s
Pediatric inflammatory bowel disease: Diagnostics, treatment and psychosocial
consequences
Hummel, T.Z.
Publication date
2013
Link to publication
Citation for published version (APA):
Hummel, T. Z. (2013). Pediatric inflammatory bowel disease: Diagnostics, treatment and
psychosocial consequences.
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Parts of this introduction has been published as: T. Z. Hummel, M.A. Benninga, A. Kindermann. The role of endoscopy in the diagnostic assessment
of childhood inflammatory bowel disease. Eur Gastroenterol Hepatol Review 2011;7:47-50
introDuction
Crohn’s disease (CD) and ulcerative colitis (UC), the two main subtypes of inflammatory bowel disease (IBD), are lifelong diseases characterized by chronic relapsing inflammation of the gastrointestinal tract. The distinction between CD and UC is based on clinical, radiological, endoscopic and pathological findings. In approximately 5-30% of children differentiation between CD and UC is not possible because of the presence of overlapping features between the two diseases, and a diagnosis of indeterminate colitis (IC) or IBD-unclassified (IBD-U) is made (1-6). Based on the Montreal World Congress of Gastroenterology Working Party 2005 and International Organization of Inflammatory Bowel Disease Working Party 2007 the following classification is currently used(7):
• The term IC or colitis of uncertain type etiology should be used only when colectomy has been performed and the pathologist is unable to make a definite diagnosis of
either UC or CD after careful examination of the surgical specimen
• The term IBD-U should be used when no colectomy is performed and a distinction between CD and UC cannot be made despite an extensive diagnostic work-up In contrast, the IBD Working Group for the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in the Porto criteria recommended the use of the term IC for children and adolescents with IBD, when a full endoscopic examination including biopsies of the upper gastrointestinal tract, colon and terminal ileum, in addition to a small bowel followthrough or enteroclysis, cannot establish a diagnosis of either CD or UC with certainty (8).
Pediatric-onset IBD represents a distinct disease entity with differences in disease phenotype: disease location and disease behavior and genetically attributable risk, compared with IBD in adults (9).
Epidemiology
IBD is most frequently diagnosed in adolescence and early adulthood, with a peak onset between 15 and 25 years of age (10,11). The incidence of CD and UC in children varies greatly around the globe, from 0.24 to 13.3 per 100.000 per year (12). Also in Europe the incidence of pediatric IBD varies, with higher incidence rates per 100.000 per year in Western European centers compared to Eastern European centers, respectively 6.9 and 4.7 (13). The variation in incidence rates may be due to heterogeneity of data collection techniques, differences in disease classification, differences in the age limit used, or referral bias, but also due to regional differences. Incidence rates of pediatric CD are usually higher than those for UC. The incidence of pediatric-onset CD seems to be increasing in several countries, while most studies have reported stable incidence of pediatric-onset UC (12).
Pathogenesis
IBD is thought to result from an inappropriate and continuing inflammatory response to commensal microbes in genetically susceptible individuals. There is sufficient evidence that IBD, in part, is the result of a genetic predisposition (14). Genome-wide association studies have identified multiple susceptibility genes, some common to both diseases (CD and UC) and some linked separately to one disease or the other. Most of these genes code for molecules that are crucial for epithelial barrier function, the innate immune regulation, autophagy and regulation of adaptive immunity (14). The first specific gene unequivocally associated with IBD was the NOD2/CARD15 gene for CD. NOD2 is an intracellular ‘alarm button’, a receptor recognizing invading bacteria that entered the mucosal wall. Also the pathway of autophagy has received a lot of attention following the discovery of ATG16L1 (15). The concordance rate in monozygotic twins of 16-18% in UC and 35-63% in CD points to strong environmental influences (16,17). Western life style has been identified as a potential risk factor in the evolution of IBD; however the environmental triggers of IBD have not been well delineated (15).
The most consistent environmental triggers believed to be associated with IBD are smoking, diet, perinatal events (e.g. perinatal infections), domestic hygiene and childhood infections (18). The genes implicated in childhood-onset and adult-onset IBD overlap, suggesting similar contributory genetic predispositions and pathophysiological pathways (14). However, based on the relative short exposure time to environmental factors in children, genetic mutations are thought to play an increasing role in childhood-onset disease (9,19).
Clinical presentation
Children with IBD may present with a range of symptoms, depending on the location, severity and chronicity of inflammation. The most common presenting symptoms of CD are abdominal pain, weight loss and diarrhea; and for UC diarrhea, bleeding and abdominal pain. However, only one quarter of CD patients present with the ‘classical triad’ of CD symptoms, and nearly half do not report diarrhea. Other symptoms may be fever, lethargy, anorexia, arthritis/arthralgia, psychiatric symptoms, secondary amenorrhea, nausea and vomiting (20). Unique to pediatric-onset IBD is the potential for linear growth impairment as a complication of chronic intestinal inflammation. However, in UC linear growth impairment is seldom present at the time of diagnosis (20,21). Despite its name, IBD is not limited to the bowel. Extraintestinal manifestations may sometimes dominate the clinical picture especially in CD, causing diagnostic delay (8). Extraintestinal manifestations can be found in 17% of patients at the time of diagnosis, with arthritis/arthralgia, aphthous stomatitis and cutaneous changes (e.g., erythema nodosum) being most common (22). Perianal fistulas and/or abscesses can be found in 4-10% of children with CD at time of diagnosis
(1,20,21,23). Suspicion of IBD is markedly increased in case of IBD in a first degree relative, 12% to 30% of the patients have a positive family history (21).
Diagnostics
It is essential to diagnose IBD early in the course of disease and to distinguish CD from UC, since the course and prognosis of the disease and the choice of treatment depend on type, localization and extent of the disease at first presentation.
There is no single diagnostic test, as “gold standard”, which can reliably distinguish between CD and UC. A definite diagnosis of the type of IBD is based upon a combination of clinical presentation, endoscopic findings, histological abnormalities and small bowel imaging studies (8,24).
