3.1 Management of Crohn Disease
The benefits and risks of any treatment should be discussed openly with patients and their family, particularly in relation to steroids and immunomodulators. Factors such as the potential risk of immunosuppression, bone marrow suppression, and malignancy must be discussed and the discussion recorded in the case notes. Disease activity can be expressed using a disease activity index such as the Paediatric Crohn's Disease Activity Index (26).
3.1.0 Induction of Remission at Diagnosis or Disease Relapse (27–72)
The choice of treatment in most cases is between exclusive enteral nutrition and oral corticosteroids. This is concordant with the BSG guidelines, which also state that there is insufficient evidence to recommend the use of other agents outside trials/specialist centres. Recently, some centres have started using azathioprine at diagnosis for those with severe disease. Azathioprine prevents relapse, but it is not fully effective until at least 3 months after starting the drug.
3.1.1 Exclusive Enteral Nutrition (27–35) Evidence Levels (EL) 1+ to 1-, 2-, 3, and 4
* Exclusive enteral nutrition is an effective first-line therapy for small and large bowel disease, inducing remission in 60% to 80% of cases.
* Factors that influence the use of exclusive enteral nutrition include patient and parent choice, compliance, palatability, lack of corticosteroid toxicity, and potential benefits in terms of improved nutritional status and growth.
* The choice is between polymeric (eg, Modulen IBD, Alicalm) or elemental (eg, EO28) feeds. There appears to be no significant difference in efficacy between the 2. Both feeds are available in different flavours and it has been suggested that polymeric feeds may be more palatable. Administration via a nasogastric tube or gastrostomy is an option.
* Duration of exclusive enteral nutrition is usually 6 weeks. Most children need approximately 120% of reference nutrient intake; this, however, needs to be tapered according to individual needs, and dietetic support is essential. Food may be reintroduced cautiously during the course of 1 to 3 weeks, dependent on patient symptoms whilst weaning the enteral feed.
3.1.2 Corticosteroids (35–40) EL1-, 2-, 3, and 4
* Prednisolone 1 to 2 mg · kg−1 · day−1 (maximum 40 mg/day) is an effective first-line therapy for small and large bowel disease.
* Treatment should be at full dose for 2 to 4 weeks until remission achieved (with review at least every 2 weeks in clinic or via telephone, until clinical remission) and thereafter gradual reduction of the dose for 4 to 8 weeks depending on the response.
* Ensure adequate dietary intake of calcium and vitamin D and if insufficient, consider supplement (eg, Calcichew D3 tablet daily).
* Gastric acid suppression with proton pump inhibitors (eg, omeprazole) may be required in the presence of gastritis.
3.1.3 Other Management Strategies at Induction (41–50)
* Antibiotics (EL3): metronidazole (7.5 mg · kg−1 · dose−1 tds) ± ciprofloxacin (5 mg · kg−1 · dose−1 bd) for perianal disease
* Aminosalicylates (EL1-, 3) in high dose (mesalazine 50–100 mg · kg−1 · day−1, maximum 3–4 g/day or sulphasalazine 40–60 mg · kg−1 · day−1, maximum 3 g/d, can increase to 100 mg · kg−1 · day−1 if tolerated): may be effective in mild disease. Topical mesalazine is effective in mild to moderate left-sided colitis. Regular blood monitoring of liver and renal functions every 6 months is essential.
* Budesonide 9 mg/day (EL1-, 3): less effective than prednisolone as first-line therapy for isolated ileocaecal disease, but it has fewer side effects
* Intravenous (iv) steroids (EL3): iv steroids (hydrocortisone 2 mg/kg qds, maximum 100 mg qds, or methylprednisolone 2 mg/kg od, 60 mg/day maximum) should be given to children with severe disease at presentation.
* Azathioprine (EL3): may be introduced immediately (after checking thiopurine methyltransferase [TPMT] levels are satisfactory) in those with severe disease, but takes at least 3 months to be fully effective.
* Surgery for complication (eg, abscess/fistula) after MRI pelvis to assess extent of perianal disease
* Parenteral nutrition (EL3) may be required as nutritional support for patients with severe complicated disease.
3.1.4 Refractory or Nonresponsive CD (51–78)
Patients in whom standard induction therapy, including high-dose intravenous steroids, has failed to induce remission either at diagnosis or during subsequent relapse are defined as having nonresponsive CD. Steroid refractory CD may be defined as active disease despite an adequate dose (1–2 mg · kg−1 · day−1; minimum 20 mg/day) and duration (at least 2 weeks) of steroid therapy. Such patients should be considered for treatment with immunomodulators if surgery is not an immediate consideration.
* Azathioprine (2–2.5 mg · kg−1 · day−1) or 6-mercaptopurine (1–1.25 mg · kg−1 · day−1) (EL3), after checking that TPMT levels are satisfactory. Of the patients who are intolerant to azathioprine, up to 50% will tolerate 6-mercaptopurine.
* Methotrexate 15 mg/m2 (EL3), once weekly given subcutaneously. Remission usually occurs within 4 weeks but further improvement may be seen after 16 weeks. Parenteral weekly administration is of benefit if nonadherence to oral medications is a major issue. If it is not an issue, then patients can switch to oral methotrexate, provided there is no significant small bowel disease, which may interfere with absorption.
* Infliximab 5 mg · kg−1 · dose−1 at weeks 0, 2, and 6 (EL2-, 3) can be effective in patients who are refractory or intolerant to steroids in combination with immunomodulators and in whom surgery is inappropriate. There should be a plan at the outset for using infliximab, with the length of course clearly defined (eg, 3 doses and then reassessment). Before initiating infliximab, sepsis should be excluded including TB (chest x-ray/Mantoux skin test and molecular quantification tests). Patients already taking immunosuppressive drugs may have a false-negative Mantoux. Before starting treatment, the patient and his or her family should be counseled about infliximab, including a discussion about the risks of malignancy, and written consent should be obtained. Guidelines for infliximab use in adults have been produced by the National Institute for Clinical Excellence.
* Surgery should be considered, especially for isolated ileocaecal disease, strictures, or fistulae and for those in whom medical treatment has failed. Close collaboration between gastroenterologists and a surgeon experienced in paediatric IBD is essential.
* In CD, surgery is not curative and management is directed at minimising the impact of disease. At least 30% of patients require surgery in the first 10 years of the disease and approximately 70% to 80% will undergo surgery in their lifetime.
3.1.5 Other Disease Sites
* Oral: CD can be managed with exclusive enteral nutrition, exclusion diet (benzoate and cinnamon free), topical steroids, and/or intralesional steroid injections. Azathioprine, infliximab, and thalidomide may be considered for resistant disease (EL3).
