by
two distinct mechanisms, either structural joint damage, or through increased pain. Research so
far has predominantly focused on pharmacological treatments in reducing in
ammation. More
research is needed to explore the role of psychosocial factors and pain perception in order to
create a more holistic treatment programme for RA patients. | en_US |