Laboratory investigations
Initial laboratory investigations should include a full blood count, liver enzymes, serum albumin, serum levels of urea and creatinine, erythrocyte sedimentation rate (ESR) and C-reactive protein (8,24). A reduced level of hemoglobin, raised markers of inflammation (erythrocyte sedimentation rate, C-reactive protein), elevated platelet count and reduced serum albumin are suggestive of IBD (25). However, laboratory tests may be normal in children with active colitis, especially in mild disease (26-28). Serum inflammatory markers are higher in CD compared with UC (27,29). Presence of serological markers anti-neutrophil cytoplasmic antibody (ANCA) and anti-saccharomyces cerevisae antibody raises the suspicion for a diagnosis of CD or UC, respectively. The diagnostic sensitivity of these serological markers ranges between 60 and 80% (30-33). Calprotectin, a fecal inflammatory parameter, is a useful screening tool to differentiate colitis from non-inflammatory diarrhea (34). This fecal inflammatory marker is superior to markers of inflammation in the blood (35). Furthermore, stool culture is mandatory to exclude infectious diarrhea, and testing for Clostridium difficile toxin is recommended on at least 3 independent stool samples. In children younger than 2 years additional immunological investigations and allergy testing may be necessary to exclude colitis related to primary immunodeficiency or allergic conditions. Testing for the interleukin (IL)-10 axis should be considered for those younger than 1 year (36).
Rectosigmoidoscopy versus (ileo)-colonoscopy
Unlike adult-onset UC, childhood-onset UC is more likely to be extensive, meaning that inflammation extends beyond the splenic flexure or involves the whole colon (table 1). Therefore differentiation between CD and UC can be difficult in children. Data from 8 pediatric studies showed extensive UC in 43% of the children (24). However, more recent studies found extensive UC in up to 90% of children (1,20,22,39).
Table 1. Distribution of UC at diagnosis
Author (Ref.) Year of publication No. of patients Total or extensive % Left-sided % Rectal % Barton* Sawczenko Griffiths Mamula** Levine Kugathasan 37 20 21 38 39 1 1990 2003 2004 2002 2013 2003 396 27 195 36 578 60 43 81 61 40 78 90 34 15 26 60 18 10 23 4 13 *** 5 *** * Pooled data of 8 pediatric studies, ** children all < 5 years, *** data missing.
The higher rates of extensive colitis in the recent studies may reflect a change in diagnostic assessment of children with suspected IBD, using full colonoscopy instead of flexible sigmoidoscopy.
In CD, ileoscopy is of great importance, as isolated small bowel inflammation may occur in the presence of a normal colon in up to 38% of children (table 2).
Table 2. Distribution of CD at diagnosis
Author (Ref.) Year of publication No. of patients Small bowel % Large bowel % Small + large bowel % Sawczenko Dotson Griffiths Barton* Mamula** De Bie *** Kugathasan 20 22 21 37 38 40 1 2003 2010 2004 1990 2002 2013 2003 167 728 386 1221 27 582 129 9 11.6 38 37.5 11 16 25 7 27 20 21 30 27 32 **** 61.4 42 38 59 53 29 * Pooled data of 13 pediatric studies, ** children all < 5 years, *** 4% isolated upper GI disease, **** data missing.
In children, as in adults, the most commonly affected sites are the terminal ileum and right colon. In contrast, when CD is diagnosed in very young children a higher proportion have colonic disease (38,41). Ileoscopy also gives information regarding the extent of inflammation in CD.
Ileocolonoscopy: differentiating Ulcerative Colitis from Crohn’s disease
Many endoscopic lesions in IBD are not specific. Endoscopic features supporting CD are segmental distribution with “skip” areas of normal mucosa, edematous areas (cobblestone), ulcers (aphthous, linear or serpiginious), terminal ileitis, strictures and fistulas (42). Endoscopic features supporting the diagnosis UC includes diffuse and continuous inflammation, beginning in the rectum and extending proximally to a variable extent, erythema, edema and loss of vascular pattern, granularity (wet sand-paper appearance), friability (bleeding with gentle rubbing) and shallow ulcerations or erosions on a background of generalized inflammation (42). During ileocolonoscopy multiple biopsies for histology should be obtained from all segments of the lower intestinal tract (ileum, cecum, ascending colon, transverse colon, descending colon, sigmoid and rectum), from areas of inflammation as well as from healthy looking mucosa. Chong et al. introduced a spectrum of histological criteria which proved to be useful for the clinical assessment of IBD in children (table 3) (43). In children with UC unusual features have been reported like peri-appendiceal inflammation, rectal sparing and rectal patchiness (39,44-48). The prevalence of complete rectal sparing, defined as normal appearance during endoscopy and normal histology, ranges between 3-7% in children (20,45,47). Inflammation of the distal ileum, called backwash ileitis, may develop due to incompetence of the ileocecal valve, which might cause retrograde flow of colonic contents into the terminal ileum. Backwash ileitis is present in 10% of children with UC and pancolitis (39).
Upper gastrointestinal tract endoscopy
The value of upper gastrointestinal tract endoscopy is a topic of debate. The ESPGHAN-IBD Working Group recommends upper gastrointestinal tract endoscopy (UGT) at initial presentation in every child suspected of IBD (8). In contrast, a report from the working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the Crohn’s and Colitis Foundation of America (CCFA) refrained from recommending routine diagnostic use of UGT endoscopy in the diagnostic assessment of children with suspected IBD (49). In general we state that the inflammatory process in UC is limited to the large bowel, whereas CD may occur throughout the entire gastrointestinal tract including the UGT. However, several reports have shown that pathological changes in the UGT can also be found in patients with UC (50-54). Microscopic mucosal lesions in the UGT have been identified in 64%-90% of children with CD and 38%-70% of children with UC (50,51,54,55). Most of these microscopic findings are non-specific and not discriminating between CD and UC. Non-caseating-epitheloid granulomas, the histological hallmark of CD, can be identified by UGT endoscopy in up to 40% of all pediatric CD patients (40,54,56). The fraction of pediatric CD patients whose diagnosis relies on the detection of granulomas in UGT ranges between 3% and 20% (40,51,55,57).
