Infliximab , a monoclonal, chimeric antibody which acts as an antagonist to TNF-α, has been used for the treatment of pediatric Crohn’s disease (CD) for over 20 years; however, the medication only recently received FDA approval in 2006 for the treatment of moderately to severely active pediatric CD. Initial reports of use in pediatric CD focused on small numbers of patients receiving spot or induction dosing of infliximab, with these patients having excellent response rates. Kugathasan et al. reported outcomes of 15 consecutive children with medical refractory CD treated with a single 5 mg/kg dose of infliximab [4]. Fourteen of these patients had improvement after this single dose, and 10 of 15 children were in clinical remission (defined as Pediatric Crohn’s Disease Activity Index (PCDAI) ≤ 15) by 10 weeks. Steroid doses were also significantly lower at 4 and 10 weeks. Unfortunately, in a subsequent 52-week follow-up, 11 of the 14 responders experienced clinical relapse, with patients with disease over 2 years having a shorter duration of response. A multicenter study of 21 pediatric patients with moderate to severe CD randomized to receive a single infusion of 1 mg/kg, 5 mg/kg, or 10 mg/kg of infliximab showed similar results with 100% of patients achieving clinical response (≥10-point improvement in PCDAI or ≥70 improvements in modifie d CDAI) and 48% achieving clinical remission, defined as a PCDAI < 10 or a modified CDAI <150, at some point during the 12-week observation period [5]. Patients who received 5 mg/kg and 10 mg/kg doses of infliximab had higher rates of remission at the 12-week follow-up evaluation compared to those who received 1 mg/kg. Nine patients had endoscopic assessment of disease prior to and 4 weeks after receiving inflixim ab. Endoscopic lesion severity scores improved by a median of 7%, 69%, and 52% in 1, 5, and 10 mg/kg infliximab groups, respectively. Serum infliximab concentrations were found to be similar in both pediatric and adult populations with duration of detectable levels being proportional with dose—levels were detected through week 4 in 1 mg/kg group and compared through week 8 and week 12 in 5 and 10 mg/kg groups, respectively. While the above studies assessed response to a single infusion of infliximab, Cezard et al. prospectively evaluated the response of 21 children with severe CD, most with corticosteroid-dependent disease, who received induction dosing with 5 mg/kg infliximab on days 0, 15, and 45 [6]. Nineteen children were in clinical remission (Harvey Bradshaw (HB) index <4) at day 4, and steroid use was significantly decreased at 3 months. However, similar to the above studies, response was not durable, and 19 of the patients (90%) experienced relapse despite continuing immunosuppressive therapy, with 37% of relapses occurring before 3 months.

As highlighted above, the optimal frequency of medication administration was not known during the early years of infliximab use in the pediatric population. It was initially hypothesized that children could potentially develop a prolonged response to infliximab compared to adults, obviating the need for regularly scheduled infusions; however, preliminary studies showed frequent relapse after single dose or induction dosing. Episodic on-demand infliximab dosing, i.e., giving additional doses if patient relapsed, was another consideration in pediatric patients. This strategy was further evaluated in a randomized, multicenter, open-label study by Ruemmele et al. [7] Thirty-one children wh o were in remission after three infliximab infusions (induction dosing) were randomized to scheduled infusions every 2 months or “on-demand” dosing. During the course of the trial, 92% of patients who received episodic infliximab therapy experienced a relapse compared to 23% of patients receiving scheduled infliximab therapy every 8 weeks. Additionally, the time to relapse was shorter in patients who received episodic infliximab infusions with an average time to relapse of 120 days compared to 150 days in the scheduled infusion study group. At week 60, 61% of patients on epis odic infliximab therapy were in remission compared to 83% of patients receiving scheduled infliximab.

