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Do biologicals really prevent complications in pediatric Crohns disease?
Current Medicine Research and Practice 7 (2017) 211–212
Contents lists available at ScienceDirect
Current Medicine Research and Practice journal homepage: www.elsevier.com/locate/cmrp
Journal Scan
Do biologicals really prevent complications in pediatric Crohns disease? Aniruddh Setya Department of Pediatric Gastroenterology, Sir Ganga Ram Hospital, New Delhi, India
1. Article information Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study Kugathasan, Subra et al. The Lancet, 2017; 389 (10080): 1710–1718. 2. Background Inflammatory Bowel disease (IBD) is a perplexing disease characterized by chronic mucosal inflammation. It results from a complex interplay of various factors including genetic and environmental, and adaptive immunity of the host. Crohn’s disease (CD) and Ulcerative colitis (UC) are the two broad phenotypes of IBD. Crohn Disease (Regional Enteritis, Regional Ileitis, Granulomatous Colitis) is characterized by its ability to involve any part of the gastrointestinal tract in a discontinuous fashion. The inflammatory process tends to be eccentric and segmental, often with skip areas (normal regions of bowel between inflamed areas). Although inflammation in ulcerative colitis is limited to the mucosa (except in toxic megacolon), GI involvement in Crohn disease is often transmura .1 Crohn disease tends to have a bimodal age distribution, with the first peak beginning in the teenage years, However, both Crohn disease (CD) and ulcerative colitis (UC) have been reported as early as infancy. A study from Ontario, Canada reported that the incidence of IBD increased from 21.3 per 100,000 population in 1999 to 26.2 per 100,000 in 2008, with the most rapid increase in incidence in children under 10 years of age.2 Data from India is limited. The first case series on CD was published from Southern India in 2005, detailing 10 children (5–15 years) with Crohn’s disease. Initial studies suggested a lower rate of IBD in nonCaucasian populations, but these results may reflect underrepresentation of non-Caucasians in the regions of study. 3. Introduction The classic triad of pediatric CD; abdominal pain, chronic diarrhea and weight loss is seen in only one-fourth of the cases;
E-mail address: [email protected] (A. Setya). http://dx.doi.org/10.1016/j.cmrp.2017.09.007 2352-0817/
25% of the children may present with only nonspecific symptoms – vague abdominal discomfort, lethargy and anorexia.3 Perianal lesions in the form of skin tags, sentinel piles and fistulae are more common in CD. Crohn disease can be characterized as inflammatory, stricture forming, or penetrating. Stricturing and penetrating complications account for substantial morbidity and health-care costs in pediatric and adult onset Crohn's disease. Natural history of Crohns disease have shown complicated disease ranging from 48 to 52% five years after diagnosis. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. Factors associated with complicated disease behavior include age at diagnosis, ileal disease location, serological responses to various microbial antigens and possibly cumulative genetic risk. 4. Methods This is a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor a (TNFa) therapy exposure within 90 days of diagnosis on complication risk. 5. Results They enrolled 1813 patients but those who did not have gut inflammation on endoscopy served as controls and those with diagnoses other than Crohns were excluded as were those who experienced complications either at or within 90 days of diagnosis. Thus, 913 patients were analysed, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51–82) and specificity of 63% (55–71), with a negative predictive value of 95% (94–97). Patients who received early anti-TNFa therapy were less likely to have penetrating complications (hazard ratio [HR] 030, 95% CI 010–089; p = 0 0296) but not stricture forming complication (113, 051–251; 076) than were those who did not receive early anti-TNFa therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications.
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A. Setya / Current Medicine Research and Practice 7 (2017) 211–212
Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 170, 95% CI 112–257; p = 0 0120). When this gene signature was included, the model's specificity improved to 71%. 6. Interpretation The findings support the usefulness of risk stratification of pediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFa therapy (defined as complication free initiation of therapy within 90 days of diagnosis and successful completion of both induction doses i.e. three doses of infliximab and two doses of adalimumab and at least one maintenance dose) 7. Commentary Patients with crohns disease typically show inflammatory disease behavior at diagnosis with some patients’ disease then progressing to Stricturing or internal penetrating complications. Despite increased use of anti-TNFa therapy over the past decade, a population level decline in rates of obstructive complications and surgeries is not recorded. Therefore, models to predict which patients with Crohns disease are at the highest risk of complications and estimated of benefit of early anti-TNFa therapy are urgently needed. This study derived and validated a risk
stratification model based on clinical and serological factors defined at diagnosis and this model had a high negative predictive value. They showed that early anti-TNFa therapy was associated with reduced rates of internal penetrating but not stricturing complications. The positive predictive value of this model was improved with the addition of novel ileal gene signatures which although merits further exploration, these results advance our understanding of the pathogenesis of disease complications and inform more of personalized approaches for children newly diagnosed with crohns disease. Conflicts of interest The author has nothing to disclose. References [1]. Andrew Grossman B, Robert N. In: Kliegman Robert M, ed. et al. Baldassano18261831 Nelson’s Textbook of Pediatrics. 20th ed. Philadelphia, PA: Elsevier/ Saunders; 2016. [2]. Benchimol EI, Manuel DG, Guttmann A, et al. Changing age demographics of inflammatory bowel disease in Ontario, Canada: a population-based cohort study of epidemiology trends. Inflamm Bowel Dis. 2014;20:1761. [3]. Kapoor A, Bhatia V, Sibal A. Pediatric inflammatory bowel disease. Indian Pediatr. 2016;53:993–1002.
