Gastroenterology & Hepatology

August 2020 - Volume 16, Issue 8

Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease

Jessica Breton, MD, Arthur Kastl, MD, Maire A. Conrad, MD, and Robert N. Baldassano, MD

Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

Corresponding author:
Dr Jessica Breton
Division of Gastroenterology, Hepatology, and Nutrition
Children’s Hospital of Philadelphia
Department of Pediatrics
Perelman School of Medicine at the University of Pennsylvania
Roberts Center
2716 South Street
Philadelphia, PA 19146
Tel: (215) 590-7801
Fax: (267) 426-9001


Abstract: The incidence and prevalence of pediatric inflammatory bowel disease (IBD) are rising worldwide, with a steep increase in children under 5 years of age. Compared to adult IBD, pediatric IBD presents with a more severe, aggressive phenotype and unique complications, notably growth impairment. Treatment goals include achieving intestinal healing, reaching growth potential, and optimizing quality of life, all while limiting drug toxicities. In the last 2 decades, the advent of anti–tumor necrosis factor (TNF) α agents has significantly increased the potential to reach these goals. However, nonresponse or loss of response to anti–TNFα agents is still encountered in approximately one-third of patients. Although the development of novel biologic therapies has offered new alternatives in recent years, the use of these therapies in the pediatric setting has been limited due to delayed approval. This article summarizes the key evidence for biologic agents currently used in the treatment of pediatric IBD and discusses challenges and barriers unique to pediatric drug development.


Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic, progressive, and incurable inflammatory disorder of the gastrointestinal tract, with approximately 25% of patients presenting before 18 years of age.1,2 While epidemiologic data suggest that the incidence of IBD may have stabilized among adults in North America, it has continued to rise in children, with the highest percentage increase observed among children under 5 years of age.2,3 Importantly, this rising incidence has caused the pediatric prevalence of IBD to increase by 133% in the last decade in the United States, reaching 77 per 100,000 children in 2016.2 Compared to adults, children with IBD are more likely to have extensive intestinal involvement and an aggressive disease course, in addition to experiencing different complications, such as growth impairment and delayed puberty.4 The treatment of childhood-onset IBD also presents unique challenges, including limited therapeutic options with considerably fewer treatments approved by the US Food and Drug Administration (FDA). This landscape poses significant limitations for pediatric gastroenterologists and, by extension, is relevant for adult gastroenterologists as young patients transition into adult care.

Within the past 2 decades, the advent of anti–tumor necrosis factor (TNF) α agents has radically modified the management and disease course of IBD in both adults and children, resulting in greater remission and mucosal healing rates, fewer surgeries and hospitalizations, improved quality of life, and, notably for children, correction of growth failure.5,6 Nevertheless, approximately one-third of patients are anti-TNFα primary nonresponders, and an additional 30% to 40% experience secondary loss of response.7 In recent years, there has been a robust expansion of FDA–approved drugs for adult CD and UC, but there is significant lag time to approve these same drugs for children.8

This article evaluates the evidence for biologic agents currently used in the treatment of pediatric IBD after summarizing the previously published adult data. Key treatment attributes, efficacy, clinical pharmacology, and safety are reviewed. Finally, challenges and barriers unique to pediatric drug development are discussed.

Anti–Tumor Necrosis Factor α Agents

In children and adolescents, the anti-TNFα agents infliximab and adalimumab are currently the only biologics approved by the FDA for the treatment of pediatric IBD (Table 1). High-quality evidence for their efficacy and safety is accumulating and has shifted the treatment paradigm of pediatric IBD. However, controversies remain regarding their optimal use in this population, including indications as first-line therapies, therapeutic drug monitoring (TDM), combination therapy, and safety.

Efficacy in Crohn’s Disease

Anti-TNFα therapy has been extensively studied in double-blinded, randomized, controlled trials (RCTs) in adults, demonstrating efficacy and safety in both induction and maintenance of remission.9,10 In pediatric patients, there is high-quality evidence from trials involving open-label induction and randomized, dose-ranging maintenance therapy, with none of these trials being placebo-controlled (Table 2).11-15 The majority of these RCTs were conducted with children who had previously been refractory to nonbiologic therapies and were on concomitant immunomodulators. Nonetheless, even in these refractory populations, the clinical remission rate with infliximab ranged between 59% and 85%, and was sustained at 1 year in 56% to 83% of those who responded to standard induction treatment.11,12 The IMAgINE-1 trial was a double-blinded RCT assessing dose-ranging maintenance therapy with adalimumab after open-label, weight-adjusted induction therapy, and included both infliximab-naive patients and patients who had failed infliximab (44%).13 In patients responding to induction, clinical remission occurred in 38.7% and 33.5% at weeks 26 and 52, respectively, with no significant difference between the high- and low-dose groups. Importantly, a significantly higher remission rate among infliximab-exposed patients was shown when compared to infliximab-naive patients at both weeks 26 and 52 (56.9% vs 16.7% and 45.1% vs 19.0%, respectively).13 Likewise, in the recently published PAILOT trial,16 which only included children naive to anti-TNFα agents, rates of clinical remission after adalimumab induction (48%-82%) were higher than rates reported in the IMAgINE-1 trial.13 These results are consistent with observations from previous adult trials9,10 and underscore the importance of optimization and treatment durability with the first biologic agent.