* Gastroduodenal disease: proton pump inhibitors, used with standard therapy, may reduce symptoms.
* Fistulising and perianal disease:
* Metronidazole (7.5 mg · kg−1 · dose−1 tds) (EL4) for at least 6 weeks and/or ciprofloxacin (5 mg · kg−1 · dose−1 bd) is appropriate treatment for simple perianal disease.
* Azathioprine (2–2.5 mg · kg−1 · day−1) or 6-mercaptopurine (1–1.25 mg · kg−1 · dose−1) (EL3) may be an effective treatment for perianal and enterocutaneous fistulae (check TPMT before treatment), but there is a delay in onset of action.
* Infliximab, intravenous: 3 infusions of 5 mg/kg each at 0, 2, and 6 weeks (EL2-, 3) may be an effective treatment for perianal and enterocutaneous fistulae but should be reserved for patients who are refractory to other treatments. A pelvic MRI scan should be carried out to exclude any abscess and to diagnose fistulae before starting infliximab.
* Surgery: abscess drainage, fistulotomy, and seton insertion may be appropriate particularly before infliximab treatment. Image with pelvic MRI.
3.1.6 Maintenance of Remission in CD (77–97)
* There is no role for maintenance steroids for patients with CD in remission. For patients who are steroid dependent, every effort must be made to find other effective treatment.
* Azathioprine (2–2.5 mg · kg−1 · day−1) or 6-mercaptopurine (1–1.25 mg · kg−1 · day−1) (EL3): should be initiated as maintenance therapy in individuals who relapse in less than 6 months, relapse 2 or more times per year following initial successful therapy, and in all steroid-dependent patients; it also should be administered postoperatively for complex, fistulating, or extensive disease. TPMT should be checked before initiating treatment and is probably best done at diagnosis. In azathioprine nonresponders it may be useful to check serum thioguanine nucleotides levels to determine whether they are noncompliant or not absorbing. When to stop azathioprine is controversial. There is some evidence that more than half of all adults will relapse within 3 years of stopping azathioprine, and hence the usual practice of stopping at 4 years may not be valid. This should be discussed with the patient and parents and also adult gastroenterology colleagues as part of the transition plan. Certainly, it should not be discontinued at key times during pubertal growth and/or education, and most continue until the time of transfer to adult GI physicians.
* Methotrexate: 15 mg/m2 once weekly subcutaneously (EL1-, 3), if azathioprine or 6-mercaptopurine is ineffective or poorly tolerated, with folic acid 5 mg 24 hours after each dose to ameliorate any GI side effects. FBC and liver function test results must be monitored every 2 weeks for the first 4 weeks, thereafter once per month.
* Enteral nutrition (EL2-): supplementary therapy may reduce the risk of relapse and may improve growth and nutritional status.
* 5-aminosalicylic acid, mesalazine (EL4): little role in maintaining remission, but may be of limited benefit in high doses (50–100 mg · kg−1 · day−1 as tolerated) for mild disease.
* Infliximab (EL3): if remission is induced with infliximab, maintenance with infliximab may be necessary (5 mg/kg intravenous, 8 weekly). It may be necessary to escalate to a higher dose (10 mg/kg) for loss of responsiveness and if successful, should revert to lower dose for subsequent infusions. Consider reinvestigating first to exclude ongoing sepsis, stricture, and bacterial overgrowth. Stopping coexisting immunosuppression after 6 months should be considered (there are emerging data of lymphoma risk with infliximab, which may or may not be related to concomitant administration of azathioprine or 6-mercaptopurine with infliximab). Assess at least annually to consider whether infliximab can be discontinued. If patient develops hypersensitivity to infliximab, then these symptoms may be abolished or ameliorated with a dose of intravenous hydrocortisone ± antihistamine before infliximab infusion.
* Other anti-TNF therapy (EL3): in patients initially responsive to infliximab who become resistant or intolerant, alternative anti-TNF agents can be considered (eg, adalimumab (subcutaneous) 80 mg stat followed by 40 mg every other week). Reassess endoscopically and, if necessary, radiologically, before starting second-line biological therapy.
* Other agents (EL4): there is little evidence for a beneficial effect of probiotics, fish oil, and Trichuris (worm) therapy to maintain remission in CD.
3.2 Management of Ulcerative Colitis
Treatment of UC depends on disease activity and distribution. Disease activity can be expressed using a clinical activity index (98–100). If on evaluation the disease is severe, the patient needs to be admitted to a paediatric gastroenterology unit for intensive intravenous therapy. If the disease is fulminant, the patient needs urgent resuscitation, an abdominal x-ray to exclude perforation, and joint medicosurgical assessment and management. The majority (90%) of children with UC have pancolitis, fewer than 10% have left-sided colitis, 4% have disease confined to the rectum alone, and 4% have rectal sparing (7). Half of those without pancolitis at presentation will rapidly progress to pancolitis (25). Infective aetiology should be sought because this may coexist with active disease, but in severe disease, immediate treatment with corticosteroids should not be delayed (Fig. 3).
3.2.1 Induction of Remission at Diagnosis or Disease Relapse (101–123)
188.8.131.52 Mild or Left-sided UC (101–107)
* Topical mesalazine (EL1-,3), or to a slightly lesser extent, steroids in liquid form, foam, or suppositories are effective therapy for mild to moderate left-sided colitis or isolated rectal disease (1–2 g daily); however, single therapy with topical mesalazine or steroids for distal disease is less effective than a combination of oral and topical therapy.
* Oral mesalazine (50–100 mg · kg−1 · day−1, maximum 3–4 g daily) or sulphasalazine 40–60 mg · kg−1 · day−1 (maximum 3 g/day, can increase to 100 mg · kg−1 · day−1 if tolerated) (EL1-,3). Sulphasalazine is better tolerated if introduced for 10 days to attain full dosage and is particularly effective for UC or IC and for arthropathy. Only sulphasalazine is available in liquid form. Olsalazine and balsalazide are alternatives if intolerant to those above and newer, once-daily preparations are becoming available. Monitor liver and renal function every 6 months.
* Oral steroids (EL1-, 3): prednisolone 1 to 2 mg · kg−1 · day−1, maximum 40 mg/day) for patients in whom 5-aminosalicylic acid preparations (± topical agents) are ineffective.
184.108.40.206 Moderate to Severe UC (108–123)
* Corticosteroids (EL3): usually prednisolone 1 to 2 mg · kg−1 · day−1 (maximum 40 mg/day).
