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Pediatric inflammatory bowel disease: highlighting pediatric differences in ibd

Pe d iatri c I n flam mator yBowe l Dis eas e :Hig h lig hting Pe d iatricDiff ere nces in IBD  Crohn disease  Ulcerative colitis Inflammatory bowel disease  Pediatric Evidence-based treatment algorithms Inflammatory bowel disease (IBD) includes Crohn disease (CD) and ulcerative colitis(UC), and is often diagnosed in late childhood and early adulthood. IBD is thoughtto develop as a result of dysregulation of the immune response to normal gut florain a genetically susceptible host. Approximately 25% of incident cases of IBD occurduring childhood and the rest occur throughout adulthood, peaking in the secondand third decades of life. What determines the age of onset remains unexplained.
Studying early-onset presentation and epidemiology of complex predominately adultdiseases such as IBD is particularly necessary, as the early onset may represent the‘‘pure’’ form of the disease process and hence may hold secrets of the initiating eventsof IBD pathogenesis. Basic, translational, and clinical scientists continue to focus onpediatric IBD, because it may shed light not only on the cause but also the preventionof this lifelong disease. Over the last decade, data from pediatric IBD studies havedemonstrated many similarities and differences between pediatric and adult onset,which continue to add pieces to an increasingly complex IBD puzzle. The mechanismresponsible for these similarities and differences remains unanswered.
The purpose of this article is to discuss clinically relevant epidemiology and treat- ment aspects of pediatric IBD, with a special focus on similarities and differences inpediatric and adult IBD. Epidemiologic similarities and differences may ultimatelyprovide the link to a better understanding of the pathogenesis of IBD. This articlealso highlights evidence-based treatment algorithms, with special focus on pediatricstudies and care for children.
a Department of Pediatrics, Emory University School of Medicine, Emory Children’s Center,2015 Uppergate Drive, Atlanta, GA 30322, USAb Division of Pediatric Gastroenterology, Emory University School of Medicine, EmoryChildren’s Center, 2015 Uppergate Drive, Suite 248, Atlanta, GA 30322, USA* Corresponding author.
E-mail address: (S. Kugathasan).
Gastroenterol Clin N Am 38 (2009) 611–628doi:10.1016/j.gtc.2009.07.010 0889-8553/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
The male to female ratio of IBD differs in multiple studies when comparing pediatricIBD to adult IBD. Whereas in adult IBD there is an equal ratio of male to female diseaseor perhaps more women with disease, prepubertal males seem to be more affected bypediatric CD. Van Limbergen and colleaguesdemonstrated that in pediatric CD thereis a strong trend toward males, with a male to female ratio of 1.5:1. Vernier-Massouilleand colleaguesalso confirmed a male predilection, with a similar ratio of 1.4:1 in chil-dren younger than 15 years. This figure directly compares with a ratio nearing 1:1 inpatients older than 15 years in the same population. Other adult epidemiologic studiessimilarly have shown a gender ratio of approximately 1:1. A summary of recent epide-miologic studies demonstrating a male preponderance in pediatric CD is provided in.
Pediatric UC does not demonstrate the male predominance seen in pediatric CD. In fact, similar to adult UC, males and females are equally affected in pediatric UC inmultiple studies. demonstrates the equal distribution of males and femalesin pediatric UC.
Very early onset IBD (age <5–8 years) has been recently suggested as perhaps a different spectrum of IBD. Multiple epidemiologic studies have demonstrateda male preponderance of very early onset IBD. It is unclear whether this male prepon-derance is only seen in CD or in both CD and UC, as many of the studies do notprovide specific gender information based on specific Together, these gender differences generate more questions than they answer. The effect of puberty and sex hormones on disease pathogenesis continues to be unan-swered. Further study will continue to explore these interesting epidemiologic findingsand may ultimately provide important information as to the cause of pediatric IBD.
