Medicine (RMH) - Theses
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ItemOptimisation of Medical Therapies in Inflammatory Bowel Disease( 2022)Treatment expectations and outcomes for patients with IBD have greatly improved in recent decades due to the increased availability of highly effective medical therapies and the emergence of better strategies for using these agents. Concurrently, improvements in the personalisation of individual treatment decisions have occurred via the incorporation of numerous precision medicine tools into clinical practice. The optimisation of thiopurine immunomodulators has been enhanced via the use of pharmacogenomics and therapeutic drug monitoring. The use of concomitant allopurinol in thiopurine hypermethylators or patients with intolerance to thiopurine monotherapy has increased the efficacy and persistence of thiopurine therapy, although the exact mechanism of the favourable metabolic interaction remains to be confirmed. Despite an increased number of small molecule and biologic treatment options now available thiopurines will remain important medical therapies for IBD patients for the foreseeable future, hence their optimisation remains important. Anti-TNF agents have revolutionised the management of patients with luminal and fistulising disease, but their optimal dose and optimisation strategy remains to be determined. Reactive TDM in patients with secondary loss of response to anti-TNFs is now standard of care, although supportive data are stronger for infliximab than adalimumab. Proactive TDM of anti-TNFs, although intuitively appealing, is not supported by results from prospective studies, although recent results from studies involving multiple IMIDs are encouraging. Perhaps the proof of efficacy of proactive TDM will finally emerge from further refinement of dashboard-driven precision dosing pharmacokinetic models. Increased practicability of TDM should come from more widespread update of rapid testing, including remote sampling and monitoring. The modern-day potential to de-escalate medical therapies in IBD reflects the ability to first achieve prolonged objective remission in a substantial proportion of patients with current therapies. Data informing de-escalation treatment decisions have only emerged from recent studies, usually involving the cessation of either immunomodulators or anti-TNFs from patients receiving combination therapy. Although relapse rates are higher with anti-TNF withdrawal, the high anti-TNF re-treatment success rates demonstrated from recent well-designed studies suggest that biologic de-escalation, with its associated cost and safety benefits, may be considered in appropriate patients. To date the personalisation of IBD treatment decisions has been guided by outcomes research from epidemiological and clinical cohort studies and the results of clinical trials. More recently genome wide association studies and whole genome sequencing have increased the genotypic individualisation of patients, although the translation of this knowledge to clinical practice has been slow. Precision medicine tools have also expanded to include microbiome-based characterisation of disease phenotypes and predictors of treatment response, although the impact of this knowledge in clinical practice is only currently emerging. Future precision-medicine advances will incorporate the development of multiomics signatures of IBD into systems biology platforms that can be analysed and validated across multiple cohorts. This knowledge should help further personalise treatment decisions, and ultimately may be informative for the future prediction, and even prevention, of IBD.