The REACH study, a large multicenter, randomized, open-label trial, prospectively evaluated the safety and efficacy of induction and maintenance of infliximab in moderately to severely active pediatric CD and demonstrated superiority of every 8-week maintenance infliximab infusions compared to every 12-week infusion schedule [8]. One hundred and twelve patients with moderate to severe CD despite immunomodulatory therapy received three-dose induction regimen of infliximab 5 mg/kg. Responders were then randomized to receive maintenance infliximab 5 mg/kg every 8 or 12 weeks. After completion of induction therapy (week 10 assessment), 88% of patients had responded, defined as a decrease in PCDAI score of at least 15 points, and 59% of patients were in clinical remission, defined as a PCDAI <10. At week 54, 64% of patients receiving infliximab every 8 weeks had a clinical response, and 56% were in clinical remission without the need for a dose adjustment compared to a clinical response rate of 33% and clinical remission rate of 23.5% in the every 12-week study group. Corticosteroid use significantly decreased, and IMPACT III quality of life scores improved in both 8- and 12-week groups over the course of the study. Sixty participants entered the REACH open-label extension—33 patients receiving infliximab 5 mg/kg every 8 weeks, 12 patients receiving 10 mg/kg every 12 weeks, and 15 patients rece iving 10 mg/kg every 8 weeks [9]. In these patients receiving scheduled infliximab for up to 3 years, most had sustained clinical benefit, with approximately 80% having no or mild disease based on the physician global assessment (PGA) at assessments.

Additional studies have evaluated the long-term outcomes of infliximab therapy. In one population-based retrospective study of 66 pediatric CD patients treated with infliximab (five receiving episodic treatment) followed for a mean of 41 months, prolonged clinical response was seen in approximately 70% of patients [10]. However, in patients considered infliximab dependent (n = 37), 57% had recurrence of symptoms prior to the 8-week interval, requiring increased dose to 10 mg/kg or shortened infusion intervals to maint ain response. In a similar study by Crombe et al. of 120 patients with pediatric CD, 54% had long-term efficacy of therapy; 27% of the entire cohort required dose optimization (shortened interval and/or increased dose) [11]. Forty-two percent of these patients were receiving episodic infusions, which may account for the lower long-term response rate compared to other efficacy studies. Finally, a multicenter cohort study of patients enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Registry evaluated long-term outcomes of pediatric CD patients treated with infliximab maintenance therapy [12]. In total, 202 of 729 patients received infliximab; the majority of whom received infliximab early in their disease course, with 60 patients (30%) receiving infliximab within 3 months of their diagnosis, 64 patients (32%) between 3 and 12 months from diagnosis, 47 patients (23%) between 12 and 24 months from diagnosis, and 31 patients (15%) after 24 months from diagnosis. One hundred and twenty eight patients were ultimately included in the outcome cohort with 121 patients receiving continuous infliximab maintenance therapy. After 1 year of infliximab maintenance therapy, 32% of patients had mild disease, and 54% had inactive disease as assessed by PGA; by 2 years, 21% of patients had mild disease and 67% had inactive disease; and at 3 years of maintenance therapy, 30% had mild disease and 57% had inactive disease. However, almost half (63/128) of the patients required anti-TNF dose adjustments during their course on infliximab therapy. The above results emphasize the long-term benefits and durability of infliximab therapy in pediatric CD, but also the need for dose optimization to maintain response in a substantial proportion of patients. Loss of response has been reported to be as high as 33–50% in pediatric CD patients over a follow-up period of 3–5 years. With so many variables involved in the treatment of pediatric inflammatory bowel disease, attempts have been made to identify predictors of response to infliximab. Grover et al. studied 47 patients with refractory, luminal CD who had an initial response to induction infliximab therapy [13]. Twenty-eight patients (60%) developed a sustained primary response for an average of 2.8 years, and 19 patients (40%) had a loss of response at a median of 11 months. It was found that a loss of response was associated with a lower BMI and lower height z-scores prior to infliximab induction and a higher CRP after induction, which may be surrogates for severity of inflammation. Patients were more likely to have a sustained primary response if immunomodulator therapy was continued beyond induction therapy with infliximab, likely related to effects on infliximab drug levels. In this study, duration of disease, time to infliximab therapy, disease severity, disease location, complicating phenotypes, and steroid dependency were not associated with loss of response.

