The systematic review of RCT of EN versus corticosteroids for induction of remission of CD in paediatric patients was of low quality (63). It comprised 147 children: 60 from 3 small RCTs (58–60) and 87 from 2 abstracts of RCT; 2 nonrandomised trials containing 47 more children were also added to the analysis. A further RCT of EN versus corticosteroids for induction of remission of CD in paediatric patients was of better methodological quality and comprised 37 children (57). All of the trials showed roughly equivalent remission rates, slightly favouring corticosteroids.
The 4 RCTs of differing EN strategies to induce remission showed the superiority of total EN as opposed to partial EN in the only appropriately powered trial (102; P < 0.04), but no benefit of the addition of glutamine to polymeric EN (103), no benefit of altered fat composition in EN (104), and no benefit for elemental as opposed to polymeric feed (105) in studies of low power.
There was significant benefit from the addition of n3-fatty acid to mesalazine to maintain remission in CD in an RCT of low methodological quality and at high risk for bias (106).
The only data in UC were 2 of 12 children in a series from a pilot trial when given an oral nutritional substrate (N-acetyl glucosamine); both improved.
There are no relevant studies.
The only serious adverse event reported with EN, PN, or fish oil was a case of refeeding syndrome during EN therapy to induce remission in CD (120).
None of the studies reported this as a primary or well-defined secondary outcome.
There were no publications on other treatment modalities that met the inclusion criteria, therefore, there is no evidence table.
We have rigorously searched the available literature for relevant evidence on the treatment of paediatric IBD to January 1, 2007. The results are disappointing, with a lack of high-quality evidence. There are no methodologically robust clinical guidelines and no systematic reviews nor RCTs that can meet the highest methodological criteria, in this case those of the SIGN. Only a handful of RCT and cohort studies were well conducted with a low risk of bias in the results (EL1+ or EL2+, respectively). By contrast, there is evidence of high quality for the treatment of adult IBD, including Cochrane reviews and other systematic reviews, some of which may combine both adult and paediatric evidence. Paediatric practitioners emphasize that there are important differences in terms of managing children and adults with IBD, given the differences in relative physiology, pharmacokinetics, and pharmacodynamics, and the relevant aims for treatment. In paediatric IBD, treatment aims include restoration of normal growth, normal progression through the pubertal stages, achievement of full educational potential, restoration of normal lifestyle, and prevention of harm (both physical and psychological). Given the profound effects of proinflammatory cytokines on growth and pubertal development, we may need to aim for not just clinical remission, radiological remission, remission of serology, and other biological markers but also for mucosal remission. For all of these reasons, extrapolated data from the adult IBD literature alone is insufficient to guide treatment of paediatric IBD. Although limited in terms of the quality of the methodology, the enclosed evidence base of management of paediatric IBD does provide much important information for paediatric IBD teams and includes some highly influential publications that have helped to advance paediatric IBD care.
There are no clinical guidelines available that can be strongly recommended for use in clinical paediatric IBD practice. Given the lack of available high-quality evidence, a strict clinical guideline based on both systematic reviews and large, robustly designed and clinically appropriate RCTs is many years away. This comprehensive evidence review has therefore led to our present consensus guideline document (see pp. S1–S13). In this accompanying guideline, a small number of the BSPGHAN IBD Working Group reviewed this paediatric evidence base, together with the ECCO consensus on diagnosis and management of CD (9–11, which is on adult CD except for a brief section on paediatric CD) and the British Society of Gastroenterology guidelines for the management of IBD in adults (12). The draft guideline was sent to all of the members of BSPGHAN (a multidisciplinary group) and to lay/patient/family groups interested in paediatric IBD, and the responses were evaluated. It was recirculated a second time and consensus was achieved.
With just 1 RCT, there is little reliable evidence regarding the use of these agents in childhood IBD, despite the marked current increase in their use (21). Current practice is based on adult practice, and tending towards earlier use of azathioprine/6-MP, possibly even as first-line agents. Methotrexate is used as a second-line immunomodulator in the event of intolerance to or failure of azathioprine/6-MP. By contrast, use of cyclosporine and tacrolimus remains limited to children with complex and treatment-resistant disease. Cyclosporin has a limited role as the therapy of last resort after failure of conventional treatment in refractory or fulminant UC, potentially allowing deferral of operation until the patient is physically and psychologically better prepared for surgery.