There is accumulating evidence that mucosal healing is associated with better outcomes, providing the foundational evidence for achieving deep remission as the ultimate target in IBD.6 While initial pediatric trials focused on clinical remission, a few observational and retrospective studies have subsequently demonstrated endoscopic healing rates varying between 22% and 42% at 3 to 12 months after treatment initiation.17-21 Additionally, a greater likelihood of achieving mucosal healing at 1 year was shown with the use of anti-TNFα agents as first-line therapy in luminal CD as compared to escalation therapy in 2 pediatric retrospective cohorts,20,21 similar to findings in previously published adult data. These findings, therefore, suggest the superiority of a top-down therapeutic approach in achieving deep remission in pediatric CD.

Linear growth failure is a frequent complication of CD in prepubescent children and represents an important therapeutic target that must be achieved early in the disease so that irreversible sequelae can be mitigated. This concept is best demonstrated by Walters and colleagues in a secondary analysis of data from the large RISK observational cohort.5 In this study, a significantly greater rate of clinical remission and linear growth normalization was shown at 1 year in newly diagnosed CD patients treated with anti-TNFα therapy within the first 3 months after diagnosis compared to patients treated with an immunomodulator only (85.3% vs 60.3%; relative risk, 1.41; P=.0017). Several additional studies,11-13,22-25 including the landmark REACH trial,11 have shown the efficacy of anti-TNFα therapy at facilitating catch-up growth, further supporting its use as first-line therapy in children presenting with linear growth failure.

Finally, little data have demonstrated the long-term efficacy and treatment durability of anti-TNFα therapy beyond 1 year in the pediatric CD population. Overall, the 1- and 3-year sustained durable remission rates have been reported to be 50% to 80% and 40% to 70%, respectively, with stabilization occurring beyond 2 years of treatment.24,26-30 As previously assessed in an adult systematic review and meta-analysis,7 the main reason for discontinuation is secondary loss of response. Retrospective pediatric cohorts have shown a variable recaptured response rate of 37% to 75% with dose intensification.11,30,31 These findings, therefore, emphasize the need for effective and optimized long‐term treatment strategies for pediatric patients, where avoidance of secondary loss of response is of utmost importance.

Efficacy in Ulcerative Colitis

Key adult RCTs, systematic reviews, and meta-analyses have highlighted the efficacy of infliximab and adalimumab in inducing clinical remission and mucosal healing and reducing the need for colectomies in patients with chronically active UC.32,33 To date, infliximab is the only anti-TNFα agent approved by the FDA in pediatric UC (Table 1). Evidence for its use comes mainly from adult clinical trials and pediatric retrospective and observational cohort studies,30,34-40 with only 1 published RCT,41 resulting in FDA approval for this indication. In this RCT, 73% of children with moderate to severe UC responded to a standard induction protocol of infliximab, and 38% maintained clinical remission at 1 year.41 Mucosal healing was achieved in more than two-thirds of patients at week 8. Long-term efficacy of infliximab in UC has also been demonstrated, with retrospective studies reporting sustained durable remission in 40% of patients for a mean period of 2 years.30,42 It should be noted, however, that the majority of these studies only included ambulatory patients. Thus, these numbers may not be applicable to hospitalized patients with corticosteroid-refractory acute severe colitis, defined in children by a Pediatric UC Activity Index score of 65 or higher,43 and for whom only infliximab is used as salvage therapy.