As the incidence of pediatric inflammatory bowel disease has risen, there has also been an increase in early-onset disease in patients younger than 8 years of age. A retrospective study by Kelsen et al. evaluated the safety and efficacy of infliximab in this subgroup of patients with early-onset disease [14]. Thirty-three patients with either CD, ulcerative colitis (UC), or inflammatory bowel disease unclassified (IBD-U) who had initiated infliximab therapy prior to 7 years of age were assessed. After 1 year of infliximab therapy, 10%, 25%, and 0% of patients with CD, UC, and IBD-U, respectively, had a clinical response. Nineteen patients (58%) required either dose escalation or a reduction in interval between infusions. The proportion of patients who were maintained on infliximab steadily decreased over time with 36% on infliximab maintenance after 1 year, 18% after 2 years, and 12% after 3 years. In a subset of patients younger than 5 years of age, only 25% were continued on infliximab after 1 year, and only 10% were maintained on infliximab after years 2 and 3 combined. Ultimately, it was found that children less than 7 years of age with early-onset IBD were less likely to continue infliximab as maint enance therapy compared to older pediatric patients assessed in the REACH trial. These findings may be related to specific pharmacokinetics of infliximab in younger patients or potentially related to the colonic-predominant phenotype seen in early-onset IBD.

Adult studies have demonstrated the efficacy of infliximab for treatment of perianal CD, and several small studies have shown similar benefit of infliximab in pediatric patients with this complicated phenotype [6, 15, 16]. Post hoc analysis evaluated the effect of infliximab in a subpopulation of 31 patients with concurrent perianal Crohn’s disease from REACH [15]. In 22 patients that had baseline perianal disease, 41% had complete or partial response after a single dose of infliximab, with 73% having response at 10 weeks (after completion of induction dosing), and the proportion of patients responding after randomization to 8- and 12-week infusion intervals remained consistent during maintenance infusion (73% at 54 weeks, 1 partial, 15 complete). Nine patients developed perianal disease during treatment with infliximab, but most (78%) had response with additional infusions. Cezard et al. showed similar results in a subset of 12 pati ents with perianal fistula who received three-dose induction regimen of infliximab, with all patients having closure of fistula by 3 months [6]. However, as 90% of the total study population experienced a relapse during the 12-month follow-up, it is possible that some patients had recurrence of perianal disease without scheduled maintenance infusions. Several factors may be associated with a positive response to infliximab therapy in treatment of perianal disease in pediatric CD including shorter duration of disease (<1 year), number of fistulas (≤1), and baseline HB index (<5) [16, 17]. Prior to initiating infliximab therapy for perianal disease, it is important to assess for complicating factors such as rectal inflammation or complex fistula via colonoscopy and pelvic magnetic resonance imaging (MRI) and/or rectal exam under anesthesia as the combination of infliximab and surgery may lead to improved outcomes [18].

Infliximab was FDA approved for the treatment of moderate to severe p ediatric ulcerative colitis in 2011; however, similar to pediatric CD, this medication was used off-label for pediatric patients with refractory colitis for several years prior to approval based on adult data and smaller pediatric case series demonstrating efficacy of this therapy. A preliminary case series by Mamula et al. showed that seven of nine patients (77%) with moderate to severe UC that was refractory to traditional therapy had a clinical response to infliximab as measured by the PGA, with six of these patients having inactive disease 2 weeks after the infusion [19]. A steroid-sparing effect was seen and 66% of these patients were able to discontinue corticosteroid therapy. Nine patients in this cohort were reevaluated after a minimum of 2 years of follow-up, and 73% of these patients were considered to be responders to the initial dose [20]. Two of these patients lost response within 9 months, and the remaining five responders had a sustained response, three of whom were doing well without ongoing infliximab therapy. A clinical response rate of 88% was seen in an additional eight patients with refractory UC treated with infliximab [20]. In total, 14 of 17 patients (82%) developed a short-term response, and 10 patients (63%) developed a long-term response to infliximab therapy. Another retrospective single-center study evaluated the response to infliximab in 12 pediatric patients with UC, 3 with fulminant colitis, 3 with an acute relapse of disease, 5 with steroid-dependent colitis, and 1 with corticosteroid-refractory colitis [21]. Nine patients (75%) developed a complete short-term response, two had a partial response, and eight patients had a long-term response to infliximab (median follow-up 10.4 months). In this small study, long-term response to infliximab therapy was more likely in patients who were receiving concomitant mercaptopurine. A larger single-center retrospective series by McGinnis et al. evaluated the short- and long-term response to infliximab induction in 40 pediatric UC patients with steroid-dependent or steroid-resistant disease [22]. Twenty-eight patients (70%) had a clinical response to infliximab, including 9 of 12 patients with steroid-dependent disease and 18 or 27 with steroid-refractory disease. Over the study period, 20% of responders had undergone colectomy compared to 82% of nonresponders. A multicenter cohort, inception cohort study of 332 pediatric patients with UC prospectively evaluated outcomes of 52 patients who received continuous maintenance therap y or episodic treatment with infliximab [23]. Approximately 35% of these patients had corticosteroid-free inactive or mild disease at 3-, 6-, 12-, and 24-month assessments, and 61% were colectomy-free at 24 months. Looking at the subset of patients receiving continuous maintenance therapy, approximately 50% of the patients had inactive or mild disease across these time points, and the likelihood of being colectomy-free was 74% at 24 months, suggesting additional benefit on maintenance dosing. These remission rates were lower than previously reported; however, 50% of this cohort was hospitalized at initiation of infliximab, perhaps suggesting more severe or chronic disease.

