For ulcerative colitis (UC), the obtaining of endoscopic and histologic remission is associated with a reduced relapse rate. In Crohn’s disease (CD), obtaining endoscopic healing is also associated with a decrease in the number of future attacks and surgical interventions. In the STORI trial, two predictive parameters of the absence of relapse upon arrest of infliximab included a normal level of the C-reactive protein and a low endoscopy score. Since CD is a “transmural” disease, it will be necessary in the future to obtain regression of lesions beyond the mucosa if we want to then stop treatment and cure the patient.
Combined use of therapeutic agents possessing differing mechanisms of action could lead to overall prolonged remission, enabling gradual step-down of treatments until their arrest. In addition to anti-TNFa agents, a number of other therapeutic methods are currently being explored: cytokines, anti-cytokines, blockage or stimulation of T lymphocyte populations, anti-adhesion molecules, new immunomodulators, etc. Up until now, such strategy has rarely been used due to possible secondary effects.
The approach chosen by rheumatologists for rheumatoid polyarthritis (RP) involves treating earlier and more strongly, before irreversible damage is done to the target organ. Indeed, in the BEST study, which compared different therapeutic strategies in recent-onset RP, 120 patients were randomized into an arm which consisted of maximal treatment by infliximab and methotrexate from the outset. After a median time of 9.9 months, 67 responders interrupted infliximab, and 16 of them were able to stop methotrexate and remain in remission without treatment 3 years later. Other data showed that it was also possible to interrupt conventional non-biological treatment, without relapse, in PR patients treated early on, prior to significant radiographic lesions. This concept was applied to CD in two recent therapeutic trials, “Step-up/top-down” and SONIC, which proved the efficacy of early biological treatment of CD. It remains to be determined whether such an approach can lead to overall prolonged and persistent remission upon arrest of treatment.
Earlier treatment also implies targeting the physiopathological mechanisms that intervene early on in triggering the disease. Most currently available treatments seek to control the late phase of IBD, at which time dysregulation of adaptive immunity occurs, whereas the earliest disturbances occur within the innate immune system. One example is the decrease in synthesis of defensins during the course of CD, the endogenous production of which might be restored by administering probiotics (Escherichia coli Nissle, lactobacilli).
Finally, the most ambitious approach would be to anticipate the onset of IBDs in predisposed subjects. Markers of the disease (antibodies, fecal calprotectin, intestinal permeability) have been found in up to 30% of first-degree relatives of patients with CD. It might thus be presumed that, in these subjects, there exist early infraclinical modifications of the intestinal immune system and/or flora upon which it is possible to act prior to the onset of clinical symptoms.
COLOMBEL Jean-Frédéric, PEYRIN-BIROULET L., CORTOT A. 2010