Importantly, a relationship between the increased use of anti-TNFα agents and the reduction of surgery risk for children with UC has been suggested,34-38 with the exception of 1 retrospective study in hospitalized patients with acute severe colitis.39 These contradictory results may be related to the heterogeneity of the studied populations (hospitalized vs ambulatory), disease severity (acute vs chronically active), and infliximab dosing regimens, all of which may impact drug clearance and, thus, true drug exposure. Indeed, the dosing optimization likely plays a critical role in hospitalized patients with acute severe colitis, for whom drug clearance is increased from high TNFα burden, pancolonic involvement, and hypoalbuminemia.44,45 To this end, intensified induction regimens, with doses of infliximab up to 10 mg/kg and increased frequency in an effort to achieve adequate drug exposure, are highlighted in the recent guidelines from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)43 and a retrospective study by Church and colleagues.40 This study reported higher clinical remission rates and a lower colectomy rate at 1 year with intensified induction (mean induction dose >7 mg/kg or interval <5 weeks between doses 1 and 3), as compared to standard dosing (hazard ratio, 3.2; P=.02).40 These findings strongly justify both intensified dosing and early measures of pharmacokinetics to maximize efficacy and possibly mitigate disease complications.

The efficacy and safety profiles of adalimumab for induction and maintenance therapy in moderate to severe active UC have been shown in the landmark adult ULTRA trials46,47 and subsequently reiterated in systematic reviews and meta-analyses,9,33 with better results seen in anti-TNFα–naive patients. Pediatric evidence regarding adalimumab in UC remains scarce, and is limited to 2 small retrospective studies in patients experiencing secondary loss of response to infliximab.30,31 In these 2 studies, response to anti-TNFα therapy was recaptured in 55% to 80% of patients, with clinical remission maintained for a median follow-up of 2 years.30,31 While these results appear promising, data from ongoing clinical trials including biologically naive patients may provide further supportive evidence.

Risk Stratification in Crohn’s Disease

Recent inception cohort studies in pediatric IBD have highlighted baseline phenotyping of patients to predict the severity of their disease course and help identify who will benefit the most from early biologic treatment.48-50

Results from the RISK observational study provide some of the highest-quality data supporting the early use of anti-TNFα therapy in children with CD at risk for severe disease progression.48 In this multicenter, propensity-matched, inception cohort, 913 children with inflammatory, nonstricturing CD at disease onset were enrolled and prospectively followed for complications and response to therapies. Early anti-TNFα therapy use (started within the first 3 months after diagnosis) led to a substantial reduction in penetrating, but not fibrostenotic, complications. A risk stratification model found that African-American race as well as anti–Saccharomyces cerevisiae antibodies and bacterial flagellin (anti-CBir1) were all associated with disease complications. -Additional predictors for disease progression were found when studying the microbial communities and intestinal gene expression.

Risk Stratification in Ulcerative Colitis

The PROTECT trial was a multicenter inception cohort designed to study the natural history of children who were newly diagnosed with UC and who were initially treated with mesalamine or corticosteroids, with further therapy escalation guided by the Pediatric UC Activity Index.49,50 In this study of 428 children, corticosteroid-free remission at weeks 12 and 52 on mesalamine was achieved in 34% and 38% of patients, respectively, with those presenting with mild disease at diagnosis being more likely to remain on mesalamine (49% vs 30%). The strongest predictor for corticosteroid-free remission at weeks 12 and 52 was induction of clinical remission by week 4, highlighting the importance of prompt treatment decision-making early in the course of the disease. Over 1 year, approximately half of the patients required escalation to an immunomodulator or anti-TNFα therapy, and 6% underwent colectomy. Predictors of escalation to anti-TNFα therapy were low vitamin D level, anemia, and decreased rectal biopsy eosinophil count at presentation. Importantly, specific gut microbial community and intestinal gene expression signatures were found to improve the prediction to escalate to a biologic therapy.

Together, these studies demonstrate the need to individualize therapeutic choices based on risk factors for severe disease course and treatment goals, rather than using a broad one-size-fits-all step-up approach. Future risk stratification studies and RCTs validating the aforementioned key clinical and biological predictors will help to develop more personalized treatment approaches with the potential to alter the natural history of pediatric IBD.

Clinical Pharmacology

Therapeutic Drug Monitoring  TDM refers to the measurement of drug and antidrug antibody serum concentrations to guide clinical decision-making and achieve specific treatment goals.51 Along with several adult studies,52-54 a few pediatric cohort studies and post hoc analyses of RCTs, summarized in a recent review by Carman and colleagues, have demonstrated the positive exposure–response relationship between anti-TNFα concentrations and clinical and biological outcomes.55 Inversely, lower drug levels have been associated with drug antibody formation and, consequently, greater likelihood of loss of response.7,55-57 Collectively, these studies have supported the clinical use of TDM to achieve the highest possible response and increase drug retention.

