- Email: [email protected]
Clinical Presentation and Five-Year Therapeutic Management of Very Early-Onset Inflammatory Bowel Disease in a Large North American Cohort
Clinical Presentation and Five-Year Therapeutic Management of Very Early-Onset Inflammatory Bowel Disease in a Large North American Cohort Maria Oliva-Hemker, MD1, Susan Hutfless, PhD2, Elie S. Al Kazzi, MD, MPH2, Trudy Lerer, MS3, David Mack, MD4, Neal LeLeiko, MD, PhD5, Anne Griffiths, MD6, Jose Cabrera, MD7, Anthony Otley, MD8, James Rick, MD9, Athos Bousvaros, MD10, Joel Rosh, MD11, Andrew Grossman, MD12, Shehzad Saeed, MD13, Marsha Kay, MD14, Ryan Carvalho, MD15, David Keljo, MD, PhD16, Marian Pfefferkorn, MD17, William Faubion, Jr., MD18, Michael Kappelman, MD19, Boris Sudel, MD20, Marc E. Schaefer, MD21, James Markowitz, MD22, and Jeffrey S. Hyams, MD3 Objective To evaluate the presentation, therapeutic management, and long-term outcome of children with very early-onset (VEO) (#5 years of age) inflammatory bowel disease (IBD).
Study design Data were obtained from an inception cohort of 1928 children with IBD enrolled in a prospective observational registry at multiple centers in North America.
Results One hundred twelve children were #5 years of age with no child enrolled at <1 year of age. Of those, 42.9% had Crohn’s disease (CD), 46.4% ulcerative colitis (UC), and 10.7% had IBD-unclassified. Among the children with CD, children 1-5 years of age had more isolated colonic disease (39.6%) compared with 6- to 10-yearolds (25.3%, P = .04), and 11- to 16-year-olds (22.3%, P < .01). The change from a presenting colon-only phenotype to ileocolonic began at 6-10 years. Children 1-5 years of age with CD had milder disease activity (45.8%) at diagnosis compared with the oldest group (28%, P = .01). Five years postdiagnosis, there was no difference in disease activity among the 3 groups. However, compared with the oldest group, a greater proportion of 1- to 5-year-olds with CD were receiving corticosteroids (P < .01) and methotrexate (P < .01), and a greater proportion of 1- to 5-year-olds with UC were receiving mesalamine (P < .0001) and thiopurine immunomodulators (P < .0002). Conclusions Children with VEO-CD are more likely to have mild disease at diagnosis and present with a colonic phenotype with change to an ileocolonic phenotype noted at 6-10 years of age. Five years after diagnosis, children with VEO-CD and VEO-UC are more likely to have been administered corticosteroids and immunomodulators despite similar disease activity in all age groups. This may suggest development of a more aggressive disease phenotype over time. (J Pediatr 2015;-:---). See editorial, p
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nflammatory bowel disease (IBD) is a chronic disorder of intestinal inflammation characterized by a relapsing and remitting course. IBD encompasses the diagnoses which include Crohn’s disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U). Epidemiologic data suggest that the incidence of IBD is increasing in the pediatric population and that children are being diagnosed at a younger age than ever before.1-4 Because IBD is considered a lifelong condition, children are impacted by the burden of disease and the therapeutic interventions for much longer time periods compared with adults. PreFrom the Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Children’s Center; Johns vious studies of very early-onset (VEO)-IBD (children #5 years of age at Hopkins University, Baltimore, MD; Connecticut diagnosis) had inconsistent findings regarding severity of disease at diagChildren’s Medical Center, Hartford, CT; Children’s 3,5-8 Hospital of Eastern Ontario, Ottawa, Ontario, Canada; nosis. Recent studies reporting genetic phenotypes in VEO-IBD and Hasbro Children’s Hospital, Providence, RI; Hospital for Sick Children, Toronto, Ontario, Canada; Medical describing monogenic-associated conditions such as interleukin (IL)-10 and College of Wisconsin, Milwaukee, WI; Izaak Walton Killam Health Center, Halifax, Nova Scotia, Canada; IL-10 receptor-deficiency, suggest that a better understanding of the clinical Dayton Children’s Hospital, Dayton, OH; Children’s phenotype of these children may aid in discovery of pathogenesis and Hospital, Boston, MA; Goryeb Children’s Hospital, 9-11 Morristown, NJ; Children’s Hospital of Philadelphia, genotype-phenotype correlation. However, as most children with VEO-IBD Philadelphia, PA; Children’s Hospital Medical Center, 1
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CD IBD IBD-U IL PGA PIBDCRG UC VEO
Crohn’s disease Inflammatory bowel disease IBD-unclassified Interleukin Physician global assessment Pediatric Inflammatory Bowel Disease Collaborative Research Group Ulcerative colitis Very early-onset
Cincinnati; Cleveland Clinic, Cleveland; 15Nationwide Children’s Hospital, Columbus, OH; 16Children’s Hospital of Pittsburgh, Pittsburgh, PA; 17Riley Hospital for Children, Indianapolis, IN; 18Mayo Clinic, Rochester, MN; 19University of North Carolina, Chapel Hill, NC; 20 University of Minnesota, Minneapolis, MN; 21Penn State Hershey Children’s Hospital, Hershey, PA; and 22 Cohen Children’s Medical Center of New York, New Hyde Park, NY List of conflicts of interest is available at www.jpeds.com (Appendix). 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.04.045
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do not appear to have single gene disorders, better characterization of the clinical phenotype and clinical course of this larger group of children remains important. The primary goal of our study was to compare the clinical presentation, therapeutic management, and longer-term disease course of newly diagnosed children with VEO-IBD to older children (6-16 years of age) using a prospective, multicenter patient registry.
Methods Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group (PIBDCRG) Registry, which is a prospective, multicenter observational study initiated in 2002 to describe the contemporary natural history of newly diagnosed patients with IBD who were #16 years of age. Approval of the registry was received from the institutional review board at each participating institution. Written informed consent was obtained from parents or legal caregivers and written assent obtained from children when appropriate. To be included in the current study, we required that all children have a physician global assessment (PGA) of disease severity available at baseline and at 1 year of followup. For each enrolled child, a number of clinical and demographic characteristics were collected on standardized forms at the time of initial diagnosis, at 30 days, and every 3 months from the date of diagnosis and then submitted to a centralized data management center. Family history of IBD was defined as having a parent or sibling with CD or UC. Diagnoses of CD, UC, and IBD-U were established by standard clinical, laboratory, radiologic, endoscopic, and histologic criteria at the time of diagnosis.12 Initial IBD diagnosis was defined as the original classification of CD, UC, or IBD-U.13 Final diagnosis was defined as the most recent diagnosis classification through August 2012 available for that subject. Disease activity was collected using a PGA at diagnosis, 30 days, and then quarterly for up to 5 years and was classified as inactive, mild, moderate, or severe disease.13,14 Disease extent was described using the Montreal Classification and represented the greatest extent recorded for that patient during the follow-up period.15 Additional data collected included laboratory studies, administered IBD treatments (including medications and use of enteral therapy), and hospitalizations. Low albumin levels were defined as those falling below age-related reference ranges, and low hemoglobin levels were defined as a hemoglobin level adjusted for age and sex that was 2 SDs below the mean.16 Data concerning surgeries are not presented because they have been previously published for the PIBDCRG cohort.17 Patients were managed according to the practice of their physicians and not by standardized protocols. Statistical Analyses We compared demographic and clinical characteristics between children diagnosed from birth to age 5 years to those diagnosed ages 6-10 years and 11-16 years of age by type of 2
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IBD. We chose to evaluate a middle age range (6-10 years of age) to determine whether this group’s clinical features represent a mixture of the younger and older age ranges or whether the middle group’s features would align more with one of the other age groups. Comparisons were made at baseline, at 1 year, and at 5 years after diagnosis. We calculated frequencies for categorical variables and medians for continuous variables. If a demographic or clinical characteristic appeared to have a clinically meaningful difference by age, a Cochran-Mantel-Haenszel general association P value was calculated. We used a 2-sample Kolmogorov-Smirnov test to compare differences in medians. To examine differences in treatment strategy by age, we used the Cochran-MantelHaenszel general association P value. We examined the effect of age at diagnosis on the use of infliximab using Cox proportional hazards’ models adjusted for sex and baseline PGA score. The time scale of interest was time since IBD diagnosis. Time between diagnosis and enrollment in the PIBDCRG was accounted for in the analysis. Figures of the cumulative proportion who received infliximab were generated from the adjusted Cox regression models.