table 3. Histological criteria by chong et al Definite ulcerative colitis
- Acute, diffuse, mucosal inflammation - Severe crypt distortion
- Diffuse globlet cell depletion (mucus depletion) - Increased vascularity
Probable ulcerative colitis
- Diffuse, mucosal inflammation - Mild or moderate crypt distortion - Mucosal atrophy or mucus depletion or
- Diffuse acute and chronic inflammation - Increased vascularity
- Little mucus depletion (suggesting resolving phase)
Probable crohn’s disease
- Focal inflammation
- Submucosal or transmural inflammation - Lymphocytic aggregates (without germinal cells)
- Mucus retention in the presence of more than minimal acute inflammation
Definite crohn’s disease
- Any or all of the above together with non-caseating epitheloid granulomas
Small bowel imaging
Small bowel investigation, small bowel follow through (SBFT) or MRI enteroclysis, is indicated in all patients at diagnosis (except in definite cases of UC) to guide therapeutic management and to detect possible complications of small bowel involvement in CD including stenosis, structuring or internal fistulae (8). Batres et al. showed that SBFT is limited by its low sensitivity (46%) in detecting terminal ileum involvement, with the terminal ileum biopsy as the “gold standard”. Approximately 31% of patients had a normal SBFT study and abnormal terminal ileum histology (58). Contrast enhanced magnetic resonance imaging (CE-MRI) is a newer, more sensitive and specific test for the detection of distal ileitis compared to SBFT (59,60), but more validation studies are needed. With CE-MRI superficial mucosal lesions can be missed due to inadequate spatial resolution of the CE-MRI (61). Capsule endoscopy is another promising imaging technique that allows endoluminal examination of the small bowel using a wireless capsule-shaped tool which is usually swallowed and then propelled through the gastrointestinal tract by gut motility (62,63).
Imaging studies of the small bowel play an important role in the complete diagnostic assessment of childhood IBD, although up till now these imaging techniques cannot replace ileocolonoscopy.
treatment
The management principles of treatment of IBD are to induce (control inflammation) and to maintain remission, and specifically in children to restore growth. Although remission can be considered at clinical and biochemical levels, histological remission (normalization of histological abnormalities or mucosal healing) is seen as ideal goal of treatment. In clinical practice, a ‘step-up’ approach of adding therapies if first-line or less-toxic approaches are unsuccessful within an appropriate period, is commonly used.
Figure 1. and 2. show a treatment flow chart for CD and UC in children, based on the national guideline on diagnosis and treatment of pediatric IBD (24).
management of cD:
Corticosteroids
Historically, corticosteroids have been the most commonly used class of medication for induction of remission in CD. Corticosteroids are effective for induction of remission, but not recommended for maintenance therapy in pediatric CD (64). Although most pediatric patients with CD respond to corticosteroids, initial steroid resistance occurs in 12-20% of pediatric patients with CD (65). In adults with CD, conventional corticosteroids have been found to be more effective for induction of remission than budesonide, although budesonide may be equivalent to systemic corticosteroids for ileal, cecal and ascending colon inflammation (66). In children with disease confined to the ileum or ascending colon conventional corticosteroids seem to be superior to budesonide (67). Budesonide is not recommended for maintenance of remission in pediatric CD (68).
Figure 1. Treatment flowchart for CD in children
Exclusive enteral nutrition
Whilst corticosteroids have traditionally been utilized to induce remission in active IBD, there is increasing support and rationale for exclusive enteral nutrition (EEN) in CD. EEN involves the sole administration of a nutritional formula (elemental, semi-elemental or polymeric formula), with exclusion of normal diet, for a period of up to 10 weeks (69). EEN has remission rates equivalent to those of corticosteroids, but has numerous advantages such as avoiding steroid related side effects and more importantly leads to superior rates of mucosal healing and promotes growth (69-71).
Clinical improvement < 3 weeks Remission Remission Relapse Relapse Continue exclusive enteral
nutrition (6 weeks) and 6-MP/AZA
Exclusive enteral nutrition or corticosteroids and methotrexate
Infliximab/adalimumab and 6-MP/AZA or methotrexate maintenance treatment Exclusive enteral nutrition
and 6-MP/AZA
Refusal or intolerance of exclusive enteral nutrition
Corticosteroids and 6-MP/AZA 6-MP/AZA maintenance treatment Methotrexate maintenance treatment Crohn’s disease i i i i i i i i i iYes No No No Yes Yes i i i i i i i
Aminosalicylates
The role of 5-aminosalicylate (5-ASA) compounds as maintenance treatment in children with CD is unclear, because no studies are available in children. Extrapolation from the adult literature suggests that 5-ASA therapy has no advantage over placebo (72).
Imunomodulators: thiopurines and methotrexate
There are two types of thiopurines approved for the treatment of pediatric IBD; azathioprine and 6-mercaptopurine. Both are effective for the maintenance of remission in pediatric CD. Early introduction of thiopurines at the time of remission induction in moderate-severe CD leads to more prolonged remission and less steroid requirement (73-75). Methotrexate, another immunomodulator, is an alternative if these drugs are not tolerated or are ineffective, and has shown steroid-sparing effects in retrospective cohort studies (76-79).
Biologicals
Currently, two anti-tumor necrosis factor (TNF) agents are approved for the treatment of pediatric CD, infliximab and adalimumab. Infliximab is a monoclonal chimeric anti-TNF antibody (75% human, 25% murine), whereas adalimumab is a fully humanized monoclonal anti-TNF antibody. Both anti-TNF agents are effective for induction of remission and as a maintenance therapy in pediatric CD patients with moderate-severe disease who are refractory to or intolerant of conventional therapy (80-84). Maintenance infliximab and adalimumab have a steroid-sparing effect (81,83), as well as a benefit on growth (81,83,85,86). Data on the use of alternative anti-TNF agents, such as certolizumab and natalizumab, are only available for adults, results from pediatric trials are awaited.
