What is the Optimal Therapy for Crohn's Disease: Step-up or Top-down?

Ming Valerie Lin; Wojciech Blonski; Gary R Lichtenstein


Expert Rev Gastroenterol Hepatol. 2010;4(2):167-180. 

In This Article

Whom & When to Treat?

If the effectiveness of a top-down approach is established, the real challenge lies in the development of an improved classification system that would allow for the identification of particular subgroups with differing disease phenotypes and different prognoses in order to maximize the treatment benefit–risk profile. There are no simple answers. It is likely that only certain subgroups of patients with CD would benefit from early aggressive therapy. In a recent population-based study from Norway, the cumulative relapse rate during the first 10 years was 90%.[138] However, the cumulative probability of surgery was 37.9% and a large proportion of patients (44%) were in clinical remission during the last 5 years of follow-up,[138] indicating that the indiscriminate use of infliximab as a first-line therapy would represent an overtreatment in the majority of CD patients.

In patients of 40 years of age, the presence of perianal disease at diagnosis and an initial requirement for corticosteroids were identified as factors predictive of a subsequent 5-year disabling course of CD.[8] Such criteria may be considered in future clinical trials that evaluate therapeutics and have the potential to alter the natural course of CD. Despite promising results suggesting that serologic and pharmacogenetic markers, such as ASCA and NOD2 variants, which may aid in the determination of the clinical course and severity of CD, they are not yet recommended for use in clinical practice to predict the course of disease.[139] A second retrospective cohort study of 83 patients who underwent surgery within the first 3 years of CD diagnosis, found, by univariate analysis, that oral corticosteroid use within the first 6 months of diagnosis was associated with almost fourfold increased risk of surgery (unadjusted OR: 3.79; 95% CI: 1.90–7.55),[140] along with smoking, nausea and vomiting, abdominal pain and isolated ileal involvement.[140] However, multivariate regression analysis determined that only smoking was associated with increased risk of early surgery (OR: 3.42; 95% CI: 1.54–6.35).[140]

In addition to the identified clinical factors associated with a disabling course, one could argue that top-down therapy should be considered in patients with a large burden of disease (extensive small bowel disease, small bowel and colon disease, additional rectal involvement), foregut CD and patients with multiple previous surgeries or large resections who cannot be adequately maintained with the traditional postoperative therapies. Certain genetic and serologic profiles may also be included in the consideration for a more aggressive therapy.[202]

There is a growing body of evidence to suggest the effectiveness of the top-down therapy (Figure 1); however, our ability to risk stratify patients remains rudimentary. There is an urgent need to improve our ability to assess prognosis at the time of diagnosis, to personalize treatment and target the patients who are at greatest risk for complicated disease with earlier, more potent anti-inflammatory therapy before the standard step-up approach is altered.


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