The Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry , a natural history study started in 2002 enrolled 1928 subjects diagnosed with IBD before their 16th birthday. The age distribution of the cohort at diagnosis was 6 % <5 years, 28 % from 5–9 years, and 66 % from 10–16 years with a slight predominance of males over females (57 % vs. 43 %) [1]. In a population-based state-wide US epidemiologic study, the incidence of IBD in the pediatric population was 7.5 per 100,000 with that of Crohn’s disease (4.6 per 100,000) being twice that of ulcerative colitis (2.1 per 100,000). Eighty-nine percent of new cases were nonfamilial [2].

The location or extent of disease differs according to age of disease onset in children newly diagnosed with Crohn’s disease. Children under the age of 10 years, and in particular children under the age of 5 years, characteristically present with isolated colitis, whereas ileal disease (with or without accompanying colitis) begins to occur more often in children whose disease is diagnosed after the age of 9–10 years [3, 4]. Upper tract involvement (proximal to the ligament of Treitz) is present most commonly in those children with ileocolonic disease (up to 50–60 %), with esophageal involvement seen in 27 % (macroscopic in 18 %), and gastroduodenal involvement in 56 % (macroscopic 42 %). Isolated UGI involvement is rare [5]. Pediatric onset ulcerative colitis is characterized by extensive colitis or pancolitis in the majority of cases and isolated proctitis is less common than in adult populations [6, 7].

As in adults antibodies to a variety of microbial antigens have been found in children with Crohn’s disease. However, in children there appears to be an age-related expression of these antibodies. In a cohort of 705 children from three prospectively characterized cohorts in North America, the rate of ASCA (both IgG and IgA) positivity was <20 % for children <7years of age compared to 40 % for those 8–15 years of age, likely representing the preponderance of isolated colonic disease in young children. Anti-CBIR1 was detected in 66 % and 54 %, respectively, from the two age groups [8].

In French and North American population-based pediatric studies, disease behavior at diagnosis was inflammatory (B1) in 70–72 % and stricturing (B2) or penetrating (B3) in 22–30 % [9, 10]. A French population-based study of children with ulcerative colitis found 26 % had proctitis, 35 % left-sided disease, and 37 % extensive colitis at diagnosis [7]. This disease distribution is quite different than reported previously from North America where extensive disease at diagnosis has been observed in up to 80 % of children at presentation [2, 11]. More recent studies propose further subdividing children by age of diagnosis, with those diagnosed at age <10 years consider early onset IBD (EOIBD), and those diagnosed age <6 years as very early onset IBD (VEOIBD) . Patients in the VEOIBD group are more likely to have monogenic IBD, with increased risk of primary immunodeficiency, autoimmune enteropathy, and primarily colonic disease distribution. These findings are distinct from patients diagnosed after age 7 years that more commonly have conventional, polygenic IBD [12–14]. The discovery of mutations in the genes coding for one of the two IL10 receptors causing loss of function in IL10 signaling has prompted increasing work looking for genetic polymorphisms that produce a severe IBD-like phenotype [15].

While measuring the severity of gastrointestinal symptoms and laboratory abnormalities is similar in children and adults, the profound effect of IBD on linear growth is clearly a pediatric-only problem. Growth abnormalities are quite common in pediatric Crohn’s disease and may be the major clinical manifestation. Thus, growth data have been incorporated into the most widely used instrument to measure disease activity in children with Crohn’s disease, the Pediatric Crohn’s Disease Activity Index (PCDAI ) [16]. As measuring changes in growth velocity can only be done accurately over periods of 6 months or more, this has led to concerns that the PCDAI might not be sensitive enough to discern changes in clinical activity over the short-term (e.g., 3 months or less); however, this has not been borne out by additional studies [17]. The PCDAI can range in score from 0 to 100 with <10 denoting remission, 10–30 mild disease, and >30 moderate to severe disease. Given the limitations in calculating the complete PCDAI at each visit, more recently the weighted PCDAI (wPCDAI) has also been proposed as a more feasible instrument [18]. Additionally, the short PCDAI, a simplified disease assessment tool excluding need for laboratory and perianal assessment, has been developed and validated against the full and abbreviated PCDAI has been proposed to be utilized in observational and quality improvement research [19].