Patients with chronic ulcerative colitis refractory to treatment with steroids, immunomodulators, and aminosalicylates may have decreased response to infliximab therapy. Fanjiang et al. retrospectively evaluated response to infliximab in acute UC (n = 16), defined as new-onset UC that was refractory to intravenous steroid therapy or an acute exacerbation of nonsteroid-dependent UC, compared to response in chronic, steroid-dependent UC (n = 11) [24]. Patients received standard induction dosing followed by every 8-week infusions. Patients with acute UC had lower-average Lichtiger colitis activity index (LCAI) scores at 1 and 2 months after therapy and more durable long term response. Over a mean follow-up of 27 months, 75% of patients with acute UC did not require steroid therapy or colectomy compared to 27% of chronic UC patients.

Based on retrospective analysis of a population-based UC cohort, 28% of children <15 years old require hospitalization for an acute severe exacerbation of their disease, and almost 50% these patients are refractory to intravenous corticosteroids [25]. As demonstrated by colectomy rate in the study by Fanjiang et al. [24], there is some evidence that patients presenting with acute, fulminant, severe colitis may have an improved response to treatment with inf liximab compared to those with chronic, steroid-dependent colitis. In a prospective, multicenter study of 128 children with acute, severe colitis requiring intravenous corticosteroid therapy, 37 patients (29%) failed to respond to corticosteroids and required rescue therapy, 33 of whom receive infliximab [26]. Twenty-five (75%) of these patients responded, with 7 patients entering clinical remission and 18 patients being discharged with mild disease severity. At 1 year, 55% of these patients had sustained response (11 receiving maintenance therapy and 7 receiving only induction therapy). Patients with newly diagnosed with UC, shorter duration of disease, and more severe disease activity at admission and after 3 days of IV steroid treatment were less likely to respond to infliximab. A smaller respective cohort of 29 hospitalized patients with a severe colitis showed that response to infliximab may decrease with time, and dose escalation in this population was commonly needed, occurring in 62% of this cohort [27]. Even after dose escalation, only 39% of these patients remained on infliximab therapy after 1 and 2 years and 29% after 3 years. Lower BMI Z-score and serum albumin as well as a higher ESR at baseline were associated with dose escalation, but not infliximab failure.

