REQUERIMIENTOS TECNICOS

Overall, the completion of this body of work has led to the identification of a range of FFB characteristics that are evident in patients with RA, the clinical value of which differs. Clear distinction should be drawn however between what can be interpreted as the direct clinical importance of FFB (for example their pathological state) and the clinical value that can be gained from the study of FFB (for example what observing FFB can tell us about our patients).

From the findings of this programme of research it is not possible to conclusively determine to what extent FFB directly contribute to the burden of foot disease in patients with RA. There is however preliminary data that appears to support this hypothesis, for example the number of MRI enhancing FFB observed is new documentation of inflammation within the soft tissues outside of the forefoot joints in patients with RA (Chapter seven). It is possible that selectively targeting therapeutic intervention at inflamed FFB may ease the burden of foot complications in this patient group. Kanbe et al. (2006) and Huang et al. (2011) have demonstrated significant clinical benefit following the surgical excision of inflamed bursae. However, there is limited additional evidence documented to date advocating the targeted management of inflamed FFB, other than that which is hypothetically proposed (Koski 1998, Harper 2003, Awerbuch et al. 1982, Boutry et al. 2005). Future research is required to demonstrate the efficacy of selectively treating FFB.

None the less, the findings of this programme of research have highlighted the prognostic clinical value of US-detected FFB for the determination of foot-related disability longitudinally (Chapter four). It is possible to conclude that those patients identified as having four or more US- detectable FFB have greater likelihood of worsening foot-related disability over three years. Thus, the evaluation of US-detectable FFB presence can be used as a clinical adjunct to the assessment of foot health in patients with RA. It is also noteworthy that the study findings suggest that US-detectable FFB presence, as well as foot-related disability, is fluctuant. Therapeutically, this suggests that both factors have potential to be modified and improved. However, additional insight into the mechanisms underpinning this relationship is required before a process of targeted intervention and evaluation can be developed.

The study of MRI-detected FFB suggests that a subset of FFB, (inflamed soft tissue lesions), is associated with disease duration (Chapter seven). The rationale for this is unknown; it is unclear whether this is related to disease chronicity, disease aggression or biomechanical impairment, as suggested by previous authors (Studler et al. 2008, Harper 2003, Canoso and Yood 1979b, Awerbuch et al. 1982, Koski 1998, Bottger et al. 1998). Koski et al. (1998), amongst other authors (Awerbuch et al. 1982, Bowen et al. 2010c, Boutry et al. 2003a, OBrien et al. 1997, Scutellari and Orzincolo 1998), has suggested that FFB become inflamed as a consequence of RA disease affecting the synovial lining of these lesions. However, the presence of synoviocytes within plantar FFB has not been reported to date. The nature of the plantar tissues identified as inflamed within this study is currently unclear and future histological examination needed. An improved understanding of the mechanisms driving inflammation in this tissue, that was previously considered clinically unimportant or adventitial in healthy volunteers (Studler et al. 2008), may improve our understanding of the pathogenesis of RA disease within the forefoot.

Additionally, plantar fluid lesions were determined to be significantly associated with systemic markers of RA disease activity (Chapter seven). Again, this finding appears contradictory to the hypothesis associated with plantar FFB suggested by previous authors; plantar fluid FFB were thought to arise as a consequence of repetitive, excessive linear and torsional biomechanical stress to the fibro-fat pad that resulted in separation of the fibro-collagenous tissue layers and accumulation of slit-like cavities of fluid (Studler et al. 2008, Ahmed et al. 1994). Perhaps this aetiological assumption is correct, but in patients with RA, the inflammation accompanying this repetitive micro-trauma is poorly regulated, becoming excessive at these sites. Conversely, these lesions may indeed be directly related to RA disease activity; the direct effect of excessive disease-mediated inflammation may not be limited to the synovial tissue of the forefoot.

Moreover, RA disease activity may directly affect the structure and proliferation of fibro- collagenous tissue within the plantar forefoot (Mutlu et al. 2006, Matsushita et al. 2006, Zielaskowski et al. 2000, Sanders et al. 1998, Oloff-Solomon et al. 1984). Future evaluation of the pathogenesis of different FFB characteristics would further inform the understanding of their

clinical value. None the less, the use of the FFB-score is demonstrated to be a potentially beneficial clinical adjunct in the evaluation of RA disease activity.

As highlighted by Khan et al. (2012) the identification of minimal disease activity is a growing clinical concern. There is a need for improved clinical indicators of continued disease activity because a number of patients continue to report ongoing complications despite up-regulation of pharmacological therapy (Aletaha and Smolen 2011, Aletaha et al. 2011, Wells et al. 2009). This is evidenced within the RA cohort contributing to this body of research; although not a primary focus of this work, the findings of the study in Chapter six suggest that a number of patients (n=25) continue to have ongoing minimal disease activity within the forefoot (identified using MRI) despite receiving biologic intervention and achieving remission from disease according to DAS 28 evaluation. Arguably, the evaluation of FFB in patients with RA, using the FFB-score, is therefore advocated. Use of the FFB-score provides clinically relevant information regarding the perpetuation of inflammatory disease within the forefoot in patients with RA beyond that which is detected using current methods of assessment. It is therefore possible that a number of patients who require further up-regulation of treatment, that would otherwise not be reviewed, will be identified with the use of the FFB-score. Future work, which cross-validates the findings of the MRI-based FFB-score with US-detected FFB, would reduce the time and financial burden of FFB evaluation, potentially improving the clinical utility of an US-based FFB-score. The long term economic impact of improved identification of minimal disease activity, via evaluation of FFB, is also warranted.