Impaired linear growth is a common complication of CD in children. There are multiple reasons for this. Cytokines released from the inflamed intestine may directly inhibit and limit growth through interference with insulin-like growth factor (IGF-1). Chronic nutritional deficiencies may also limit growth and medications, particularly corticosteroids are associated with growth inhibition. Therefore, restoration or maintenance of growth is a marker of therapeutic success.

A number of studies, including REACH, have reported beneficial effects of infliximab in restoring growth and height in children with CD, as early as 6 months after start of therapy [35,36,41]. An important finding is that weight and height gain are significantly higher in patients on systematic re-treatment than in those treated only with three baseline infusions of infliximab [34]. The effect of infliximab therapy on linear growth was a specific endpoint in the REACH study [41]. Linear growth was measured and prospectively recorded and height but also height velocity (cm/year) was recorded at predefined time points. When looking only at the subgroup of 38 patients with at least 1 year delay in bone age (measured by wrist X-ray) at the start of the trial, the mean height status Z score significantly improved from −1.5 to +0.3 from week 0 to week 30 (p  <  0.001) and to +0.5 at week 54 (p  <  0.001) in the combined infliximab groups. The benefit was greater in the children randomized to the q8 weekly treatment arm (43.5% improvement in Z score by at least 0.5 standard deviation) in contrast to the children randomized to the q12 treatment arm (20% improvement in Z score by at least 0.5 standard deviation). Three factors are potentially contributing to the observed short-term increase in bone formation markers: reversal of TNT-α effect on bone growth, decreases in corticosteroid doses as disease activity improves and increases in linear growth [42]. A study done by Pfefferkorn et al. showed in a large study population of 176 children with CD (and tanner score I to III) a marked clinical improvement of growth during the first 1–2 years of therapy but growth abnormalities persists in many children. Additional strategies to improve the growth outcome are needed [43].

Although corticosteroids are an effective short-term therapy to control active inflammation, they do not maintain remission on long-term basis and are associated with serious side effects. Infliximab is steroid-sparing as clearly demonstrated in the adult ACCENT I and II studies. There are also data from pediatric CD that infliximab therapy allows children to wean and completely stop steroids. A retrospective study by Stephens et al. of 432 infusions administered to 82 patients showed that 57.6% of children taking corticosteroids (n  =  33) at the start of infliximab became independent and remained free of corticosteroids [44]. Lamireau et al. looked at the outcome of 88 children and adolescents receiving infliximab (39 girls and 49 boys), median age 14 years (range 3.3–17.9) [32]. Infliximab was indicated for active disease (66%) and/or fistulas (42%) which were refractory to corticosteroids (70%), and/or other immunosuppressive (82%) agents, and/or parenteral nutrition (20%). Patients received 1–17 infusions (median 4) of 5 mg/kg of infliximab during a median time period of 4 months (range 1–17 months). At month 3, 78% of patients had a response (49%) or remission (29%). The dosage of corticosteroids decreased from 0.59 mg/kg/day before to 0.17 mg/kg/day 3 months after infliximab (p  <  0.001) and 53% of patients could be weaned off corticosteroids and 92% off parenteral nutrition. A more recent prospective multicenter study looked at the 3-month and 1-year outcomes of children with CD treated with corticosteroids within 30 days of diagnosis, and investigated the influence of infliximab on steroid withdrawal [45]. Although at 3 months, 84% of children had a complete (60%) or partial (24%) response, at 1 year and despite concomitant immunomodulators, 31% of children were corticosteroid dependent and 8% required surgery. The authors demonstrated that infliximab improved the outcomes of corticosteroid-dependent/resistant patients since 16/24 (67%) patients who were corticosteroid resistant or dependent could discontinue their corticosteroids after starting infliximab therapy. Also, the REACH study showed that infliximab is allowing patients to decrease their dose of corticosteroids. The proportion of patients in the REACH study who, at week 54 were in remission and off steroids was higher in the q8 weeks arm (46%) as compared to the q12 weeks arm (17%). Punati et al. showed that 80% of children with newly diagnosed CD (moderate to severe) are treated with immunomodulators within 1 year. This early use is associated with reduced corticosteroid exposure and fewer hospitalizations per patient [46].