However, the superiority of proactive vs reactive TDM is still under debate.51,58 Currently, societal guidelines support the role of reactive TDM-based dose optimization at the time of loss of response.15,43,59,60 Nevertheless, reactive TDM-based management does not take into account the substantial inter- and intraindividual variability in drug clearance, which can be influenced by antidrug antibody status, concomitant immunosuppressant use, body weight (obesity), sex (male), extent and severity of bowel disease, C-reactive protein, serum albumin, and TNF burden (acting as an antigen sink).45,61 To this end, proactive TDM may allow individualized dosing adjustment and may potentially lead to higher rates of remission, fewer IBD-related complications, lower rates of immunogenicity, and better drug retention.51 Key pediatric observational prospective studies62-65 and a post hoc analysis66 have provided further evidence for the utility of proactive TDM during maintenance therapy, showing positive associations between adequate drug exposure and sustained durable remission, mucosal healing, and drug retention. In a recent pediatric prospective CD cohort, the benefit of proactive TDM during induction was also demonstrated with infliximab concentrations greater than 18 µg/L at infusion 3 (week 6) being strongly associated with clinical and biological response and infliximab levels greater than 5 µg/L at the start of maintenance.65 Additionally, use of TDM to maintain a higher trough level (TL) has been associated with greater likelihood of fistula closure in adult and pediatric patients with perianal fistulizing disease.67-70

Recently, Assa and colleagues provided additional evidence suggesting the superiority of proactive over reactive TDM in PAILOT, the first pediatric RCT.16 In this study, a higher proportion of patients in the proactive arm achieved the primary endpoint of sustained corticosteroid-free clinical remission, defined as a Pediatric CD Activity Index score of less than 10 at all visits (82% vs 48%; P=.002), in addition to a fecal calprotectin level of less than 150 µg/g (47% vs 22%; P=.02). Dose intensification was required in almost 90% of the proactive group in order to achieve a modest trough threshold of 5 µg/mL. Furthermore, in line with recent adult data71 and a post hoc analysis of the IMAgINE-1 trial,57,66 a maintenance TL above 10.0 µg/mL was associated with a higher rate of clinical remission. Overall, this is the first proactive TDM RCT in the pediatric and adult literature achieving its primary endpoint.72,73

TDM is a key component of managing IBD patients on anti-TNFα therapy. While reactive TDM of anti-TNFα agents has been adopted by societal guidelines, there is an increasing body of literature to support the benefit of proactive TDM, particularly in pediatric populations.

Combination Therapy Vs Monotherapy  The potential benefit of combination therapy was first demonstrated in the landmark SONIC trial,74 which showed higher rates of clinical and endoscopic remission with use of infliximab in combination with a thiopurine (57% vs 44%; P=.02). The reason for the improved efficacy with combination therapy remains unclear but may be related to a synergistic effect between the 2 agents or the achievement of higher biologic concentration due to antidrug antibody suppression and decreased drug clearance.74

A post hoc analysis of the SONIC trial found that among patients with similar serum trough concentrations of infliximab, combination therapy was not significantly more effective than infliximab alone.75 Although the use of combination therapy was associated with a lower risk of immunogenicity, no significant difference in rates of clinical remission between combination therapy and monotherapy was demonstrated. Similarly, in the pediatric setting, 2 post hoc analyses of the IMAgINE-1 (56% biologically naive) and PAILOT (100% biologically naive) RCTs showed no additional benefit of combination therapy in terms of adalimumab pharmacokinetics, prevention of immunogenicity, or efficacy.76,77 Therefore, whether proactive TDM with monotherapy is equal to or better than the use of combination therapy as a strategy to improve the pharmacokinetic and treatment durability of anti-TNFα therapy remains in question. In a pediatric prospective study of 77 children with CD starting infliximab therapy (55% monotherapy), Stein and colleagues suggested the benefit of individualized dosing adjustment using proactive TDM at week 10.64 Patients who remained on infliximab at 1 year had a higher median week 10 infliximab TL, as compared with patients who discontinued infliximab (20.4 µg/mL vs 8.7 µg/mL; P=.01),64 regardless of use of combination therapy. Subsequently, Lega and colleagues demonstrated in an adult cohort that early proactive optimization of infliximab monotherapy at week 10 was as effective as combination therapy at sustaining therapeutic TL and clinical remission at 1 year.78

Until further pediatric data are available, the benefits of using combination therapy should be balanced with the potential for higher rates of adverse events such as infection, malignancy, and toxicity.79,80 In pediatric IBD, the use of combination therapy may be appropriate in children who exhibit a higher risk of disease complication, children with immunogenic loss of response to previous anti-TNFα therapy, or children who may benefit from the synergistic effect between the 2 agents.80 This decision should take into account additional individual factors for which a higher risk of malignancies and infections has been suggested (eg, risk of hepatosplenic lymphoma in young men and lymphoproliferative disorder in patients naive to Epstein-Barr virus [EBV] who were exposed to thiopurines).81-83 Finally, withdrawal of immunomodulators after 6 months in patients achieving therapeutic drug levels has been advocated as the optimum time to achieve long-term benefits.15,60,84