Results Between January 2002 and August 2012, a total of 1928 children diagnosed with IBD were enrolled in the registry (Table I); 56.6% were male, 85.3% were Caucasian, and median follow-up was 3.25 years. The median age of diagnosis was 4.2 years in the preschool age group, 9.4 years in the middle group, and 13.6 years in the oldest group. There were no patients enrolled under 1 year of age. Median follow-up for the entire group was 3.25 years, and more than 5 years of follow-up was available in 31.3% ages 1-5 years, 29.3% ages 6-10 years, and 12.4% ages 1117 years. Twelve percent had a family history of IBD with no significant differences noted among the different age groups. Subtype classification revealed 67.7% diagnosed with CD, 26.6% with UC, and 5.7% with IBD-U. The 112 children in the 1- to 5-year-old group comprised 5.8% of the entire study population. Of these, 42.9% had CD, 46.4% UC, and 10.7% IBD-U. Children in the 1- to 5-yearold group had significantly more isolated colonic disease (67%) than the middle group (42.7%; P < .01) or oldest group (41%; P < .01) (Table I). There were no significant differences in the proportion of hospitalized patients throughout the follow-up period or in time to first hospitalization. There were a few differences in the laboratory values by age. The median albumin level at initial visit was higher in the 1- to 5-year-old group (median = 3.7 g/dL) compared with the middle aged group (median = 3.4 g/dL, P < .01) and the oldest group (median = 3.5 g/dL, P = .05), however, there was no statistical differences among the groups with regards to the percent of patients with low albumin levels. Although the median hemoglobin level at the initial visit Oliva-Hemker et al
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Table I. Baseline characteristics of all patients with IBD Age at diagnosis Demographics
1-5 y
6-10 y
11-16 y
All ages
N (%) Median age at diagnosis (y) Median y of follow-up (range) Male White Positive IBD family history CD UC IBD-U Isolated colonic disease Hospitalization Median time to first hospitalization (range) Median hemoglobin (range)-g/dL Low hemoglobin (<2 SD mean) Median ESR (range)-mm/h Median albumin (range)-g/dL % Low albumin
112 (5.8%) 4.2 3.25 (Baseline-10) 56.3% 90.2% 9.8% 42.9% 46.4% 10.7% 67% 33.7% 0.1 y (0-5.8 y) 11.0 (6.7-13.6) 62.5% 30.0 (1.0-112.0) 3.7 (2.2-5.2) 50.9%
543 (28.2%) 9.4 3.75 (Baseline-10.25) 56.0% 85.1% 12.2% 69.8% 23.6% 6.6% 42.7%† 41.0% 0.6 y (0-9.6 y) 11.2 (4.4-14.8) 58.0% 32.0 (1.0-130.0) 3.4{ (1.5-5.0) 60.0%
1273 (66.0%) 13.6 3.0 (Baseline-10.25) 56.9% 84.9% 12.2% 69% 26.1% 4.9%* 41%† 42.7% 0.4 y (0-9.0 y) 11.4z (5.1-17.3) 72.4%x 29.0 (1.0-129.0) 3.5{ (1.3-5.20) 57.2%
1928 12.4 3.25 (Baseline-10.25) 56.6% 85.3% 12% 67.7% 26.6% 5.7% 43% 41.7% 0.4 y (0-9.6 y) 11.3 (4.4-17.3) 67.8% 30.0 (1.0-130.0) 3.5 (1.3-5.2) 57.6%
ESR, erythrocyte sedimentation rate. *Youngest vs older group P < .01. †Youngest vs middle and older groups P < .01. zYoungest vs oldest group P = .04. xYoungest vs oldest group P = .03. {Youngest vs middle group P < .01; vs oldest group P < .05.
was lower in the youngest group (11.0 g/dL) compared with the oldest group (11.4 g/dL, P = .04), a smaller percentage of the younger patients had a low hemoglobin level compared with the oldest (62.5% vs 72.4%, P = .03) (Table I). There was no statistically significant difference in the erythrocyte sedimentation rate levels at the initial visit. Among those who had laboratory values at year 5, there was not a statistically significant difference in albumin or erythrocyte sedimentation rate by age. There was a statistically significant difference in hemoglobin at 5 years after diagnosis. The preschool age group had a lower level (median 11.4 g/dL) compared with the older groups (610 years median = 13.1 g/dL, P = .04; 11-16 years median 13.4 g/dL, P < .01). CD The 1- to 5-year-old group comprised 3.7% of the CD population. Compared with the older groups, the youngest children had a significantly greater prevalence of isolated colonic disease (39.6%) compared with the 6- to 10-year-olds (25.3%; P = .04) and the 11- to 16-year-olds (22.3%, P < .01) (Table II; available at www.jpeds.com). Most children in all age groups presented with moderateto-severe disease activity, however, 45.8% of those in the 1- to 5-year-old group had mild disease activity at the time of diagnosis compared with 28% in the other age groups (P = .01). After baseline, there were no statistically significant differences in disease activity (Figure 1, A). At baseline and at 1 year following diagnosis, use of antibiotics, mesalamine, thiopurine immunomodulators, and corticosteroids were similar in all age groups (Figure 2, A; available at www.jpeds.com). However, at 5 years postdiagnosis, a greater proportion of the youngest group
was receiving corticosteroids compared with the 11- to 16year-old group (13.6% vs 7.6%, P < .01). In addition, at the 5-year mark, a significantly greater proportion of the youngest group were receiving methotrexate compared with the oldest group (22.7% vs 11.2%, P < .01). After adjusting for sex, age category, and PGA score, there was
Figure 1. Change over time in disease severity based on PGA in patients with A, CD and B, UC.