There has been one randomized open-label prospective study evaluating the efficacy and safety of infliximab in induction and maintenance therapy for moderately to severely active pediatric UC [28]. Results of this study led to FDA approval of infliximab for the treatment of pediatric UC in 2011. Sixty patients with medically refractory, moderately to severely active UC were given 5mg/kg of infliximab at 0, 2, and 6 weeks, and those with response were then randomized to receive infusions either 8 weeks or every 12 weeks. Forty-four patients (73%) responded to induction therapy, and at week 8, 41 patients (68.3%) had achieved mucosal healing. Forty-five patients were subsequently randomized to receive infliximab at 8-week or 12-week intervals. At week 54, 38.1% of patients receiving every 8-week infusions were in remission compared to 18.2% receiving every 12-week dosing; a reduction in corticosteroid use at 54 weeks was observed in patients receiving 8-week infusions, but not in the 12-week infusion group. Similar to previous data, dose escalation was common, and approximately 50% of patients required either an increase in infliximab dose or more frequent infusions, with more patients requiring a step-up in therapy in the every 12-week infusion group. Infliximab concentrations were obtained at multiple points during the course of this study; higher concentrations at week 8 were associated with clinical response and mucosal healing, and higher median week 30 troughs were note d in patients receiving every 8-week dosing, likely accounting for higher proportion of patients in this group who had sustained efficacy [29]. In summary, this prospective rand omized open-label study and additional retrospective and prospective observational cohorts clearly indicate that infliximab is an effective therapy for moderate to severe UC with benefits in both corticosteroid-dependent and corticosteroid-refractory disease and may help prevent colectomy in pediatric UC patients.

Despite the promising outcomes associated with infliximab in the treatment of pediatric IBD , historically, up to 50% of patients require dose escalation, and approximately 33% of patients discontinue infliximab therapy, most commonly due to loss of response. The need for additional anti-TNF agents was recognized prompting the development of adalimumab, a recombinant, fully human, monoclonal anti-TNF antibody. Compared to infliximab, adalimumab provides an inherently decreased risk of neutralizing antibody formation because of the therapy’s strictly human antibody components. Initial reports of adalimumab use in pediatric inflammatory bowel disease focused on patients who had become intolerant to infliximab. Noe et al. evaluated the response on adalimumab therapy of ten patients (seven CD, three UC) previously treated with infliximab, nine of whom developed a hypersensitivity reaction to this medication [30]. Eight patients responded to adalimumab with decreased PCDAI in patients with CD and decreased LCAI in patients with UC. Seven patients were on concomitant corticosteroids at time of adalimumab initiation, and four patients were able to successfully taper off this medication within a mean of 5.5 months. A second small retrospective study of 14 pediatric patients with CD who had an allergic infusion reaction or decreased response to infliximab despite dose escalation showed less robust response to adalimumab; however, a majority of patients still responded, with 50% having complete response and 14% having a partial response; in the subset of patients with perianal disease, three of five patients maintained fistula closure with this therapy [31]. The differences in the outcomes of these studies may be due to variation of adalimumab dosing, which was not controlled, and patient selection, with the former study focusing only on patients who had an infusion reaction to infliximab rather than including those with suboptimal response. Subsequent larger population-based cohort studies ha ve noted initial response to adalimumab in approximately two-thirds of patients who have failed infliximab therapy [32, 33]. RESEAT, a large, multicenter retrospective evaluation of the safety and effect of adalimumab therapy, examined the outcomes of 115 patients with pediatric Crohn’s disease from 12 centers who had received at least one dose of adalimumab [34]. Ninety-five percent of this cohort had previously received infliximab therapy, and most had discontinued therapy due to secondary loss of response (47%) or infusion reactions/delayed hypersensitivity (45%). The majority of patients initially received an induction regimen (160/80 mg or 80/40 mg) followed by 40 mg every other week; 27% of patients required dose escalation, most commonly to weekly administration. Clinical response, defined by a decrease in PGA from moderate/severe to mild/inactive or from mild to inactive, at 3, 6, and 12 months, occurred in 65, 71, and 70% of patients, respectively. Clinical remission rates (PGA inactive) at similar time points were 32, 43, and 49%, respectively. Overall, steroid exposure decreased over the study time points, and 42% of the cohort was in steroid-free clinical remission at 12 months, again highlighting the efficacy of this therapy in pediatric CD.