Probiotics
Probiotics have not been proven to be beneficial in treating children and adults with CD (87).
Surgery
Surgical treatment may be indicated in the treatment of complications such as strictures, perianal fistulas and abcesses and sometimes in children with disease resistant to medical therapies. Early intervention should be considered in the presence of growth failure in pre-pubertal or early pubertal children with localized ileo-cecal disease, because the ‘window of opportunity’ might have lapsed once puberty has started (72).
management of uc
Aminosalicylates
For mild to moderately active UC, mesalazine and sulfasalazine, both oral 5-ASA compounds, are recommended as first-line induction therapy and for maintenance of remission (88). Sulfasalazine is associated with more adverse effects compared to mesalazine. 5-ASA
therapy is effective for inducing remission in mild to moderate UC in children (89-91) and for maintaining remission (92). Monotherapy with topical 5-ASA may be effective in selected children with mild to moderate proctitis, however this is a rare pediatric phenotype (93).
Corticosteroids
Patients who fail to respond to 5-ASA or who have severe disease can be initially treated with oral steroids. Oral steroids are effective for inducing remission in pediatric UC, but not recommended for maintaining remission (88,95,96). Initial steroid resistance occurs in 4-21% of pediatric patients with UC (65). At present, there is no evidence to recommend the clinical use of oral budesonide for the induction of remission in active UC (94). In IBD patients receiving steroids growth is a special concern (97).
Imunomodulators: thiopurines and methotrexate
In children with 5-ASA intolerance, frequently relapsing or steroid-dependent disease, thiopurines are recommended for maintaining remission. Thiopurines are effective for the maintenance of remission in children with UC and has shown steroid-sparing effects, but is ineffective for induction of remission (75,98,99). The presently available evidence is insufficient to recommend the use of methotrexate in pediatric UC (100).
Biologicals
Currently, one anti-tumor necrosis factor (TNF) agent is approved for the treatment of pediatric UC, infliximab. Infliximab should be considered for treatment of children with persistently active, or steroid-dependent UC, uncontrolled by 5-ASA and thiopurines. Infliximab is effective for induction of remission and as a maintenance therapy in pediatric UC patients (101-103) and has been effective in avoiding or at least delaying the need for surgery (103). Data on the use of alternative anti-TNF agents, such as adalimumab, certolizumab and natalizumab, are not available.
Cyclosporin
Cyclosporin is successful in children with severe acute colitis but its use should be restricted to 3-4 months while bridging to thiopurine treatment, because of its relatively high toxicity profile. In those already on thiopurine, infliximab should be preferred. The short-term success rate of infliximab is similar to cyclosporine. However, infliximab seems to be superior on the long term (104).
Figure 2. Treatment flowchart for UC in children Remission Remission Remission Relapse Relapse Relapse Relapse 5-aminosalicylate and corticosteroids (po/iv) Infliximab and 5-aminosalicylate and 6-MP/AZA maintenance treatment 5-aminosalicylate and 6-MP/AZA maintenance treatment and corticosteroids (po/iv) Colectomy Ulcerative colitus 5-aminosalicylate 5-aminosalicylate maintenance treatment 5-aminosalicylate maintenance treatment 5-aminosalicylate and 6-MP/AZA maintenance treatment i i i i i i i i i i i i No No No Yes Yes Yes i i i i i i
Probiotics
Three small pediatric trials have suggested efficacy of probiotics in pediatric UC, VSL#3 (in addition to standard treatment) and Escherichia coli Nissle 1917 (105-107). Another pediatric study showed that in children with active distal ulcerative colitis, rectal infusion of Lactobacillus reuteri is superior to placebo in improving mucosal inflammation (108). However, there is insufficient evidence to recommend routine probiotic therapy to pediatric patients with UC for induction or maintenance of remission (88).
Surgery
As a last resort elective colectomy may be indicated in children with active or steroid-dependent UC despite maximal treatment. The colectomy rate in pediatric-onset UC is 20-29% at 5 years (109-111), although one pediatric study reported a colectomy rate of 5% at 5 years (112).
One important factor in achieving optimal outcomes for children with IBD is medication adherence. The documented rates of medication adherence in adolescents have been reviewed and are presented in chapter 6.
Psychosocial consequences
Pediatric IBD can affect many areas of psychosocial functioning. Adolescents with IBD seem to be more depressed than adolescents with other chronic diseases and healthy adolescents (113-115), with rates as high as 25% (116). In addition, depressed adolescents with IBD have been shown to be at higher risk for anxiety (117,118). Data suggest that adolescents with IBD have lower health related quality of life (HRQoL) compared to healthy peers based on both adolescents and parent-report, specifically in total, psychosocial and physical health domains (116,119). Several domains of risk factors for impaired HRQoL have been cross-sectionally investigated, including disease-related, psychosocial, and relationship factors. Higher disease activity (120-124), the use of less adaptive coping strategies (121), and family problems related to problem-solving, communication, and general functioning (123) have all been associated with poorer HRQoL. Furthermore, symptoms of IBD, in addition to changes in physical appearance due to treatment, can cause withdrawal from social activities and problematic social functioning. Adolescents with IBD report significantly worse social functioning compared to healthy children (116). Onset of IBD during adolescence is associated with worse social functioning (125). Pediatric IBD can also affect parents and siblings and can be a source of increased stress among family members. This can disrupt overall family function and adversely affect the physical and psychosocial health of adolescents (126). However, research findings on family function in pediatric IBD are inconsistent. Some have documented significantly more dysfunction among families of patients with IBD compared to healthy controls (127),
whereas others report no differences (125). In pediatric IBD, parents are found to exhibit heightened levels of emotional stress (128) and increased rates of depression (129). Poorer psychosocial functioning among mothers of adolescents with IBD has been linked to greater adolescent depressive symptoms, more negative IBD outcomes (130) and greater IBD-related functional disability in daily activities (131). Moreover, higher levels of parental stress are associated with poorer adolescent HRQoL (123). Health care physicians working with children and adolescents with IBD should be attentive to the increased risk for internalizing disorders (e.g. depression, anxiety), poor HRQoL and social problems. Patients at risk for an unfavorable psychosocial development should be identified and psychosocial support should be offered. Psychoeducational group interventions can have a positive effect on the HRQoL and feelings of competence of adolescents with IBD (132).
