Positionspapier der Gesellschaft für Pädiatrische Gastroenterologie und Ernährung (GPGE) zum zulassungsüberschreitenden Gebrauch von für Erwachsene mit CED zugelassenen Biologika und Signalinhibitoren bei Kindern und Jugendlichen

Zusammenfassung

Die Therapie für Kinder und Jugendliche mit chronisch entzündlichen Darmerkrankungen (CED) unterscheidet sich grundsätzlich kaum von denen der erwachsenen Patienten. Derzeit sind jedoch in Deutschland von der stetig steigenden Zahl von Biologika und Signalinhibitoren für Erwachsene nur zwei TNFα-Antikörper für die Behandlung der CED ab dem vollendeten 6. Lebensjahr zugelassen. Damit stehen ein großer Teil der bei Erwachsenen mit CED zugelassenen Medikamente für moderat bis schwer erkrankte Kinder und Jugendliche nicht zur Verfügung. Die geringe Zahl zugelassener Medikamente erschwert auch das Erreichen des prognostisch wichtigen Ziels, rasch nach Diagnosestellung eine anhaltende steroidfreie Remission der CED zu erreichen, welche durch Beschwerdefreiheit des Patienten und auch dem objektivierbaren Ziel der Mukosaheilung charakterisiert ist. Dieses Positionspapier soll die aktuelle Studienlage zur medikamentösen Behandlung von Kindern und Jugendlichen mit CED außerhalb der Alterszulassung darstellen und als Grundlage für den Medizinischen Dienst bei der Begutachtung von Einzelfallanträgen sowie den behandelnden Ärztinnen und Ärzten, den Kostenträgern, gesundheitspolitischen und sozialgerichtlichen Entscheidungsträgern zur Information und Entscheidungsgrundlage dienen.

Abstract

Therapy for children and adolescents with chronic inflammatory bowel disease (IBD) is basically no different from that for adult patients. However, of the steadily increasing number of biologics and signalling inhibitors for adults, only two TNFα antibodies are currently approved in Germany for the treatment of IBD from the age of 6. This means that a large proportion of the drugs authorised for adults with IBD are not available for children and adolescents with moderate to severe disease. The small number of approved drugs also makes it difficult to achieve the prognostically important goal of achieving a sustained remission of IBD soon after diagnosis, which is characterised by the patient being free of symptoms and also the objectifiable goal of mucosa healing. This position paper is intended to present the current study situation on the drug treatment of children and adolescents with IBD outside the age limit and to serve as a basis for information and decision-making for the Medical Service in the assessment of individual case applications as well as for the treating physicians, the cost bearers, health policy and social court decision-makers.

Schlüsselwörter

Pädiatrie - CED - Off-Label-Therapie

Keywords

pediatrics - IBD - off-label therapy

Publikationsverlauf

Eingereicht: 09. August 2024

Angenommen nach Revision: 07. November 2024

Artikel online veröffentlicht:
17. Februar 2025

• Literatur

• 1 Caes L, Chambers CT, Otley A. et al. Pain and quality of life in youth with inflammatory bowel disease: the role of parent and youth perspectives on family functioning. PAIN Rep 2019; 4: e715
• 2 Däbritz J, Gerner P, Enninger A. et al. Inflammatory Bowel Disease in Childhood and Adolescence. Dtsch Arzteblatt Int 2017; 114: 331-338