The ratio of CD:UC significantly differs in children and adults. Van Limbergen andcolleaguesdemonstrated a significant predilection for CD in children, with a ratioof 2.8:1. Adult IBD demonstrated a ratio of 0.85:1. Other epidemiologic studies thathave been performed using various methods (ie, population based, insurance claims, Table 1Male preponderance in pediatric CD compared to adult CD Table 2Equal distribution of males and females in pediatric and adult UC and so forth) have suggested a similar higher ratio of CD than UC in children. Thisdirectly differs from adult studies that have demonstrated more UC than CD diag-noses. illustrates recent studies that reveal this significant difference inCD:UC ratios in children and adults.
There is clearly a significantly higher CD:UC ratio in children than in adults. Similar to gender differences, this observation clearly requires further investigation, with fewdata available to suggest a mechanism for this significant difference between pediatricand adult IBD.
Disease location at presentation differs in pediatric IBD compared with adult IBD. Inpediatric CD a majority of patients have ileocolonic disease or colonic disease,whereas adults more often present with terminal ileal disease without colonic involve-ment. During follow-up of pediatric CD, Vernier-Massouille and and Van Table 3CD preponderance in pediatric IBD and UC preponderance in adult IBD Limbergen and colleaguesboth demonstrated a progression of disease location withincreasing ileocolonic disease at follow-up. Meanwhile, Van Limbergen andcolleagues showed that more than one-third of adults had terminal ileal diseaseonly. In multiple pediatric studies, up to 80% to 90% of children experience colonicdisease (colon only or ileocolonic) whereas only approximately 50% of adults experi-ence colonic CD. It is unclear why there is an increased ileocolonic/colonic disease inchildren and no accepted theory has been offered as to this observation. No treatmentstudies have suggested that children with ileocolonic disease require differenttreatment from terminal ileal disease alone. demonstrates the high rate ofileocolonic disease in children at both diagnosis and follow-up in 2 studies.
Pediatric UC location also differs from that of adult disease. Pediatric UC presents more often with pancolitis versus left-sided colitis/proctitis. In fact, most pediatric UCstudies demonstrate up to 80% to 90% of children present with pancolitis, anda recent study by Van Limbergen and suggested that pediatric UC prog-resses with increasing percentage of pancolitis at follow-up. The significance of thehigh percentage of pancolitis at presentation is unknown. demonstrates anincreased pancolitis presentation in pediatric UC.
In summary, pediatric CD more often involves the ileocolonic/colonic regions whereas adult CD does not demonstrate a high proportion of colonic disease. Mean-while, pediatric UC more often presents with pancolitis whereas adult UC more oftenpresents with left-sided colitis. The mechanism behind these observations is not wellunderstood and no data are available to support any concrete hypotheses.
Disease phenotype in both CD and UC differs when comparing children with adults.
Pediatric CD presents predominantly with inflammatory or nonstricturing, nonpene-trating disease. Stricturing and penetrating disease is relatively uncommon at presen-tation in pediatric CD. However, even with treatment, multiple studies have shown that Table 4Higher ileocolonic disease prevalence in pediatric CD compared to adult CD Table 5Pancolitis predominance in pediatric UC CD progresses to stricturing and penetrating disease in many children. Adult diseasepresents more often with stricturing and penetrating disease. Two recent naturalhistory articles reveal a significant progression of pediatric CD from inflammatorydisease to sticturing disease, as illustrated in .
Pediatric UC more often presents with pancolitis, and has been suggested to be a more severe phenotype in children than in adults. Recent epidemiologic datademonstrate that indeed, time from diagnosis to first surgery in UC is significantlyshorter in children than in adults. By 10 years after diagnosis more than 40% of chil-dren had undergone colectomy, whereas only 20% of adult-onset UC patients hadundergone colectomy.
In summary, pediatric CD frequently displays an inflammatory phenotype at diag- nosis that progresses to fistulizing/stricturing disease in some patients, whereasadult CD more often presents with fistulizing/stricturing disease. Although someinvestigators have suggested disease duration and a delay in diagnosis may bethe reason for this difference in CD, no data have been published to support thishypothesis. Pediatric UC frequently displays an aggressive phenotype, with panco-litis and early time to first surgery compared with adult UC, which is more oftenlimited to the left colon.