The Pediatric Ulcerative Colitis Activity Index (PUCAI) has been developed and validated to measure the activity of pediatric ulcerative colitis [20]. It ranges from 0 to 85 points with <10 signifying inactive disease, 10–34 mild disease, 35–64 moderate disease, and 65 or greater severe disease. Debate regarding how to most fully assess clinical remission in IBD exists. Variable definitions of remission in IBD including clinical, serologic, endoscopic, and histologic remission have been proposed and have resulted in the concept of “treat to target”, with some centers suggesting histologic remission should be the ultimately therapeutic goal [21].

An expanding body of literature has evaluated the use of biomarkers including fecal calprotectin as an indirect assessment of luminal activity. Recent studies have found that many patients in clinical or even endoscopic remission continue to have histologically active disease. Fecal calprotectin was found to be significantly higher in those with active histologic disease compared to those with histologic healing (median 278 μg/g vs. 68 μg/g (p = 0.002)), suggesting calprotectin may be a more reliable marker of histologic disease activity [22]. Additional studies have suggested cut off calprotectin values of approximately <200 μg/g correlate well with endoscopic and histologic healing. Use of the calprotectin therefore may reduce the need for repeat endoscopic evaluation [23]. Application of calprotectin as a reliable marker of remission in the pediatric population requires further investigation.

Though data to support the use of aminosalicylates for the treatment of pediatric Crohn’s disease or ulcerative colitis are scant, they are commonly used for both. Specific dosing guidelines for children have not been established and therefore in practice there is large variation. The most common dose used is 50 mg/kg/day of mesalamine though anecdotally some clinicians use up to 100 mg/kg/day (maximum 4 g). No pediatric-specific side effects have been identified.

Corticosteroids have been the historical mainstay of the treatment of moderate to severe Crohn’s disease and ulcerative colitis though no placebo-controlled randomized trials have been published. Nonetheless the ability of corticosteroids to induce remission in most children has been well established [37, 38]. A natural history study of the effect of corticosteroids in pediatric Crohn’s disease found that at 1 year, 61 % of patients were corticosteroid responsive, 31 % corticosteroid dependent, and 8 % had gone on to surgery [37]. A similar study published on the use of corticosteroids in newly diagnosed ulcerative colitis disease in children found that by 1 year 45 % of children were corticosteroid dependent and 5 % of the corticosteroid-treated patients had come to colectomy [38]. In both reports the use of immunomodulators (50–75 % of patients) and infliximab (17–25 %) was common in patients with corticosteroid dependence. Two studies have compared budesonide with prednisolone in the treatment of Crohn’s disease in children and shown similar efficacy [39, 40], though bias in patient selection (i.e., milder patients) may have influenced the results. Pediatric-specific side effects of corticosteroids are common and effects on growth, bone metabolism, and the cosmetic issues such as Cushingoid appearance and acne are of particular concern .

Multiple publications have looked at the use of immunomodulators in the treatment of pediatric Crohn’s disease though only one randomized placebo-controlled study has been performed [41]. In this study of 55 newly diagnosed children with moderate to severe CD who all received an initial course of prednisone and then either 6-mercaptopurine or placebo, initial remission rates at 3 months were similar, but by 1 year the 6-mercaptopurine-treated group had received significantly less corticosteroid and had a much lower relapse rate. Largely based on this study, thiopurines became standard of care in the treatment of moderate to severe CD in children and are customarily introduced quite soon after diagnosis. However, several follow-up observational or retrospective studies have found rates of sustained remission to be decreased compared to the original RCT [42–44]. Two recent studies looking at the effect of early introduction of thiopurines in adults with Crohn’s disease have shown no beneficial effect [45, 46]. The potential of thiopurines to contribute to lymphoma, skin cancer, as well as hemophagocytic lymphohistiocytosis (HLH) has caused some clinicians to limit their use (see below).