• 3 Wewer MD, Jansson S, Malham M. et al. Disease Activity Patterns of Paediatric Inflammatory Bowel Disease: A Danish Nationwide Cohort Study (1996–2018). J Crohns Colitis 2024; 18: 246-255
• 4 Buderus S, Scholz D, Behrens R. et al. Chronisch-entzündliche Darmerkrankungen bei pädiatrischen Patienten. Charakt Von Neuer Patienten Aus Dem Regist CEDATA-GPGE Dtsch Ärztebl Int 2015; 112: 121-127
• 5 Atia O, Buchuk R, Lujan R. et al. Predictors of Complicated Disease Course in Children and Adults With Ulcerative Colitis: A Nationwide Study From the epi-IIRN. Inflamm Bowel Dis 2024; izae094
• 6 Atia O, Lujan R, Buchuk R. et al. Predictors of Complicated Disease Course in Adults and Children With Crohn’s Disease: A Nationwide Study from the epi-IIRN. Inflamm Bowel Dis 2024; izae014
• 7 van Rheenen PF, Aloi M, Assa A. et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis 2020;
• 8 Krohn K, Pfeifer M, Manzey P. et al. Chronisch entzündliche Darmerkrankungen – die biopsychosoziale Realität im Kindes- und Jugendalter. Bundesgesundheitsblatt – Gesundheitsforschung – Gesundheitsschutz 2020; 63: 839-845
• 9 Thavamani A, Umapathi KK, Khatana J. et al. Burden of Psychiatric Disorders among Pediatric and Young Adults with Inflammatory Bowel Disease: A Population-Based Analysis. Pediatr Gastroenterol Hepatol Nutr 2019; 22: 527-535
• 10 Ungaro RC, Aggarwal S, Topaloglu O. et al. Systematic review and meta-analysis: efficacy and safety of early biologic treatment in adult and paediatric patients with Crohn’s disease. Aliment Pharmacol Ther 2020; 51: 831-842
• 11 Ley D, Leroyer A, Dupont C. et al. New Therapeutic Strategies Have Changed the Natural History of Pediatric Crohn’s Disease: A Two-Decade Population-Based Study. Clin Gastroenterol Hepatol 2022; 20: 2588-2597.e1
• 12 Ley D, Leroyer A, Dupont C. et al. New Therapeutic Strategies Are Associated With a Significant Decrease in Colectomy Rate in Pediatric Ulcerative Colitis. Am J Gastroenterol 2023;
• 13 Bethell GS, Ashton JJ, Adams S. et al. The Influence of the Introduction of Biologic Agents on Surgical Intervention in Paediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2022; 75: 308-312
• 14 Claßen M, De Laffolie J, Claßen M. et al. Significant advantages for first line treatment with TNF-alpha inhibitors in pediatric patients with inflammatory bowel disease – Data from the multicenter CEDATA-GPGE registry study. Front Pediatr 2022; 10: 903677
• 15 Croft NM, De Ridder L, Griffiths AM. et al. Paediatric Inflammatory Bowel Disease: A Multi-Stakeholder Perspective to Improve Development of Drugs for Children and Adolescents. J Crohns Colitis 2023; 17: 249-258
• 16 Brückner A, Werkstetter KJ, de Laffolie J. et al. Incidence and Risk Factors for Perianal Disease in Pediatric Crohn Disease Patients Followed in CEDATA-GPGE Registry:. J Pediatr Gastroenterol Nutr 2018; 66: 73-78
• 17 Kucharzik T, Dignass A, Atreya R. et al. Aktualisierte S3-Leitlinie Colitis ulcerosa (Version 6.1) – Februar 2023 – AWMF-Registriernummer: 021–009. Z Für Gastroenterol 2023; 61: 1046-1134
• 18 Sturm A, Atreya R, Bettenworth D. et al. Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) – August 2021 – AWMF-Registernummer: 021–004. Z Für Gastroenterol 2022; 60: 332-418