When studying early-onset presentations of disease, there is an assumption that theserepresent a more severe, more genetically influenced group of patients. It is appealing Table 6CD phenotype demonstrates progression of disease from inflammatory to structuringand penetrating disease to geneticists to study these patients because of the increased chance of finding novelrisk variants. One of the most compelling hypotheses is that pediatric-onset IBD ismore likely to be influenced by genetics compared with late- or adult-onset IBD, asthere is less time for environmental modifiers to have influenced the disease.
IBD is highly heritable. This concept is strongly supported by family, twin, and phenotype concordance studies, and now is confirmed by the discoveries of manysusceptibility genes.Initial family-based linkage studies of IBD implicated theNOD2 gene in CD and the MHC region on chromosome 6p in UC for increasedGenome-wide association scanning (GWAS), which employs high-density single nucleotide polymorphism (SNP) array technology, has recentlyincreased the possible genetic factors linked to IBD pathogenesis. This method ofbroad, unbiased screening for the contribution of common genetic variation fordisease susceptibility has provided strong evidence for many CD and UC suscepti-bility loci.GWAS has identified loci in both UC and CD that are already known tobe involved in adaptive immunity genes such as IL23R, IL12B, STAT3, loci on 3p21(MST1), and 10q24 (NKX2-3). Variants in innate immunity genes, particularly thosemediating autophagy and bacterial sensing (ATG16L1, IRGM, and NOD2) have alsobeen discovered through these methods in CD. To date, the majority of this geneticanalysis in IBD has been done in adult cohorts with adult-onset disease as the primaryphenotype, therefore even less is known about early-onset variants.
Several CD susceptibility alleles have been confirmed in both pediatric and adult populations. However, most of the genetic variation seen in adults has not beenstudied in children in a large cohort with adequate power. Two pediatric studies at-tempting to replicate the effect of adult-onset IBD loci in children have been performedrecently. These studies have demonstrated that autophagy genes play a role in pedi-atric CD but also that known genetic risk factors found in adults may not distinguishearly- and late-onset The first pediatric GWAS IBD scan was performed recently, revealing 2 risk variants not previously reported in adults, in addition to confirming the most significant adultrisk variants. Two novel loci, the TNFRSF6B and PSMG1 genes, were discoveredusing more than 1000 cases of pediatric IBD.The gene TNFRS6B, which encodesa decoy receptor for the FasL pathway (DCR3), was found to increase the risk for pedi-atric-onset CD and UC. On comparison with adult GWAS scans these same loci wereidentified, but were below the expected threshold when correcting for multiple tests.
However, until a GWAS is performed in an exclusively pediatric-onset IBD cohort, it isvery difficult to deny that additional pediatric-onset IBD susceptibility genes do notexist. As such, GWAS studies involving larger pediatric-onset CD cohorts and early-onset UC are presently underway.
Adult and pediatric GWAS studies have yet to discover risk variants that are specific to pediatric or adult IBD. Instead, all risk variants that have been discovered arepresent in both adult and pediatric scans, although not necessarily in the statisticallysignificant range. This observation, if confirmed in additional larger GWAS studies,may further suggest that pediatric and adult IBD have similar genetics and thus arethe same disease with different age of presentation.
More detailed functional exploration of genes associated with susceptibility loci re- ported in GWAS will be instrumental in shedding light on their role in IBD pathogenesis.
Taken together, recent pediatric GWAS results substantially advance the currentunderstanding of pediatric-onset IBD by highlighting key pathogenetic mechanisms,and allowing for the first time a comparison between genetic susceptibility in an exclu-sively pediatric cohort and the previously described populations with predominantlyadult-onset disease.
Clinical presentation is similar in adult and pediatric IBD, and for the most partcorrelates with disease location. Pediatric CD presents with more ileal and colonicdisease than adult CD, and therefore more often presents with hematochezia. Smallbowel disease presents with diarrhea regardless of childhood or adult onset. Pediatricand adult IBD share many of the same gastrointestinal symptoms which, as one wouldexpect, are associated more with mucosal disease than with age.