By virtue of the central role of TNFα in macrophage activation, neutrophil recruitment, and formation of granulomas, anti-TNFα therapy use has been linked to an increased risk of infection.85 Based on a meta-analysis of 65 pediatric studies (9516 patient years of follow-up [PYF]), the rate of serious infections in children with IBD exposed to anti-TNFα agents has been suggested to be significantly lower than the rate in adults.86 This risk has been estimated to be 3.5 per 100 patient years (PYs) and similar to that of children receiving immunomodulator monotherapy.86 Notably, the rate of serious infections associated with anti-TNFα agents represents half the rate of serious infections for children receiving corticosteroids (7.3/100 PYs).86 Additionally, a higher risk of infections has been reported in the adult and pediatric literature when using anti-TNFα therapy in combination with an immunomodulator or corticosteroid.79,86,87

Prevention and surveillance should be key elements in the management of patients on any immunosuppressive therapy, and care should be guided by the latest pediatric evidence-based recommendations.88 Finally, while immunosuppressive therapies may increase the risk of infections, it is also essential to remember that underlying active disease, malnutrition, and complications, including surgeries, also predispose patients with IBD to infections.88

Prior reports have raised concerns for an increased risk of lymphoproliferative disorders (eg, EBV-associated lymphomas or hepatosplenic T-cell lymphomas) with IBD-related immunosuppressive therapies, most notably thiopurines and anti-TNFα therapies. However, these initial data were largely limited to case series or retrospective studies with small sample sizes and short durations of follow-up. The most robust evidence in regard to malignancy risk in children with IBD exposed to anti-TNFα therapy comes from the DEVELOP registry,82 an ongoing prospective safety registry for pediatric IBD that includes both patients exposed and never exposed to infliximab. In 5766 patients (24,543 PYF; median, 4.5 years/patient), there were 15 patients with malignancy events. Thirteen were exposed to thiopurines (10 with infliximab, 3 to thiopurine only), 1 to infliximab only, and 1 to neither biologics nor thiopurines. Comparison with rates from healthy controls indicated a standardized incidence rate for malignancy of 2.43 (95% CI, 1.29-4.15) for thiopurine exposure (with or without biologic exposure), but no significant increase in neoplasia with infliximab exposure in the absence of thiopurine exposure (standardized incidence rate, 1.49; 95% CI, 0.04-8.28). Of note, 5 cases of hemophagocytic lymphocytic histiocytosis were reported, all with viral infection (EBV or cytomegalovirus) in patients only exposed to thiopurine. No case of hepatosplenic T-cell lymphoma was reported during this study period. Overall, while the risk for malignancies appears low across the available pediatric literature,79,82,86 the average length of treatment exposure and follow-up reported in those studies is short in comparison to real-world experience, and, therefore, pediatric patients should continue to be monitored closely as more safety data accumulate over time.

Very–Early-Onset Inflammatory Bowel Disease

An emerging population of children younger than 6 years of age with IBD represents a unique form of disease, termed very–early-onset IBD (VEO-IBD), which is phenotypically and genetically distinct from older-onset IBD. VEO-IBD can be associated with increased disease severity and poor responsiveness to conventional therapies. As such, this population subset may require different treatment strategies.89 Thus far, there are only retrospective evaluations of these patients on anti-TNFα therapies. These reports have demonstrated higher rates of anti-TNFα failure in VEO-IBD than in older-onset IBD, during both induction and maintenance phases, with overall shorter duration of therapy due to failure to reach and sustain clinical remission.90-92

In addition, there have been reports that younger children require dose optimization more commonly than older children, which may also impact failure rates.93 Future prospective studies evaluating the role of proactive TDM and use of different dosing strategies are needed. Due to the possibility of poor response or durability of anti-TNFα therapies, additional consideration should be taken in the diagnostic evaluation of these patients, many of whom likely have different drivers of disease and require thorough immunologic and genetic workup.94 This evaluation can help determine if alternative targeted therapeutics would be more likely to be beneficial earlier in the treatment strategy.