Using data of studies in adults with IBD, a meta-analysis has confirmed the role of azathioprine/6-MP in maintaining long-term disease remission in adults (121). A Cochrane review has also done so and has supported their steroid-sparing benefit (122). However, it takes at least 17 weeks for effectiveness to manifest (123).
There have been several studies of methotrexate therapy in treatment-resistant CD in adults, including 3 randomized placebo-controlled trials. A Cochrane review supports the findings that weekly injections of 25 mg of methotrexate intramuscularly may induce remission and steroid withdrawal in patients with refractory CD (124). There is limited evidence that cyclosporin is more effective than standard treatment alone for severe UC (125). The use of low-dose oral cyclosporin for the treatment of chronic active CD is not justified (126).
The quality of available evidence is poor. Oral 5-ASA and sulphasalazine at a dose of 50 to 100 mg · kg−1 day−1 appear to be safe and effective in the induction and maintenance of remission of active UC. Topical 5-ASA may be used for left-sided or distal UC. There is no adequate evidence for or against the use of 5-ASA in childhood CD.
Corticosteroids are widely used as primary therapy for induction of remission in children with IBD. There are, however, concerns regarding toxicity, such as the suppression of linear growth, that are of particular relevance to paediatric practice. The quality of available evidence is poor. Corticosteroids appear to induce clinical remission in childhood CD and UC. Rectal therapy can be used for distal disease. There is a risk of osteopenia with corticosteroid usage plus other toxicities, including obesity, striae, susceptibility to infection, and mood disturbance.
There is a lack of good-quality studies on the use of infliximab and adalimumab in paediatric IBD. A single-dose intravenous infusion of 5 mg/kg of infliximab has been shown to lead to improvements in symptoms in children with active CD and in some children with UC refractory to conventional medical therapy. For perianal fistulating and/or severe refractory CD, 3 doses of 5 mg/kg have been shown to induce remission. The effect may be transitory, with most patients relapsing by 1 year. Adverse events in these studies were rare but occasionally serious, especially risk of sepsis. Recent reports suggest that infliximab may be associated with an increased risk of hepatosplenic T cell lymphoma (HSTCL). Eight cases of HSTCL in young patients using infliximab to treat IBD were reported to the Food and Drug Administration between 1998 and October 2006 (133). Interestingly, all 8 patients were receiving concomitant treatment with azathioprine or 6-MP. Whilst definite evidence on the association between the development of lymphoma and the use of infliximab in CD disease is lacking (134), there may be a small risk (about 8/10,000), especially in patients treated with a combination of infliximab and purine analogues (135). This has been a cause of great concern to paediatric gastroenterologists, together with reports of HSTCL in young patients with IBD treated with adalimumab (Abbott Laboratories, unpublished observation) and of occurrences of demyelination, toxic retinopathy, and cancers that reversed on cessation of biological therapy. It is vital that the risk of rare but serious adverse events be discussed with children and their families before initiating the use of biological agents, and that an exit strategy for future cessation of biological therapy be discussed. The use of written informed consent is now common amongst BSPGHAN members, together with the provision of detailed written summaries of benefits and risks of biological therapy in paediatric IBD.
In an RCT, infliximab was shown to be effective in the maintenance of remission in adults with CD (138). For clinical practice in the United Kingdom, the National Institute of Clinical Excellence has issued its guidance on the use of infliximab in CD in adults (www.nice.org.uk, guideline no. 40). It recommends that infliximab use be reserved for patients with severe disease that is unresponsive to conventional therapy and for whom surgery is inappropriate.
Despite the widespread use of antibiotics and probiotics by paediatric gastroenterologists and families, there was no paediatric literature available for either.