Extraintestinal manifestations similarly are present in both children and adults in similar numbers. Extraintestinal manifestations are present in 6% of children prior todiagnosis in one recent study, and cumulative incidence approaches 25%, similarto adult Growth is the most significant difference in presentation between adult and pedi- atric IBD. Poor growth prior to diagnosis has been documented in multiple studiesexamining growth in pediatric IBD.Furthermore, puberty has been shown to beand some patients have decreased final adult height.In addition,a recent study has demonstrated that despite new treatments, catch-up growthdoes not occur in patients diagnosed with IBD, although it remains to be seen whetherthese patients have delayed puberty and ultimately achieve their expected adultheight.Persistent poor growth may also be one of the only signs of increaseddisease activity, thus it is important not only in presentation but also in disease activityduring treatment.
Pediatric IBD treatment employs many of the same treatment paradigms as adult IBD.
Most medication clinical trials have largely been performed only on adults, and there-fore much of the evidence given here is based on adult data. Only a few well-designedclinical trials have been performed in children, and most of those show similar efficacyto adult trials.
The authors have chosen to separate the Treatment section into Induction and Maintenance of remission. What follows is not meant to be an exhaustive review ofcurrent literature; rather a review some of the current data and a report on any addi-tional data specific to children.
Crohn diseaseInduction of remission Two recent Cochrane review articles examined budesonide andconventional corticosteroids (prednisone) as therapy for the induction of remission inCD. A majority of these were adult studies, although in some studies children olderthan 16 years were included. The reviews clearly show efficacy for induction of remis-sion with both budesonide and conventional steroids, and show slightly less efficacyof budesonide compared with conventional steroids, at least in severe disease.
Maintenance of remission Corticosteroids, including both conventional steroids andbudesonide, are not recommended for maintenance of remission. Any benefits inmaintenance of remission are offset by treatment-related adverse events and thusthese medications should be avoided for maintenance of remission, especially in chil-dren in whom corticosteroids can significantly affect growth.
Ulcerative colitisInduction of remission The use of corticosteroids for induction of remission in UC wasfirst described in 1974,and has been the mainstay for induction of remission in moderate to severe UC. More recently, approximately 84% of adults with UC demon-strated a complete or partial improvement of disease activity with corticosteroids, andapproximately 49% had prolonged response at 1 year.Budesonide, which hassignificant first-pass metabolism, is delivered to the distal ileum and proximal colonand thus likely has little efficacy in UC, although a randomized controlled trial hasnever been published.
Maintenance of remission As with CD, corticosteroids are not recommended for themaintenance of remission in UC as any benefits are more than offset by side effects,especially in growing children.
SummaryIn practice, corticosteroids are often used in induction of remission in CD and UC butare often avoided if possible after induction, due to growth side effects and othermorbidity associated with persistent corticosteroid usage. Studies have clearly shownthat morbidity in CD is associated with corticosteroid use. Therefore, children withnew diagnosis CD and UC are often started on corticosteroids with a taper over 2months. Corticosteroids are avoided, if possible at all other times other than inductionof remission.
Crohn diseaseInduction of remission A recent Cochrane review compared nutritional therapy (liquidformula by mouth or via tube) to corticosteroid therapy for induction of remission.
Although sole nutritional therapy has been shown to be effective in induction of remis-sion in CD, it remains inferior to corticosteroids in induction of remission. In addition,the same review concluded that protein composition (ie, elemental or nonelementalprotein) has no effect on efficacy of nutritional The only study that favorsenteral nutrition over corticosteroids was a pediatric study.
However, practically speaking, the induction of remission with sole nutritional therapy remains difficult due to adherence in children. Most parents are reluctant tocommit total enteral nutrition for their children for 6 to 8 weeks as required. In addition,few children are able to consume adequate formula volume by mouth, and thus wouldrequire insertion of nasogastric tubes or possibly a gastrostomy tube.
Maintenance of remission Only 2 randomized studies have been published regardingmaintenance of remission in CD with nutrition in adults, and no studies have examinedthis in children. Takagi and conducted a randomized controlled trial of 51adults in remission, assigning one group a half-elemental diet and another groupa regular diet with no instructions or limitations, with all patients taking mesalamine.