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no significant difference by age group with regards to exposure to infliximab over time (Figure 3, A). There was no exposure to adalimumab, methotrexate, cyclosporine, or tacrolimus in the 1- to 5-year-olds at baseline. There also were no significant differences in use of enteral nutrition or hospitalizations among the groups. UCs The 1- to 5-year-old group constituted 10.1% of the UC population and approximately 80% had pancolitis, similar to the 2 older groups (Table III; available at www.jpeds.com). Most children presented with moderate-to-severe disease activity, and there were no differences in disease activity among the groups at baseline and during the follow-up time point (Figure 1, B). There was no significant difference in use of antibiotics, mesalamine, corticosteroids, or thiopurine immunomodulators at baseline and at 1 year following diagnosis (Figure 2, B). Treatment outcomes at 5 years, however, showed a greater proportion of the youngest group was receiving mesalamine (71.4% vs 50%, P < .0001) and thiopurine immunomodulators (52.4% vs 36.2%, P = .0002) compared with the 11- to 16-year-olds. There was a trend to greater use of mesalamine (71.4% vs 57.1%, P = .5) and thiopurine immunomodulators (52.4% vs 24.5%, P = .07) in the youngest group compared with the
Figure 3. Time from diagnosis to first use of infliximab by age of diagnosis among patients with A, CD and B, UC. 4
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middle group. Exposure to methotrexate, adalimumab, cyclosporine, and tacrolimus and use of enteral nutrition was minimal for all ages even at 5 years postdiagnosis. Neither infliximab exposure over time nor the number of hospitalizations differed among the groups (Figure 3, B). IBD-U At the most recent visit, 110 children had IBD-U. Of children diagnosed at 1-5 years of age, 10.7% had IBD-U compared with 4.9% in the oldest group (P < .01; Table I). Nearly all of the children with IBD-U had pancolitis and moderateto-severe disease. No statistically significant differences were noted in the PGA at presentation, therapeutic management, or hospitalizations between the age groups. Of the 176 patients that were given a diagnosis of IBD-U at baseline, 41.5% remained as IBD-U at the most recent visit, 18.2% had a diagnosis change to CD, and 41.3% had a diagnosis change to UC. On the other hand, of children initially diagnosed with CD or UC, more than 90% maintained their original diagnosis over time.
Discussion This study evaluated the clinical presentation and medical therapeutic management of VEO-IBD. Median follow-up time was 3.25 years for the entire group, and more than 30% of the VEO-IBD group had at least 5 years of followup. Data were collected in a prospective manner in children with newly diagnosed IBD from more than 2 dozen pediatric centers in the US and Canada. Our results confirm phenotypic variation by age, with the children 1-5 years of age having more isolated colonic disease, especially colonic CD, and a greater number of them being diagnosed with IBD-U. This is different from the more typical ileocolonic pattern seen in older children and adults with CD.4 The colonic phenotype likely contributed to 11% of the youngest group being initially diagnosed with IBD-U. This aligns with recent reports that children with CD who do not carry NOD2/CARD15 mutations and have colitis without ileal involvement are more likely to be <10 years of age, suggesting that isolated colonic disease distribution may be associated with specific unknown susceptibility genes.18 Although the Paris Classification of IBD labels CD diagnosed in children <10 years as “very early onset,” interestingly, our cohort showed that the change from a presenting colon-only Crohn’s phenotype to one that is more ileocolonic begins in the 6- to 10-year-old age group.19-8 The percentage diagnosed in our cohort with IBD-U was not as high as the 22%-23% reported by other investigators. This may imply variation in interpretation of histopathologic findings.7,20 However, similar to what was found in an Italian pediatric IBD cohort, we had a relatively large proportion (41%) of children in the 1- to 5-year-old IBD-U group who retained this classification suggesting difficulty with making a definitive diagnosis when the disease phenotype is primarily colonic.20 Oliva-Hemker et al
- 2015 Evidence shows that the incidence of IBD is increasing in the pediatric population. In our cohort, nearly 6% of participants were aged 1-5 years at diagnosis. Whereas early studies reported a prevalence of approximately 1% in those <5 years of age, more recent studies have reported prevalence as high as 9%-11% suggesting that the diagnosis of IBD in very young children is increasing.8,20-22 A population-based retrospective cohort study of children in Ontario, Canada, found the incidence of IBD in children <10 years of age to have increased by 7.4% per year compared with 2.2% per year for those $10 years of age between 1994 and 2009.23 It has been reported in the past that IBD onset in pediatric cohorts have a stronger family IBD history compared with adults and are associated with a greater degree of genetic susceptibility.10,24 Thus, we were expecting the 1- to 5-year-old group to have a greater IBD family history prevalence, but there was no statistical differences among the 3 age groups. This may be because other studies have been cross-sectional in nature and did not follow an incident cohort as is the case with our study. Whether this suggests that environmental triggers may have greater impact in the development of VEO-IBD needs further investigation. Previous literature describing the clinical presentation of children diagnosed with IBD has reported a high degree of morbidity and mortality, however, these reports often included cases with IBD onset in infancy.3,25,26 These infantile cases are now assumed to be the result of immunodeficiency syndromes or other enteropathies, such as autoimmune enteropathy or eosinophilic gastroenteritis, known to mimic IBD. In the last few years, it has been shown that mutations leading to loss-of-function in the IL-10 receptor genes (IL10RA and IL10RB) are associated with severe colitis and perianal inflammation in infants.9,27,28 Our cohort did not include a case <1 year of age likely because such patients would have undergone an extensive evaluation for immunodeficiencies, thus, leading to other diagnoses and likely minimizing the impact of these nonclassic IBD cases on our outcomes. There is a paucity of data regarding response to IBD treatments for very young children compared with older groups. A report from a pediatric IBD consortium registry noted that children #5 years of age compared with those aged 6-17 years were less likely to receive treatment with antibiotics, mesalamine, thiopurine immunomodulators, methotrexate, infliximab, and corticosteroids.8 After adjusting for disease severity at diagnosis, at 1-year follow-up we did not find significant differences in exposure to medical treatments for either CD or UC and similar proportions of children with mild or inactive disease, suggesting a similar initial therapeutic management approach regardless of age, as well as a similar positive response to therapy. However, it should be noted that although the youngest CD group presented with significantly milder disease activity, at 5 years postdiagnosis, this group had significantly more exposure to corticosteroids and methotrexate and no statistically significant difference in the proportion receiving infliximab compared with the oldest group. Similarly, for children with UC, at 5 years a greater