reFerences
1. Kugathasan S, Judd RH, Hoffmann RG. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Winsconsin: a statewide population-based study. J Pediatr 2003;143:525-31
2. Mamula P, Telega GW, Markowitz JE. Inflammatory bowel disease in children 5 years of age or younger. Am J Gastroenterol 2002;97:2005-10
3. Carvalho RS, Abadom V, Dilworth HP, et al. Indeterminate colitis: a significant subgroup of pediatric IBD. Inflamm Bowel Dis 2006;12:258-62
4. Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease: analysis of a pediatric IBD consortium registry. J Pediatr 2005;146:35-40
5. Hildebrand H, Fredrikzon B, Holmquist H, et al. Chronic inflammatory bowel disease in children and adolescents in Sweden. J Pediatr Gastroenterol Nutr 1991;13:293-7
6. De Bie CI, Buderus S, Sandhu BK, et al. Diagnostic work-up of pediatric inflammatory bowel disease patients in Europe: results of a 5-year audit of the Eurokids registry. J Pediatr Gastroenterol Nutr 2012;54:374-80
7. Geboes K, Colombel JF, Greenstein A, et al. Indeterminate colitis: a review of the concept—what’s in a name? Inflamm Bowel Dis 2008;14:850-7
8. IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), Inflammatory bowel disease in children and adolescents: recommendations for diagnosis – The Porto criteria. J Pediatr Gastroenterol Nutr 2005;41:1-7
9. Nieuwenhuis EE, Escher JC. Early onset IBD: what’s the difference? Dig Liver Dis 2008;40:12-5 10. Calkins BM, Mendeloff AL. Epidemiology of inflammatory bowel disease. Epidemiol Rev
1986;8:60-91
11. Binder V. Epidemiology of IBD during the twentieth century: an integrated view. Best Pract Res Clin Gastroenterol 2004;18:463-79
12. Benchimol EI, Fortinsky KJ, Godzdyra MA, et al. Epidemiology of Pediatric Inflammatory Bowel Disease: A Systematic Review of International Trends. Inflamm Bowel Dis 2011;17:423-39
13. Burisch J, Pedersen N, Cukovic-Cavka S, et al. East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort. Gut 2013; Apr 20: Epub ahead of print
14. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011;474:307-17
15. Rogler G. Interaction between susceptibility and environment: examples from the digestive tract. Dig Dis 2011;29:136-43
16. Spehlmann ME, Begun AZ, Burghardt J, et al. Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study. Inflamm Bowel Dis 2008;14:968-76 17. Jess T, Riis L, Jespersgaard C, et al. Disease concordance, zygosity, and NOD2/CARD15 status:
follow-up of a population-based cohort of Danish twins with inflammatory bowel disease. Am J Gastroenterol 2005;100:2486-92
18. Kugathasan S, Amre D. Inflammatory bowel disease- environmental modification and gene determinants. Pediatr Clin North Am 2006;53:727-49
19. de Ridder LWR, Dijkstra G, van der Steege G, et al. Genetic susceptibility has a more important role in pediatric-onset Crohn’s disease than in adult-onset Crohn’s disease. Inflamm Bow Dis 2007;13:1083-92
20. Sawczenko A, Sandhu BK. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child 2003;88:995-1000
21. Griffiths AM. Specificities of inflammatory bowel disease in childhood. Best Pract Res Clin Gastroenterol 2004;18:509-23
22. Dotson JL, Hyams JS, Markowitz J, et al. Extraintestinal manifestations of pediatric inflammatory bowel disease and their relation to disease type and severity. J Pediatr Gastroenterol Nutr 2010;51:140-5
23. Keljo DJ, Markowitz J, Langton C, et al. Course and treatment of perianal disease in children newly diagnosed with Crohn’s disease. Inflamm Bow Dis 2009;15:383-7
24. CBO guideline on diagnosis and treatment of pediatric IBD. 2008. Available at: http://www.cbo. nl/downloads/506/rl_ibd_k_08.pdf. Accessed June 22, 2010
25. Beattie RM, Walker-Smith JA, Murch SH. Indications for investigation of chronic gastrointestinal symptoms. Arch Dis Child 1995;73:354-5
26. Cabrera-Abreu JC, Davies P, Matek Z, et al. Performance of blood tests in diagnosis of inflammatory bowel disease in a special clinic. Arch Dis Child 2004;89:69-71
27. Mack DR, Langton C, Markowitz J. Laboratory values for children with newly diagnosed inflammatory bowel disease. Pediatrics 2007;119:1113-9
28. Turner D, Mack DR, Hyams J, et al. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) or both? A systematic evaluation in pediatric ulcerative colitis. J Crohns Colitis 2011;5:423-9 29. Weinstein TA, Levine M, Pettei MJ, et al. Age and family history at presentation of pediatric
inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2003;37:609-13
30. Olives JP, Breton A, Hugot JP, et al. Antineutrophil cytoplasmatic antibodys in children with inflammatory bowel disease: prevalence and diagnostic value. J Pediatr Gastroenterol Nutr 1997;25:142-8
31. Ruemmele FM, Targan SR, Levy G, et al. Diagnostic accuracy of serological assays in pediatric inflammatory disease. Gastroenterology 1998;115:822-9
32. Hoffenberg EJ, Fidanza S, Sauaia A. Serological testing for inflammatory bowel disease. J Pediatr 1999;134:447-52
33. Khan K, Schwarzenberg SJ, Sharp H, et al. Role of serology and routine laboratory tests in childhood inflammatory bowel disease. Inflamm Bowel Dis 2002;8:325-9
34. Van Rheenen PF, Vann de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease; diagnostic meta-analysis. BMJ 2010;341:c3369 35. Henderson P, Casey A, Lawrence SJ, et al. The diagnostic accuracy of fecal calprotectin during
the investigation of suspected pediatric inflammatory bowel disease. Am J Gastroenterol 2012;107:941-9