The study demonstrated a significantly lower relapse rate in the half-elemental dietgroup (34.6% vs 64.0%). A recent Cochrane review suggested that there may besome efficacy in enteral nutrition for maintenance therapy, although larger studiesare needed to confirm this possibility.
Ulcerative colitisNo studies have been reported for the induction or maintenance of remission withenteral therapy for UC.
SummaryAlthough both the European Society for Pediatric Gastroenterology, Hepatology, andNutrition and the Japanese Society for Pediatric Gastroenterology, Hepatology, andNutrition recommend nutritional therapy as sole primary therapy for CD, it is often a difficult treatment to initiate in the United States. The most significant deterrentcontinues to be the resistance by many parents and children to commit to 8 weeksof specialized formula alone (either by mouth or through a feeding tube such as a naso-gastric tube) without taking any other food by mouth. Furthermore, it is unclearwhether a child can be maintained on nutritional therapy alone and therefore, othermaintenance medications need to be initiated. In addition, the short-term side effectswith corticosteroid induction are debatably minimal.
Crohn diseaseInduction of remission No randomized controlled studies have been performed exam-ining the induction of remission by aminosalicylates in pediatric CD. Hanauer andpublished a meta-analysis examining aminosalicylates in active CDand showed a modest effect (if any) on improvement of Crohn Disease Activity Index(CDAI).
Although some pediatric gastroenterologists continue to use aminosalicylates for the induction of remission in CD, there are no good data to support the use for induc-tion of remission, although there may be modest beneficial effects.
Maintenance of remission No randomized studies have been published for mainte-nance of remission in pediatric CD. A recent Cochrane review examined aminosalicy-lates in the maintenance of remission in CD. The results do not show any benefit ofaminosalicylates compared with placebo.
Ulcerative colitisInduction of remission A recent Cochrane review that includes only adult studiesdemonstrated a benefit from high-dose aminosalicylates (>3 g) in the induction ofremission in UC, although remission rates remain significantly lower than in thoseusing Most importantly in pediatric UC, a majority of patients present with moderate to severe disease, as demonstrated by the high percentage of pancolitis. Whereas ami-nosalicylates can be used for induction of remission, due to severity of disease in pedi-atric UC they are rarely used as sole induction, but rather in conjunction withcorticosteroids for induction of remission.
Maintenance of remission As with many of the medications mentioned here, norandomized trials have been conducted in children examining the use of aminosalicy-lates in maintenance of remission in children. A Cochrane review has demonstratedefficacy of aminosalicylates in maintaining remission in UC compared with placebo.
SummaryThere are no randomized controlled trials for the induction or maintenance of remis-sion of aminosalicylates in pediatric IBD. Aminosalicylates are still often used in pedi-atric IBD. These agents are well tolerated in children, have few side effects, and thushave continued to be used by pediatric gastroenterologists despite the lack ofevidence in CD and efficacy only in mild to moderate UC. Even though aminosalicy-lates are well tolerated, the most significant ‘‘side effect’’ is decreased quality of lifedue to the number of pills or capsules ingested each day, which often is consideredin treatment of children with IBD.
However, it should be noted that aminosalicylates likely have most efficacy in colonic disease regardless of whether the diagnosis is CD or UC. Given the datademonstrating more colonic disease in children (up to 80%), the use of aminosalicylates in colonic CD may be of some benefit, although there are no dataexamining this question. Whether aminosalicylates could be used as sole therapy incolonic CD has never been examined.
Based on the current data, the authors cannot support the usage of aminosalicylates in ileal CD, as there seem to be no compelling data to support their use. However, thereare data to support the use of high-dose aminosalicylates in the management of UC, andthere may be some efficacy in colonic CD, although there are no data for this possibility.
