FIRST INTERNATIONAL JANSSEN IMMUNOLOGY SYMPOSIUM Panama, September 2012
How can deep remission in inflammatory bowel disease be achieved? Dr. Miguel Sans
How can deep remission in inflammatory bowel disease be achieved? Dr. Miguel Sans Barcelona, Spain.
What is deep remission? It is the clinical, endoscopic, and laboratory parameters of remission maintained over time. Have the objectives in inflammatory bowel disease (IBD) changed? At present, the objectives not only include the improvement of symptoms and clinical remission but also the normalization of laboratory parameters and endoscopy results. Even though there might be a clinical remission, it is well known that, with each disease outbreak, bowel lesions progress causing a reversible damage, which, together with the disease evolution, 2
leads to stenosis, fistulas and the need of surgery. For this reason, we should be more proactive and act as soon as possible while there is no irreversible damage in order to stop disease progression and prevent complications. Which are the consequences of failing to reach deep remission? Several studies have proven that in patients with Crohnâ€™s disease (CD), in clinical remission treated with infliximab, the risk of relapses is higher when PCR is not normalized. Similarly, in those patients with CD under stable remission, who
discontinue azathioprine or infliximab, the risk of relapses increases when there is anemia or endoscopic activity. Thus, treatment should not be discontinued if the patient presents some of these factors, despite being asymptomatic. In addition, the presence of a single ulcerative lesion in the endoscopy or the persistence of mucosal lesions increases the risk of surgery in the following years, both in CD and ulcerative colitis (UC). Is mucosal healing possible? The question is: are there any available therapies that can heal mucosal lesions? Studies assessing corticoids in CD show that they are really effective in obtaining clinical remission. However, studies with endoscopic follow-up in CD demonstrate that more than 70% of patients with a good clinical response still present mucosal lesions. In addition, be it either due to the lack of response or dependence, more than half of
patients do not receive corticoids at a year after treatment initiation. Azathioprine, as maintenance therapy, after induction combined with corticoids, is more effective than the placebo in reducing the long-term risk of relapses in CD. Additionally, it has a good rate of intestinal mucosal healing. Infliximab is effective both in improving symptoms and in mucosal healing, when the three induction doses are indicated and continued in maintenance therapy in CD. Infliximab effectiveness in complete mucosal healing is higher (71%) when infliximab is indicated from the beginning of treatment (top down) instead of adding it to corticoids and azathioprine in later stages (step up). Serum infliximab levels before the following dose may predict the probability of mucosal healing, since almost 90% of patients who achieved the following dose with detectable levels of inflixi-
mab present an improvement > 75% of endoscopic lesions, compared to 33% of patients with nondetectable levels of infliximab. These benefits in mucosal healing with infliximab are also present in patients with UC, and may be observed with other biologics such as adalimumab, golimumab, and vedolizumab. Now then, could the drugs combination be a better strategy in order to achieve deep remission? Studies SONIC1 and SUCCES2 prove this: The SONIC study compared the effectiveness of azathioprine vs. infliximab vs. the combination of both in patients with CD, and showed that patients receiving the combined treatment had a significantly higher clinical remission rate and a higher mucosal healing rate, significantly higher than azathioprine alone, at 26week follow-up (see Graphic 1). Similar results were found in the SUCCES study, which compared
Mucosal healing at week 26 - SONIC Study
Infliximab + azathioprine
N. Engl J Med 2010;362:1383-95.
azathioprine, infliximab or the combination of both in patients with UC, where it was also shown that the most effective strategy for mucosal healing was the combined therapy. If achieved, which benefits can be obtained by mucosal healing? In addition to the benefit in the patientâ€™s clinical evolution, mucosal healing in IBD may generate a significant reduction in cost in terms of public health services. In a study of costs incurred by CD3, it was observed that drugs produce 10% while hospitalization and surgeries produce 80% of the costs of this disease. In the ACCENT I study, the treatment scheduled with infliximab significantly reduces hospitalization and surgery rates, compared to the episodic treatment with infliximab4. This benefit is related to the mucosal healing capacity of inflixi-
mab: patients with mucosal healing at weeks 10 and/or 54 had a lower risk of hospitalization and did not requires surgery during follow-up. The study ACCENT II showed that patients treated with infliximab at scheduled doses (induction) followed by a maintenance therapy had a smaller rate of hospitalization than those receiving placebo and maintenance with infliximab (see Graphic 2). Similarly, those patients treated with infliximab based on the habitual schedule were subject to less surgical procedures than those treated with placebo5. In patients with UC, ACT studies revealed that treatment with infliximab significantly reduces hospitalization rates when compared to placebo. The reduction of the risk of hospitalization in CD was also observed in studies with adalimumab.
Scheduled Infliximab reduces the proportion of patients hospitalised Estudio SONIC p<0.05
% of pacients hospitalized
Placebo maintenance (n=143)
5 mg/kg infliximab maintenance (n=139)
All randomized patients
Placebo maintenance (n=99)
5 mg/kg infliximab maintenance (n=96)
Week 14 responders
Conclusions • There is much evidence suggesting that patients with UC or CD that maintain deep remission (clinical + laboratory + endoscopic) have a better clinical evolution. • … but yet, there are no intervention studies (to achieve deep remission) + long-term prospective follow-up revealing the impact of such intervention. • Such studies should be conducted and the “treatment objective” should be changed from clinical remission to deep remission as soon as possible.
Bibliographical references 1. 2. 3. 4. 5.
N Engl J Med 2010;362:1383-95 Pannaccione R, et al. Abstract 15183 ECCO 2011 Hay JW et al. J Clin Gastroenterol 1992;14:309 Gastroenterology 2004;126:402-413 Lichtenstein GR, et al. Gastroenterology 2005;128:862-869
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The data and results presented herein were obtained from a conference on Medicine and the information summarized might be preliminary and subject to changes. This information is exclusively included for physician’s training and educational purposes only. The opinions here reflected belong to the authors and lecturers and do not comprise any suggestion or recommendation on the part of the sponsoring laboratory. Summary prepared by the Staff of Circle Press based on their attendance to the Symposium. Cover Image: Shutterstock.com
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