Increased interest has focused on methotrexate as an alternative immunomodulator. Two pediatric studies found that 45–50 % of patients intolerant of thiopurines were in steroid-free remission at 12 months after change from thiopurines to MTX [47, 48]. Furthermore, a recent study evaluating data from a large prospective IBD registry found that the use of MTX as maintenance therapy has been increasing, with 14 % of patients treated with MTX as first-line immunomodulator therapy in 2002 and expanding to 60 % in 2010 [49]. A 2014 multicenter retrospective cohort study comparing outcomes for patients treated with subcutaneous versus oral MTX found rates of overall steroid free remission to be similar. However, oral MTX use was associated with a longer time to remission, less improvement in linear growth and a trend toward reduced sustained SFR. The authors therefore suggested the subcutaneous route is initially preferred [50]. No head-to-head comparisons of outcomes with thiopurines and methotrexate in pediatric CD have been published .

The REACH clinical trial included 112 initial study subjects with moderate/severe disease despite therapy with corticosteroids and immunomodulators who were treated with 5 mg/kg at 0, 2, and 6 weeks. Eighty-eight percent were in response and 59 % in remission at 10 weeks. Patients in response or remission at 10 weeks were then randomized to receive either 5 mg/kg every 8 weeks or every 12 weeks, with an opportunity to step up dose to 10 mg/kg or decrease interval (for those in the 12 week group) in case of loss of response. At week 54, 33 of 52 (64 %) and 29 of 52 (56 %) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33 %) and 12 of 51 (24 %) patients receiving treatment every 12 weeks (p = .002 and p < .001, respectively) [51].

Longer-term follow-up following infliximab therapy in children has also been examined. A multicenter study involving 66 patients in the Netherlands had a mean follow-up of 41 months with 15 % having a prolonged response following episodic therapy, 56 % were infliximab dependent (requiring repeated infusions to maintain efficacy), and 29 % lost response [52]. A second multicenter study examined the long-term course of 202 children with follow-up periods ranging up to 3 years. One hundred twenty-eight of the study cohort were treated with maintenance therapy and had follow-up of ≥1 year. The likelihood of continuing infliximab was 93 %, 78 %, and 67 % at 1, 2, and 3 years respectively (Kaplan Meier analysis). A step-up in therapy (either increased dose or decreased interval) was needed in about half the patients. Corticosteroid-free clinical remission for the periods from 0–1, 1–2, and 2–3 years after starting infliximab was 26 %, 44 %, and 33 % [53].

Recent adult studies have identified the relationship between sustained remission and infliximab trough and antibody to infliximab levels (ATI) [54]. Similar associations are found in pediatric IBD. A prospective cohort study of pediatric patients with IBD found that higher infliximab levels and lower CRP at week 14 were associated with week 54 efficacy and rates of remission [55]. A retrospective pediatric study of 134 patients with IBD found similar associations. ATI ≥ 5 was associated with lower infliximab trough levels than those with ATI < 5 (p < 0.001). Additionally, ATI ≥ 12 was associated with need for surgical resection compared to those with ATI < 12 (p = 0.01) [56].

The use of adalimumab in pediatric Crohn’s disease was initially reported in multiple small single center series and one larger retrospective report of 115 patients. Nearly all patients had previously been treated with infliximab . The majority of children received induction dosing of 80 and 40 mg separated by 2 weeks followed by 40 mg every other week. Corticosteroid-free remission was noted in 22 %, 33 %, and 42 % of patients at 3, 6, and 12 months, respectively [57]. More recently, the open-label IMAgINE 1 study evaluated the efficacy of adalimumab with moderate to severe Crohn’s disease. Study design evaluated outcomes for groups treated with high- or low-dosage after 26 weeks. In total, adalimumab was found to induce and maintain remission in 33 % of patients at 26 weeks. In patients that were infliximab naïve at the initiation of the trial, clinical remission rates at 26 weeks were significantly increased in the high dose versus low dose groups (57 % vs. 35 % p = 0.026) [58].

Outcomes with the use of infliximab in children with ulcerative colitis from a large multicenter pediatric IBD Registry have been reported. Corticosteroid-free inactive disease by physician global assessment was noted in 12/44 at 6 months (27 %), 15/39 at 12 months (38 %), and 6/28 (21 %) at 24 months. Kaplan-Meier analysis showed the likelihood of remaining colectomy-free following infliximab was 75 % at 6 months, 72 % at 12 months, and 61 % at 2 years [59]. In a more recent prospective pediatric UC trial including patients with moderate to severe UC, 73 % of patients responded to infliximab by week 8 after induction dosing of 5 mg/kg at weeks 0, 2, and 6. At week 54, 38 % of responders that continued to receive standard dosing maintenance infliximab therapy remained in remission [60].

