REVIEW URRENT C OPINION
Exclusive enteral nutrition for inducing remission in inflammatory bowel disease in paediatric patients Amit Assa a,b and Raanan Shamir a,b
Purpose of review Enteral nutrition as a treatment for inflammatory bowel diseases is an ongoing area of interest. Even in the era of biologic agents, exclusive enteral nutrition (EEN) offers a unique, drug-free measure for induction of remission in luminal Crohn’s disease. The purpose of this review is to discuss the role of EEN in the evolving therapeutic scheme for Crohn’s disease, to report on new evidence for short and long-term efficacy and highlight findings on the mechanisms of the anti-inflammatory effects of EEN in light of current understanding of disease pathogenesis. Recent findings Recent clinical studies have suggested that EEN has an established advantage over corticosteroids for inducing remission in children with luminal Crohn’s disease with comparable clinical efficacy but superior mucosal healing effect as well as better safety profile. Preoperative EEN therapy can also improve postoperative outcome of intestinal resection. Basic research has demonstrated that EEN has direct antiinflammatory properties, can correct localization of tight junction proteins, alter micro RNAs expression, and profoundly affect the intestinal microbiota. Summary EEN is an effective treatment for induction of remission in pediatric luminal Crohn’s disease and should be offered as a first-line treatment. Accumulating evidence suggest that EEN has direct anti-inflammatory properties with an effect on the intestinal microbiota. However, the relationships between these effects and the specific triggers for these changes have yet to be elucidated. Keywords children, Crohn’s disease, efficacy, mechanism
INTRODUCTION For many years, enteral feeding has been used as part of the nutritional therapy of inflammatory bowel disease. Exclusive enteral nutrition (EEN) which is defined as the provision of 100% of a person’s nutritional requirements from a liquid nutritional formula either orally or via a feeding tube for 6–8 weeks, is now an established treatment for remission induction for luminal Crohn’s disease in children. The efficacy of EEN in induction of clinical remission has been thoroughly studied in pediatric Crohn’s disease. The clinical effect of EEN have been confirmed in two meta-analyses demonstrating that EEN is as effective as corticosteroids in inducing disease remission in pediatric Crohn’s disease [1,2], with superior endoscopic response [3], irrespective of disease phenotype [4]. EEN is now recommended as the first choice of inducing remission in pediatric patients with luminal Crohn’s disease [5]. www.co-clinicalnutrition.com
As the introduction of antitumor necrosis factor alpha (TNFa) therapy for Crohn’s disease, both treatment schemes and goals have profoundly changed with more aggressive treatment being regarded as a standard of care and aiming at deep remission as a feasible therapeutic target. The purpose of this review is to evaluate the current role of EEN in the evolving therapeutic algorithm and to provide updated evidence on its mechanism of action.
a
Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center, Petach Tikva and bSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to Amit Assa, MD, MHA, Sackler Faculty of Medicine, Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children’s Medical Center, Tel Aviv University, 14 Kaplan St. Petach Tikva, 4920235, Israel. Tel: +972 3 9253672; fax: +972 3 9253104; e mail: [email protected] Curr Opin Clin Nutr Metab Care 2017, 20:384–389 DOI:10.1097/MCO.0000000000000402 Volume 20 Number 5 September 2017
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Exclusive enteral nutrition Assa and Shamir
KEY POINTS EEN is an effective strategy for induction of remission in children with luminal Crohn’s disease. EEN induces mucosal healing in a substantial higher rate than corticosteroids.