• 19 Adamji M, Day AS. An overview of the role of exclusive enteral nutrition for complicated Crohn’s disease. Intest Res 2019; 17: 171-176
• 20 Ashton JJ, Gavin J, Beattie RM. Exclusive enteral nutrition in Crohn’s disease: Evidence and practicalities. Clin Nutr 2019; 38: 80-89
• 21 Kang Y, Park S, Kim S. et al. Therapeutic Efficacy of Exclusive Enteral Nutrition with Specific Polymeric Diet in Pediatric Crohn’s Disease. Pediatr Gastroenterol Hepatol Nutr 2019; 22: 72
• 22 Klomberg RCW, Van Der Wal HC, Aardoom MA. et al. Improved Clinical Outcomes With Early Anti-Tumour Necrosis Factor Alpha Therapy in Children With Newly Diagnosed Crohn’s Disease: Real-world Data from the International Prospective PIBD-SETQuality Inception Cohort Study. J Crohns Colitis 2024; 18: 738-750
• 23 Geem D, Hercules D, Pelia RS. et al. Progression of Pediatric Crohn’s Disease Is Associated With Anti–Tumor Necrosis Factor Timing and Body Mass Index Z-Score Normalization. Clin Gastroenterol Hepatol 2024; 22: 368-376.e4
• 24 De Laffolie J, Zimmer KP, Sohrabi K. et al. Early Immunosuppression in Children and Adolescents With Crohn’s Disease. Dtsch Ärztebl Int 2021;
• 25 Haas JP, Minden K. Langfristentwicklungen in der Kinder- und Jugendrheumatologie. Kompass Autoimmun 2023; 5: 3-12
• 26 Mulberg AE, Conklin LS, Croft NM. et al. Pediatric Extrapolation of Adult Efficacy to Children Is Critical for Efficient and Successful Drug Development. Gastroenterology 2022; 163: 77-83
• 27 Claßen M, Hoerning A. Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies. Children 2023; 10: 634
• 28 Wlazło M, Kierkuś J. Dual Biologic Therapy for the Treatment of Pediatric Inflammatory Bowel Disease: A Review of the Literature. J Clin Med 2022; 11: 2004
• 29 Conrad MA, Kelsen JR. The Treatment of Pediatric Inflammatory Bowel Disease with Biologic Therapies. Curr Gastroenterol Rep 2020; 22: 36
• 30 Aronson JK, Ferner RE. Unlicensed and off-label uses of medicines: definitions and clarification of terminology. Br J Clin Pharmacol 2017; 83: 2615-2625
• 31 European medicines agency. Report on the survey of all paediatric uses of medicinal products in Europe.
• 32 European Medicines Agency. Off-label use. 2024
• 33 Male C, Neubert A, Grytli H. et al. Evidenzbasierte Off-label-Anwendung von Arzneimitteln bei Kindern und Jugendlichen: Internationales Konsortium von Kinderformularien als Grundlage für die bestverfügbare Evidenz. Monatsschr Kinderheilkd 2022; 170: 207-216
• 34 Bauer ML. Empfehlungen zur sicheren Anwendung von Arzneimitteln im Off-Label-Use in Deutschland – Dissertation Uni Bonn. 2019
• 35 Gemeinsamer Bundesausschuss. GBA-Stellungnahme zum off label use von Medikamenten.
• 36 OLG Köln. OLG Köln 30.05.1990 27 U 169891.
• 37 OLG Dresden. OLG Dresden, 15.05.2018, 4 U 248/16.
• 38 Toma M, Felisi M, Bonifazi D. et al. Paediatric Medicines in Europe: The Paediatric Regulation-Is It Time for Reform?. Front Med 2021; 8: 593281
• 39 Klein A, Horneff G. Off-Label-Behandlung in der Kinderrheumatologie. Arthritis Rheuma 2023; 43: 411-417
• 40 Gemeinsamer Bundesausschuss. Arzneimittel-Richtlinie Richtlinie über die Verordnung von Arzneimitteln in der vertragsärztlichen Versorgung – AM-RL (Fassung vom 02.07.2024).