ORIGINAL ARTICLES proportion were receiving mesalamine and thiopurine immunomodulators, but there was no statistically significant difference in the proportion receiving infliximab compared with the oldest group. One could speculate that it would be less likely for providers to overuse such therapies on younger children without indication, thus, exposure to these medications may indicate that those with VEO-IBD were developing more aggressive disease over time. The possibility that the youngest children with CD may have more aggressive disease may seem at odds with results of a recently published Canadian study that reported lower health system utilization in outpatient and emergency settings in children <6 years with CD, but not UC, compared with older groups prompting the authors to suggest more mild disease in their younger group with CD. However, the health administrative data did not include clinical information such as phenotype or severity nor did the authors have access to prescription medication records.23 In addition, it may be that in spite of concerns about medication adverse events, pediatric IBD specialists have become more cognizant regarding the importance of mucosal healing to potentially prevent future CD complications or they may have been concerned that the younger children would be developing more aggressive disease and, thus, would opt for earlier introduction of immunomodulators or biologic agents. This study has limitations. The registry was designed to be observational in nature and not dictated by protocol, thus, there may be site-specific differences in how patients were categorized and managed. Subject inclusion was not population-based, and the data are from large referral centers However, in the US and Canada, children with IBD are typically treated at these referral centers and rarely managed by their primary care providers, suggesting that this study is representative of most children with IBD in these countries. In conclusion, our study confirms that children diagnosed with IBD between 1 and 5 years of age have a primarily colonic phenotype compared with children diagnosed at later ages who are more likely to have ileocolonic disease. It is possible that the change from this presenting phenotype may start as early as 6 years of age. Although children at the youngest age do not necessarily present with greater disease severity compared with the older children—something that should be regarded as encouraging to clinical providers—over time they may develop aggressive disease requiring immunomodulator and biologic therapies. A number of questions remain. Is there an environmental trigger potentially causing the colonic phenotype in the youngest children? Will these children require increasing immunomodulator or biologic therapies as they reach adulthood? Will their risk of malignancies be greater given their length of disease as well as their longer cumulative exposure to immunosuppressive agents? Certainly, even longer longitudinal cohort studies will be required to answer these and other questions. Enhanced characterization and comparison of genotypes, immune responses, and greater understanding of the functional role of the intestinal microbiome in
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VEO-IBD may facilitate answers to pathophysiology and lead to enhanced therapeutic interventions. n Submitted for publication Jan 7, 2015; last revision received Feb 23, 2015; accepted Apr 16, 2015. Reprint requests: Maria Oliva-Hemker, MD, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Hospital, 600 N Wolfe St, CMSC 2-116, Baltimore, MD 21287-2531. E-mail: [email protected]
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Vol. -, No. 13. Hyams J, Markowitz J, Otley A, Rosh J, Mack D, Bousvaros A, et al. Evaluation of the pediatric Crohn disease activity index: a prospective multicenter experience. J Pediatr Gastroenterol Nutr 2005;41: 416-21. 14. Otley A, Loonen H, Parekh N, Corey M, Sherman PM, Griffiths AM. Assessing activity of pediatric Crohn’s disease: which index to use? Gastroenterology 1999;116:527-31. 15. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006;55:749-53. 16. Tschudy MM, Arcara KM. The Harriet Lane handbook. 19th ed. Philadelphia: Elsevier Mosby; 2012. 17. Schaefer ME, Machan JT, Kawatu D, Langton CR, Markowtiz J, Crandall W, et al. Factors that determine risk for surgery in pediatric patients with Crohn’s disease. Clin Gastroenterol Hepatol 2010;8: 789-94. 18. Levine A, Kugathasan S, Annese V, Biank V, Leshinsky-Silver E, Davidovich O, et al. Pediatric onset Crohn’s colitis is characterized by genotype-dependent age-related susceptibility. Inflamm Bowel Dis 2007;13:1509-15. 19. Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011;17: 1314-21. 20. Aloi M, Lionetti P, Barabino A, Guariso G, Costa S, Fontana M, et al. Phenotype and disease course of early-onset pediatric inflammatory bowel disease. Inflamm Bowel Dis 2014;20:597-605. 21. Farmer RG, Whelan G, Fazio VW. Long-term follow-up of patients with Crohn’s disease: relationship between the clinical pattern and prognosis. Gastroenterology 1985;88:1818-25. 22. Griffiths AM. Specificities of inflammatory bowel disease in childhood. Best Pract Res Clin Gastroenterol 2004;18:509-23. 23. Benchimol EI, Mack DR, Nguyen GC, Snapper SB, Li W, Mojaverian N, et al. Incidence, outcomes and health services burden of very early onset inflammatory bowel disease. Gastroenterology 2014;20:1761-9. 24. de Ridder L, Weersma RK, Dijkstra G, van der Steege G, Benninga MA, Nolte IM, et al. Genetic susceptibility has a more important role in pediatric-onset Crohn’s disease than in adult-onset Crohn’s disease. Inflamm Bowel Dis 2007;13:1083-92. 25. Ruemmele FM, El Khoury MG, Talbotec C, Maurage C, Mougenot JF, Schmitz J, et al. Characteristics of inflammatory bowel disease with onset during the first year of life. J Pediatr Gastroenterol Nutr 2006;43:603-9. 26. Uchida M, Iwasa H, Nemoto K. A case of perforation of the small intestine in Crohn’s disease. Nippon Geka Gakkai Zasshi 1983;84: 1101-6. 27. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009;361:2033-45. 28. Moran CJ, Walters TD, Guo CH, Kugathasan S, Klein C, Turner D, et al. IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis 2013;19:115-23.
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ORIGINAL ARTICLES Appendix
M.O.-H. receives research support from and serves on the advisory board of Abbvie; serves as a consultant for Hoffman-LaRoche. D.M. received an education grant from and serves on the board of Abbvie; serves on the advisory board of Janssen Biotech. A.G. receives research and program support from and serves as a consultant for Janssen Biotech and Abbvie; serves as a speaker for Abbvie; serves as a consultant for Receptos, Nestle, and Ferring. A.O. receives education and research grants from and serves on the advisory board for Janssen Canada and Abbvie; serves on the advisory board for Nestle. A.B. receives research support from Prometheus; serves as a consultant for Takeda/Millenium, Cubist, Dyax, and Peabody Arnold. J.Ro. receives research support from and serves as a consultant for Abbvie and Janssen Biotech; receives research support from Astra Zeneca; serves as a consultant for Soligenix and Receptos; serves on the speaker’s bureau for Prometheus. S.S. serves on the speaker’s bureau for Abbvie. R.C. employee at will for Nestle Nutrition. W.F. serves as a consultant for Abbvie, Shire Development, LLC, Janssen, Genentech, Velocity Pharmaceutical, Implicit Biosciences; serves on the advisory board for UCB and Abbvie. M.K. serves as a consultant for Janssen Biotech and Abbvie; receives research support from Abbvie. J.M. serves on the advisory board for Janssen Biotech, Abbvie, UCB; serves as a consultant for Receptos and Solgenix. J.H. serves on the advisory board for Janssen Biotech, Abbvie, UCB, Takeda; receives research support and serves on the speaker’s bureau for Janssen Biotech; serves as a consultant for Soligenix, Receptos, Celgene, Avaxia. The other authors declare no conflicts of interest.
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Figure 2. Percent of patients receiving antibiotics, mesalamine, corticosteroids, and immunomodulators at baseline, year 1, and year 5 for A, CD and B, UC. *N at baseline, at year 1, at year 5. Age at diagnosis 1-5 years (N = 48, 39, 22), 6-10 years (N = 379, 327, 157), and 11-16 years (N = 878, 746, 223). †N at baseline, at year 1, and at year 5. Age at diagnosis 1-5 years (N = 52, 46, 21), 6-10 years (N = 128, 106, 49), and 11-16 years (N = 333, 280, 58). ASA, aminosalicylate; Aza, azathioprine; MP, mercaptopurine; MTX, methotrexate.
