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

Top-Down Treatment: Limitations

To date, several factors limit the use of biologicals as primary therapy for IBD patients. Since approximately 50% of all IBD patients never require corticosteroids, first-line treatment with biologicals in this group exposes patients to toxicity or immunogenicity without the benefit of a potentially changed natural course in the long run. Although safety data from large postmarketing trials are encouraging,[48**] opportunistic infections such as tuberculosis, histoplasmosis and Pneumocystis carinii were found to be associated with the use of infliximab.[49,50] Another worrysome potential side effect has been reported recently: eight young IBD patients treated with infliximab developed a hepatosplenic T-cell lymphoma. This exceedingly rare and aggressive tumour is associated with immunomodulatory and biologic therapy. Six out of eight patients died.[51*] In view of the fact that all these patients were on concomitant immunosuppressive therapy, the exclusive role of infliximab could not be established. The incidence of neoplasia in Crohn's disease patients using infliximab, however, was not increased in a large case control study, as compared with infliximab-nave Crohn's disease patients.[52] Recently, new data on the side effects of azathioprine have been published. A metaanalysis[53] showed a significant increase in risk for lymphoma in IBD patients treated with azathioprine or 6-mercaptopurine [odds ratio (OR) 3.3, 95% confidence interval (CI) 1.2-9.1] and for serious infections (OR 2, 95% CI 1.3-3.1). From these data it is clear that the potential benefits of these drugs should be carefully balanced against long-term risks.

Thus, the challenge is to identify patients who will develop a complicated course of disease and have a high response to specific compounds such as infliximab and azathioprine. Some disease-specific and biological factors predicting relapses in Crohn's disease have been identified,[54,55,56*] but putting together a custom-made medication regimen for an individual in clinical practice is not within our grasp. The course of disease is probably even more unpredictable in newly diagnosed IBD patients. In ulcerative colitis, endoscopic, mucosal parameters and laboratory markers like C-reactive protein, erythrocyte sedimendation rate, and faecal calprotectin may be predictive of relapse,[57] but up to now none seems to be superior to current diagnostic tools. A complicating factor is the fact that IBD is not one disease but a whole syndrome comprising many different genotypes and phenotypes ranging from a limited inflammation of the ileocoecal border to an extensive colonic involvement or perianal fistula formation in Crohn's disease, and from a mild proctitis to extensive and severe pancolitis in ulcerative colitis. Stratification into subgroups using phenotypic, serological or genotypic parameters may enable researchers to create more homogeneous populations but cannot yet be expected to guide the clinician in therapeutic decision making in individual patients.

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