• 41 Knowles SR, Graff LA, Wilding H. et al. Quality of Life in Inflammatory Bowel Disease: A Systematic Review and Meta-analyses—Part I. Inflamm Bowel Dis 2018; 24: 742-751
• 42 Knowles SR, Keefer L, Wilding H. et al. Quality of Life in Inflammatory Bowel Disease: A Systematic Review and Meta-analyses—Part II. Inflamm Bowel Dis 2018; 24: 966-976
• 43 Stallmach A, Atreya R, Grunert PC. et al. Treatment strategies in inflammatory bowel diseases. Dtsch Ärztebl Int 2023;
• 44 Hyams JS, Russell RK. The State of Clinical Trials in Pediatric Inflammatory Bowel Disease. Gastroenterol Clin North Am 2023; 52: 589-597
• 45 Breton J, Kastl A, Conrad MA. et al. Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease. Gastroenterol Hepatol 2020; 16: 400-414
• 46 Turner D, Ruemmele FM, Orlanski-Meyer E. et al. Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care- an Evidence-Based Guideline from ECCO and ESPGHAN. J Pediatr Gastroenterol Nutr 2018; 1
• 47 Turner D, Ruemmele FM, Orlanski-Meyer E. et al. Management of Paediatric Ulcerative Colitis, Part 2: Acute Severe Colitis; An Evidence-based Consensus Guideline from ECCO and ESPGHAN. J Pediatr Gastroenterol Nutr 2018; 1
• 48 Magro F, Peyrin-Biroulet L, Sokol H. et al. Extra-intestinal malignancies in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (III). J Crohns Colitis 2014; 8: 31-44
• 49 Barberio B, Gracie DJ, Black CJ. et al. Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn’s disease: systematic review and network meta-analysis. Gut 2023; 72: 264-274
• 50 Burr NE, Gracie DJ, Black CJ. et al. Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis. Gut 2022; 71: 1976-1987
• 51 Attauabi M, Steenholdt C, Poulsen A. et al. Network meta-analysis: Comparative onset of early effect of biologics and small molecules in moderately to severely active luminal Crohn’s disease. Aliment Pharmacol Ther 2024; 60: 124-143
• 52 Pichler J, Memaran N, Huber WD. et al. Golimumab in adolescents with Crohn’s disease refractory to previous tumour necrosis factor antibody. Acta Paediatr Oslo Nor 1992 2021; 110: 661-667
• 53 Merras-Salmio L, Kolho K. Golimumab Therapy in Six Patients With Severe Pediatric Onset Crohn Disease. J Pediatr Gastroenterol Nutr 2016; 63: 344-347
• 54 Feagan BG, Sandborn WJ, Gasink C. et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med 2016; 375: 1946-1960
• 55 Sandborn WJ, Gasink C, Gao LL. et al. Ustekinumab Induction and Maintenance Therapy in Refractory Crohn’s Disease. N Engl J Med 2012; 367: 1519-1528
• 56 Dayan JR, Dolinger M, Benkov K. et al. Real World Experience With Ustekinumab in Children and Young Adults at a Tertiary Care Pediatric Inflammatory Bowel Disease Center:. J Pediatr Gastroenterol Nutr 2019; 69: 61-67
• 57 Fang S, Zhang S, Zhang C. et al. Effectiveness and Safety of Ustekinumab for Pediatric Inflammatory Bowel Disease: A Systematic Review. Pediatr Drugs 2023; 25: 499-513
• 58 Yerushalmy-Feler A, Pujol-Muncunill G, Martin-de-Carpi J. et al. Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr 2022; 75: 717-723
• 59 Koudsi M, Martinez-Vinson C, Pigneur B. et al. Ustekinumab Use in Pediatric Inflammatory Bowel Disease: A French Multicenter Study From the Pediatric GETAID. J Pediatr Gastroenterol Nutr 2023; 76: 763-770
• 60 Turner D, Rosh JR, Cohen SA. et al. Ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: UniStar study long-term extension results. J Pediatr Gastroenterol Nutr 2024;