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Table II. Baseline characteristics of patients with CD Age at diagnosis
Demographics N Median age at diagnosis (y) % Male % White % Positive IBD family history Montreal Location Classification % L1-Ileal L2-Colonic L3-Ileocolonic L4-Upper tract
1-5 y
6-10 y
11-16 y
48 4.5 (1.3-5.9)
379 9.5 (6.0-10.9)
878 13.5 (11.0-16.0)
52.1 91.7 8.3
59.4 86.5 12.9
58.2 85.3 12.5
6.3 39.6 54.2 43.8
10.8 25.3* 63.3 59.9
12.5 22.3† 64.5 57.4
*Youngest vs middle group P = .04. †Youngest vs older group P < .01.
Table III. Baseline characteristics of patients with UC Age at diagnosis
Demographics N Median age at diagnosis (y) % Male % White % Positive IBD family history Disease extent, % Rectosigmoid Left colon Pancolitis
1-5 y*
6-10 y
11-16 y
52 3.8 (1.4-5.9)
128 9.1 (6.1-10.9)
333 13.8 (11.0-16.1)
59.6 88.5 11.5
45.3 81.3 10.9
51.7 84.7 9.6
7.7 13.5 78.9
7.0 7.0 85.9
9.9 10.8 79.3
*No children were identified with a diagnosis less than 1 y of age.
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Study design Data were obtained from an inception cohort of 1928 children with IBD enrolled in a prospective observational registry at multiple centers in North America.
Results One hundred twelve children were #5 years of age with no child enrolled at <1 year of age. Of those, 42.9% had Crohn’s disease (CD), 46.4% ulcerative colitis (UC), and 10.7% had IBD-unclassified. Among the children with CD, children 1-5 years of age had more isolated colonic disease (39.6%) compared with 6- to 10-yearolds (25.3%, P = .04), and 11- to 16-year-olds (22.3%, P < .01). The change from a presenting colon-only phenotype to ileocolonic began at 6-10 years. Children 1-5 years of age with CD had milder disease activity (45.8%) at diagnosis compared with the oldest group (28%, P = .01). Five years postdiagnosis, there was no difference in disease activity among the 3 groups. However, compared with the oldest group, a greater proportion of 1- to 5-year-olds with CD were receiving corticosteroids (P < .01) and methotrexate (P < .01), and a greater proportion of 1- to 5-year-olds with UC were receiving mesalamine (P < .0001) and thiopurine immunomodulators (P < .0002). Conclusions Children with VEO-CD are more likely to have mild disease at diagnosis and present with a colonic phenotype with change to an ileocolonic phenotype noted at 6-10 years of age. Five years after diagnosis, children with VEO-CD and VEO-UC are more likely to have been administered corticosteroids and immunomodulators despite similar disease activity in all age groups. This may suggest development of a more aggressive disease phenotype over time. (J Pediatr 2015;-:---). See editorial, p
I
nflammatory bowel disease (IBD) is a chronic disorder of intestinal inflammation characterized by a relapsing and remitting course. IBD encompasses the diagnoses which include Crohn’s disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U). Epidemiologic data suggest that the incidence of IBD is increasing in the pediatric population and that children are being diagnosed at a younger age than ever before.1-4 Because IBD is considered a lifelong condition, children are impacted by the burden of disease and the therapeutic interventions for much longer time periods compared with adults. PreFrom the Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Children’s Center; Johns vious studies of very early-onset (VEO)-IBD (children #5 years of age at Hopkins University, Baltimore, MD; Connecticut diagnosis) had inconsistent findings regarding severity of disease at diagChildren’s Medical Center, Hartford, CT; Children’s 3,5-8 Hospital of Eastern Ontario, Ottawa, Ontario, Canada; nosis. Recent studies reporting genetic phenotypes in VEO-IBD and Hasbro Children’s Hospital, Providence, RI; Hospital for Sick Children, Toronto, Ontario, Canada; Medical describing monogenic-associated conditions such as interleukin (IL)-10 and College of Wisconsin, Milwaukee, WI; Izaak Walton Killam Health Center, Halifax, Nova Scotia, Canada; IL-10 receptor-deficiency, suggest that a better understanding of the clinical Dayton Children’s Hospital, Dayton, OH; Children’s phenotype of these children may aid in discovery of pathogenesis and Hospital, Boston, MA; Goryeb Children’s Hospital, 9-11 Morristown, NJ; Children’s Hospital of Philadelphia, genotype-phenotype correlation. However, as most children with VEO-IBD Philadelphia, PA; Children’s Hospital Medical Center, 1
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CD IBD IBD-U IL PGA PIBDCRG UC VEO
Crohn’s disease Inflammatory bowel disease IBD-unclassified Interleukin Physician global assessment Pediatric Inflammatory Bowel Disease Collaborative Research Group Ulcerative colitis Very early-onset
Cincinnati; Cleveland Clinic, Cleveland; 15Nationwide Children’s Hospital, Columbus, OH; 16Children’s Hospital of Pittsburgh, Pittsburgh, PA; 17Riley Hospital for Children, Indianapolis, IN; 18Mayo Clinic, Rochester, MN; 19University of North Carolina, Chapel Hill, NC; 20 University of Minnesota, Minneapolis, MN; 21Penn State Hershey Children’s Hospital, Hershey, PA; and 22 Cohen Children’s Medical Center of New York, New Hyde Park, NY List of conflicts of interest is available at www.jpeds.com (Appendix). 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.04.045
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do not appear to have single gene disorders, better characterization of the clinical phenotype and clinical course of this larger group of children remains important. The primary goal of our study was to compare the clinical presentation, therapeutic management, and longer-term disease course of newly diagnosed children with VEO-IBD to older children (6-16 years of age) using a prospective, multicenter patient registry.
Methods Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group (PIBDCRG) Registry, which is a prospective, multicenter observational study initiated in 2002 to describe the contemporary natural history of newly diagnosed patients with IBD who were #16 years of age. Approval of the registry was received from the institutional review board at each participating institution. Written informed consent was obtained from parents or legal caregivers and written assent obtained from children when appropriate. To be included in the current study, we required that all children have a physician global assessment (PGA) of disease severity available at baseline and at 1 year of followup. For each enrolled child, a number of clinical and demographic characteristics were collected on standardized forms at the time of initial diagnosis, at 30 days, and every 3 months from the date of diagnosis and then submitted to a centralized data management center. Family history of IBD was defined as having a parent or sibling with CD or UC. Diagnoses of CD, UC, and IBD-U were established by standard clinical, laboratory, radiologic, endoscopic, and histologic criteria at the time of diagnosis.12 Initial IBD diagnosis was defined as the original classification of CD, UC, or IBD-U.13 Final diagnosis was defined as the most recent diagnosis classification through August 2012 available for that subject. Disease activity was collected using a PGA at diagnosis, 30 days, and then quarterly for up to 5 years and was classified as inactive, mild, moderate, or severe disease.13,14 Disease extent was described using the Montreal Classification and represented the greatest extent recorded for that patient during the follow-up period.15 Additional data collected included laboratory studies, administered IBD treatments (including medications and use of enteral therapy), and hospitalizations. Low albumin levels were defined as those falling below age-related reference ranges, and low hemoglobin levels were defined as a hemoglobin level adjusted for age and sex that was 2 SDs below the mean.16 Data concerning surgeries are not presented because they have been previously published for the PIBDCRG cohort.17 Patients were managed according to the practice of their physicians and not by standardized protocols. Statistical Analyses We compared demographic and clinical characteristics between children diagnosed from birth to age 5 years to those diagnosed ages 6-10 years and 11-16 years of age by type of 2
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IBD. We chose to evaluate a middle age range (6-10 years of age) to determine whether this group’s clinical features represent a mixture of the younger and older age ranges or whether the middle group’s features would align more with one of the other age groups. Comparisons were made at baseline, at 1 year, and at 5 years after diagnosis. We calculated frequencies for categorical variables and medians for continuous variables. If a demographic or clinical characteristic appeared to have a clinically meaningful difference by age, a Cochran-Mantel-Haenszel general association P value was calculated. We used a 2-sample Kolmogorov-Smirnov test to compare differences in medians. To examine differences in treatment strategy by age, we used the Cochran-MantelHaenszel general association P value. We examined the effect of age at diagnosis on the use of infliximab using Cox proportional hazards’ models adjusted for sex and baseline PGA score. The time scale of interest was time since IBD diagnosis. Time between diagnosis and enrollment in the PIBDCRG was accounted for in the analysis. Figures of the cumulative proportion who received infliximab were generated from the adjusted Cox regression models.