Immunomodulators (6-Mercaptopurine, Azathioprine, Methotrexate) Crohn diseaseInduction of remission Because of its delay in efficacy, 6-mercaptopurine (6-MP) andazathioprine (AZA) are not used for induction of remission; however, they are oftenused in conjunction with corticosteroids or other therapy used to induce remissionwith the knowledge that by the time corticosteroids are weaned, 6-MP and AZA willbe effective in maintaining remission A Cochrane review concluded efficacy for methotrexate in induction of remission in CD based on one study.Methotrexate has demonstrated efficacy in inducing remis-sion after failure of induction therapy with steroids in one large double-blind, placebo-controlled multicenter study (n 5 141) when compared with placebo.Other smallerstudies did not show a significant difference. In children, only retrospective studieshave been conducted. One retrospective, multicenter study (n 5 61) demonstratedimprovement in disease or complete remission in 80% of children who were notresponding to AZA.A second retrospective study (n 5 60) demonstrated remissionat 6 and 12 months in 42% of children placed on methotrexate after 6-MP/AZA failu Maintenance of remission 6-MP and AZA have demonstrated efficacy in maintainingremission in CD in multiple studies, and a recent Cochrane review confirms significantefficacy compared with In children, one prospective multicenter, double-blind, placebo-controlled trial demonstrated induction of remission with prednisone and 6-MP, and maintenanceof remission with 6-MP. Seventy-five children were randomized to prednisone and6-MP or prednisone alone, with similar induction of remission rates (89%). At 548days after remission, 91% of the 6-MP group continued to be in remission whereas only 53% of the steroid only group remained in remission. Initiation of 6-MP atdiagnosis also has a significant steroid-sparing Ulcerative colitisInduction of remission Similar to CD, due to the slow onset of action of 6-MP and AZAthese medications are rarely used as primary therapy for induction. No studies evalu-ating methotrexate in adults or children are available for the induction of remission. Arecent Cochrane review concluded that there are no published reports to demonstrateefficacy of methotrexate in the induction of remission in UC.
Maintenance of remission No large studies have examined the use of 6-MP and AZA forthe maintenance of remission in UC. A Cochrane review identified 4 studies thatshowed efficacy of 6-MP/AZA compared with placebo. Another Cochrane reviewconcluded no efficacy in methotrexate in maintaining remission in UC.
In children, one retrospective study of 20 corticosteroid dependent or refractory patients revealed efficacy, with discontinuation of corticosteroids in 75% and 67%continuing to be steroid free at Summary6-MP and AZA clearly show efficacy in maintaining remission in pediatric CD in a well-designed pediatric study. In addition, these medications have a significant steroid-sparing affect. Because of these data they are often initiated at diagnosis for themanagement of moderate to severe CD. 6-MP and AZA also have a role in the main-tenance of remission in moderate to severe pediatric UC.
Methotrexate induced and maintained remission in one pediatric trial. Methotrexate is often used due to its quick action, unlike 6-MP and AZA that have slow onset ofaction. The most significant issue with methotrexate is its bioavailability, as oral medi-cation may not be as efficacious as subcutaneous injections. Despite this, metho-trexate is an excellent option when immediate action is necessary and when onewants to avoid biologics.
Crohn diseaseInduction and maintenance of remission A Cochrane review clearly shows efficacy for theuse of infliximab in the induction and maintenance of remission in CD.In addition,there are multiple pediatric studies that demonstrate efficacy in induction of remission inchildren with CD. The first pediatric trial of infliximab in moderate to severe CD demon-strated clinical remission at 30 weeks in 60% of patients, and prolonged remission in56% of patients at 54 weeks when continued on an every 8 week Althoughthese results are significantly higher than the adult studies, it should be mentionedthat 90% of patients in this study were on concomitant immunomodulators. Therefore,the results may be higher than seen in clinical practice. A recent study evaluated main-tenance of remission in children receiving infliximab for more than 1 year, and demon-strated withdrawal of corticosteroids and clinically inactive disease in 30% to 40% ofchildren who were maintained on infliximab.A recent French study confirms thenecessity of scheduled and not random infliximab doses in Ulcerative colitisInduction and maintenance of remission As with many of the other therapeutic agents forIBD, there are no randomized controlled trials of biologics in children with IBD. Thereare several retrospective studies that demonstrate efficacy in inducing and maintain-ing remission in children with moderate to severe UC. Data are available in adults with moderate to severe UC, demonstrating efficacy of infliximab in inducing remission,promoting mucosal healing, and reducing the need for SummaryBiologics clearly demonstrate efficacy in inducing and maintaining remissions in pedi-atric IBD. Perhaps the more pressing debate is the proper use of biologics and theresults of more long-term follow-up. Although it is clear that some children fail othertreatments for IBD and require biologics, it is difficult to recommend biologics asfirst-line therapy given the paucity of long-term follow-up data. With no current ‘‘exitstrategy,’’ biologic initiation requires treatment for an indefinite period of time.