The landmark SONIC study included adults with Crohn’s disease and demonstrated significantly improved corticosteroid-free remission rates in anti-TNFα naive patients treated with azathioprine plus infliximab versus infliximab alone or azathioprine alone, and therefore use of dual therapy in this population greatly increased [61]. However, there are also convincing data that adult patients who have failed thiopurines and move on to infliximab do not have additional success by maintaining the thiopurine [62]. Moreover, the recently published COMMIT study in adults with Crohn’s disease showed no added efficacy when comparing infliximab alone to infliximab plus methotrexate with both groups having clinical remission rates near 70 % at week 50. However, antibodies to infliximab were higher in the monotherapy group compared to combination (20 % vs. 4 % p = 0.01) [63].

The impressive remission rates and potential promise of mucosal healing have prompted early consideration for biological therapy in treating IBD. For pediatric patients in particular, establishing corticosteroid-free remission prior to or during the years of rapid linear growth and sexual development is very important. The use of an anti-TNFα agent as primary therapy in the setting of extensive disease, complicated early disease, severe fistula, or disease onset in an adolescent with growth failure already showing signs of puberty in whom the window for growth is short has become increasingly common. Data have also suggested that antibody titers to specific microbial antigens measured at the time of diagnosis may predict the development of complicated disease requiring surgery (obstruction, perforation) and may play a role in helping identify subjects more likely to benefit from biological therapy at the time of diagnosis [64].

The striking impact of early anti-TNF use upon growth in inflammatory CD was recently demonstrated using data from a large observational cohort study, which included patients newly diagnosed with Crohn’s disease at age <17. Twelve month outcomes for 3 groups of propensity-matched patients were compared: early infliximab , early immunomodulator therapy (IM), or no IM or infliximab therapy in the first 3 months. Clinical and growth outcomes were both found to be superior in those treated with early infliximab therapy compared to those with early IM or no early IM or infliximab therapy. In patients treated with early infliximab, 85 % were in remission at month 12 compared to 60 % in the early IM and 54 % in the no early IM or infliximab groups (p = 0.0003). Normalization of C-reactive protein was most frequent in the early infliximab group. Further data are needed to determine which patients should be considered for anti-TNF therapy at the time of diagnosis [65].

Pediatric trials evaluating combination versus monotherapy with anti-TNF have not been performed. However, recently published observational data evaluated durability of infliximab therapy in 502 patients with Crohn’s disease. In total, approximately 60 % of patients remained on infliximab 5 years after its initiation. The probability ± standard error that patients remained on infliximab 5 years after initiating treatment was significantly higher for those receiving concomitant therapy for >6 months compared to both anti-TNF monotherapy or those treated with combination therapy for <6 months (0.7 ± 0.04 vs. 0.48 ± 0.08 vs. 0.55 ± 0.06 (p < 0.001)). Importantly, the durability of infliximab therapy in males treated for >6 months with combination therapy was greater in those treated with infliximab/MTX than those treated with infliximab/thiopurines (0.97 ± 0.03 vs. 0.58 ± 0.08 p < 0.01) [66].

Clinical experience with anti-integrin therapy including natalizumab and more recently vedolizumab is emerging. There is a single report on the use of natalizumab in adolescents with moderate to severe Crohn’s disease. Using an open-label dosing schedule of 3 mg/kg at weeks 0, 4, and 8 weeks in 31 subjects, 55 % had a clinical response and 29 % were in remission at 10 weeks [67]. Natalizumab targets both alpha4beta1 and alpha4beta7 integrin therefore modulating both brain and gut lymphocyte migration. Its use has been associated with progressive multifocal leukoencephalopathy (PML) caused by reactivation of latent JC virus. In contrast to natalizumab, vedolizumab targets only alpha4beta7 integrin and thus acts only upon gut, not brain lymphocytes and should therefore have reduced risk of PML. The adult 2013 RCTs in both CD and UC found vedolizumab to be effective toward inducing remission and has been recently approved for treatment of both UC and CD in adults [68, 69]. Currently, pediatric data with the use of vedolizumab is limited to abstract presentations.