Results Between January 2002 and August 2012, a total of 1928 children diagnosed with IBD were enrolled in the registry (Table I); 56.6% were male, 85.3% were Caucasian, and median follow-up was 3.25 years. The median age of diagnosis was 4.2 years in the preschool age group, 9.4 years in the middle group, and 13.6 years in the oldest group. There were no patients enrolled under 1 year of age. Median follow-up for the entire group was 3.25 years, and more than 5 years of follow-up was available in 31.3% ages 1-5 years, 29.3% ages 6-10 years, and 12.4% ages 1117 years. Twelve percent had a family history of IBD with no significant differences noted among the different age groups. Subtype classification revealed 67.7% diagnosed with CD, 26.6% with UC, and 5.7% with IBD-U. The 112 children in the 1- to 5-year-old group comprised 5.8% of the entire study population. Of these, 42.9% had CD, 46.4% UC, and 10.7% IBD-U. Children in the 1- to 5-yearold group had significantly more isolated colonic disease (67%) than the middle group (42.7%; P < .01) or oldest group (41%; P < .01) (Table I). There were no significant differences in the proportion of hospitalized patients throughout the follow-up period or in time to first hospitalization. There were a few differences in the laboratory values by age. The median albumin level at initial visit was higher in the 1- to 5-year-old group (median = 3.7 g/dL) compared with the middle aged group (median = 3.4 g/dL, P < .01) and the oldest group (median = 3.5 g/dL, P = .05), however, there was no statistical differences among the groups with regards to the percent of patients with low albumin levels. Although the median hemoglobin level at the initial visit Oliva-Hemker et al
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Table I. Baseline characteristics of all patients with IBD Age at diagnosis Demographics
1-5 y
6-10 y
11-16 y
All ages
N (%) Median age at diagnosis (y) Median y of follow-up (range) Male White Positive IBD family history CD UC IBD-U Isolated colonic disease Hospitalization Median time to first hospitalization (range) Median hemoglobin (range)-g/dL Low hemoglobin (<2 SD mean) Median ESR (range)-mm/h Median albumin (range)-g/dL % Low albumin
112 (5.8%) 4.2 3.25 (Baseline-10) 56.3% 90.2% 9.8% 42.9% 46.4% 10.7% 67% 33.7% 0.1 y (0-5.8 y) 11.0 (6.7-13.6) 62.5% 30.0 (1.0-112.0) 3.7 (2.2-5.2) 50.9%
543 (28.2%) 9.4 3.75 (Baseline-10.25) 56.0% 85.1% 12.2% 69.8% 23.6% 6.6% 42.7%† 41.0% 0.6 y (0-9.6 y) 11.2 (4.4-14.8) 58.0% 32.0 (1.0-130.0) 3.4{ (1.5-5.0) 60.0%
1273 (66.0%) 13.6 3.0 (Baseline-10.25) 56.9% 84.9% 12.2% 69% 26.1% 4.9%* 41%† 42.7% 0.4 y (0-9.0 y) 11.4z (5.1-17.3) 72.4%x 29.0 (1.0-129.0) 3.5{ (1.3-5.20) 57.2%
1928 12.4 3.25 (Baseline-10.25) 56.6% 85.3% 12% 67.7% 26.6% 5.7% 43% 41.7% 0.4 y (0-9.6 y) 11.3 (4.4-17.3) 67.8% 30.0 (1.0-130.0) 3.5 (1.3-5.2) 57.6%
ESR, erythrocyte sedimentation rate. *Youngest vs older group P < .01. †Youngest vs middle and older groups P < .01. zYoungest vs oldest group P = .04. xYoungest vs oldest group P = .03. {Youngest vs middle group P < .01; vs oldest group P < .05.
was lower in the youngest group (11.0 g/dL) compared with the oldest group (11.4 g/dL, P = .04), a smaller percentage of the younger patients had a low hemoglobin level compared with the oldest (62.5% vs 72.4%, P = .03) (Table I). There was no statistically significant difference in the erythrocyte sedimentation rate levels at the initial visit. Among those who had laboratory values at year 5, there was not a statistically significant difference in albumin or erythrocyte sedimentation rate by age. There was a statistically significant difference in hemoglobin at 5 years after diagnosis. The preschool age group had a lower level (median 11.4 g/dL) compared with the older groups (610 years median = 13.1 g/dL, P = .04; 11-16 years median 13.4 g/dL, P < .01). CD The 1- to 5-year-old group comprised 3.7% of the CD population. Compared with the older groups, the youngest children had a significantly greater prevalence of isolated colonic disease (39.6%) compared with the 6- to 10-year-olds (25.3%; P = .04) and the 11- to 16-year-olds (22.3%, P < .01) (Table II; available at www.jpeds.com). Most children in all age groups presented with moderateto-severe disease activity, however, 45.8% of those in the 1- to 5-year-old group had mild disease activity at the time of diagnosis compared with 28% in the other age groups (P = .01). After baseline, there were no statistically significant differences in disease activity (Figure 1, A). At baseline and at 1 year following diagnosis, use of antibiotics, mesalamine, thiopurine immunomodulators, and corticosteroids were similar in all age groups (Figure 2, A; available at www.jpeds.com). However, at 5 years postdiagnosis, a greater proportion of the youngest group
was receiving corticosteroids compared with the 11- to 16year-old group (13.6% vs 7.6%, P < .01). In addition, at the 5-year mark, a significantly greater proportion of the youngest group were receiving methotrexate compared with the oldest group (22.7% vs 11.2%, P < .01). After adjusting for sex, age category, and PGA score, there was
Figure 1. Change over time in disease severity based on PGA in patients with A, CD and B, UC.
