Abstract
Pharmacologic treatment of children and adolescents with inflammatory bowel diseases (IBD) [Crohn’s disease and ulcerative colitis] requires consideration of disease and medication effects on growth and nutrition, the importance of durability of biologics, and concerns for long-term sequelae of disease and therapies. Achieving early remission in children with Crohn’s disease correlates with improved outcomes and therefore allows a window of opportunity for maximizing growth. Thus, there is a great need to treat children and adolescents with the right drug at the right time while achieving adequate exposure. Improved understanding of disease phenotypes, disease natural history, and risk stratification will play a critical role in treatment selection for children, particularly as more therapeutic options become available. Here we summarize data supporting newer concepts of treating the individual child with IBD through targeted early biologic treatment, including utilization of therapeutic drug monitoring to optimize treatment effects and the use of early antitumor necrosis factor (TNF)-α therapies to mitigate long-term sequelae of the disease. Recent inception cohort studies provide important data regarding the risk stratification of children and adolescents with IBD, which support a move toward a personalized therapeutic approach to IBD in children and adolescents.
Keywords
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ballengee CR, Stidham RW, Liu C et al (2018) Association between plasma level of collagen type III alpha 1 chain and development of strictures in pediatric patients with Crohn’s disease. Clin Gastroenterol. pii: S1542-3565(18)30969-8. https://doi.org/10.1016/j.cgh.2018.09.008. [Epub ahead of print]
Benchimol EI, Bernstein CN, Bitton A et al (2017) Trends in epidemiology of pediatric inflammatory bowel disease in Canada: distributed network analysis of multiple population-based provincial health administrative databases. Am J Gastroenterol 112(7):1120–1134
Borrelli O, Bascietto C, Viola F et al (2004) Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn’s disease. Dig Liver Dis 36(5):342–347
Bossuyt P, Baert F, D’Heygere F et al (2019) Early mucosal healing predicts favorable outcomes in patients with moderate to severe ulcerative colitis treated with golimumab: data from the real-life BE-SMART cohort. Inflamm Bowel Dis 25(1):156–162
Brandse JF, Mould D, Smeekes O et al (2017) A real-life population pharmacokinetic study reveals factors associated with clearance and immunogenicity of infliximab in inflammatory bowel disease. Inflamm Bowel Dis 23(4):650–660
Buurman DJ, Maurer JM, Keizer RJ et al (2015) Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice. Aliment Pharmacol Ther 42(5):529–539
Carman N, Tomalty D, Church PC et al (2019) Clinical disease activity and endoscopic severity correlate poorly in children newly diagnosed with Crohn’s disease. Gastrointest Endosc 89(2):364–372
Cheng J, Hamilton Z, Smyth M et al (2017) Concomitant therapy with immunomodulator enhances infliximab durability in pediatric inflammatory bowel disease. Inflamm Bowel Dis 23(10):1762–1773
Chi LY, Zitomersky NL, Liu E et al (2018) The impact of combination therapy on infliximab levels and antibodies in children and young adults with inflammatory bowel disease. Inflamm Bowel Dis 24(6):1344–1351
Church PC, Guan J, Walters TD et al (2014) Infliximab maintains durable response and facilitates catch-up growth in luminal pediatric Crohn’s disease. Inflamm Bowel Dis 20(7):1177–1186
Colombel JF, Sandborn WJ, Reinisch W et al (2010) Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 362(15):1383–1395
Colombel JF, Rutgeerts P, Reinisch W et al (2011) Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 141(4):1194–1201
Colombel JF, Adedokun OJ, Gasink C et al (2018) Combination therapy with infliximab and azathioprine improves infliximab pharmacokinetic features and efficacy: a post hoc analysis. Clin Gastroenterol Hepatol. pii: S1542-3565(18)31024-3. https://doi.org/10.1016/j.cgh.2018.09.033. [Epub ahead of print]
Crombé V, Salleron J, Savoye G et al (2011) Long-term outcome of treatment with infliximab in pediatric-onset Crohn’s disease: a population-based study. Inflamm Bowel Dis 17(10):2144–2152
DoBoer MD, Lee AM, Herbert K et al (2018) Increases in IGF-1 after anti-TNF-α therapy are associated with bone and muscle accrual in pediatric crohn disease. J Clin Endocrinol Metab 103(3):936–945. https://doi.org/10.1210/jc.2017-01916
Dotan I, Ron Y, Yanai H et al (2014) Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis 20(12):2247–2259
Dubinsky MC, Phan BL, Singh N et al (2017) Pharmacokinetic dashboard-recommended dosing is different than standard of care dosing in infliximab-treated pediatric IBD patients. AAPS J 19(1):215–222
Dubner SE, Shults J, Baldassano RN et al (2009) Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn’s disease. Gastroenterology 136(1):123–130
El-Matary W, Walters TD, Huynh HQ et al (2019) Higher postinduction infliximab serum trough levels are associated with healing of fistulizing perianal Crohn’s disease in children. Inflamm Bowel Dis 25(1):150–155
Fasanmade AA, Adeodokun OJ, Blank M et al (2011) Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther 33(7):946–964
Feuerstein JD, Nguyen GC, Kupfer SS et al (2017) American gastroenterological association institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology 153(3):827–834
Gasparetto M, Guariso G (2014) Crohn’s disease and growth deficiency in children and adolescents. World J Gastroenterol 20(37):13219–13233