It is clear that altering the natural history of IBD will not merely be achieved by mucosal healing alone. The time of initiation of therapy will be of crucial importance if one takes into consideration that longer disease duration inevitably leads to more irreversible damage. When comparing the initial response rates from REACH study with those of the adult ACCENT studies, the superior response in children is noted. The reasons for this can be multiple. In the REACH study, the median disease duration was 1.6 years as compared to 7.9 years in ACCENT 1 and 12.3 years in ACCENT 2. There is evidence from previous pediatric studies in CD that more aggressive treatment early in the disease is associated with better response and remission rates. In an Italian study, the best response to infliximab was observed in children with a disease duration of less than 1 year and 5/6 children with early CD had complete closure of all fistulas following therapy as compared to only two out of seven children with a disease duration of more than 1 year [47]. A longer sustained remission in children with early CD was also the conclusion of the study by Kugathasan et al. [30]. However, in the REACH study, the clinical response rate of patients with early disease <1 year was equal to the response observed in patients with disease duration of more than 1 year. It is therefore possible that children in general respond better than adults. A better response of children to medication is a phenomenon which is known and which is possibly related to a more active adaptive and innate immune system in children. There is an immune senescence in humans, explained by a reduction in the synthesis and release of hormones or neurotransmitters, alterations in the number, density and affinity of receptors and diminished receptor responsiveness [48]. Another reason for the high response rates in the REACH study is the fact that 98% were on concomitant immunomodulators and this is much higher than what was observed in the adult population of ACCENT 1 (29%) and ACCENT 2 (37%). Again, concomitant use of immunomodulators improves clinical efficacy of infliximab in adults [49–52].

The benefit of early therapy with infliximab has been investigated in a Benelux study in adult CD [53]. In this study, patients with early onset CD were randomized to the classical treatment algorithm which includes first induction of remission with corticosteroids, followed by repeat course of steroids and azathioprine in case of new flares, and eventually infliximab if active disease under immunomodulator therapy, or a more aggressive first-line treatment where a three-course induction therapy with infliximab together with azathioprine was initiated. Two years following randomization, complete mucosal healing was observed in 75% in the Top Down group, compared to only 21% in the Step-Up treatment. A similar Top-Down approach was presented by Romeo et al. in pediatric CD patients [54]. In this retrospective study of 32 children with newly-diagnosed active ileocaecal CD, 13 patients received infliximab 5 mg/kg at weeks 0–2–6 (Group A  =  13 patients) and 19 patients (Group B) received the traditional treatment regimens for induction, together with maintenance therapy with azathioprine. The clinical relapse at 1 year was much higher in Group B (17/19) as compared to group A (1/13; p  <  0.01) with also significant lower Crohn’s disease Endoscopic Index of Severity at one year in Group A (Top–Down group). Kim et al. evaluated in a small group of CD patients the Top–Down and Step-Up strategies and concluded that Top–Down therapy resulted in superior outcomes when compared with Step-Up strategy for inducing and maintain remission at 8 weeks and 1 year posttreatment [55].

The cumulative incidence of surgery 10 years after diagnosis in CD ranges from 40 to 70% in adults. The ACCENT studies showed that infliximab reduces the number of surgeries. In a large pediatric cohort of 989 CD patients (age 0–17 years at diagnosis), collected from six different pediatric centers, 13% of children needed intestinal resection already after a median of 2.8 years, a number which increased to 17% at 5 years and 28% at 10 years from diagnosis [56]. The treatment with infliximab in this cohort was associated with a 64% reduced risk for surgery. Schaffer et al. examined the contemporary incidence of CD-related surgery in a multicenter cohort of 854 children. The predominant site of occurrence of requiring bowel resection is the terminal ileum and cecum (43–55%), with less frequent occurrence of the colon (34%). They found no evidence that the early use of immunomodulators is a factor in the 5-year surgical outcomes. Disease at the transverse colon and rectum was associated with a significant decreased risk for surgery [57].