• 61 Pujol-Muncunill G, Navas-López VM, Ledder O. et al. STEP-CD study: ustekinumab use in paediatric Crohn’s disease-a multicentre retrospective study from paediatric IBD Porto group of ESPGHAN. Eur J Pediatr 2024;
• 62 Sedano R, Guizzetti L, McDonald C. et al. Clinical, Endoscopic, and Radiological Effectiveness of Ustekinumab in Bio-naïve Versus Bio-experienced Patients With Crohn’s Disease: Real-world Experience From a Large Canadian Center. Inflamm Bowel Dis 2023; 29: 866-874
• 63 Auth MKH, Ashton JJ, Jones KDJ. et al. Variation in access and prescription of vedolizumab and ustekinumab in paediatric patients with inflammatory bowel disease: a UK-wide study. Arch Dis Child 2023; 108: 994-998
• 64 Chavannes M, Martinez-Vinson C, Hart L. et al. Management of Paediatric Patients With Medically Refractory Crohn’s Disease Using Ustekinumab: A Multi-Centred Cohort Study. J Crohns Colitis 2019; 13: 578-584
• 65 Fang S, Zhang S, Zhang C. et al. Effectiveness and Safety of Ustekinumab for Pediatric Inflammatory Bowel Disease: A Systematic Review. Pediatr Drugs 2023; 25: 499-513
• 66 Rosh JR, Turner D, Griffiths A. et al. Ustekinumab in Paediatric Patients with Moderately to Severely Active Crohn’s Disease: Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study. J Crohns Colitis 2021; 15: 1931-1942
• 67 Takeuchi I, Arai K, Kyodo R. et al. Ustekinumab for children and adolescents with inflammatory bowel disease at a tertiary children’s hospital in Japan. J Gastroenterol Hepatol 2021; 36: 125-130
• 68 Dolinger MT, Rolfes P, Spencer E. et al. Outcomes of Children with Inflammatory Bowel Disease who Develop Anti-tumour Necrosis Factor-induced Skin Reactions. J Crohns Colitis 2022; 16: 1420-1427
• 69 Eriksson C, Söderling J, Karlqvist S. et al. Ustekinumab Versus Anti-tumour Necrosis Factor Alpha Agents as Second-Line Biologics in Crohn’s Disease. Dig Dis Sci 2023; 68: 3119-3128
• 70 Sandborn WJ, Feagan BG, Rutgeerts P. et al. Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med 2013; 369: 711-721
• 71 Atia O, Shavit-Brunschwig Z, Mould DR. et al. Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study. Lancet Gastroenterol Hepatol 2023; 8: 31-42
• 72 Fang S, Song Y, Zhang C. et al. Efficacy and safety of vedolizumab for pediatrics with inflammatory bowel disease: a systematic review. BMC Pediatr 2022; 22: 175
• 73 Garcia-Romero R, Martinez de Zabarte Fernandez JM, Pujol-Muncunill G. et al. Safety and effectiveness of vedolizumab in paediatric patients with inflammatory bowel disease: an observational multicentre Spanish study. Eur J Pediatr 2021; 180: 3029-3038
• 74 Hajjat TM, Mosha M, Whaley KG. et al. Vedolizumab Experience in Children and Adolescents With Inflammatory Bowel Disease: A Multicenter Observational Study. Crohns Colitis 360 2021; 3: otab039
• 75 Attauabi M, Madsen GR, Bendtsen F. et al. Vedolizumab as the first line of biologic therapy for ulcerative colitis and Crohn’s disease – a systematic review with meta-analysis. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver 2022; 54: 1168-1178
• 76 Patel H, Karam L, Kellermayer R. A Single-Center Study of Long-Term Effectiveness of Vedolizumab in Anti-TNF Refractory Pediatric Inflammatory Bowel Disease. JPGN Rep 2023; 4: e276
• 77 Hyams JS, Turner D, Cohen SA. et al. Pharmacokinetics, Safety and Efficacy of Intravenous Vedolizumab in Paediatric Patients with Ulcerative Colitis or Crohn’s Disease: Results from the Phase 2 HUBBLE Study. J Crohns Colitis 2022; 16: 1243-1254