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no significant difference by age group with regards to exposure to infliximab over time (Figure 3, A). There was no exposure to adalimumab, methotrexate, cyclosporine, or tacrolimus in the 1- to 5-year-olds at baseline. There also were no significant differences in use of enteral nutrition or hospitalizations among the groups. UCs The 1- to 5-year-old group constituted 10.1% of the UC population and approximately 80% had pancolitis, similar to the 2 older groups (Table III; available at www.jpeds.com). Most children presented with moderate-to-severe disease activity, and there were no differences in disease activity among the groups at baseline and during the follow-up time point (Figure 1, B). There was no significant difference in use of antibiotics, mesalamine, corticosteroids, or thiopurine immunomodulators at baseline and at 1 year following diagnosis (Figure 2, B). Treatment outcomes at 5 years, however, showed a greater proportion of the youngest group was receiving mesalamine (71.4% vs 50%, P < .0001) and thiopurine immunomodulators (52.4% vs 36.2%, P = .0002) compared with the 11- to 16-year-olds. There was a trend to greater use of mesalamine (71.4% vs 57.1%, P = .5) and thiopurine immunomodulators (52.4% vs 24.5%, P = .07) in the youngest group compared with the
Figure 3. Time from diagnosis to first use of infliximab by age of diagnosis among patients with A, CD and B, UC. 4
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middle group. Exposure to methotrexate, adalimumab, cyclosporine, and tacrolimus and use of enteral nutrition was minimal for all ages even at 5 years postdiagnosis. Neither infliximab exposure over time nor the number of hospitalizations differed among the groups (Figure 3, B). IBD-U At the most recent visit, 110 children had IBD-U. Of children diagnosed at 1-5 years of age, 10.7% had IBD-U compared with 4.9% in the oldest group (P < .01; Table I). Nearly all of the children with IBD-U had pancolitis and moderateto-severe disease. No statistically significant differences were noted in the PGA at presentation, therapeutic management, or hospitalizations between the age groups. Of the 176 patients that were given a diagnosis of IBD-U at baseline, 41.5% remained as IBD-U at the most recent visit, 18.2% had a diagnosis change to CD, and 41.3% had a diagnosis change to UC. On the other hand, of children initially diagnosed with CD or UC, more than 90% maintained their original diagnosis over time.
Discussion This study evaluated the clinical presentation and medical therapeutic management of VEO-IBD. Median follow-up time was 3.25 years for the entire group, and more than 30% of the VEO-IBD group had at least 5 years of followup. Data were collected in a prospective manner in children with newly diagnosed IBD from more than 2 dozen pediatric centers in the US and Canada. Our results confirm phenotypic variation by age, with the children 1-5 years of age having more isolated colonic disease, especially colonic CD, and a greater number of them being diagnosed with IBD-U. This is different from the more typical ileocolonic pattern seen in older children and adults with CD.4 The colonic phenotype likely contributed to 11% of the youngest group being initially diagnosed with IBD-U. This aligns with recent reports that children with CD who do not carry NOD2/CARD15 mutations and have colitis without ileal involvement are more likely to be <10 years of age, suggesting that isolated colonic disease distribution may be associated with specific unknown susceptibility genes.18 Although the Paris Classification of IBD labels CD diagnosed in children <10 years as “very early onset,” interestingly, our cohort showed that the change from a presenting colon-only Crohn’s phenotype to one that is more ileocolonic begins in the 6- to 10-year-old age group.19-8 The percentage diagnosed in our cohort with IBD-U was not as high as the 22%-23% reported by other investigators. This may imply variation in interpretation of histopathologic findings.7,20 However, similar to what was found in an Italian pediatric IBD cohort, we had a relatively large proportion (41%) of children in the 1- to 5-year-old IBD-U group who retained this classification suggesting difficulty with making a definitive diagnosis when the disease phenotype is primarily colonic.20 Oliva-Hemker et al
- 2015 Evidence shows that the incidence of IBD is increasing in the pediatric population. In our cohort, nearly 6% of participants were aged 1-5 years at diagnosis. Whereas early studies reported a prevalence of approximately 1% in those <5 years of age, more recent studies have reported prevalence as high as 9%-11% suggesting that the diagnosis of IBD in very young children is increasing.8,20-22 A population-based retrospective cohort study of children in Ontario, Canada, found the incidence of IBD in children <10 years of age to have increased by 7.4% per year compared with 2.2% per year for those $10 years of age between 1994 and 2009.23 It has been reported in the past that IBD onset in pediatric cohorts have a stronger family IBD history compared with adults and are associated with a greater degree of genetic susceptibility.10,24 Thus, we were expecting the 1- to 5-year-old group to have a greater IBD family history prevalence, but there was no statistical differences among the 3 age groups. This may be because other studies have been cross-sectional in nature and did not follow an incident cohort as is the case with our study. Whether this suggests that environmental triggers may have greater impact in the development of VEO-IBD needs further investigation. Previous literature describing the clinical presentation of children diagnosed with IBD has reported a high degree of morbidity and mortality, however, these reports often included cases with IBD onset in infancy.3,25,26 These infantile cases are now assumed to be the result of immunodeficiency syndromes or other enteropathies, such as autoimmune enteropathy or eosinophilic gastroenteritis, known to mimic IBD. In the last few years, it has been shown that mutations leading to loss-of-function in the IL-10 receptor genes (IL10RA and IL10RB) are associated with severe colitis and perianal inflammation in infants.9,27,28 Our cohort did not include a case <1 year of age likely because such patients would have undergone an extensive evaluation for immunodeficiencies, thus, leading to other diagnoses and likely minimizing the impact of these nonclassic IBD cases on our outcomes. There is a paucity of data regarding response to IBD treatments for very young children compared with older groups. A report from a pediatric IBD consortium registry noted that children #5 years of age compared with those aged 6-17 years were less likely to receive treatment with antibiotics, mesalamine, thiopurine immunomodulators, methotrexate, infliximab, and corticosteroids.8 After adjusting for disease severity at diagnosis, at 1-year follow-up we did not find significant differences in exposure to medical treatments for either CD or UC and similar proportions of children with mild or inactive disease, suggesting a similar initial therapeutic management approach regardless of age, as well as a similar positive response to therapy. However, it should be noted that although the youngest CD group presented with significantly milder disease activity, at 5 years postdiagnosis, this group had significantly more exposure to corticosteroids and methotrexate and no statistically significant difference in the proportion receiving infliximab compared with the oldest group. Similarly, for children with UC, at 5 years a greater