An initial preliminary prospective observational study by Viola et al. showed a remarkable response to adalimumab therapy in 23 patients with moderate to severe pediatric CD, nine of whom had not received previous anti-TNF therapy [35]. In this study, patients were administered induction doses of adalimumab at 0 and 2 weeks followed by maintenance therapy injections every other week over the course of 48 weeks. The percentage of patients in clinical remission increased from 36.3% after two weeks of adalimumab therapy to 65.2% after 48 weeks of treatment. Clinical response rates also improved from 87 to 91% at these same time points, respectively. The average dosage of corticosteroid, PCDAI, CRP, and ESR levels significantly decreased throughout the course of the study. Overall response and remission rates were higher in this prospective cohort, which may be related to higher dosing regimens, with 65% of the cohort receiving adalimumab maintenance therapy of 80 mg every other week through at least 12 weeks. The IMAgINE 1 study, a multicenter randomized trial, evaluated the safety and efficacy of adalimumab in pediatric CD [36]. Similar to the REACH clinical trial, patients received open-label weight-based induction adalimumab (two doses), followed by double-blind maintenance dosing regimens—high dose compared to low dose (high dose, >40 kg received 40 mg every other week and <40 kg received 20 mg every other week; low dose, >40 kg received 20 mg every other week and <40 kg received 10 mg every other week). One hundred and ninety-two patients with moderate to severe Crohn’s disease (PCDAI >30) received induction therapy, and 188 patients were randomized based on clinical response to induction dosing (decrease and PCDAI ≥ 15) and prior exposure to infliximab therapy (approximately 44% of study participants). After induction (week 4), 155 patients (82.4%) had a clinical response, and 52 patients (27.7%) were in clinical remission. At week 26, 53.7% of patients had a clinical response, and 33.5% of patients were in clinical remission; 28.2% and 35.1% had a clinical response and were in clinical remission at 52 weeks, respectively. A higher proportion of patients in the high-dose regimen were in remission at both of these time points, although the difference was not statistically significant. Of the 71 patients that were on steroid therapy at baseline, 65.8% of patients in the low-dose group and 84.8% of patients in the high-dose group had successfully discontinued this therapy. The proportion of patients experiencing fistula improvement and closure was also higher in the high-dose group. Finally, in the high-dose group, infliximab-naïve patients had higher remission and response rates at both week 26 and 52 compared to patients who had previously been treated with this therapy.

Analogous to experience with infliximab, in the IMAgINE 1 trial, 50.5% of patients in the low-dose adalimumab therapy and 37.6% of patient in the high-dose adalimumab therapy required dose escalation to weekly therapy after week 12 due to nonresponse or disease exacerbation [36]. Efficacy of dose escalation was evaluated in this subpopulation at 52 weeks [37]. Of the 83 patients who escalated to weekly therapy, 51.8% had a clinical response and 24.1% achieved clinical remission, with a higher proportion of patients in the high-dose group a chieving these end points (57.1% and 31.4%, respectively). Patients on immunomodulator therapy and patients randomized to the high-dose group were less likely to require dose escalation to weekly therapy. Long-term efficacy of adalimumab was evaluated in the IMAgINE 2 study [38]. One hundred patients who responded to adalimumab at any time during IMAgINE 1 were enrolled in this open-label extension and followed through 240 weeks. Overall 41% who entered IMAgINE 2 were in remission, and 48% had achieved response at 240 weeks, and for patients who entered IMAgINE 2 in remission, remission was maintained in 45% at week 240. Corticosteroid use continued to decrease during the course of this study, and among patients who were on corticosteroids at time of entry into IMAgINE 1, corticosteroid-free remission increased from 40.5% at enrollment into IMAgINE 2 (week 52) to 63.2% at week 240.

Adalimumab is not FDA approved for the treatment of pediatric ulcerative colitis, and there is limited published data regarding the use of adalimumab therapy in children with ulcerative colitis, but in clinical practice, adalimumab therapy is used off-label as a second-line biological therapy in refractory pediatric UC. An early report by Noe et al. evaluated the short-term response of adalimumab in pediatric IBD; three patients with UC who had failed infliximab were included in this retrospective, two of whom responded to adalimumab based on decreased LCAI score, and the third patient required colectomy for refractory disease [30]. A slightly larger retrospective review of 11 pediatric patients with UC treated with adalimumab after loss of response or intolerance to infliximab showed similar outcomes with 55% of patients achieving clinical remission at 6 months and through follow-up (mean duration of therapy 21.5 months) [39]. Four patients did require colectomy for refractory disease, and the median time to colectomy was 7 months after initiation of adalimumab therapy. A prospective multicenter randomized double-blind placebo-controlled study evaluating the efficacy and safety of adalimumab in pediatric patients with moderate to severe UC is ongoing (ClinicalTrials.​gov identifier: NCT02065557) and will hopefully shed more light on the role of adalimumab in this complicated disease. Overall adalimumab appears to have significant efficacy in pediatric IBD, and based on a single-center study of utilization trends from 2007 to 2012 of anti-TNF in adults and children with inflammatory bowel disease, there has been a rise in the use of this medication; however, infliximab remains the dominant anti-TNF therapy, particularly in the pediatric population [40].