Special Considerations in the Treatment of Inflammatory BowelDisease in Children Children with IBD require special consideration in their treatment, specificallyregarding growth, hepatosplenic T-cell lymphoma, and goals of therapy.
GrowthIn children, growth remains one of the most significant outcomes, as poor growthoften can be the only ‘‘symptom’’ of disease. As discussed in the Presentation section,growth is poor prior to diagnosis, children with CD have delayed puberty anddecreased final adult height, and many do not exhibit catch-up growth after diagnosis.
Growth parameters are included in the Pediatric CDAI, as poor growth remains a clin-ical sign. Close attention to both height velocity and weight are necessary during thetreatment of pediatric CD, as this may be the only clinical sign of persistent diseaseactivity.
No specific treatment paradigms have been shown to be superior in improving growth. Biologics and surgical resection have been shown to improve growth;however, these may not be superior to immunomodulators.No other treatmentssuch as growth hormone have shown superiority. Regarding growth, treatment shouldthus focus on controlling disease activity and providing sufficient calories, which mayrequire supplementation with high-calorie formula.
Hepatosplenic T-cell lymphomaAlthough overall increased risk of lymphoma has been reported in patients with IBDwho have been exposed to biologic or immunomodulator therapy, a rare fatal formof lymphoma, hepatosplenic T-cell lymphoma (HSTCL), is now linked only in childrenand young adults with IBD. Cases of HSTCL have been reported with both combina-tion therapy with 6-MP/AZA and monotherapy with 6-MP/AZA, but not with infliximabmonotherapy alone. There are now approximately 18 cases of HSTCL with individualson both 6-MP/AZA and infliximab. These cases reveal preponderance for young malepatients, although the mechanism of this observation is unknown. Due to this potentialrisk of this fatal disease, the treatment of pediatric IBD does not currently includecombination therapy with biologics and immunomodulators. However, with recentdata from the SONIC trial showing superior efficacy of combination immunomodulatorand biologic therapy compared with either therapy alone, there is considerable debateregarding combination therapy, at least in young females.
Goals of therapyGrowth and clinical remission remain the most important goals of therapy. Clinicalremission may be best defined by the appropriate activity index. A Pediatric CrohnDisease Activity Index and a Pediatric Ulcerative Colitis Activity Indexhave been developed and validated, and are currently in use both clinically and for research purposes. These indices are similar to adult indices, with somespecific differences. In children, the PCDAI includes growth measures in addition tosymptoms, physical examination, and laboratory measures. The PUCAI was morerecently developed and is completely symptom based, as growth abnormalities areless likely to be observed in pediatric UC. Endoscopic healing remains a debatedtopic, although repeated endoscopy is not recommended in children.
Crohn diseaseThe treatment paradigm for CD remains similar to adult treatment of IBD. Prednisoneremains the most effective medication for induction of remission and is often used asa short course for induction only purposes, then avoided due to growth side effects.
Although nutritional therapy has proven to be effective in inducing remission, nowell-performed studies have shown efficacy in maintaining remission, and sole nutri-tional therapy remains an option for induction of remission for those willing to committo this treatment. Research demonstrates a minimal (if any) benefit for aminosalicy-lates in the induction of remission in CD, and no benefit in the maintenance of remis-sion. However, more children with CD have colonic disease and thereforeaminosalicylates may be of some benefit, given their proven efficacy in UC. Due tothe high frequency of moderate to severe CD disease in children, immunomodulatorsare frequently used at or shortly after diagnosis. Markowitz and colleagues demon-strated a steroid-sparing effect and maintenance of remission in children treatedwith immunomodulators, and a short course of prednisone at diagnosis. Biologicsremain an option although given the high efficacy of immunomodulators, biologicsare most often reserved for children who fail immunomodulator therapy. At thistime, biologics cannot be recommended as first-line therapy. However, continuedresearch may predict those children with more severe disease, and at that pointbiologics may be suggested as first-line therapy for those with severe disease.