* Treat at full dose for 2 to 4 weeks until remission (review at least once every 2 weeks in the clinic or via telephone, until clinical remission).
* Gradually taper for 4 to 8 weeks.
* If the child relapses during weaning, then consider moving back a step.
220.127.116.11 Acute Severe Colitis/Toxic Megacolon (108–123)
Children with severe colitis should be admitted to hospital for intravenous therapy and close monitoring of temperature, pulse rate, stool frequency, CRP, FBC, and a plain abdominal x-ray as a baseline to look for colonic dilatation. Regular reassessment is essential.
* Early surgical opinion is essential and patient should be managed jointly between physician and surgeon.
* Intravenous fluids/blood transfusion, if required.
* Intravenous steroids (EL4): hydrocortisone 2 mg/kg qds (maximum dose 100 mg qds) or methyl prednisolone 2 mg · kg−1 · day−1 (maximum dose 60 mg/day). Failure to respond by 72 hours suggests the need for escalation of therapy or colectomy (98).
* At least daily plain abdominal x-ray if toxic/unwell.
* Intravenous antibiotics (EL4) only if infection is suspected or sometimes before surgery (eg, cefotaxime 50 mg · kg−1 · dose−1 tds, metronidazole 7.5 mg · kg−1 · dose−1 tds).
* Urgent surgical review is also indicated with a view to early colectomy if there is evidence of toxic megacolon (diagnosed if diameter >5.5 cm transverse colon and/or >9 cm in caecum, based on adult data) and in patients whose condition is deteriorating.
* Intravenous cyclosporine (EL3): 2–4 mg · kg−1 · day−1, aiming for trough levels of 100–200 ng/mL, can be considered in patients not responding to steroids as a temporary measure to delay/avoid colectomy, allowing recovery and initiation of second-line immunosuppressant. Tacrolimus may be an alternative.
* Intravenous infliximab (EL3): there is some evidence that infliximab could be considered in nonresponding acute severe UC.
3.2.2 Maintenance of Remission (124–135)
* Aminosalicylates (EL4): maintenance therapy with aminosalicylates is recommended for all patients, but clinicians can consider stopping medication in distal and mild disease in remission for >2 years.
* Oral mesalazine, 50 to 100 mg · kg−1 · day−1, maximum 3 g/day (EL4), should be continued as first-line maintenance therapy (monitor liver and renal function every 6 months). Once-daily mesalazine preparations are licensed in the United Kingdom for use in adults.
* Sulphasalazine 30 to 60 mg · kg−1 · day−1 (EL4) is an alternative, but it may have greater side effects. It is the only formulation available in liquid form. It may be helpful in patients with associated arthropathy.
* Steroids (EL3, 4): there is no role for steroid therapy in the maintenance of remission.
* Azathioprine (2– mg · kg−1 · day−1) or 6-mercaptopurine (1–1.25 mg · kg−1 · day−1) (EL3): should be initiated as maintenance therapy in patients who fail to wean off steroids, or relapse in less than 6 months, or relapse 2 or more times per year despite adequate maintenance therapy with 5-aminosalicylic acid. Monitoring of FBC and liver function tests every 3 months is necessary because bone marrow suppression or autoimmune liver disease can develop. In azathioprine nonresponders, serum thioguanine nucleotide levels can be measured to determine whether they are noncompliant or not absorbing.
* Generally continue aminosalicylates with azathioprine for their cancer-protective effect.
* When to stop azathioprine is controversial. There is some evidence in adult patients that more than half will relapse within 3 years of stopping azathioprine, and hence the usual practice of stopping at 4 years may not be valid. This issue should be discussed with the patient and parents and also adult gastroenterology colleagues as part of the transition plan. Certainly, it should not be discontinued at key times during pubertal growth and/or education and most continue until the time of transfer to adult GI physicians.
3.3 Management of Indeterminate Colitis
Manage patients with IC the same as patients with UC. Re-evaluate periodically because the histological picture and/or disease distribution may change to CD or UC.
4.0 ASSOCIATED ASPECTS OF INFLAMMATORY BOWEL DISEASE
* Nutrition is an integral part of the management of children with IBD, and nutritional status should be assessed at presentation and at follow-up.
* Exclusive enteral nutritional therapy modifies disease in children with CD.
* Nutritional support should be considered as an adjunctive therapy for any patient with CD or UC with malnutrition. Nasogastric/gastrostomy tube feeding can be considered.
* Growth is an important marker of well-being in children with chronic disease.
* Routine assessment of growth (height and weight) and pubertal status (Tanner staging) are required at presentation and every 3 to 6 months throughout the course of the disease. Patients may prefer pubertal self-assessment.
* Growth suppression in IBD may be related more to poor disease control than to corticosteroid use.
* IBD may also be influenced by treatments used and thus is 1 of the parameters that may influence which therapy is chosen for children.
* Children with CD have improved short-term growth when enteral feeds were used to induce remission, compared to those given corticosteroids.
* Supplemental enteral feeding or cyclical enteral nutrition for children with CD in remission may improve growth and help maintain remission.
* In children with CD with localized disease and poor growth who are in early puberty, impressive catch-up growth has been documented postresection of the diseased segment.
* Close collaboration with an endocrinologist (preferably in a joint clinic) is important for managing children who have growth failure.
* In children with CD, osteopenia may be present at diagnosis.
* Dual-energy x-ray absorptiometry scans can be used to document bone density, but there is no indication for routine use.
* Improved nutritional state may improve bone health.
* The role of routine calcium and vitamin D supplementation is unclear. Calcium and vitamin D supplementation should be considered in children with significant nutritional impairment during the pubertal growth spurt and during steroid treatment.
* In severe osteopenia, the opinion of an endocrinologist/rheumatologist should be sought.
4.4 Pain Management
* Few patients require long-term analgesia, and persistent severe pain may indicate poor disease control or complications that need to be identified (eg pending perforation).
* Adequate management of pain is important, however, and some children require regular analgesia. Care must be taken with opiate use in the acute phase.
* Consider engaging the pain management team if control is difficult.
* An element of functional pain may coexist with that due to disease.
4.5 Routine Monitoring
* On azathioprine, monitor 2 weekly blood draws for the first 4 weeks, once monthly the next 2 months, then once every 3 months monitor FBC, liver function tests, amylase (and CRP for disease activity). Aim to keep the lymphocyte count between 1000 and 1500 as an indicator of drug efficacy.
