New Therapies for IBD: From the Bench to the Bedside
New Therapies for IBD: From the Bench to the Bedside
To conclude the description of the current and potential therapies for IBD it is sufficient to say that although there are many avenues to explore, as yet no single 'magic bullet' has been discovered. Many paths have been followed only to lead to dead ends. What is particularly perplexing is that while basic science is important, it did not play a large role in the development of the anti-TNF agents, the most potent IBD treatments developed so far. Many ideas born at the bench do not translate to the bedside. This issue is most likely to stem from the complexity of the pathogenesis and progression of IBD, processes that have not been fully characterised. In addition, while most of the drugs are investigated for luminal disease, there is also an enormous need for further investigation of approaches to treat complications of CD such as fibrotic disease and fistulas.
During the course of IBD many molecules are upregulated or downregulated in patients with IBD, but this may have nothing to do with their biological significance and their potential as clinical targets. Similarly, while murine models of IBD have been useful in pointing towards crucial targets they do not fully describe the situation in a patient. Often many of the observations made in mice do not translate and we have very limited information on how the disease changes over time in humans. Animal models have several limitations, including reproducibility, and may sometimes provide contrasting results according to the model. In addition, although animal models of IBD have been extensively used to investigate drugs for translational purposes, some key drugs routinely used in the clinic such as corticosteroids or 5-aminosalicylic acid are totally ineffective in animal models. In addition, several drugs that have been incredibly effective in experimental colitis have been lost in translation. These observations should serve to remind investigators that animal models are not fully able to reproduce the complex spectrum of human IBD.
A patient who develops IBD is probably born with one or more of a range of genetic susceptibilities. The resultant mutated protein may then form the basis of an immunoregulatory imbalance. At some point in the patient's life there is a priming event that results in abnormal permeability and is eventually followed by a triggering event that results in microscopic disease. As the symptoms worsen a diagnosis of IBD is made and clinical disease becomes evident. At this point therapy is attempted, in some patients there will be a response, in others no response. There is then a lifetime of remission, recurrences, different medications, hospitalisations, operations, increased risk of cancer and so on. At each of these stages, the characteristics of the underlying inflammation are likely to be changing as the disease progresses. For example, the mucosal levels of IFN-γ, IL-12p40 and IL-12Rβ2 chain mRNA vary between early and late CD. IFN-γ is significantly higher in early stage disease compared with late stage disease. Equally, both IL-12p40 and IL-12Rβ2 levels are significantly higher in early stage CD. This has been clearly shown in paediatric IBD but data on adults are urgently needed, because knowing what could be the right cytokine to be targeted in the right disease stage could be the key for clinical success.
The huge potential for variation in inflammatory response from patient to patient and within a single patient over time suggests the need for a personal and integrated approach depending on the status of each patient. It is possible that the future of a personalised approach to IBD therapy would include computing gene and protein function. As this future is still far off, what is the best approach to treating patients at the current time to improve outcomes? It is also important to consider the fact that more than one therapeutic option will probably be necessary during the course of a patient's disease/lifetime, particularly as a host of cells and molecules are involved in IBD. Currently, such options are used in succession as a step-up approach rather than in combination. To date there has been limited investigation of a combination approach but a recent study looked at the effect of combining infliximab and azathioprine in comparison with either drug as monotherapy. The results of the Study of Biologic and Immunomodulator Naive patients in Crohn's disease (SONIC) indicated that patients with moderate to severe CD were more likely to achieve corticosteroid-free remission if they were treated with a combination of infliximab plus azathioprine rather than infliximab or azathioprine monotherapies. Consistent with this result, the SUCCESS trial in patients with UC also demonstrated that two drugs in combination, infliximab plus azathioprine, is better than infliximab or azathioprine alone, suggesting that inflammation can be more efficiently suppressed by simultaneously tackling more than one pathway.
Pending the development of new compounds, the current treatment strategies need to be optimised, as suggested by the results of the SONIC and SUCCESS trials. In particular, new outcome measures and endpoints need to be developed so that effective treatments can be delivered appropriately in order to alter the biological processes underlying IBD and not just control the symptoms. Even with the development of biological therapies for IBD, the long-term outlook for patients has not changed, with little evidence to suggest that current therapies alter disease progression and significantly reduce the long-term need for surgery. It is important, for example, to define what constitutes early CD so that early intervention can be attempted to prevent the progression from inflammatory to structuring/penetrating disease. Similarly, the recent development of an IBD disability index will give researchers a more structured way of evaluating the long-term effects of both IBD and treatment on patient functional status. In terms of disease progression, a scoring system to measure structural damage is also being developed so that disease progression can be plotted over time and monitored rather than just captured at one specific time point.
Overall, much progress has been made in understanding the pathogenesis of IBD, and many potentially useful treatments are under development, but few are already available. What is required now is a more targeted, patient-based approach that makes use of genetic information and biomarkers both to direct the development of and deliver tailor-made therapy.
