What does “treat to target” mean to the clinician in 2016?

Richard N. Fedorak, MD

Volume 2 | Issue 1

Runs 2:21

The inability of symptomatic treatment strategies to alter the natural history of inflammatory bowel diseases (IBD) and the advent of biologic therapies with healing capabilities have combined to shift views about appropriate therapeutic goals in IBD.(1,2) The realization that optimal use of more effective therapies could produce healing, prevent complications associated with long-term inflammation, and improve patient outcomes led to considerable debate about these treatment goals and the most appropriate ways to measure their achievement.

The “treat-to-target” concept is based on identification and specific definition of appropriate treatment targets, using available evidence. In some conditions, such as hypertension or diabetes, it is relatively simple to identify treatment targets, even though the threshold values of these targets evolve with accumulating evidence.(2) Defining treatment targets in IBD is more complex, and several targets, with varying levels of evidence supporting them, have been proposed. Potential targets include one or more of mucosal healing, normalization of biomarkers, improvement in imaging targets, adequate drug levels, and histologic improvement.

Supporting the treat-to-target approach are the results of the Randomised Evaluation of an Algorithm for Crohn’s Treatment (REACT), an open-label cluster randomized controlled trial, which evaluated early combined biologic therapy via a clinical pathway in comparison with conventional symptom-driven therapy.(3) The study included 21 practices assigned to early combined biologic and 18 assigned to conventional therapy. Although 12-month clinical symptom response rates were similar for both strategies, the 24-month composite rate of major adverse outcomes, defined as surgery, hospitalization, or serious disease-related complications, was significantly lower (P=.0003) with early combined biologic therapy via a clinical pathway. As symptoms are neither sensitive nor specific for inflammation, the REACT results may be explained by improved control of inflammation in the early combined biologic practices, leading to decreased major adverse outcomes.

The Lémann Index, which quantifies bowel damage related to Crohn’s disease (CD) and assesses progression of damage over time, may allow evaluation of the impact of therapy in patients with CD.(4) Validation requires confirmation in long-term controlled trials, but recent reports suggest that bowel damage may be reversible by treatment with tumour necrosis factor-α inhibitor therapies, especially if biologic therapy is initiated within 2 years after diagnosis.(5) Challenges in using this index in clinical practice include discrepancies produced by the inclusion of reversible parameters in calculating the index, the lack of clear cut-offs to discriminate bowel damage and clinically meaningful changes over time, and the complexity of calculating the index, as it combines disease history, endoscopy, imaging, and clinical evaluation. These factors make the Lémann Index difficult to use in clinical practice, especially for untrained physicians. Nevertheless, the Lémann Index has the potential to be a powerful tool to measure the impact of therapy on long-term disease progression in CD, although additional data and possible refinement of the index are required.

A clinical consensus defining appropriate treatment targets is thus necessary to generate a treat-to-target strategy and an algorithm to guide clinical practice.(2) The first steps towards this objective were taken by the development of evidence- and consensus-based recommendations by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program, initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD).(1) STRIDE examined potential targets and the evidence supporting them and developed consensus recommendations for treatment targets for ulcerative colitis (UC) and CD. The STRIDE program determined that:

The target for UC was clinical and patient-reported remission, defined as resolution of rectal bleeding and diarrhea or altered bowel habit, plus endoscopic remission, defined as a Mayo endoscopic subscore of 0 or 1.

The target for CD was also clinical and patient-reported remission, defined as resolution of abdominal pain and diarrhea or altered bowel habit, plus endoscopic remission, defined as resolution of ulceration at ileocolonoscopy or resolution of inflammation on cross-sectional imaging, in patients who could not be assessed adequately by ileocolonoscopy.

Once a patient’s risk level has been assessed and appropriate treatment implemented, frequent evaluation of progress towards achievement of the therapeutic target is indicated, with alteration of therapy as necessary to achieve the target.(2) In addition to clinical monitoring and endoscopy, measurement of biomarkers and therapeutic drug monitoring may be useful in this context.

References

Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110:1324–38.
Bossuyt P, Vermeire S. Treat to target in inflammatory bowel disease. Curr Treat Options Gastro. 2016;14:61–72.
Fiorino G, Bonifacio C, Peyrin-Biroulet L, et al. Preventing collateral damage in Crohn’s disease: the Lemann Index. J Crohns Colitis. 2016;10(4):495–500.
Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet. 2015;386:1825–34.
Ma C, Beilman CL, Huang VW, et al. Anti-TNF therapy within 2 Years of Crohn’s disease diagnosis improves patient outcomes: a retrospective cohort study. Inflamm Bowel Dis. 2016;22(4):870–9.

Special Edition IBD Dialogue 2016 Volume 02: Treat to Target in IBD is made possible by an unrestricted educational grant from…