Growth impairment is a common extraintestinal manifestation of pediatric IBD, particularly in CD. Decrease in height velocity has been reported in pediatric CD prior to diagnosis, and up to 60% of children will have a decrease in height percentiles during their disease course [41–43]. The etiology of growth impairment is multifactorial. Prior to diagnosis, patients may have malnutrition from decreased intake, possibly related to anorexia induced by increased circulating TNF-α, increased losses, and increased metabolic demands from inflammation; additionally, inflammatory cytokines, specifically TNF-α, interleukin 1, and interleukin 6, directly impact the growth hormone axis [43–46]. This combination of factors leads to decreased circulating insulin-like growth factor 1 (IGF-1) and growth impairment. After diagnosis, the use of corticosteroids may further impact growth by inhibition of IGF-1. Restoration and promotion of normal linear growth in pediatric patients are important therapeutic goals.

Multiple studies, including REACH and IMAgINE 1, have reported beneficial effects of anti-TNF in restoring growth by improving height velocity. Walters et al. retrospectively evaluated linear growth in 32 patients with active CD, mostly (59%) in early puberty (Tanner I–III). In the analysis of all patients, height velocity increased from a mean of −0.51 to +2.4 after 12 months of therapy [47]. Height velocity improvement was dependent on pubertal stage, with improvement seen in patients in early puberty compared to no improvement in patients near the end of puberty (Tanner IV–V). Patients in early puberty who achieved complete symptomatic remission also had more substantial improvement in linear growth compared to those who only had a partial clinical response. A second small retrospective study of 36 children treated with adalimumab demonstrated comparable results with 42% of the cohort demonstrating catch-up growth [48]. Again, improvement in height standard deviation score was seen only in patients in early puberty and was more likely in those patients who had achieved remission. A larger retrospective review of 121 pediatric patients receiving anti-TNF therapy (93 on infliximab, 28 on adalimumab, 93% CD) had similar findings, with disease status (remission) and early pubertal stage predicting improvement in linear growth [49]. One of the primary outcomes in the REACH study was assessment of change in height from baseline to week 54 [8]. In patients with a delay in bone age of at least 1 year, there was significant improvement in height Z-scores at both 30 and 54 week, with a mean improvement in Z-scores of 0.3 and 0.5, respectively. Although not a primary outcome, significant improvement from baseline to week 26 and week 56 in height velocity Z-scores was also observed in both the low-dose and high-dose adalimumab groups in the IMAgINE 1 study [36]. The improvement in linear growth appears to be durable; in one study of 195 patients who received infliximab, patients who were in tanner stage 1 and 2 at induction continue to have increase in height Z-score for up to 4 years post initiation of therapy [49]. Anti-TNF therapy does lead to decreased use of corticosteroid effect; however, the corticosteroid “sparing effect” is not the sole reason for growth restoration as improvement in height velocity is seen in both children who do and do not receive corticosteroid therapy [48, 50]. A decrease in inflammatory cytokines that directly impact the growth hormone axis likely plays a role in restoration of growth. Anti-TNF therapy is associated with increase in sex hormones (testosterone and estradiol) at 10 weeks and 12 months post initiation across all tanner stages, and in a small study of adult patients with CD, infliximab therapy led to an increase in IGF-1 levels to a level comparable with controls, suggesting possible reversal of growth hormone resistance seen in active disease [51, 52]. Together, these hormonal changes may lead to improvement in linear growth and progression through puberty in pediatric patients.