• 78 Ledder O, Assa A, Levine A. et al. Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN. J Crohns Colitis 2017; 11: 1230-1237
• 79 Howard G, Weiner D, Bar-or I. et al. Dual biologic therapy with Vedolizumab and Ustekinumab for refractory Crohn’s disease in children. Eur J Gastroenterol Hepatol 2022; 34: 372-374
• 80 Conrad MA, Stein RE, Maxwell EC. et al. Vedolizumab Therapy in Severe Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22: 2425-2431
• 81 Colman RJ, Mizuno T, Fukushima K. et al. Real world population pharmacokinetic study in children and young adults with inflammatory bowel disease discovers novel blood and stool microbial predictors of vedolizumab clearance. Aliment Pharmacol Ther 2023; 57: 524-539
• 82 Jossen J, Kiernan BD, Pittman N. et al. Anti-tumor Necrosis Factor-alpha Exposure Impacts Vedolizumab Mucosal Healing Rates in Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2020; 70: 304-309
• 83 Schneider AM, Weghuber D, Hetzer B. et al. Vedolizumab use after failure of TNF-α antagonists in children and adolescents with inflammatory bowel disease. BMC Gastroenterol 2018; 18: 140
• 84 Shah P, McDonald D. Vedolizumab: An Emerging Treatment Option for Pediatric Inflammatory Bowel Disease. J Pediatr Pharmacol Ther 2021; 26: 795-801
• 85 Singh N, Rabizadeh S, Jossen J. et al. Multi-Center Experience of Vedolizumab Effectiveness in Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22: 2121-2126
• 86 Aardoom MA, Jongsma MME, De Vries A. et al. Vedolizumab Trough Levels in Children With Anti-Tumor Necrosis Factor Refractory Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2020; 71: 501-507
• 87 Yerushalmy-Feler A, Olbjorn C, Kolho KL. et al. Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2023; izad064
• 88 Kellar A, Dolinger MT, Spencer EA. et al. Real-World Outcomes of Dual Advanced Therapy in Children and Young Adults with Inflammatory Bowel Disease. Dig Dis Sci 2024; 69: 1826-1833
• 89 Wlazlo M, Meglicka M, Wiernicka A. et al. Combination biologic therapy in pediatric inflammatory bowel disease: Safety and efficacy over a minimum 12-month follow-up period. J Pediatr Gastroenterol Nutr 2024; 79: 54-61
• 90 Penagini F, Lonoce L, Abbattista L. et al. Dual biological therapy and small molecules in pediatric inflammatory bowel disease. Pharmacol Res 2023; 196: 106935
• 91 Yerushalmy-Feler A, Olbjorn C, Kolho KL. et al. Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2024; 30: 159-166
• 92 Hamel B, Wu M, Hamel EO. et al. Outcome of tacrolimus and vedolizumab after corticosteroid and anti-TNF failure in paediatric severe colitis. BMJ Open Gastroenterol 2018; 5: e000195
• 93 Yokoyama K, Yamamoto Y, Nambu R. et al. Safety and efficacy of vedolizumab in pediatric patients with ulcerative colitis: multicenter study in Japan. J Gastroenterol Hepatol 2023; 38: 1107-1115
• 94 Colombel JF, Schreiber S, D’Haens G. et al. Risankizumab Induction Therapy Achieves Early Symptom Improvements That Are Associated With Future Clinical and Endoscopic Outcomes in Crohn’s Disease: Post Hoc Analysis of the ADVANCE, MOTIVATE, and FORTIFY Phase 3 Studies. J Crohns Colitis 2024; 18: 818-827
• 95 Ferrante M, Irving PM, Abreu MT. et al. Maintenance Risankizumab Sustains Induction Response in Patients with Crohn’s Disease in a Randomized Phase 3 Trial. J Crohns Colitis 2024; 18: 416-423
• 96 Lusetti F, D’Amico F, Allocca M. et al. Positioning risankizumab in the treatment algorithm of moderate-to-severe Crohn’s disease. Immunotherapy 2024;