Time will tell us if the above directions of investigation will be successful for IBD patients.
Speculations for the Future
To conclude the description of the current and potential therapies for IBD it is sufficient to say that although there are many avenues to explore, as yet no single 'magic bullet' has been discovered. Many paths have been followed only to lead to dead ends. What is particularly perplexing is that while basic science is important, it did not play a large role in the development of the anti-TNF agents, the most potent IBD treatments developed so far. Many ideas born at the bench do not translate to the bedside. This issue is most likely to stem from the complexity of the pathogenesis and progression of IBD, processes that have not been fully characterised. In addition, while most of the drugs are investigated for luminal disease, there is also an enormous need for further investigation of approaches to treat complications of CD such as fibrotic disease and fistulas.
During the course of IBD many molecules are upregulated or downregulated in patients with IBD, but this may have nothing to do with their biological significance and their potential as clinical targets. Similarly, while murine models of IBD have been useful in pointing towards crucial targets they do not fully describe the situation in a patient. Often many of the observations made in mice do not translate and we have very limited information on how the disease changes over time in humans. Animal models have several limitations, including reproducibility, and may sometimes provide contrasting results according to the model. In addition, although animal models of IBD have been extensively used to investigate drugs for translational purposes, some key drugs routinely used in the clinic such as corticosteroids or 5-aminosalicylic acid are totally ineffective in animal models. In addition, several drugs that have been incredibly effective in experimental colitis have been lost in translation. These observations should serve to remind investigators that animal models are not fully able to reproduce the complex spectrum of human IBD.
A patient who develops IBD is probably born with one or more of a range of genetic susceptibilities. The resultant mutated protein may then form the basis of an immunoregulatory imbalance. At some point in the patient's life there is a priming event that results in abnormal permeability and is eventually followed by a triggering event that results in microscopic disease. As the symptoms worsen a diagnosis of IBD is made and clinical disease becomes evident. At this point therapy is attempted, in some patients there will be a response, in others no response. There is then a lifetime of remission, recurrences, different medications, hospitalisations, operations, increased risk of cancer and so on. At each of these stages, the characteristics of the underlying inflammation are likely to be changing as the disease progresses. For example, the mucosal levels of IFN-γ, IL-12p40 and IL-12Rβ2 chain mRNA vary between early and late CD. IFN-γ is significantly higher in early stage disease compared with late stage disease. Equally, both IL-12p40 and IL-12Rβ2 levels are significantly higher in early stage CD. This has been clearly shown in paediatric IBD but data on adults are urgently needed, because knowing what could be the right cytokine to be targeted in the right disease stage could be the key for clinical success.
The huge potential for variation in inflammatory response from patient to patient and within a single patient over time suggests the need for a personal and integrated approach depending on the status of each patient. It is possible that the future of a personalised approach to IBD therapy would include computing gene and protein function. As this future is still far off, what is the best approach to treating patients at the current time to improve outcomes? It is also important to consider the fact that more than one therapeutic option will probably be necessary during the course of a patient's disease/lifetime, particularly as a host of cells and molecules are involved in IBD. Currently, such options are used in succession as a step-up approach rather than in combination. To date there has been limited investigation of a combination approach but a recent study looked at the effect of combining infliximab and azathioprine in comparison with either drug as monotherapy. The results of the Study of Biologic and Immunomodulator Naive patients in Crohn's disease (SONIC) indicated that patients with moderate to severe CD were more likely to achieve corticosteroid-free remission if they were treated with a combination of infliximab plus azathioprine rather than infliximab or azathioprine monotherapies. Consistent with this result, the SUCCESS trial in patients with UC also demonstrated that two drugs in combination, infliximab plus azathioprine, is better than infliximab or azathioprine alone, suggesting that inflammation can be more efficiently suppressed by simultaneously tackling more than one pathway.
Pending the development of new compounds, the current treatment strategies need to be optimised, as suggested by the results of the SONIC and SUCCESS trials. In particular, new outcome measures and endpoints need to be developed so that effective treatments can be delivered appropriately in order to alter the biological processes underlying IBD and not just control the symptoms. Even with the development of biological therapies for IBD, the long-term outlook for patients has not changed, with little evidence to suggest that current therapies alter disease progression and significantly reduce the long-term need for surgery. It is important, for example, to define what constitutes early CD so that early intervention can be attempted to prevent the progression from inflammatory to structuring/penetrating disease. Similarly, the recent development of an IBD disability index will give researchers a more structured way of evaluating the long-term effects of both IBD and treatment on patient functional status. In terms of disease progression, a scoring system to measure structural damage is also being developed so that disease progression can be plotted over time and monitored rather than just captured at one specific time point.
Overall, much progress has been made in understanding the pathogenesis of IBD, and many potentially useful treatments are under development, but few are already available. What is required now is a more targeted, patient-based approach that makes use of genetic information and biomarkers both to direct the development of and deliver tailor-made therapy.
Time will tell us if the above directions of investigation will be successful for IBD patients.
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