Griffin LM, Thayu M, Baldassano RN et al (2015) Improvements in bone density and structure during anti-TNF-α therapy in pediatric Crohn’s disease. J Clin Endocrinol Metab 100(7):2630–2639
Hyams JS, Davis S, Mack DR et al (2017) Factors associated with early outcomes following standardised therapy in children with ulcerative colitis. Lancet Gastroenterol Hepatol 2(12):855–868
Kerur B, Litman HJ, Stern JB et al (2017) Correlation of endoscopic disease severity with pediatric ulcerative colitis activity index score in children and young adults with ulcerative colitis. World J Gastroenterol 23(18):3322–3329
Kerur B, Machan JT, Shapiro JM et al (2018) Biologics delay progression of Crohn’s disease, but not early surgery, in children. Clin Gastroenterol Hepatol 16(9):1467–1473
Kugathasan S, Denson LA, Walters TD et al (2017) Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet 389(10080):1710–1718. https://doi.org/10.1016/S0140-6736(17)30317-3. Epub 2017 Mar 2
Lee LYW, Sanderson JD, Irving PM (2012) Anti-infliximab antibodies in inflammatory bowel disease: prevalence, infusion reactions, immunosuppression and response, a meta-analysis. Eur J Gastroenterol Hepatol 24(9):1078–1085
Lega S, Dubinsky MC (2018) What are the targets of inflammatory bowel disease management. Inflamm Bowel Dis 24(8):1670–1675
Lega S, Phan BL, Rosenthal CJ et al (2019) Proactively optimized infliximab monotherapy is as effective as combination therapy in IBD. Inflamm Bowel Dis 25(1):134–141
Lichtenstein GR, Loftus EV, Isaacs KL et al (2018) ACG clinical guideline: management of crohn’s disease in adults. Am J Gastroenterol 113(4):481–517
Maser EA, Villela R, Silverberg MS et al (2006) Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 4(10):1248–1254
Minar P, Saeed SA, Afreen M et al (2016) Practical use of infliximab concentration monitoring in pediatric Crohn disease. J Pediatr Gastroenterol Nutr 62(5):715–722
Mould DR, Dubinsky MC (2015) Dashboard systems: pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies. J Clin Pharmacol 55(Suppl 3):S51–S59
Nanda KS, Chiefetz AS, Moss AC (2013) Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol 108(1):40–47
Papamichael K, Juncadella A, Wong D et al (2019) Proactive therapeutic drug monitoring of adalimumab is associated with better long-term outcomes compared to standard of care in patients with inflammatory bowel disease. J Crohns Colitis. https://doi.org/10.1093/ecco-jcc/jjz018. [Epub ahead of print]
Pappa H, Thayu M, Sylvester F et al (2011) Skeletal health of children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 53(1):11–25
Peyrin-Biroulet L, Sandborn W, Sands BE et al (2015) Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol 110(9):1324–1338
Ricciuto A, Dhaliwal J, Walters TD et al (2018) Clinical outcomes with therapeutic drug monitoring in inflammatory bowel disease: a systematic review with meta-analysis. J Crohns Colitis 12(11):1302–1315
Rosen MJ, Dhawan A, Saeed SA (2015) Inflammatory bowel disease in children and adolescents. JAMA Pediatr 169(11):1053–1060
Rufo PA, Denson LA, Sylvester FA et al (2012) Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. J Pediatr Gastroenterol Nutr 55(1):93–108
Seow CH, Newman A, Irwin SP et al (2010) Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 59(1):49–54
Spencer EA, Davis SM, Mack DR et al (2018) Serologic reactivity reflects clinical expression of ulcerative colitis in children. Inflamm Bowel Dis 24(6):1334–1343
Thayu M, Leonard MB, Hyams JS et al (2008) Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn’s disease: results of the REACH study. Clin Gastroenterol Hepatol 6(12):1378–1384
Ungar B, Levy I, Yavne Y et al (2016) Optimizing anti-TNF-α therapy: serum levels of infliximab and adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 14(4):550–557
van de Casteele N, Ferrante M, Van Assche G et al (2015) Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology 148(7):1320–1329
van de Casteele N, Jeyarajah J, Jairath V et al (2018) Infliximab exposure-response relationship and thresholds associated with endoscopic healing in patients with ulcerative colitis. Clin Gastroenterol Hepatol. pii: S1542-3565(18)31200-X. https://doi.org/10.1016/j.cgh.2018.10.036. [Epub ahead of print]
van Hoeve K, Dreesen E, Hoffman I et al (2018) Higher infliximab trough levels are associated with better outcome in paediatric patients with inflammatory bowel disease. J Crohns Colitis 12(11):1316–1325
Vaughn BP, Martinez-Vazquez M, Patwardhan VR et al (2014) Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis 20(11):1996–2003
Walters TD, Kim MO, Denson LA et al (2014) Increased effectiveness of early therapy with anti-tumor necrosis factor-α vs an immunomodulator in children with Crohn’s disease. Gastroenterology 146(2):383–391
Walters TD, Faubion WA, Griffiths AM et al (2017) Growth impairment with adalimumab treatment in children with moderately to severely active Crohn’s disease. Inflamm Bowel Dis 23(6):967–975
Weinstein-Nakar I, Focht G, Church P et al (2018) Associations among mucosal and transmural healing and fecal level of calprotectin in children with Crohn’s disease. Clin Gastroenterol Hepatol 16(7):1089–1097
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Batra, S., Conklin, L.S. (2019). Therapeutics for Inflammatory Bowel Diseases in Children and Adolescents: A Focus on Biologics and an Individualized Treatment Paradigm. In: Kiess, W., Schwab, M., van den Anker, J. (eds) Pediatric Pharmacotherapy . Handbook of Experimental Pharmacology, vol 261. Springer, Cham. https://doi.org/10.1007/164_2019_255
Download citation
DOI: https://doi.org/10.1007/164_2019_255
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-50493-9
Online ISBN: 978-3-030-50494-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)