* TPMT level should be checked before starting azathioprine. Start at lower dose of azathioprine if TPMT is borderline low and monitor carefully. If extremely low (ie, homozygous for deficient gene), avoid azathioprine. In azathioprine nonresponders, serum thioguanine nucleotide levels may indicate noncompliance or lack of absorption.
* Record vaccination history and any previous chickenpox infection. If negative, then check varicella status and if possible vaccinate before starting treatment. If a patient is not vaccinated, then consider immunoglobulin postexposure. Advise no live vaccines to be given while taking immunosuppressives.
* It is not known if there is an increased mortality in children in the first few years after diagnosis.
* In adults there is a morbidity rate but there is also a small increase in mortality for both UC (hazard ratio 1.44, 95% confidence interval 1.31–1.58) and CD (hazard ratio 1.73, confidence interval 1.54–1.96). This increase is largely dependent on age and distribution of disease.
* Adult data have shown that UC and, to a much lesser extent, Crohn colitis are associated with an increased risk of colonic carcinoma.
5.0 SERVICE DELIVERY
5.1 Impact of IBD on Patients and Society
* 25% of individuals with IBD present before the age of 18 years, and diagnosis is commonly made in the second and third decades.
* IBD in children can result in growth failure, delayed sexual development, and loss of education.
* Nutrition and growth are important issues in paediatric IBD, particularly CD, the aim of treatment being to induce and then maintain disease remission with minimal side effects on growth and puberty.
* The treatment priority is thus slightly different from adult practice, with not only symptom control and quality of life being priorities but also ensuring that disease control is sufficient to facilitate normal growth and pubertal development.
* Patients find symptoms of UC or CD embarrassing and humiliating and can develop significant psychological problems.
* Medical treatments such as corticosteroids or immunosuppressive drugs can cause secondary health problems.
* Side effects such as weight gain and acne can be significant issues with adolescents.
* Procedures such as unprepared sigmoidoscopy in the clinic are poorly tolerated by children and teenagers and may damage their trust in IBD clinicians.
* Surgery may be complicated by future reduced fertility, impotence, or even intestinal failure and these should be discussed with the patient and parents.
* The impact of IBD on children is disproportionately high for the patient, his or her family or other caregivers and society, because presentation is at a young age with the potential to cause lifelong ill health.
* Initial investigation and treatment should ideally be managed by a specialist pediatric gastroenterologist and follow-up shared with the referring district hospital and paediatrician as part of a regional clinical network. For the physically mature adolescent who has completed growth, is emotionally mature, and without ongoing psychological or educational problems, investigations may be possible locally with an adult GI physician experienced in the management of adolescents with IBD, provided the care is shared with the local paediatrician with a GI interest and standards are within the National Strategic Framework for children. These patients should at least be discussed with the lead paediatric gastroenterology centre.
5.2 Approach to Caregiving
The complexity of cases means that facilities and expertise are necessary beyond those normally provided in district hospitals. Shared care pathways are essential between specialist pediatric gastroenterology units and district general hospitals, particularly if the child is prepubertal. Service-specific and clinical standards are vital (eg, National Association of Colitis and Crohn's Disease (NACC)/BSG/BSPGHAN standards, government of Wales' standards for gastroenterology, hepatology, and nutrition).
Any specialty service must be arranged around the needs of the child and family with the child receiving the highest quality care but as close to home as possible (eg outreach clinics) as part of a managed clinical network. It is clear that the following are important elements in any clinical network:
* Shared care pathways between specialist paediatric gastroenterology units and district general hospitals are crucial for optimizing care. It is important to have within district general hospitals a designated paediatrician with an interest in gastroenterology (especially IBD), an adult GI physician with an interest in young people with IBD, a paediatric dietician, and, ideally, a nurse specialist with whom the specialist team and others can liaise, as part of a shared care clinical network. Investigations should be made in a setting appropriate for and experienced in the treatment of children with IBD. Younger patients should be managed in tertiary gastroenterology centres.
* At the regional lead centre there must be a specialist multidisciplinary team including paediatric gastroenterologists, paediatric surgeons, an IBD nurse specialist, a dietician with knowledge of IBD, a histopathologist, an anaesthetist, a radiologist, and a psychologist.
* Access to upper and lower GI endoscopy including urgent access in a child-friendly environment for all children with symptoms of IBD
* Rapid access to advice and clinic or day case unit appointments in the event of a relapse or complications
* Adequate time and space in outpatients and wards to meet the unpredictable pattern of disease to allow discussion, explanation, and counseling, and to provide information and education material
* Easy access to private, clean toilet facilities for inpatients and outpatients and at school
* Administrative and clinical support including a specialist IBD nurse for supporting shared care pathways
* Participation in local and national specialist audit
* Transition care arrangements must be an integral part of any service, preferably with joint clinics held between adult and paediatric gastro teams, which young people can attend for as long as it is appropriate. Transition guidelines endorsed by BSPGHAN are now available from Crohn's in Childhood Research Association (CICRA) and the National Association of Crohn's and Colitis (NACC), with separate sections for patient, parent, and professional.
5.3 Sources of Patient/Parent Information
Explanations or advice given by clinical staff can be complemented by other sources of information. Patients usually welcome additional information, but it needs to be appropriate and relevant to their condition. The following and many other sources provide access to information:
Crohn's in Childhood Research Association (CICRA)
Parkgate House, 356 West Barnes Lane, Motspur Park, Surrey KT3 6NB, UK
Web site: www.cicra.org
National Association for Colitis and Crohn's Disease (NACC)
4 Beaumont House, Sutton Rd, St Albans, Herts AL1 5HH, UK
Web site: www.nacc.org.uk
Crohn's and Colitis Foundation of America (CCFA)
386 Park Ave S, 17th floor, New York, NY 10016
Web site: www.ccfa.org
Digestive Diseases Foundation
CORE, 3 St Andrews Pl, London NW1 4LB, UK
Web site: www.digestivedisorders.org.uk
The authors acknowledge the assistance of all BSPGHAN members and thank the authors of the BSG adult IBD guidelines for their contributions. Drs A. Akobeng, D. Casson, N.M. Croft, M. Elawad, S.H. Murch, M.S. Murphy, J. Puntis, A.S. Sawczenko, and A.G. Thomas were contributing authors to this guideline.
1. IBD Working Group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Inflammatory bowel disease in children and adolescents: recommendations for diagnosis—the Porto criteria. J Pediatr Gastroenterol Nutr
2. SIGN 50
. A Guideline Developer's Handbook
. Scottish Intercollegiate Guidelines Network Web site. www.sign.ac.uk
. Accessed October 28, 2009.
3. Carter MJ, Lobo AL, Travis SPL, et al
. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004; 53(Suppl V):1–16.