(PCDAI reduction 15 or final PCDAI 10) was achieved by 64% on PEN, 88% EEN, and 84% antiTNF (P ¼ 0.08). Fecal calprotectin of 250 mg/g or less was achieved with PEN in 14%, EEN 45%, and antiTNF 62% (P ¼ 0.001). Interestingly, the anti-TNFa group did not present with more severe disease prior to therapy initiation [9 ]. In another prospective cohort of 24 newly diagnosed children with luminal Crohn’s disease treated with either EEN (n ¼ 20) or corticosteroids (n ¼ 4), endoscopic remission (defined as simple endoscopic score for Crohn’s disease 0–2) was achieved in 46% but patients’ outcome was not stratified between the EEN and the corticosteroids-treated groups [10]. Overall, and despite lack of large prospective, randomized studies, in which those assessing the mucosal response are blinded to the treatment group, there is sufficient cumulative evidence to suggest that EEN is at least comparable to corticosteroids for inducing remission in luminal pediatric Crohn’s disease. Thus, when considering the obvious superior safety profile and the probable advantage in achieving mucosal healing it should be suggested as the first option to all children and adolescents with luminal Crohn’s disease. As for reinduction with EEN during disease relapse, there is limited evidence suggesting that EEN therapy is more effective in newly diagnosed Crohn’s disease patients compared with patients with long-standing Crohn’s disease. Lower remission rate was demonstrated after the second course of EEN (77%) when compared with the first one (92%) at 3 months with comparable relapse rates at 1 year [11]. Still, response rates following second course of EEN are fair, hence, EEN should be considered for reinduction of remission in previously treated children. &&
EEN has only a modest long-term effect on disease outcome, if at all. Based on studies in adults, preoperative treatment with EEN can improve postoperative outcomes and reduce associated complications. EEN has a direct anti-inflammatory effect and an effect on the intestinal microbiota. However, the relationships between these effects and the specific triggers for the observed changes have yet to be elucidated.
RECENT EVIDENCE OF EFFICACY The role of EEN in inducing remission was primarily studied in children with Crohn’s disease. Despite the fact that in the Cochrane meta-analysis from 2007, EEN was inferior to corticosteroids for inducing clinical remission in Crohn’s disease patients [3] the cumulative evidence suggests similar clinical efficacy of approximately 70% and higher rates of endoscopic response ranging from 50 to 80% compared with 20 to 30% in corticosteroids-treated patients [5,6]. As ‘deep remission’ (defined as the combination of clinical remission and mucosal healing) stands in the current center of interest as being the desired treatment target [5], EEN with its higher mucosal healing properties indeed immerges as a superior first-line treatment in luminal pediatric Crohn’s disease. In a prospective cohort of 54 with newly diagnosed Crohn’s disease who completed at least 6 weeks of EEN, clinical remission [pediatric Crohn’s disease activity index (PCDAI) < 10] was observed in 83%, and biochemical remission [PCDAI < 10 and C-reactive protein
Exclusive enteral nutrition for inducing remission in inflammatory bowel disease in paediatric patients Amit Assa a,b and Raanan Shamir a,b
Purpose of review Enteral nutrition as a treatment for inflammatory bowel diseases is an ongoing area of interest. Even in the era of biologic agents, exclusive enteral nutrition (EEN) offers a unique, drug-free measure for induction of remission in luminal Crohn’s disease. The purpose of this review is to discuss the role of EEN in the evolving therapeutic scheme for Crohn’s disease, to report on new evidence for short and long-term efficacy and highlight findings on the mechanisms of the anti-inflammatory effects of EEN in light of current understanding of disease pathogenesis. Recent findings Recent clinical studies have suggested that EEN has an established advantage over corticosteroids for inducing remission in children with luminal Crohn’s disease with comparable clinical efficacy but superior mucosal healing effect as well as better safety profile. Preoperative EEN therapy can also improve postoperative outcome of intestinal resection. Basic research has demonstrated that EEN has direct antiinflammatory properties, can correct localization of tight junction proteins, alter micro RNAs expression, and profoundly affect the intestinal microbiota. Summary EEN is an effective treatment for induction of remission in pediatric luminal Crohn’s disease and should be offered as a first-line treatment. Accumulating evidence suggest that EEN has direct anti-inflammatory properties with an effect on the intestinal microbiota. However, the relationships between these effects and the specific triggers for these changes have yet to be elucidated. Keywords children, Crohn’s disease, efficacy, mechanism
INTRODUCTION For many years, enteral feeding has been used as part of the nutritional therapy of inflammatory bowel disease. Exclusive enteral nutrition (EEN) which is defined as the provision of 100% of a person’s nutritional requirements from a liquid nutritional formula either orally or via a feeding tube for 6–8 weeks, is now an established treatment for remission induction for luminal Crohn’s disease in children. The efficacy of EEN in induction of clinical remission has been thoroughly studied in pediatric Crohn’s disease. The clinical effect of EEN have been confirmed in two meta-analyses demonstrating that EEN is as effective as corticosteroids in inducing disease remission in pediatric Crohn’s disease [1,2], with superior endoscopic response [3], irrespective of disease phenotype [4]. EEN is now recommended as the first choice of inducing remission in pediatric patients with luminal Crohn’s disease [5]. www.co-clinicalnutrition.com
As the introduction of antitumor necrosis factor alpha (TNFa) therapy for Crohn’s disease, both treatment schemes and goals have profoundly changed with more aggressive treatment being regarded as a standard of care and aiming at deep remission as a feasible therapeutic target. The purpose of this review is to evaluate the current role of EEN in the evolving therapeutic algorithm and to provide updated evidence on its mechanism of action.