36. Moran CJ, Walters TD, Guo CH, et al. Il-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis 2013:19;115-23
37. Barton JR, Ferguson A. Clinical features, morbidity and mortality of Scottish children with inflammatory bowel disease. Q J Med 1990;75:423-39
38. Mamula P, Telega GW, Markowitz JE. Inflammatory bowel disease in children 5 years of age or younger Am J Gastroenterol 2002;97:2005-10
39. Levine A, de Bie CI, Turner D, et al. Atypical disease phenotypes in pediatric ulcerative colitis: 5-year analyses of the EUROKIDS Registry. Inflamm Bow Dis 2013;19:370-7
40. de Bie CI, Paerregaard A, Kolacek S, et al. Disease phenotype at diagnosis in pediaric Crohn’s disease: 5-year analysis of the EUROKIDS Registry. Inflamm Bowel Dis 2013;19:378-85
41. Sawczenko A, Sandhu B, Logan R, et al. Prospective national data on inflammatory bowel disease in children aged less than five years. Arch Dis Child 2001;84:A21
42. Williams CB, Nicholls S. Endoscopic features of chronic inflammatory bowel disease in childhood. Baillieres Clin Gastroenterol 1994;8:121-31
43. Chong SKF, Blackshaw AJ, Boyle S, et al. Histological diagnosis of chronic inflammatory bowel disease in childhood Gut 1985;26:55-9
44. Haskell H, Andrews CW, Reddy SI, et al. Pathologic features and clinical significance of “backwash” ileitis in ulcerative colitis Am J Surg Pathol 2005;29:1472-81
45. Glickman JN, Bousvarous A, Farraye FA, et al. Pediatric patients with untreated ulcerative colitis may present initially with unusual morphologic findings. Am J Surg Pathol 2004;28:190-7 46. Markowitz J, Kahn E, Grancher K, et al. Atypical rectosigmoid histology in children with newly
diagnosed ulcerative colitis. Am J Gastroenterol 1993;88:2034-7
47. Rajwal SR, Puntis JWL, McClean P, et al. Endoscopic rectal sparing in children with untreated ulcerative colitis. J Pediatr Gastroenterol Nutr 2004;38:66-9
48. Kahn E, Markowitz J, Daum F. The appendix in inflammatory bowel disease in children. Mod Pathol 1992;5:380-3
49. Bousvarous A, Antonioli DA, Colletti RB, et al. Differentiating ulcerative colitis from Crohn disease in children and young adults : report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation
of America. J Pediatr Gastroenterol Nutr 2007;44: 653-74
50. Abdullah BA, Gupta SK, Croffie JM, et al. The role of esophagogastroduodenoscopy in the initial evaluation of childhood inflammatory bowel disease: a 7 year study. J Pediatr Gastroenterol Nutr 2002;35:636-40
51. Castellaneta SP, Afzal NA, Greenberg M, et al. Diagnostic role of upper gastrointestinal endoscopy in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2004;39:257-61
52. Kaufman SS, Vanderhoof JA, Young R. Gastroenteric inflammation in children with ulcerative colitis. Am J Gastroenterol 1997;92:1209-12
53. Ruuska T, Vaajalahti P, Arajärvi P, et al. Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn’s disease. J Pediatr Gastroenterol Nutr 1994;19:181-6
54. Tobin JM, Sinha B, Ramani P, et al. Upper gastrointestinal mucosal disease in pediatric Crohn disease and ulcerative colitis : a blinded, controlled study. J Pediatr Gastroenterol Nutr 2001;32:443-8
55. Lemberg DA, Clarkson CM, Bohane TD, et al. Role of esophagogastroduodenoscopy in the initial assessment of children with inflammatory bowel disease. J Gastroenterol Hepatol 2005;20:1696-1700
56. De Matos V, Russo PA, Cohen AB, et al. Frequency and clinical correlations of granulomas in children with Crohn disease. J Pediatr Gastroenterol Nutr 2008;46(4): 392-8
57. Kundhal PS, Stormon MO, Zachos M. Gastral antral biopsy in the differentiation of pediatric colitides. Am J Gastroenterol 2003;98:557-61
58. Batres LA, Maller ES, Ruchelli E, et al. Terminal ileum intubation in pediatric colonoscopy and diagnostic value of conventional small bowel contract radiography in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002;35:320-3
59. Laghi A, Borreli O, Paolantonio P, et al. Contrast enhanced magnetic resonance imaging of the terminal ileum in children with Crohn’s disease. Gut 2003;52:393-7
60. Darbari A, Sena L, Argani P, et al. Gadolinium-enhanced magnetic resonance imaging: a useful radiologic tool in diagnosing pediatric IBD. Inflamm Bowel Dis 2004;10: 67-72
61. Horsthuis K, Bipat S, Stokkers PC. Magnetic resonance imaging for evaluation of disease activity in Crohn’s disease: a systematic review. Eur Radiol 2009;19:1450-60
62. Bourreille A, Ignjatovic A, Aabakken L, et al. Role of small-bowel endoscopy in the management of patients with inflammatory bowel disease; an international OMED-ECCO consensus. Endoscopy 2009;41:618-37
63. Di Nardo G, Oliva S, Ferrari F, et al. Usefulness of wireless capsule endoscopy in paediatric inflammatory bowel disease. Dig Liver Dis 2011;43:220-4
64. Benchimol EL, Seow CH, Steinhart AH, et al. Traditional corticosteroids for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2008; issue 16
65. Tung J, Loftus EV jr, Freese DK, et al. A population based study of the frequency of corticosteroid resistance and dependence in pediatric patients with Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis;12:1093-1100
66. Otley A, Steinhart AH. Budesonide for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2009; issue 1
67. Escher JC, European Collaborative Research Group on Budesonide in Pediatrc IBD. Budesonide versus prednisolone for the treatment of active Crohn’s disease in children: a randomized, double-blind, controlled, multicentre trial. Eur J Gastroenterol 2004;16:47-54