Biosimilar Agents

A biosimilar agent resembles the original biologic in terms of molecular structure and efficacy, but by definition is not a generic form. From a regulatory standpoint, once a biosimilar has been shown to be equivalent for 1 clinical indication, extrapolation of efficacy to other clinical indications is accepted.95 In 2016, the FDA recommended that CT-P13 (Celltrion), a biosimilar to infliximab, be approved for its rheumatologic conditions and, by extension, for adult and pediatric UC and CD.96 This occurred despite no RCTs studying CT-P13 in IBD, and, indeed, there are limited data regarding the -bioequivalence of this compound in IBD.97 The decision to switch is often based on an economic evaluation, which might not involve patients, parents, or physicians in the decision-making process. While a comprehensive review of biosimilar development, regulatory requirements, clinical outcomes, and perspectives is beyond the scope of this article, it is important to note that the Crohn’s & Colitis Foundation cautions against -interchangeability until further evidence regarding safety, efficacy, and immunogenicity has been gathered.98

Other Biologic Agents Used in Pediatrics

In the search to enlarge the therapeutic armamentarium, newer biologics, namely vedolizumab (Entyvio, Takeda) and ustekinumab (Stelara, Janssen), have shown -effectiveness in both UC and CD and were recently granted FDA approval, although only in adults. In pediatric practice, off-label use of these biologics has been increasing, and evidence from real-world cohort studies is growing.


Efficacy  Vedolizumab is a humanized anti-α4β7 integrin receptor molecule that inhibits lymphocyte trafficking to the gut by interfering with the ability of the lymphocytes to bind to mucosal addressin cell adhesion molecule-1 (MAdCAM-1).99 Since 2013, 3 landmark phase 3 adult GEMINI trials and their extension phases, several real-life cohort studies, and 2 systematic reviews and meta-analyses have confirmed the efficacy and safety of vedolizumab in treating patients with UC and luminal CD and the induction of mucosal healing.100-107 Nevertheless, while overall effectiveness has been demonstrated irrespective of anti-TNFα treatment history,100-102 post hoc analyses have revealed a delayed response in addition to an overall lower rate of clinical and endoscopic remission in anti-TNFα–exposed patients.108,109 A suggested physiologic mechanism for these observed differences has included downregulation of MAdCAM-1 by anti-TNFα therapy.110 However, it is noteworthy that anti-TNFα–exposed populations have also typically represented a more refractory disease phenotype. These observations further raise the question of whether or not vedolizumab could be used more effectively as first-line therapy in the treatment algorithm for moderate to severe UC, a topic that has recently been investigated in the VARSITY trial comparing vedolizumab and adalimumab in the treatment of active UC in adults.111 In this study, clinical remission at week 52 occurred in a significantly higher percentage of patients who received vedolizumab than in patients who received adalimumab (31.3% vs 22.5%), as did endoscopic improvement (39.7% vs 27.7%). These results suggest a shift in the therapeutic approach of IBD, positioning anti-adhesion molecules as an option for first-line therapy to achieve the best outcomes. Longitudinal studies will help further determine the true impact of this alternative biologic on disease course and rates of colectomy.

Pediatric evidence is currently limited to small, prospective, observational112 and retrospective studies,113-115 as well as long-term, open-label, follow-up data reports (Table 3).116 Using an adapted dosing of 5 mg/kg up to 300 mg, these combined pediatric studies have reported week 14 and 22 clinical remission rates to be 37% to 76% and 34% to 71%, respectively, in a heterogeneous patient population.112-116 Similar to what is seen in adult cohorts, remission rates have been numerically higher in UC as compared to CD and in anti-TNFα–naive children compared to patients with prior exposure. In a recently published retrospective cohort, vedolizumab was also shown to induce mucosal healing (composite score of endoscopic and histologic remission) at a rate of 38%.115

The favorable risk-benefit profile makes vedolizumab an ideal therapeutic choice for pediatric IBD. However, an important limitation is its delayed onset of action, for which corticosteroid use as bridge therapy is often necessary in this population that is already at increased risk of growth failure and bone loss. Recently, Hamel and colleagues published their small, single-center experience of using concomitant tacrolimus between anti-TNFα withdrawal to vedolizumab maintenance as a corticosteroid-sparing bridge therapy in moderate to severe IBD.117 Future larger-scale studies evaluating tacrolimus as a bridge therapy during induction for severe colitis are needed to confirm these promising results.