4. ECCO consensus on the management of Crohn's disease. Gut
5. Silverberg MS, Satsangi J, Ahmad TJF, et al
. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005; 19(Suppl A):5–36.
6. Sawczenko A, Sandhu BK, Logan RFA, et al
. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet 2001; 357:1093–1094.
7. Sawczenko A, Sandhu B. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child 2003; 88:995–1000.
8. Heyman MB, Kirschner BS, Gold BD, et al
. Children with early onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 2005; 146:35–40.
9. Barton JR, Gillon S, Ferguson A. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983: marginal fall in ulcerative colitis, three fold increase in Crohn's disease. Gut 1989; 30:618–622.
10. Cosgrove M, Al-Atia RF, Jenkins HR. The epidemiology of paediatric inflammatory bowel disease. Arch Dis Child 1996; 74:460–461.
11. Ahmed M, Davies IH, Hood K, et al
. Incidence of paediatric inflammatory bowel disease in South Wales. Arch Dis Child 2006; 91:344–345.
12. Rubin GP, Hungin AP, Kelly PJ, et al
. Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment Pharmacol Ther 2000; 14:1553–1559.
13. Ardizzone S, Porro GB. Inflammatory bowel disease: new insights into pathogenesis and treatment. J Intern Med 2002; 252:475–496.
14. Card T, Hubbard R, Logan RFA. Mortality in inflammatory bowel disease: a population-based cohort study. Gastroenterology 2003; 125:1583–1590.
15. Winther K, Jess T, Langholz E, et al
. Survival and cause-specific mortality in ulcerative colitis: follow-up of a population-based cohort in Copenhagen county. Gastroenterology 2003; 125:1576–1582.
16. Griffiths AM, Hugot J-P. Crohn's disease.. In: Walker WA, Goulet O, Kleinman RE, et al., editors. Pediatric Gastrointestinal Disease. 4th ed. Hamilton, Canada: BC Decker; 2004. pp. 789–824.
17. Griffiths AM, Nguyen P, Smith C, et al
. Growth and clinical course of children with Crohn's disease. Gut 1993; 34:939–943.
18. Sawczenko A, Ballinger AB, Savage MO, et al
. Clinical features affecting final adult height in patients with pediatric-onset Crohn's disease. Pediatrics 2006; 118:124–129.
19. Graham TO, Kandil HM. Nutritional factors in inflammatory bowel disease. Gastroenterol Clin N Am 2002; 31:203–218.
20. Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for inducing remission of Crohn's disease. Cochrane Database Syst Rev 2001; 3:CD000542.
21. Sawczenko A, Lynn R, Sandhu BK. Variations in initial assessment and management of inflammatory bowel disease across Great Britain and Ireland. Arch Dis Child 2003; 88:990–994.
22. Chong SKF, Bartram C, Campbell CA, et al
. Chronic inflammatory bowel disease in childhood. BMJ 1982; 284:101–105.
23. Jenkins D, Balsitis M, Gallivan S, et al
. Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. The British Society of Gastroenterology Initiative. J Clin Pathol 1997; 50:93–105.
24. Scotiniotis I, Rubesin SE, Ginsberg G. Imaging modalities in inflammatory bowel disease. Gastroenterol Clin N Am 1999; 28:391–442.
25. Van Limbergen JE, Russell RK, Drummond HE, et al
. Definition of phenotypic characteristics of childhood-onset IBD. Gastroenterology 2008; 135:1114–1122.
26. Hyams J, Ferry GD, Mandel FS, et al
. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr 1991; 12:439–447.
27. Sanderson IR, Udeen S, Davies PS, et al
. Remission induced by an elemental diet in small bowel Crohn's disease. Arch Dis Child 1987; 62:123–127.
28. Ruuska T, Savilahte E, Maki M, et al
. Exclusive whole protein enteral diet versus prednisolone in the treatment of acute Crohn's disease in children. J Pediatr Gastroenterol Nutr 1994; 19:175–180.
29. Thomas AG, Taylor F, Miller V. Dietary intake and nutritional treatment in childhood Crohn's disease. J Pediatr Gastroenterol Nutr 1993; 17:75–81.
30. Papadopoulou A, Rawashdeh MO, Brown GA, et al
. Remission following an elemental diet or prednisolone in Crohn's disease. Acta Paediatr 1995; 84:79–83.
31. Griffiths AM, Ohlsson A, Sherman PM, et al
. Meta-analysis of enteral nutrition as a primary treatment of active Crohn's disease. Gastroenterology 1995; 108:1056–1067.
32. 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.
33. Fell JM, Paintin M, Arnaud-Battandier F, et al
. Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn's disease. Aliment Pharmacol Ther 2000; 14:281–289.
34. Knight CJ, El-Matary W, Spray C, et al
. Long term outcome of nutritional therapy in Crohn's disease. Clin Nutr 2005; 24:775–779.
35. Borrelli 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; 4:744–753.
36. Escher JC, Taminiau JAJM, Nieuwenhuis EES, et al
. Treatment of inflammatory bowel disease in childhood: best available evidence. Inflamm Bowel Dis 2000; 9:34–38.
37. Levine A, Weizman Z, Broide E, et al
. A comparison of budesonide and prednisolone for the treatment of active paediatric Crohn's disease. J Pediatr Gastroenterol Nutr 2003; 36:248–252.
38. Escher JC. Budesonide versus prednisolone for the treatment of active Crohn's disease in children: a randomized, double blind, controlled, multicentre trial. Eur J Gastroenterol Hepatol 2004; 16:47–54.
39. Bar-Meir S, Chowers Y, Lavy A, et al
. Budesinide versus prednisolone in the treatment of active Crohn's disease. The Israeli Budesinide study group. Gastroenterology 1998; 115:835–840.
40. Munkholm P, Langholz E, Davidsen M, et al
. Frequency of glucocorticoid resistance and dependency in Crohn's disease. Gut 1994; 35:360–362.
41. Hildebrand H, Berg NO, Hoevels J, et al
. Treatment of Crohn's disease with metronidazole in childhood and adolescence. Evaluation of a 6 month trial. Gastroenterol Clin Biol 1980; 4:19–25.
42. Bernstein LH, Frank MS, Brandt LJ, et al
. Healing of perianal Crohn's disease with metronidazole. Gastroenterology 1980; 70:599.
43. Duffy LF, Daum F, Fisher SE, et al
. Peripheral neuropathy in Crohn's disease patients treated with metronidazole. Gastroenterology 1985; 88:681–684.