a
Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center, Petach Tikva and bSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to Amit Assa, MD, MHA, Sackler Faculty of Medicine, Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children’s Medical Center, Tel Aviv University, 14 Kaplan St. Petach Tikva, 4920235, Israel. Tel: +972 3 9253672; fax: +972 3 9253104; e mail: [email protected] Curr Opin Clin Nutr Metab Care 2017, 20:384–389 DOI:10.1097/MCO.0000000000000402 Volume 20 Number 5 September 2017
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Exclusive enteral nutrition Assa and Shamir
KEY POINTS EEN is an effective strategy for induction of remission in children with luminal Crohn’s disease. EEN induces mucosal healing in a substantial higher rate than corticosteroids.
(PCDAI reduction 15 or final PCDAI 10) was achieved by 64% on PEN, 88% EEN, and 84% antiTNF (P ¼ 0.08). Fecal calprotectin of 250 mg/g or less was achieved with PEN in 14%, EEN 45%, and antiTNF 62% (P ¼ 0.001). Interestingly, the anti-TNFa group did not present with more severe disease prior to therapy initiation [9 ]. In another prospective cohort of 24 newly diagnosed children with luminal Crohn’s disease treated with either EEN (n ¼ 20) or corticosteroids (n ¼ 4), endoscopic remission (defined as simple endoscopic score for Crohn’s disease 0–2) was achieved in 46% but patients’ outcome was not stratified between the EEN and the corticosteroids-treated groups [10]. Overall, and despite lack of large prospective, randomized studies, in which those assessing the mucosal response are blinded to the treatment group, there is sufficient cumulative evidence to suggest that EEN is at least comparable to corticosteroids for inducing remission in luminal pediatric Crohn’s disease. Thus, when considering the obvious superior safety profile and the probable advantage in achieving mucosal healing it should be suggested as the first option to all children and adolescents with luminal Crohn’s disease. As for reinduction with EEN during disease relapse, there is limited evidence suggesting that EEN therapy is more effective in newly diagnosed Crohn’s disease patients compared with patients with long-standing Crohn’s disease. Lower remission rate was demonstrated after the second course of EEN (77%) when compared with the first one (92%) at 3 months with comparable relapse rates at 1 year [11]. Still, response rates following second course of EEN are fair, hence, EEN should be considered for reinduction of remission in previously treated children. &&
EEN has only a modest long-term effect on disease outcome, if at all. Based on studies in adults, preoperative treatment with EEN can improve postoperative outcomes and reduce associated complications. EEN has a direct anti-inflammatory effect and an effect on the intestinal microbiota. However, the relationships between these effects and the specific triggers for the observed changes have yet to be elucidated.
RECENT EVIDENCE OF EFFICACY The role of EEN in inducing remission was primarily studied in children with Crohn’s disease. Despite the fact that in the Cochrane meta-analysis from 2007, EEN was inferior to corticosteroids for inducing clinical remission in Crohn’s disease patients [3] the cumulative evidence suggests similar clinical efficacy of approximately 70% and higher rates of endoscopic response ranging from 50 to 80% compared with 20 to 30% in corticosteroids-treated patients [5,6]. As ‘deep remission’ (defined as the combination of clinical remission and mucosal healing) stands in the current center of interest as being the desired treatment target [5], EEN with its higher mucosal healing properties indeed immerges as a superior first-line treatment in luminal pediatric Crohn’s disease. In a prospective cohort of 54 with newly diagnosed Crohn’s disease who completed at least 6 weeks of EEN, clinical remission [pediatric Crohn’s disease activity index (PCDAI) < 10] was observed in 83%, and biochemical remission [PCDAI < 10 and C-reactive protein