• 97 Peyrin-Biroulet L, Chapman JC, Colombel JF. et al. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease. N Engl J Med 2024; 391: 213-223
• 98 Kontaki E, Merchant A, Gaynor E. et al. Efficacy and safety of Upadacitinib in moderate to severe paediatric Crohn’s disease and ulcerative colitis in a tertiary Paediatric IBD (PIBD) centre – A case series Abstract P494. J Crohns Colitis 2024; 18: i986
• 99 Spencer E, Stein R, Shalem T. et al. Assa. Efficacy and safety of risankizumab in children with Crohn’s disease: A preliminary report – Abstract 775; ECCO. J Crohn Colitis 2024; 18: i1436
• 100 Loftus EV, Panés J, Lacerda AP. et al. Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med 2023; 388: 1966-1980
• 101 Spencer EA, Bergstein S, Dolinger M. et al. Single-center Experience With Upadacitinib for Adolescents With Refractory Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; izad300
• 102 Hyams JS, O’Brien CD, Padgett L. et al. Maintenance Golimumab Treatment in Pediatric UC Patients With Moderately to Severely Active UC: PURSUIT PEDS PK Long-Term Study Results. Crohns Colitis 360 2020; 2: otaa063
• 103 Hyams JS, Chan D, Adedokun OJ. et al. Subcutaneous Golimumab in Pediatric Ulcerative Colitis: Pharmacokinetics and Clinical Benefit. Inflamm Bowel Dis 2017; 23: 2227-2237
• 104 Tokita K, Shimizu H, Takeuchi I. et al. Long-Term Efficacy and Safety of Golimumab for Ulcerative Colitis in a Pediatric Inflammatory Bowel Disease Center in Japan. Pediatr Gastroenterol Hepatol Nutr 2022; 25: 461
• 105 Xu Y, Adedokun OJ, Chan D. et al. Population Pharmacokinetics and Exposure-Response Modeling Analyses of Golimumab in Children With Moderately to Severely Active Ulcerative Colitis. J Clin Pharmacol 2019; 59: 590-604
• 106 Barré A, Colombel J-F, Ungaro R. Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease. Aliment Pharmacol Ther 2018; 47: 896-905
• 107 Cohen S, Rolandsdotter H, Kolho KL. et al. Effectiveness and Safety of Ustekinumab in Pediatric Ulcerative Colitis: A Multi-center Retrospective Study from the Pediatric IBD Porto Group of ESPGHAN. Paediatr Drugs 2024;
• 108 Rehman R, Riaz MS, Esharif D. et al. Ustekinumab for anti-tumor necrosis factor refractory pediatric ulcerative colitis: a promising approach towards endoscopic healing. Intest Res 2024;
• 109 Dhaliwal J, McKay HE, Deslandres C. et al. One-year outcomes with ustekinumab therapy in infliximab-refractory paediatric ulcerative colitis: a multicentre prospective study. Aliment Pharmacol Ther 2021; 53: 1300-1308
• 110 Patel PV, Zhang A, Bhasuran B. et al. Real-world effectiveness of ustekinumab and vedolizumab in TNF-exposed pediatric patients with ulcerative colitis. J Pediatr Gastroenterol Nutr 2024; 78: 1126-1134
• 111 Dayan JR, Dolinger M, Benkov K. et al. Real World Experience With Ustekinumab in Children and Young Adults at a Tertiary Care Pediatric Inflammatory Bowel Disease Center:. J Pediatr Gastroenterol Nutr 2019; 69: 61-67
• 112 Peyrin-Biroulet L, Arkkila P, Armuzzi A. et al. Comparative efficacy and safety of subcutaneous infliximab and vedolizumab in patients with Crohn’s disease and ulcerative colitis included in randomised controlled trials. BMC Gastroenterol 2024; 24: 121
• 113 Sands BE, Peyrin-Biroulet L, Loftus EV. et al. Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N Engl J Med 2019; 381: 1215-1226
• 114 Sands BE, Peyrin-Biroulet L, Kierkus J. et al. Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn’s Disease. Gastroenterology 2022; 162: 495-508