44. Sartor RB. Antibiotics as therapeutic agents in Crohn's disease. In: Bayless TM, Hanauer SB, editors. Advanced Therapy of Inflammatory Bowel Disease. Lewiston, NY: BC Decker; 2001. pp. 359–362.
45. Singleton J. Second trial of mesalamine therapy in the treatment of active Crohn's disease. Gastroenterology 1994; 107:632–633.
46. Barden L, Lipson A, Pert P, et al
. Mesalazine in childhood inflammatory bowel disease. Aliment Pharmacol Ther 1989; 3:597–603.
47. D'Agata ID, Vanounou T, Seidman E. Mesalamine in paediatric inflammatory bowel disease: a 10-year experience. Inflamm Bowel Dis 1996; 2:229–235.
48. Griffiths A, Koletzko S, Sylvester F, et al
. Slow-release 5-aminosalicylic acid therapy in children with small intestinal Crohn's disease. J Pediatr Gastroenterol Nutr 1993; 17:186–192.
49. Steinhart AH. Is mesalazine useful for treating Crohn's disease? In: Jewell DP, Warren BF, Mortensen NJ, editors. Inflammatory Bowel Disease. Oxford: Blackwell Scientific; 2001. pp. 99–109.
50. Kundhal P, Zachos M, Holmes JL, et al
. Controlled ileal release budesinide in pediatric Crohn's disease: efficacy and effect on growth. J Pediatr Gastroenterol Nutr 2001; 33:75–80.
51. Uhlen S, Belbouab R, Narebski K, et al
. Efficacy of methotrexate in pediatric Crohn's disease: a French multicenter study. Inflamm Bowel Dis 2006; 12:1053–1057.
52. Alfdhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory Crohn's disease. Cochrane Database Syst Rev 2003; 1:CD003459.
53. Te HS, Schiano TD, Kuan SF, et al
. Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease. Am J Gastroenterol 2000; 95:3150–3156.
54. Lenmann M, Zenjari T, Bouhnik Y, et al
. Methotrexate in Crohn's disease: long-term efficacy and toxicity. Am J Gastroenterol 2000; 95:1730–1734.
55. Feagan BG, Fedorak RN, Irvine EJ, et al
. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. The North American Crohn's Study for Group Investigators. N Engl J Med 2000; 342:1627–1632.
56. Fraser AG. Methotrexate: first or second line immunomodulator? Eur J Gastroenterol Hepatol 2003; 15:225–231.
57. Wilson D, Pieterse L, Rogers P, et al. Induction of remission by methotrexate in azathioprine-resistant Crohn's disease (abstract). J Pediatr Gastroenterol Nutr
58. Ravikumara M, Hinsberger A, Spray CH. Role of methotrexate in the management of CD. J Pediatr Gastroenterol Nutr 2007; 44:427–430.
59. Targan SR, Hanauer SB, van Deventer SJ, et al
. A short term study of chimeric monoclonal antibody cA2 to tumour necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 1997; 337:1029–1035.
60. Hanauer SB, Feagan BG, Lichtenstein GR, et al
. Maintenance infliximab for Crohn's disease. The ACCENT 1 randomised trial. Lancet 2002; 359:1541–1549.
61. Present DH, Rutgeerts P, Targan S, et al
. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398–1405.
62. Derkx B, Taminiau J, Radema S, et al
. Tumor-necrosis-factor antibody treatment in Crohn's disease. Lancet 1993; 342:173–174.
63. Sands BE, Anderson FH, Bernstein CN, et al
. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004; 350:876–885.
64. Baldassano R, Vasiliauskas E, Braegger CP, et al
. A multi centre study of infliximab (anti-TNF alpha antibody) in the treatment of children with active Crohn's disease. Gastroenterology 1999; 116:A665 [abstract].
65. Hyams JS, Markowitz J, Wyllie R. Use of infliximab in the treatment of Crohn's disease in children and adolescents. J Pediatr 2000; 137:192–196.
66. Serrano MS, Schmidt-Sommerfeld E, Kilaugh TJ, et al
. Use of infliximab in pediatric patients with inflammatory bowel disease. Ann Pharmacol Ther 2001; 35:823–828.
67. Baldassano R, Braegger CP, Escher JC, et al
. Infliximab (remicade) therapy in the treatment of paediatric CD. Am J Gastroenterol 2003; 98:833–838.
68. Borrelli O, Bascietto C, Viola F, et al
. Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn's disease. Dig Liver Dis 2004; 36:342–347.
69. Hyams J, Crandall W, Kugathasan S, et al
. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology 2007; 132:863–873.
70. Lionetti P, Bronzini F, Salvestrini C, et al
. Response to infliximab is related to the disease duration in paediatric Crohn's disease. Aliment Pharmacol Ther 2003; 18:425–431.
71. Kugathasan S, Werlin SL, Martinez A, et al
. Prolonged duration of response to infliximab in early but not late paediatric Crohn's disease. Am J Gastroenterol 2000; 65:3189–3194.
72. Colombel JF, Sandborn WJ, Rutgeerts P, et al
. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007; 132:52–65.
73. Ormerod LP, Milburn HJ, Gillespie S, et al
. British Thoracic Society (BTS) recommendations for assessing risk and for managing Mycobacterium tuberculosis
infection and disease in patients due to start anti-TNF-a treatment. Thorax 2005; 60:800–805.
74. Davies G, Evans CM, Shand WS, et al
. Surgery for Crohn's disease in childhood: influence of site of disease and operative procedure on outcome. Br J Surg 1990; 77:891–894.
75. Sentongo TA, Stettler N, Christian A, et al
. Growth after intestinal resection for Crohn's disease in children, adolescents and young adults. Inflamm Bowel Dis 2000; 6:265–269.
76. Shand WS. Surgical therapy of chronic inflammatory bowel disease in children. Baillieres Clin Gastroenterol 1994; 8:149–180.
77. Ba'ath ME, Mahamalat MW, Kapur P, et al
. Surgical management of inflammatory bowel disease. Arch Dis Child 2007; 92:312–316.
78. Polle SW, Slors JFM, Weverling GJ, et al
. Recurrence after segmental resection for colonic Crohn's disease. Br J Surg 2005; 92:1143–1149.
79. Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990; 117:809–814.
80. Markowitz J, Rosa J, Grancher K, et al
. Long-term 6 mercaptopurine in Crohn's disease. Gastroenterology 1990; 99:1347–1351.
81. Markowitz J, Grancher K, Kohn N, et al
. A multicenter trial of 6-mercaptopruine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000; 119:895–902.
