Biological Therapies in Inflammatory Bowel Disease: Top-down or Bottom-up?

Bas Oldenburg; Daan Hommes

Disclosures

Curr Opin Gastroenterol. 2007;23(4):395-399. 

In This Article

Rationale of the Top-Down Approach

The failure of a significant number of IBD patients to respond to traditional therapy may justify a 'top-down' approach. A subgroup of patients can potentially benefit from early administration of immunosuppressives and anti-TNF drugs. The challenge is to identify patients who will develop therapy refractory or complicated disease at a later time point and in whom anti-TNF compounds or azathioprine, 6-mercaptopurine or methotrexate given in an early phase may change the natural course.

An early introduction of disease-modifying drugs has been found to be beneficial in patients with recently diagnosed RA, a disease with several features similar to Crohn's disease, some related to the side effects of drugs but others related to the similarities in probable pathogenic mechanisms and treatment. RA, like IBD, has an uncertain aetiology that is probably due to a combination of genetic and environmental factors and is associated with chronic inflammation in the absence of any clearly recognizable pathogen. Already in 1997, intensive combination therapy consisting of sulfasalazine, methotrexate and high-dose prednisolone was found to suppress joint damage progression and offer additional disease control over and above that of sulfasalazine alone in early RA, persisting for up to a year after corticosteroids were stopped.[39] Subsequently, studies were published in which patients with 'early RA' were treated with anti-TNF compounds with or without methotrexate. Patients receiving this top-down therapy were found to have a more rapid rate of improvement in disease activity and less progression of joint damage compared with patients treated with methotrexate alone.[40,41,42,43] Most interestingly, the early introduction of anti-TNF therapy may result in a modulation of the natural course of RA.[41]

These results in RA patients have received considerable attention from IBD specialists and prompted comparable studies in Crohn's disease patients. Small retrospective studies in children with Crohn's disease indicate better efficacy if aggressive treatment is initiated early in the course of the disease. Azathioprine as well as infliximab appeared to be associated with a prolonged maintenance of remission.[44,45] A controlled trial evaluating addition of 6-mercaptopurine to a regimen of corticosteroids in children with newly diagnosed moderate to severe Crohn's disease confirmed these results, with significant longer maintenance of remission and a clear corticosteroid-sparing effect in the 6-mercaptopurine arm.[46]

Recently, the preliminary data from a comparison of top-down versus step-up therapy were presented.[47] Early use of combined immunosuppression was compared with a conventional step-up approach in 129 Crohn's disease patients with a CDAI of at least 200. Patients had to be steroid nave and had not been exposed previously to infliximab or antimetabolites. The top-down arm of treatment consisted of azathioprine and three infusions of infliximab, followed by retreatment with infliximab and, if necessary, corticosteroids. The step-up algorithm included induction of remission with corticosteroids, followed by repeat courses of steroids and azathioprine in the case of new exacerbations, and eventually infliximab if these therapeutic interventions failed. Endpoints were clinical remission at 6 and 12 months following randomization. The top-down approach was found to lead to a more rapid remission and higher remission rates than standard therapy. At 6 and 12 months significantly more patients in the top-down arm were in corticosteroid-free remission compared with patients receiving standard therapy (60 versus 36% and 61.5 versus 42%). Beyond this timepoint, however, a difference could no longer be detected. This appeared to be due to a combination of decreasing remission rates in the top-down group and a gradual increasing remission rate in the conventional study arm. One may assume that the latter was secondary to the frequent use of immunomodulators in patients receiving conventional therapy at the end of the trial. Mucosal healing was found in 73% of patients assigned to top-down treatment versus 30% in the conventional group at 24 months, confirming the relative inability of corticosteroids to heal intestinal ulcers. If mucosal healing predicts a true change of natural history, this finding is of major importance. From this landmark study, however, it cannot be deduced whether it was infliximab, azathioprine or the combination of both drugs that was responsible for these differences. Results from the current SONIC study, in which the treatment of infliximab with and without azathioprine is being compared, should provide answers to this question.

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