Contents lists available at ScienceDirect
Current Medicine Research and Practice journal homepage: www.elsevier.com/locate/cmrp
Journal Scan
Do biologicals really prevent complications in pediatric Crohns disease? Aniruddh Setya Department of Pediatric Gastroenterology, Sir Ganga Ram Hospital, New Delhi, India
1. Article information Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study Kugathasan, Subra et al. The Lancet, 2017; 389 (10080): 1710–1718. 2. Background Inflammatory Bowel disease (IBD) is a perplexing disease characterized by chronic mucosal inflammation. It results from a complex interplay of various factors including genetic and environmental, and adaptive immunity of the host. Crohn’s disease (CD) and Ulcerative colitis (UC) are the two broad phenotypes of IBD. Crohn Disease (Regional Enteritis, Regional Ileitis, Granulomatous Colitis) is characterized by its ability to involve any part of the gastrointestinal tract in a discontinuous fashion. The inflammatory process tends to be eccentric and segmental, often with skip areas (normal regions of bowel between inflamed areas). Although inflammation in ulcerative colitis is limited to the mucosa (except in toxic megacolon), GI involvement in Crohn disease is often transmura .1 Crohn disease tends to have a bimodal age distribution, with the first peak beginning in the teenage years, However, both Crohn disease (CD) and ulcerative colitis (UC) have been reported as early as infancy. A study from Ontario, Canada reported that the incidence of IBD increased from 21.3 per 100,000 population in 1999 to 26.2 per 100,000 in 2008, with the most rapid increase in incidence in children under 10 years of age.2 Data from India is limited. The first case series on CD was published from Southern India in 2005, detailing 10 children (5–15 years) with Crohn’s disease. Initial studies suggested a lower rate of IBD in nonCaucasian populations, but these results may reflect underrepresentation of non-Caucasians in the regions of study. 3. Introduction The classic triad of pediatric CD; abdominal pain, chronic diarrhea and weight loss is seen in only one-fourth of the cases;
E-mail address: [email protected] (A. Setya). http://dx.doi.org/10.1016/j.cmrp.2017.09.007 2352-0817/
25% of the children may present with only nonspecific symptoms – vague abdominal discomfort, lethargy and anorexia.3 Perianal lesions in the form of skin tags, sentinel piles and fistulae are more common in CD. Crohn disease can be characterized as inflammatory, stricture forming, or penetrating. Stricturing and penetrating complications account for substantial morbidity and health-care costs in pediatric and adult onset Crohn's disease. Natural history of Crohns disease have shown complicated disease ranging from 48 to 52% five years after diagnosis. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. Factors associated with complicated disease behavior include age at diagnosis, ileal disease location, serological responses to various microbial antigens and possibly cumulative genetic risk. 4. Methods This is a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor a (TNFa) therapy exposure within 90 days of diagnosis on complication risk. 5. Results They enrolled 1813 patients but those who did not have gut inflammation on endoscopy served as controls and those with diagnoses other than Crohns were excluded as were those who experienced complications either at or within 90 days of diagnosis. Thus, 913 patients were analysed, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51–82) and specificity of 63% (55–71), with a negative predictive value of 95% (94–97). Patients who received early anti-TNFa therapy were less likely to have penetrating complications (hazard ratio [HR] 030, 95% CI 010–089; p = 0 0296) but not stricture forming complication (113, 051–251; 076) than were those who did not receive early anti-TNFa therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications.
212
A. Setya / Current Medicine Research and Practice 7 (2017) 211–212
Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 170, 95% CI 112–257; p = 0 0120). When this gene signature was included, the model's specificity improved to 71%. 6. Interpretation The findings support the usefulness of risk stratification of pediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFa therapy (defined as complication free initiation of therapy within 90 days of diagnosis and successful completion of both induction doses i.e. three doses of infliximab and two doses of adalimumab and at least one maintenance dose) 7. Commentary Patients with crohns disease typically show inflammatory disease behavior at diagnosis with some patients’ disease then progressing to Stricturing or internal penetrating complications. Despite increased use of anti-TNFa therapy over the past decade, a population level decline in rates of obstructive complications and surgeries is not recorded. Therefore, models to predict which patients with Crohns disease are at the highest risk of complications and estimated of benefit of early anti-TNFa therapy are urgently needed. This study derived and validated a risk
stratification model based on clinical and serological factors defined at diagnosis and this model had a high negative predictive value. They showed that early anti-TNFa therapy was associated with reduced rates of internal penetrating but not stricturing complications. The positive predictive value of this model was improved with the addition of novel ileal gene signatures which although merits further exploration, these results advance our understanding of the pathogenesis of disease complications and inform more of personalized approaches for children newly diagnosed with crohns disease. Conflicts of interest The author has nothing to disclose. References [1]. Andrew Grossman B, Robert N. In: Kliegman Robert M, ed. et al. Baldassano18261831 Nelson’s Textbook of Pediatrics. 20th ed. Philadelphia, PA: Elsevier/ Saunders; 2016. [2]. Benchimol EI, Manuel DG, Guttmann A, et al. Changing age demographics of inflammatory bowel disease in Ontario, Canada: a population-based cohort study of epidemiology trends. Inflamm Bowel Dis. 2014;20:1761. [3]. Kapoor A, Bhatia V, Sibal A. Pediatric inflammatory bowel disease. Indian Pediatr. 2016;53:993–1002.