82. Jeshion WC, Larsen KL, Jawad AF, et al
. Azathioprine and 6-mercaptopurine for the treatment of perianal Crohn's disease in children. J Clin Gastroenterol 2000; 30:294–298.
83. Colombel JF, Ferrari N, Debuysere H, et al
. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000; 118:1025–1033.
84. Lennard L, Gibson BE, Nicole T, et al
. Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child 1993; 69:577–579.
85. Hanauer SB, Kane SV. The pharmacology of anti-inflammatory drugs in inflammatory bowel disease. In: Bayless TM, Hanauer SB, editors. Advanced Therapy of Inflammatory Bowel Disease. Lewiston NY: B.C. Decker; 2001. pp. 510–528.
86. Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998; 115:813–821.
87. Present DH, Meltzer SJ, Krumholz MP, et al
. 6-Mercaptopurine in the management of inflammatory bowel disease: short and long term toxicity. Ann Intern Med 1989; 111:641–649.
88. Larvol L, Soule JC, Le Tourneau A. Reversible lymphoma in the setting of azathioprine therapy for Crohn's disease. N Engl J Med 1994; 331:883–884.
89. Connell WR, Kamm MA, Dickson M, et al
. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343:1249–1252.
90. Lewis JD, Schwartz JS, Lichtenstein GR. Azathioprine for maintenance of remission in Crohn's disease: benefits outweigh the risk of lymphoma. Gastroenterology 2000; 118:1018–1024.
91. Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998; 115:813–821.
92. Mahdi G, Israel OM, Hassall E. Cyclosporine and 6-mercaptopurine for active, refractory Crohn's colitis in children. Am J Gastroenterol 1996; 91:1355–1359.
93. 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.
94. Dubinsky MC, Lamothe S, Yang HY, et al
. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000; 118:705–713.
95. Thayu M, Markowitz JE, Mamula P, et al
. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn's disease. J Pediatr Gastroenterol Nutr 2005; 40:220–222.
96. Mackey AC, Green L, Liang LC, et al
. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007; 44:265–267.
97. Rolfe VE, Fortun PJ, Hawkey CJ, et al
. Probiotics for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2006; 4:CD004826.
98. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. BMJ 1955; ii:1041–1048.
99. Walmsley RS, Ayres RCS, Pounder RE, et al
. A simple clinical colitis index. Gut 1998; 43:29–32.
100. Turner D, Otley AR, Mack D, et al
. Development and evaluation of a Paediatric Ulcerative Colitis Activity Index (PUCAI): a prospective multicentre study. Gastroenterology 2007; 133:423–432.
101. Odera G, Giuliani B, Santini B, et al
. Topical treatment with 5-aminosalicylic acid (5-ASA) and hydrocortisone enemas in proctocolitis in childhood (double blind study). Rivista Ital Pediatr 1986; 12:674–678.
102. Sutherland L, Roth D, Beck P, et al
. Oral 5-aminosalicylic acid for inducing remission in ulcerative colitis. Cochrane Database Syst Rev 2000; 2:CD000544.
103. Lennard-Jones JE, Longmore AJ, Newell AC, et al
. An assessment of prednisone, Salazopyrin and topical hydrocortisone hemisuccinate used as outpatient treatment for ulcerative colitis. Gut 1960; 1:217–222.
104. Truelove SC, Watkinson G, Draper G. Comparison of corticosteroid and SASP therapy in ulcerative colitis. BMJ 1962; 2:1708–1711.
105. Baron JH, Connell AM, Kanaghinis TG, et al
. Outpatient treatment of ulcerative colitis: comparison between three doses of oral prednisone. BMJ 1962; 2:441–443.
106. Hyams J, Markowitz J, Lerer T, et al
. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol 2006; 4:1118–1123.
107. Beattie RM, Nicholls SW, Domizio P, et al
. Endoscopic assessment of the colonic response to corticosteroids in children with ulcerative colitis. J Pediatr Gastroenterol Nutr 1996; 22:373–379.
108. Faure C, Andre J, Pelatan C, et al
. Pharmacokinetics of intravenous methyl prednisolone and oral prednisolone in paediatric patients with inflammatory bowel disease during the acute phase and in remission. Eur J Clin Pharmacol 1998; 54:555–560.
109. Jarnerot G, Rolny P, Sandberg-Gertzen H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985; 89:1005–1013.
110. Travis SPL, Farrant JM, Ricketts C, et al
. Predicting outcome in severe ulcerative colitis. Gut 1996; 38:905–910.
111. Hawthorne AB, Travis SPL, and the BSG IBD Clinical Trials Network. Outcome of inpatient management of severe ulcerative colitis: a BSG IBD Clinical Trials Network survey. Gut 2002; 50:A16.
112. Chapman RW, Selby WS, Jewell DP. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986; 27:1210–1212.
113. Daperno M, Sostegni R, Rocca R, et al
. Medical treatment of severe ulcerative colitis. Aliment Pharmacol Ther 2002; 16:7–12.
114. Lichtiger S, Present DH, Kornbluth A, et al
. Cyclosporin in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330:1841–1845.
115. Benkov KJ, Rosh JR, Schwersenz AH, et al
. Cyclosporin as an alternative to surgery in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994; 19:290–294.
116. Treem WR, Cohen J, Davis PM, et al
. Cyclosporine for the treatment of fulminant ulcerative colitis in children. Immediate response, long-term results and impact on surgery. Dis Colon Rectum 1995; 38:474–479.
117. Ramakrishna L, Langhans N, Calenda K, et al
. Combined use of cyclosporin and azathioprine or 6-mercaptopurine in pediatric inflammatory bowel disease. J Pediatr Gastroentrol Nutr 1995; 28:54–58.
118. Sands BE, Tremaine WJ, Sandborn WJ, et al
. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis 2001; 7:83–88.
119. Chey W, Hussain A, Ryan C, et al
. Infliximab is an effective therapeutic agent for ulcerative colitis. Gastroenterology 2000; 95:A230 [abstract].
120. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev
121. Mamula P, Markowitz JE, Brown KA, et al
. Infliximab as a novel therapy for pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2002; 34:307–311.
122. Russell GH, Katz AJ. Infliximab is effective in acute but not chronic childhood ulcerative colitis. J Pediatr Gastroenterol Nutr 2004; 39:166–170.
123. Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis 2005; 11:213–218.
124. Sutherland L, Roth D, Beck P, et al
. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2002; 4:CD000544.
125. Christensen LA, Fallingborg J, Jacobsen BA, et al
. Bioavailability of 5-aminosalicyclic acid from slow release 5-aminosalicyclic acid drug and sulfasalazine in normal children. Dig Dis Sci 1993; 38:1831–1836.