Clinical Pharmacology  To date, there are no published pediatric studies assessing vedolizumab TDM, but an exposure-efficacy relationship has been suggested. In a post hoc analysis of the GEMINI trials,118 trough concentrations at week 6 greater than 17 µg/mL for UC and greater than 16 µg/mL for CD were associated with a higher likelihood of achieving clinical remission.118 High body mass index and more severe disease at initiation of therapy reflected by low baseline albumin and anemia levels and high C-reactive protein levels were associated with lower vedolizumab serum levels and worse therapeutic outcomes. Using propensity score–based case-matching analysis from GEMINI 1 and adjusting for confounders affecting drug clearance, a potential target TL for vedolizumab concentrations in patients with UC was identified.119 The proposed concentrations were 37.1 µg/mL, 18.4 µg/mL, and 12.7 µg/mL at weeks 6 and 14 and during maintenance treatment, respectively. A positive correlation between a higher TL and mucosal healing has also been reported in a GEMINI 1 post hoc analysis, with UC patients having steady-state trough concentrations in the upper quartiles (quartiles 2-4, TL >19 µg/mL) being more likely to achieve deep remission at week 52.120 Similar dose-efficacy relationships in CD have been shown in real-world cohort studies.121,122 Additionally, histologic remission, a distinct treatment target for which growing evidence is suggesting better clinical outcomes, was recently shown to be associated with a TL greater than 25 µg/mL during maintenance therapy.123

Importantly, in contrast to anti-TNFα therapy where immunogenicity has been associated with accelerated drug clearance and loss of response, immunogenicity of vedolizumab appears to be low (<5%) and mostly transient, with less than 1% of patients having persistent drug antibodies.124 These findings likely explain the observed lack of additional benefit with combination therapy. Future prospective studies evaluating the mechanisms underlying primary nonresponse and loss of response to vedolizumab as well as the impact of dose optimization are needed before positioning drug monitoring in the therapeutic algorithm of vedolizumab.125

Safety  Safety data regarding use of vedolizumab in children are limited. In the largest multicenter case series of 64 children, the Pediatric IBD Porto Group of
ESPGHAN reported no serious adverse events at a median follow-up of 24 weeks.116 Future data from the currently enrolling prospective multicenter VEDOKIDS cohort study will help to further define the risk-benefit profile of vedolizumab in pediatric IBD.126 Pooled data from adult clinical trials and real-world observational studies have reported no increase in serious adverse events, serious infections, or malignancies, therefore supporting the notion that gut-selective biologics are safe, and perhaps safer than anti-TNFα agents.127,128 In a systematic review of vedolizumab-exposed patients (N=3979) with follow-up ranging from 10 weeks to 46 months, the risks for treatment-related serious adverse events and severe infections were 20 per 100 PYs (<8%) and 7.4 per 100 PYs (<0.6%), respectively, with no reported cases of progressive multifocal leukoencephalopathy.127 Risk of infusion-related reactions was less than 5%. Moreover, the recently published results from the open-label extension study GEMINI-LTS (total of 5670 PYs) confirmed no increased risk of malignancies with vedolizumab exposure.128 Theoretical concerns for an increased risk of perioperative complications, including wound dehiscence and infections secondary to inhibition of lymphocyte trafficking, have been raised with vedolizumab. While initial small adult and pediatric retrospective studies may support these concerns,129-132 recent systematic reviews and meta-analyses have not detected an increased risk of postoperative complications compared to either preoperative anti-TNFα therapy or no prior biologic therapy.133,134 Overall, given its favorable long-term risk-benefit profile, vedolizumab may be a safe alternative in patients for whom it might be best to avoid systematic immunosuppression, including those predisposed to infection and/or malignancy.


Efficacy  Ustekinumab, a human monoclonal antibody targeting the common p40 subunit of interleukin (IL) 12 and IL-23, has demonstrated clinical efficacy in the phase 2 CERTIFI and phase 3 UNITI trials for induction and maintenance of remission in adult CD.135-137 Endoscopic healing has also been reported in a post hoc analysis of the UNITI trials.138 Moreover, accumulating data suggest efficacy of ustekinumab in treating refractory perianal fistulizing CD.139,140 Finally, new data for the use of anti–IL-12/23 have been emerging for UC from the phase 3 UNIFI trial.141,142

Off-label use of ustekinumab in the pediatric population is increasing. However, evidence for its efficacy and safety in this age group is limited to 3 observational cohort studies in children with CD refractory to anti-TNFα therapies143-145 and an ongoing large randomized trial146 (Table 4). Recently, Dayan and colleagues highlighted increased efficacy among biologic-naive patients compared to biologic-exposed patients (90% vs 50%; P=.03) in an observational study including 52 children and young adults (38 children, 81% with CD).143 Fusillo and colleagues, in a preliminary analysis of a prospective cohort of 20 pediatric biologic-exposed patients, including 16 with CD, described clinical response in 52% of patients at week 6 and 45% at a median follow-up of 26 weeks.145 Similar long-term outcomes at 12 months were reported in a separate retrospective cohort of 44 pediatric patients.144 Overall, these results suggest that ustekinumab is efficacious in pediatric patients with IBD, but larger cohort studies will be required to validate the efficacy, safety profile, and optimized dosing regimen in this population.