ORIGINAL ARTICLES proportion were receiving mesalamine and thiopurine immunomodulators, but there was no statistically significant difference in the proportion receiving infliximab compared with the oldest group. One could speculate that it would be less likely for providers to overuse such therapies on younger children without indication, thus, exposure to these medications may indicate that those with VEO-IBD were developing more aggressive disease over time. The possibility that the youngest children with CD may have more aggressive disease may seem at odds with results of a recently published Canadian study that reported lower health system utilization in outpatient and emergency settings in children <6 years with CD, but not UC, compared with older groups prompting the authors to suggest more mild disease in their younger group with CD. However, the health administrative data did not include clinical information such as phenotype or severity nor did the authors have access to prescription medication records.23 In addition, it may be that in spite of concerns about medication adverse events, pediatric IBD specialists have become more cognizant regarding the importance of mucosal healing to potentially prevent future CD complications or they may have been concerned that the younger children would be developing more aggressive disease and, thus, would opt for earlier introduction of immunomodulators or biologic agents. This study has limitations. The registry was designed to be observational in nature and not dictated by protocol, thus, there may be site-specific differences in how patients were categorized and managed. Subject inclusion was not population-based, and the data are from large referral centers However, in the US and Canada, children with IBD are typically treated at these referral centers and rarely managed by their primary care providers, suggesting that this study is representative of most children with IBD in these countries. In conclusion, our study confirms that children diagnosed with IBD between 1 and 5 years of age have a primarily colonic phenotype compared with children diagnosed at later ages who are more likely to have ileocolonic disease. It is possible that the change from this presenting phenotype may start as early as 6 years of age. Although children at the youngest age do not necessarily present with greater disease severity compared with the older children—something that should be regarded as encouraging to clinical providers—over time they may develop aggressive disease requiring immunomodulator and biologic therapies. A number of questions remain. Is there an environmental trigger potentially causing the colonic phenotype in the youngest children? Will these children require increasing immunomodulator or biologic therapies as they reach adulthood? Will their risk of malignancies be greater given their length of disease as well as their longer cumulative exposure to immunosuppressive agents? Certainly, even longer longitudinal cohort studies will be required to answer these and other questions. Enhanced characterization and comparison of genotypes, immune responses, and greater understanding of the functional role of the intestinal microbiome in
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VEO-IBD may facilitate answers to pathophysiology and lead to enhanced therapeutic interventions. n Submitted for publication Jan 7, 2015; last revision received Feb 23, 2015; accepted Apr 16, 2015. Reprint requests: Maria Oliva-Hemker, MD, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Hospital, 600 N Wolfe St, CMSC 2-116, Baltimore, MD 21287-2531. E-mail: [email protected]
References 1. Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423-39. 2. Kugathasan S, Judd RH, Hoffmann RG, Heikenen J, Telega G, Khan F, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr 2003;143:525-31. 3. Marx G, Seidman EG, Martin SR, Deslandres C. Outcome of Crohn’s disease diagnosed before two years of age. J Pediatr 2002; 140:470-3. 4. Heyman MB, Kirschner BS, Gold BD, Ferry G, Baldassano R, Cohen SA, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 2005;146:35-40. 5. Ein SH, Lynch MJ, Stephens CA. Ulcerative colitis in children under one year: a twenty-year review. J Pediatr Surg 1971;6:264-71. 6. Uchida K, Miki C, Inoue M, Otake K, Yoshiyama S, Araki T, et al. Surgical intervention for neonatal and infantile-onset severe colonic Crohn’s disease: report of three cases. Dis Colon Rectum 2008;51: 247-50. 7. Mamula P, Telega GW, Markowitz JE, Brown KA, Piccoli DA, Baldassano RN. Inflammatory bowel disease in children 5 years of age and younger. Am J Gastroenterol 2002;97:2005-10. 8. Gupta N, Bostrom AG, Kirschner BS, Cohen SA, Abramson O, Ferry GD, et al. Presentation and disease course in early- compared to later-onset pediatric Crohn’s disease. Am J Gastroenterol 2008;103:2092-8. 9. Engelhardt KR, Shah N, Faizura-Yeop I, Kocacik Uygun DF, Frede N, Muise AM, et al. clinical outcome in IL-10 and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol 2013;131:825-30. 10. Kugathasan S, Baldassano RN, Bradfield JP, Sleiman PM, Imielinski M, Guthery SL, et al. Loci on 20q13 and 21q22 are associated with pediatriconset inflammatory bowel disease. Nat Genet 2008;40:1211-5. 11. Imielinski M, Baldassano RN, Griffiths A, Russel RK, Annese V, Dubinsky M, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 2009;41:1335-40. 12. Punati J, Markowitz J, Lerer T, Hyams J, Kugathasan S, Griffiths A, et al. Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm Bowel Dis 2008;14:949-54.
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M.O.-H. receives research support from and serves on the advisory board of Abbvie; serves as a consultant for Hoffman-LaRoche. D.M. received an education grant from and serves on the board of Abbvie; serves on the advisory board of Janssen Biotech. A.G. receives research and program support from and serves as a consultant for Janssen Biotech and Abbvie; serves as a speaker for Abbvie; serves as a consultant for Receptos, Nestle, and Ferring. A.O. receives education and research grants from and serves on the advisory board for Janssen Canada and Abbvie; serves on the advisory board for Nestle. A.B. receives research support from Prometheus; serves as a consultant for Takeda/Millenium, Cubist, Dyax, and Peabody Arnold. J.Ro. receives research support from and serves as a consultant for Abbvie and Janssen Biotech; receives research support from Astra Zeneca; serves as a consultant for Soligenix and Receptos; serves on the speaker’s bureau for Prometheus. S.S. serves on the speaker’s bureau for Abbvie. R.C. employee at will for Nestle Nutrition. W.F. serves as a consultant for Abbvie, Shire Development, LLC, Janssen, Genentech, Velocity Pharmaceutical, Implicit Biosciences; serves on the advisory board for UCB and Abbvie. M.K. serves as a consultant for Janssen Biotech and Abbvie; receives research support from Abbvie. J.M. serves on the advisory board for Janssen Biotech, Abbvie, UCB; serves as a consultant for Receptos and Solgenix. J.H. serves on the advisory board for Janssen Biotech, Abbvie, UCB, Takeda; receives research support and serves on the speaker’s bureau for Janssen Biotech; serves as a consultant for Soligenix, Receptos, Celgene, Avaxia. The other authors declare no conflicts of interest.
Clinical Presentation and Five-Year Therapeutic Management of Very Early-Onset Inflammatory Bowel Disease in a Large North American Cohort
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Figure 2. Percent of patients receiving antibiotics, mesalamine, corticosteroids, and immunomodulators at baseline, year 1, and year 5 for A, CD and B, UC. *N at baseline, at year 1, at year 5. Age at diagnosis 1-5 years (N = 48, 39, 22), 6-10 years (N = 379, 327, 157), and 11-16 years (N = 878, 746, 223). †N at baseline, at year 1, and at year 5. Age at diagnosis 1-5 years (N = 52, 46, 21), 6-10 years (N = 128, 106, 49), and 11-16 years (N = 333, 280, 58). ASA, aminosalicylate; Aza, azathioprine; MP, mercaptopurine; MTX, methotrexate.
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Table II. Baseline characteristics of patients with CD Age at diagnosis
Demographics N Median age at diagnosis (y) % Male % White % Positive IBD family history Montreal Location Classification % L1-Ileal L2-Colonic L3-Ileocolonic L4-Upper tract
1-5 y
6-10 y
11-16 y
48 4.5 (1.3-5.9)
379 9.5 (6.0-10.9)
878 13.5 (11.0-16.0)
52.1 91.7 8.3
59.4 86.5 12.9
58.2 85.3 12.5
6.3 39.6 54.2 43.8
10.8 25.3* 63.3 59.9
12.5 22.3† 64.5 57.4
*Youngest vs middle group P = .04. †Youngest vs older group P < .01.
Table III. Baseline characteristics of patients with UC Age at diagnosis
Demographics N Median age at diagnosis (y) % Male % White % Positive IBD family history Disease extent, % Rectosigmoid Left colon Pancolitis
1-5 y*
6-10 y
11-16 y
52 3.8 (1.4-5.9)
128 9.1 (6.1-10.9)
333 13.8 (11.0-16.1)
59.6 88.5 11.5
45.3 81.3 10.9
51.7 84.7 9.6
7.7 13.5 78.9
7.0 7.0 85.9
9.9 10.8 79.3
*No children were identified with a diagnosis less than 1 y of age.
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