126. Barden L, Lipson A, Pert P, et al
. Mesalazine in childhood inflammatory bowel disease. Aliment Pharmacol Ther 1989; 3:597–603.
127. Bondesen S, Nielsen OH, Schou JB, et al
. Steady-state kinetics of 5-aminosalicylic acid and sulfapyridine during sulfasalazine prophylaxis in ulcerative colitis. Scand J Gastroenterol 1986; 21:693–700.
128. Clarke DF, George D, Milsap RL, et al
. Sulfasalazine pharmacokinetics in children. Pediatr Pharmacol 1982; 2:323–333.
129. Leickly FE, Buckley RH. Development of IgA and IgG2 subclass deficiency after sulfasalazine therapy. J Pediatr 1986; 108:481–482.
130. Tolia V, Massoud N, Klotz U. Oral 5-aminosalicyclic acid in children with colonic chronic inflammatory bowel disease: clinical and pharmacokinetic experience. J Pediatr Gastroenterol Nutr 1989; 8:333–338.
131. D'Agata I, Vanounou T, Seidman E. Mesalamine in paediatric inflammatory bowel disease: a 10-year experience. Inflamm Bowel Dis 1996; 2:229–235.
132. Wiersma H, Escher JC, Dilger K, et al
. Pharmacokinetics of mesalazine pellets in children with inflammatory bowel disease. Inflamm Bowel Dis 2004; 10:626–631.
133. Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on a controlled therapeutic trial. BMJ 1974; 2:627–630.
134. McGovern DPB, Travis SPL. Thiopurine therapy: when to start and when to stop. Eur J Gastroenterol Hepatol 2003; 15:219–224.
135. Hawthorne AB, Logan RFA, Hawkey CJ, et al
. Randomised controlled trial of azathioprine-withdrawal in ulcerative colitis. BMJ 1992; 305:20–22.
136. Azcue M, Rashid M, Griffiths A, et al
. Energy expenditure and body composition with Crohn's disease: effect of enteral nutrition and treatment with prednisolone. Gut 1997; 41:203–208.
137. Graham TO, Kandil HM. Nutritional factors in inflammatory bowel disease. Gastroenterol Clin North Am 2002; 31:203–218.
138. Burke A, Lichtenstein GR, Rombeau JL. Nutrition and ulcerative colitis. Baillieres Clin Gastroenterol 1997; 11:153–174.
139. Gassull MA, Cabre E. Nutrition in inflammatory bowel disease. Curr Opin Nutr Metab Care 2001; 4:561–569.
140. Chintapatla S, Scott NA. Intestinal failure in complex gastrointestinal fistulae. Nutrition 2002; 18:991–996.
141. Khoshoo V, Reifen R, Neuman MG, et al
. Effect of low- and high-fat, peptide-based diets on body composition and disease activity in adolescents with active Crohn's disease. J Parenter Enteral Nutr 1996; 20:401–405.
142. Kim YI. Can fish oil maintain Crohn's disease in remission? Nutr Rev 1996; 54:248–252.
143. Belli DC, Seidman E, Bouthillier L, et al
. Chronic intermittent elemental diet improves growth failure in children with Crohn's disease. Gastroenterology 1988; 94:603–610.
144. Motil KJ, Grand RJ, Davis-Kraft L, et al
. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993; 105:681–691.
145. Aiges H, Markowitz J, Rosa J, et al
. Home nocturnal supplemental naso-gastric feedings in growth-retarded adolescents with Crohn's disease. Gastroenterology 1989; 97:905–910.
146. Motil KJ, Grand RJ, Maletskos CJ, et al
. The effects of disease, drug and diet on whole body protein metabolism in adolescents with Crohn's disease and growth failure. J Pediatr 1982; 101:345–351.
147. Lipson AB, Savage MO, Davies PS, et al
. Acceleration of linear growth following intestinal resection for Crohn's disease. Eur J Pediatr 1990; 149:687–690.
148. Sentongo TA, Stettler N, Christian A, et al
. Growth after intestinal resection for Crohn's disease in children, adolescents, and young adults. Inflamm Bowel Dis 2000; 6:265–269.
149. Alemzadeh N, Rekers-Mombarg LT, Mearin ML, et al
. Adult height in patients with early onset of Crohn's disease. Gut 2002; 51:26–29.
150. Newby EA, Sawczenko A, Thomas AG, et al
. Interventions for growth failure in childhood Crohn's disease. Cochrane Database Syst Rev 2005; 3:CD003873.
151. Bonet S, Pathomvanich A, Kiel MF, et al
. Self-assessment of pubertal stage in overweight children. Pediatrics 2002; 110:743–747.
152. Cowan FJ, Warner JT, Dunstan FD, et al
. Inflammatory bowel disease and predisposition to osteopenia. Arch Dis Child 1997; 76:325–329.
153. Hodsman AB, Toogood JH, Jennings B, et al
. Differential effect of inhaled budesonide and oral prednisone on serum osteocalcin. J Clin Endocrinol Metab 1991; 72:530–540.
154. Boot AM, Bouquet J, Krenning EP, et al
. Bone mineral density and nutritional status in children with chronic inflammatory bowel disease. Gut 1998; 42:188–194.
155. Gokhale R, Favus MJ, Karrison T, et al
. Bone mineral density assessment in children with inflammatory bowel disease. Gastroenterology 1998; 114:902–911.
156. Schoon EJ, Wolffenbuttel BHR, Stockbrugger RW. Osteoporosis as a risk in inflammatory bowel disease. Drugs Today 1999; 35(Suppl A):17–28.
157. Walther F, Fusch C, Radke M, et al
. Osteoporosis in pediatric patients suffering from chronic inflammatory bowel disease with and without steroid treatment. J Pediatr Gastroenterol Nutr 2006; 43:42–51.
158. Lennard-Jones JE, Morson BC, Ritchie JK, et al
. Cancer surveillance in ulcerative colitis: experience over 15 years. Lancet 1983; 2:149–152.
159. Fireman Z, Grossman A, Lilos P, et al
. Intestinal cancer in patients with Crohn's disease. A population study in central Israel. Scand J Gastroenterol 1989; 24:346–350.
160. Ekbom A, Helmick C, Zack M, et al
. Increased risk of large-bowel cancer in Crohn's disease with colonic involvement. Lancet 1990; 336:357–359.
© 2010 Lippincott Williams & Wilkins, Inc.
161. Jess T, Loftus EV Jr, Velayos FS, et al
. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Gastroenterology 2006; 130:1039–1046.