EN is regarded as the primary therapy for induction of remission of CD by paediatric gastroenterologists in the United Kingdom and Europe, but less so by paediatric gastroenterologists elsewhere and by adult gastroenterologists in the United Kingdom and elsewhere. PN is usually used as supportive therapy during acute severe exacerbations of IBD, or else when CD is complicated by short gut syndrome or extensive enterocutaneous fistulae. Fish oil preparations are usually purchased by families as supportive complementary/alternative therapy for IBD in their children. Of note, there are no RCTs of EN versus placebo; 4 are of EN versus steroids and 4 are of 1 EN regimen against another. Many of the practical aspects of EN administration, such as duration of feed administration or food reintroduction regimen, have yet to be subjected to primary analysis by RCT. There are no RCTs of PN usage nor of use of fish oil in induction of remission in paediatric IBD.
The systematic review of RCT of EN versus corticosteroids in paediatric patients was of low quality (63). It comprised 147 children in 3 small RCTs and 2 abstracts of RCTs; of these, only 60 children were from fully published articles and the remainder from 2 abstracts. Neither abstract has been converted to an original article in more than 10 years, so it is doubtful that either ever will be. The authors calculated that a sample size of 182 children was needed to demonstrate a treatment effect of 20%. There is a need for a definitive well-conducted RCT, rather than the lumping of small and heterogeneous studies together in a meta-analysis. Mucosal remission may be important in the restoration of growth in paediatric IBD, with return of proinflammatory cytokines towards normal levels. Mucosal rather than clinical remission was used as the primary outcome to generate sample size in 1 RCT of EN versus corticosteroids (57), and was significantly more likely at 10 weeks in children taking polymeric formula. There was no difference in clinical outcome.
From these studies, EN appears to be safe and effective in the induction of remission of CD and is almost as effective as corticosteroids, with none of the steroid-associated toxicities during treatment.
Many drugs and nutritional and complementary/alternative therapies beyond those described in the 6 treatment groups above are used by physicians and families in paediatric IBD, but we could find no relevant publications.
No relevant reviews were discovered.
With our systematic literature search ending on January 1, 2007, there have been significant recent additions to the paediatric and combined paediatric and adult literature. These include an RCT of infliximab usage in children with CD (141) and an open-label study of natalizumab usage in children with CD (142). There are new or updated Cochrane reviews of combined paediatric and adult interventions, such as those for fish oil (143) and enteral nutrition (144), respectively. Many gaps still exist in areas that are generating high-quality adult data but as yet no paediatric data, such as antituberculous therapy for CD (145) and either the induction or maintenance of remission in CD using adalimumab (146,147).
This exercise has identified significant gaps in the literature on the treatment of paediatric IBD, which suggests the need for a rolling programme of clinically relevant, methodologically robust, and well-performed and well-presented RCTs of treatment. Although attention will inevitably concentrate on the newer agents, such as biological therapies, there is a great need to evaluate traditional and useful agents, such as the immunomodulators azathioprine and methotrexate. Consideration of clinically relevant outcomes is needed; for example, restoration of normal growth is vital in paediatric IBD, yet this has not been the primary outcome of any study to date (148). The publication of the first Consolidated Standards of Reporting Trials (better known as CONSORT) statement was in 1996 (149), with revision in 2001 (150), yet RCTs in paediatric IBD continue to be designed and their results disseminated despite failing to meet the agreed-upon methodological and presentation criteria. Of the 16 RCTs in this evidence base, many have obvious methodological flaws (no or inadequate randomisation details, no concealment details, no sample size calculation, no intention-to-treat analysis) and few have a CONSORT-type flow diagram of subject progress through the RCT.
The present review has directly led to the construction of a methodologically robust, consensus-based clinical guideline on the treatment of paediatric IBD (see pp. S1–S13), comprising the best-available evidence from the paediatric literature (including the use of this evidence-based review), relevant methodologically high-quality data from the adult IBD literature, together with the clinical expertise and experience of multidisciplinary teams that manage paediatric IBD in children and teenagers. The content of evidence-based practice is controversial to some, and we agree with Glasziou (151) that what we need is evidence-informed practice, with wisdom derived from clinical expertise and experience, in this case in the treatment of paediatric IBD.
The authors acknowledge the help of Michael Goodwin, MD, in importing references to our dedicated database.
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