68. Benchimol EL, Seow CH, Otley AR. Budesonide for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2005; issue 4
69. Dziechciarz P, Horvath A, Shamir R, et al. Meta-analyses: enteral nutrition in active Crohn’s disease in children. Aliment Pharmacol Ther 2007;26:795-806
70. Heuschkel RB, Menache CC, Megerian JT, et al. Enteral nutrition and corticosteroids in the treatment of acute Crohn’s disease in children. J Pediatr Gastroenterol Nutr 2000;31:8-15 71. Borelli O, Cordischi L, Cirulli M, et al. Polymeric diet alone versus corticosteroids in the treatment
of active pediatric Crohn’s disease: a randomized controlled open-label trial. Clin Gastroenterol Hepatol 2006;4:744-53
72. Van Assche G, Dignass A, Reinisch W, et al. The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: special situations. J Crohns Colitis 2010;4:63-101
73. Punati J, Markowitz J, Lerer T, et al. Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm Bowel Dis 2008;14:949-54
74. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 2000;119:895-902 75. Barabino A, Torrente F, Ventura A, et al. Azathioprine in pediatric inflammatory bowel disease:
an italian multicentre survey. Aliment Pharmacol Ther 2002;16:1125-30
76. Mack DR, Young R, Kaufmann SS, Ramey L, et al. Methotrexate in patients with Crohn’s disease after 6-mercaptopurine. J Pediatr 1998;132:830-5
77. Uhlen S, Belbouab R, Narebski K, et al. Efficacy of methotrexate in pediatric Crohn’s disease: a French multicenter study. Inflamm Bowel Dis 2006;12:1053-7
78. Ravikumara M, Hinsberger A, Spray CH. Role of methotrexate in the management of Crohn disease. J Pediatr Gastroenterol Nutr 2007;44:427-30
79. Turner D, Grossman AB, Rosh J, et al. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn’s disease. Am J Gastroenterol 2007;102:2804-12
80. de Bie CI, Escher JC, de Ridder L. Antitumor necrosis factor treatment for pediatric inflammatory bowel disease. Inflamm Bowel Dis 2012;18:985-1002
81. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintainance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology 2007;132:863-73
82. Ruemmele FM. Lachaux A, Cezard JP, et al. Efficacy of infliximab in pediatric Crohn’s disease: a randomized multicenter open-label trial comparing scheduled to on demand maintenance therapy. Inflamm Bowel Dis 2009;15:388-94
83. Hyams JS, Griffiths A, Markowitz J. Safety and efficacy of adalimumab for moderate to severe Crohn’s disease in children. Gastroenterology 2012,143:365-74
84. Russell RK, Wilson ML, Loganathan S, et al. A British Society of Pediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease. Aliment Pharmacol Ther 2011;33:946-53
85. Walters TD, Gilman AR, Griffiths AM. Linear growth improves during infliximab therapy in children with chronically active severe Crohn’s disease. Inflamm Bowel Dis 2007,13:424-30
86. Malik S, Ahmed SF, Wilson ML. The effects of anti-TNF-alpha treatment with adalimumab on growth in children with Crohn’s disease. J Crohns Colitis 2012,6:337-44
87. Scaldaferri F, Gerardi V, Lopetuso LR, et al. Gut microbial flora, prebiotics, and probiotics in IBD: their current usage and utility. Biomed Res Int 2013;epub
88. Turner D, Levine A, Escher JC, et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nutr 2012;55:340-61 89. Romano C, Famiani A, Comito D, et al. Oral beclomethasone dipropionate in pediatric active
ulcerative colitis: a comparison trial with mesalazine. J Pediatr Gastroenterol Nutr 2010;50:385-9 90. Quiros JA, Heyman MB, Pohl JF, et al. Safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate active ulcerative colitis: results of a randomized, double-blind study. J Pediatr Gastroenterol Nutr 2009;49:571-9
91. Ferry GD, Kirschner BS, Grand RJ, et al. Olsalazine versus sulfasalazine in mild to moderate childhood ulcerative colitis: results of the Pediatric Gastroenterology Collaborative Research Group Clinical Trial. J Pediatr Gastroenterol Nutr 1993;17:32-8
92. Zeisler B, Lerer T, Markowitz J. Outcome following aminosalicylate therapy in children newly diagnosed as having ulcerative colitis. J Pediatr Gastroenterol Nutr 2013;56:12-8
93. Heyman MB, Kierkus J, Spénard J, et al. Efficacy and safety of mesalamine suppositories for treatment of ulcerative proctitis in children and adolescents. Inflamm Bowel Dis 2010;16:1931-9 94. Sherlock ME, Seow CH, Steinhart AH, et al. Oral budesonide for induction of remission in
ulcerative colitis. Cochrane Database Syst Rev 2010; issue 10
95. Beattie RM, Nicholis SW, Domizio P, et al. Endoscopic assessment of the colonic response to corticosteroids in children with ulcerative colitis. J Pediatr Gastroenterol Nutr 1996;22:373-9 96. Sidoroff M, Kolho KL. Glucocorticoids in pediatric inflammatory bowel disease. Scand
97. Pappa H, Thayu M, Sylvester F, et al. Skeletal health of children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011;53:11-25
98. Hyams JS, Lerer T, Mack D, et al. Outcome following thiopurine use in children with ulcerative colitis: a prospective multicenter registry study. Am J Gastroenterol 2011;106:981-7
99. Kader HA, Mascarenhas MR, Piccoli DA, et al. Experiences with 6-mercaptopurine and azathioprine therapy in pediatric patients with severe ulcerative colitis. J Pediatr Gastroenterol Nutr 1999;54-8
100. Aloi M, Di Nardo G, Conte F, et al. Methotrexate in paediatric ulcerative colitis: a retrospective survey at a single tertiary referral centre. Aliment Pharmacol Ther 2010;32:1017-22