Clinical Pharmacology  Compared to infliximab, the immunogenicity of ustekinumab is remarkably low, with antibody formation reported in only 0.7% of patients by week 36 and in 2.3% by 1 year.147 Although data regarding TDM remain scarce, a recent study of phase 3 adult CD data showed that trough concentrations of 0.8 µg/mL or greater were associated with maintenance of clinical remission in a higher proportion of patients than in patients with lower trough concentrations. Additionally, unlike anti-TNFα agents, concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators.147,148

Safety  While long-term safety data for ustekinumab are limited in IBD, safety data from psoriasis and psoriatic arthritis registries underscore no increased risk of serious infection, malignancy, or mortality.149 Data from clinical trials in adult IBD demonstrated a similarly favorable safety profile.135-137

Future Interleukin Inhibitors  Although the efficacy and safety of ustekinumab are well-established in IBD, it remains unclear whether modulation of the IL-12 axis adds potential risk related to the role of IL-12 in host defense mechanisms. Hence, selectively blocking IL-23(p19) might offer important differentiation in efficacy, safety, and dosing. The current biologic development pipeline includes 3 monoclonal antibodies directed against IL-23(p19): brazikumab (AstraZeneca), risankizumab (AbbVie), and mirikizumab (Eli Lilly), all of which are in active IBD clinical trials. Mirikizumab is the only agent in this family that has parallel pediatric arms to the adult trials at this time.150

Facilitating Clinical Drug Trials for Children With Inflammatory Bowel Disease

Conducting clinical drug trials in the pediatric IBD setting presents several challenges that include the relatively small eligible population, greater reluctance from parents to enroll children in trials due to concerns for potential side effects and invasive procedures, ethical issues of subjecting sick children to placebo, fear of subtherapeutic dosing of IBD drugs, and required long pre-enrollment washout periods.8,151 Consequently, pediatric therapies have faced long delays in approval, and this time lag has led to extensive off-label use of drugs, often without clear guidance and appropriate dosing. This is particularly concerning because extrapolation from dose-finding adult studies has often been shown to be too low in real-world experience.63,90,152 While stakeholders agree on the critical need to expedite drug development for pediatric IBD, the optimal trial design for assessing novel therapies is still a subject of debate among pediatric IBD experts, pharmaceutical companies, regulatory agencies, and the patient and family community.151

In order to address this need, a group of international pediatric IBD experts (Pediatric Inflammatory Bowel Disease Network) recently published a consensus process on how to facilitate pediatric IBD clinical drug designs.8 Key points include acceptance of extrapolation of efficacy from adult data and real-world safety data, requirements for pharmacokinetic and/or pharmacodynamic studies in children of all age groups prior to adult approval, consideration for higher dosing per kilogram (or use of body surface area–based dosing) in children weighing less than 30 kg, and improved feasibility for successful RCTs by way of adapted small sample size, reduced number of invasive procedures, and minimized washout period prior to inclusion. Hopefully, once in practice, these novel approaches to pediatric IBD drug development will help expedite drug approval and enlarge the therapeutic armamentarium for this vulnerable population.


In the last decade, a significantly increased number of children with IBD have been treated with biologic drugs. Anti-TNFα agents have revolutionized the management of IBD, positively modifying the natural disease history in children. Importantly, inception cohort studies of pediatric CD and UC (RISK and PROTECT, respectively) have highlighted the variable course of disease and necessity of adopting an individualized approach with early use of biologic therapy in patients at risk of severe disease progression. Moreover, newer categories of biologic drugs (ie, anti-integrin, anti-IL) that have shown efficacy and safety in the adult population may also be the new horizon of IBD treatment in children. The landscape of IBD treatment is widening rapidly; however, few medications have a registered pediatric indication. Important barriers to drug approval in this vulnerable population have been identified, and solutions to optimize clinical trial design for emerging and existing therapies in pediatrics have been proposed by international societies. There is a need for collaboration among pediatric IBD experts as well as among physicians, patients and families, research organizations, and the pharmaceutical industry to facilitate global drug development and advancement in pediatric IBD.


Dr Baldassano receives consulting fees from Celgene, Eli Lilly, and Janssen. The other authors have no relevant conflicts of interest to disclose.


The authors thank Jennifer Vales, resource coordinator for the Center for Pediatric IBD at the Children’s Hospital of Philadelphia in Philadelphia, Pennsylvania, who reviewed the final manuscript.


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