Ulcerative colitisUlcerative colitis treatment continues to be similar for children and adults, althoughresearch has demonstrated more pancolitis and shorter time to surgery in pediatricUC, perhaps supporting more aggressive treatment for children with UC. Prednisoneremains the most effective induction of remission therapy, but is only recommended atdiagnosis with a short course due to growth effects. Aminosalicylates show efficacy ininduction and maintenance of remission, but are reserved as sole treatment only in themildest cases of pediatric UC. Immunomodulators are often necessary in pediatric UCdue to its moderate to severe presentation in children, and are effective in maintainingremission. Biologics are effective in inducing and maintaining remission in pediatricUC but are reserved at this time primarily for immunomodulator failures.
Perhaps the most pressing issue in the treatment of IBD in children is the identification ofa more severe phenotype that would respond best to biologics at diagnosis and thusprevent the need for surgical therapy. Over the next decade, determining which patientsare at most risk for surgery and other complications may reveal a tool to predict diseaseseverity and potentially prove that these individuals fare better with top-down therapy.
However, at this time it is difficult to argue the top-down approach, given the unknowneffects of biologic therapy used for decades in children diagnosed at an early age.
While this question about differing age of onset among the chronic complex inflamma-tory disorders such as IBD encourages debate, a fundamental issue in IBD remainsunanswered. Does pediatric IBD represent the same disease process occurring inadults but merely at an earlier age (ie, age of onset is a random event), or does pedi-atric IBD display different pathogenesis (hence different natural history) but simplywith the same clinical presentation as adults? An argument can be made suggestinga different spectrum of the same disease or different pathogenesis that leads to similardisease phenotypes.
Although no hard scientific evidence exists regarding differing etiology, pediatric- onset IBD does ‘‘differ’’ from adult IBD in many aspects.As highlighted in this article,there is growing evidence from clinical observations as well as epidemiologic andnatural history studies that pediatric-onset IBD represents a distinct disease withdifferences in disease type, disease location, disease behavior, gender preponder-ance, and genetically attributable risk compared with its adult counterpart.Thesedifferences need to be further explored, as they may someday hold the key to under-standing the pathogenesis of IBD.
More specifically, children are more likely to be diagnosed with CD versus UC, and there is a predilection for males in pediatric CD but not pediatric UC. In addition, pedi-atric CD more often presents with ileocolonic disease and inflammatory phenotype,which progresses in some to structuring and fistulizing phenotype, although predictingthis progression is difficult. Pediatric UC presents with more pancolitis and may bemore severe, as suggested by an earlier time to first surgery.
Very early onset IBD (age <5–8 years) also exhibits a male preponderance and pres- ents with colonic disease more often than when diagnosed in later childhood or adult-hood. It remains unclear whether very early onset IBD has different genetic variationsor other differences in pathogenesis.
Treatment paradigms are similar in adult and pediatric IBD, with only a few prospec- tive trials available in pediatrics, but all with similar results to adult trials. Outcomeremains the most significant driver of treatment options, and in children diseaseactivity, and specifically growth, are important outcome measures. There are someimportant risks that seem to affect children more than adults including HSTCL, whichhas a predilection for younger males. These factors affect treatment paradigms, andfurther study is necessary to determine the precise risk (if any) for and to better under-stand the pathology of this serious lymphoma.
Overall, pediatric IBD may hold the key to understanding the pathogenesis of IBD, with the hopes of leading to prevention. As expected, highlighting the differences andsimilarities between pediatric and adult IBD has generated more questions thananswers. It is important that these specific differences are further explored throughhigh-quality research in the search for the cause and cure of IBD.
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