101. Turner D, Griffiths A. Acute severe ulcerative colitis in children: a systematic review. Inflamm Bowel Dis 2011;17:440-9
102. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:391-9. 103. Hyams JS, Lerer T, Griffiths A, et al. Outcome following infliximab therapy in children with ulcerative colitis. Am J Gastroenterol 2010;105:1430-6
104. Turner D, Griffiths AM. Acute severe ulcerative colitis in children: a systematic review. Inflamm Bowel Dis 2011;17:440-9
105. Miele E, Pascarella F, Gianetti E, et al. Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. Am J Gastroenterol 2009;104:437-43 106. Huynh HQ, deBruyn J, Guan L, et al. Probiotic preparation VSL#3 induces remission in children with mild to moderate acute ulcerative colitis: a pilot study. Inflamm Bowel Dis 2009;15:760-8 107. Henker J, Müller S, Laass MW, et al. Probiotic Escherichia coli Nissle 1917 for succesful remission maintenance of ulcerative colitis in children and adolescents: an open-label pilot study. Z Gastroenterol 2008;46:874-5
108. Oliva S, Di Nardo G, Ferrari F, et al. Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis. Aliment Pharmacol Ther 2012;35:327-34
109. Van Limbergen J, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008;135:1114-22
110. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol 2009;104;2080-8 111. Langholz E, Munkholm P, Krasilnikoff PA, et al. Inflammatory bowel disease with onset in childhood. Clinical features, morbidity, and mortality in a regional cohort. Scan J Gastroenterol 1997;32:139-47
112. Jakobsen C, Bartek J Jr, Wewer V, et al. Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease- a population based studie. Aliment Pharmacol Ther 2011;34:1217-24
113. Burke P, Meyer V, Kocoshis S, et al. Depression and anxiety in pediatric inflammatory bowel disease and cystic fibrosis. J Am Acad Child Adolesc Psychiatry 1989;28:948-51
114. Engström I. Mental health and psychological functioning in children and adolescents with inflammatory bowel disease: a comparison with children having other chronic illnesses and with healthy children. J Child Psychol Psychiatry 1992;33:563-82
115. Szigethy E, Levy-Warren A, Whitton S, et al. Depressive symptoms and inflammatory bowel disease in children and adolescents: a cross-sectional study. J Pediatr Gastroenterol Nutr 2004;39:395-403
116. Greenley RN, Hommel KA, Nebel J, et al. A meta-analytic review of the psychosocial adjustment of youth with inflammatory bowel disease. J Pediatr Psychol 2010;35:857-69
117. Engström I, Lindquist BL. Inflammatory bowel disease in children and adolescents: a somatic and psychiatric investigation. Acta Paediatr Scand 1991;80:640-7
118. Mackner LM, Crandall WV, Szigethy EM. Psychosocial functioning in pediatric inflammatory bowel disease. Inflamm Bowel Dis;12:239-44
119. Ross SC, Strachan J, Russel RK, et al. Psychosocial functioning and health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011;53:480-8
120. Otley AR, Griffiths AM, Hale S, et al. Health related quality of life in the first year after diagnosis of pediatric inflammatory bowel disease. Inflamm Bowel Dis 2006;12:684-91
121. Van der Zaag-Loonen HJ, Grootenhuis MA, Last BF, et al. Coping strategies and quality of life of adolescents with inflammatory bowel disease. Qual Life Res 2004;13:1011-9
122. Kunz JH, Hommel KA, Greenley RN. Health-related quality of life of youth with inflammatory bowel disease: a comparison with published data using the PEDsQL 4.0 generic core scales. Inflamm Bowel Dis 2010;16:939-46
123. Herzer M, Denson LA, Baldassano RN, et al. Family functioning and health-related quality in adolescents with pediatric inflammatory bowel disease. Eur J Gastroenterol Hepatol 2011;23:95-100
124. Perrin JM, Kuhlthau K, Chughtai A, et al. Measuring quality of life in pediatric patients with inflammatory bowel disease: psychometric and clinical characteristics. J Pediatr Gastroenterol Nutr 2008;46:164-71
125. Mackner LM, Crandall WV. Brief report: psychosocial adjustment in adolescents with inflammatory bowel disease. J Pediatr Psychol 2006;31:281-5
126. Mackner LM, Greenley RN, Szigethy E, et al. Psychosocial issues in pediatric inflammatory bowel disease: Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2013;56:449-58
127. Engström I. Mental health and psychological functioning in children and adolescents with inflammatory bowel disease: a comparison with children having other chronic illnesses and with healthy children. J Child Psychol Psychiatr 1992; 33:563-82
128. Engström I. Parental distress and social interactions in families with children with inflammatory bowel disease. J Am Acad Child Adolesc Psychiatry 1991;30:904-12
129. Burke PM, Kocoshis S, Neigut D, et al. Maternal psychiatric disorders in pediatric inflammatory bowel disease and cystic fibrosis. Child Psychiatry Hum Dev 1994;25:45-52
130. Tojek TM, Lumley MA, Corlis M, et al. Maternal correlates of health status in adolescents with inflammatory bowel diseas. J Psychosom Res 2002;52:173-9
131. Engström I. Inflammatory bowel disease in children and adolescents: Mental health and family functioning. J Pediatr Gastroenterol Nutr 1999;28:S28-33
132. Grootenhuis MA, Maurice-Stam H, Derkx BH. Evaluation of a psychoeducational intervention for adolescents with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2009;21:430-5
