Personalizing Therapy for Inflammatory Bowel Diseases

Ashwin N Ananthakrishnan

Disclosures

Expert Rev Gastroenterol Hepatol. 2013;7(6):549-558. 

In This Article

Need for Personalizing Therapy: Changing Therapeutic Paradigms

The need for personalizing IBD therapy is highlighted by several recent studies suggesting the need to modify the conventional paradigms in the management of these chronic and progressive diseases. First, patients respond better when effective therapies are instituted early on in the course of disease. The landmark step-up/top-down trial randomized patients with Crohn's disease (CD) to either the traditional step-up approach with introduction of azathioprine (AZA) after failure of two courses of steroids, or to early induction doses of infliximab followed by AZA maintenance.[6] Despite similar clinical response 2 years after treatment, patients treated with infliximab early on were more likely to have absence of mucosal ulceration at year 2 despite comparable rates of AZA and infliximab use at the end of the study. Second, another landmark study, the SONIC trial, demonstrated a superior efficacy with use of combination immunosuppressive therapy with AZA and infliximab when compared with either agent alone in early CD.[7] Third, there has been recognition that resolution of clinical symptoms alone is insufficient to prevent progression of disease. Patients who are able to achieve mucosal healing have a lower likelihood of requiring surgery and a reduced incidence of colorectal neoplasia.[8–11] Indeed, such an approach may be more cost-effective than treating to clinical remission.[8] Nevertheless, the optimal definition of mucosal healing remains uncertain and whether all patients would achieve equal incremental benefit from escalating therapy to achieve complete absence of mucosal inflammation and resolution of histologic inflammation is unclear. Finally, agents acting through other inflammatory- or immune-targets are available or likely to be approved for use soon including natalizumab, vedolizumab and ustekinumab.[12] The spectrum of inflammatory mechanisms that can be targeted suggest that we may be able to use specific therapies in individuals based on their individual likelihood of response to such a mechanism of action.

Widespread adoption of this 'top-down' approach to treatment remains challenging. While antibody-based therapies are being increasingly used, the economic costs of such treatments remain substantial. Healthcare costs attributable to CD/ulcerative colitis (UC) were previously primarily driven by hospitalization and surgery; current estimates suggest a significant fraction attributable to drug costs.[5] Safety concerns remain including infections and immunosuppression-related malignancy.[13–15] Furthermore, the durability of such therapies in a lifelong illness remains limited with an estimated 10–15% loss of response annually.[16,17] Thus, the potential benefit of early treatment needs to be balanced against the ability to provide durable lifelong remission, prevent disease complications as well as therapy-related adverse effects while maintaining cost–effectiveness on a societal level (Figure 1).

Figure 1.

Personalizing therapy for inflammatory bowel diseases.

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