• 115 D’Haens G, Higgins PDR, Peyrin-Biroulet L. et al. Extended Induction and Prognostic Indicators of Response in Patients Treated with Mirikizumab with Moderately to Severely Active Ulcerative Colitis in the LUCENT Trials. Inflamm Bowel Dis 2024; izae004
• 116 Danese S, Dignass A, Matsuoka K. et al. Early and Sustained Symptom Control with Mirikizumab in Patients with Ulcerative Colitis in the Phase 3 LUCENT Program. J Crohns Colitis 2024; jjae088
• 117 Sands BE, D’Haens G, Clemow DB. et al. Two-Year Efficacy and Safety of Mirikizumab Following 104 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study. Inflamm Bowel Dis 2024; izae024
• 118 Kaplan J, Bousvaros A, Turner D. et al. 781 PK, Efficacy and safety of Mirikizumab as induction therapy in pediatric patients with moderately to severely active ulcerative colitis: Results from the phase 2 SHINE-1 study. Gastroenterology 2023; 164: S-169
• 119 Dubinsky M, Kaplan J, Bousvaros A. et al. Efficacy and safety of Mirikizumab therapy in pediatric patients with moderate to severe ulcerativ colitis: Results from the phase 2 SHINE-1 study. 2024
• 120 Solitano V, Vuyyuru SK, MacDonald JK. et al. Efficacy and Safety of Advanced Oral Small Molecules for Inflammatory Bowel Disease: Systematic Review and Meta-Analysis. J Crohns Colitis 2023; 17: 1800-1816
• 121 Pantavou K, Yiallourou AI, Piovani D. et al. Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses. United Eur Gastroenterol J 2019; 7: 1285-1303
• 122 Yerushalmy-Feler A, Olbjorn C, Kolho KL. et al. Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2023; izad064
• 123 Alajmi R, Alabdulhadi M, Alali AA. et al. Tofacitinib for a Child with Refractory Steroid-Dependent Ulcerative Colitis: A Case Report and Review of the Literature. Am J Case Rep 2021; 22
• 124 Constant BD, Baldassano R, Kirsch J. et al. Tofacitinib Salvage Therapy for Children Hospitalized for Corticosteroid- and Biologic-Refractory Ulcerative Colitis. J Pediatr Gastroenterol Nutr 2022; 75: 724-730
• 125 Moore H, Dubes L, Fusillo S. et al. Tofacitinib Therapy in Children and Young Adults With Pediatric-onset Medically Refractory Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2021; 73: e57-e62
• 126 Ryan N, Cooper S, Dominik A. et al. Outcomes of Tofacitinib Use in an Irish Pediatric Cohort. JPGN Rep 2023; 4: e332
• 127 Ledder O, Dolinger M, Dubinsky MC. et al. Tofacitinib in Pediatric Ulcerative Colitis: A Retrospective Multicenter Experience. Inflamm Bowel Dis 2024; izae112
• 128 Costaguta GA, Girard C, Groleau V. et al. The Role of Tofacitinib in the Treatment of Acute Severe Colitis in Children. J Can Assoc Gastroenterol 2024; 7: 196-203
• 129 Dolinger MT, Spencer EA, Lai J. et al. Dual Biologic and Small Molecule Therapy for the Treatment of Refractory Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27: 1210-1214
• 130 Sandborn WJ, Feagan BG, D’Haens G. et al. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2021; 385: 1280-1291
• 131 Bencardino S, D’Amico F, Faggiani I. et al. Efficacy and Safety of S1P1 Receptor Modulator Drugs for Patients with Moderate-to-Severe Ulcerative Colitis. J Clin Med 2023; 12: 5014
• 132 Feagan BG, Sandborn WJ, Danese S. et al. Ozanimod induction therapy for patients with moderate to severe Crohn’s disease: a single-arm, phase 2, prospective observer-blinded endpoint study. Lancet Gastroenterol Hepatol 2020; 5: 819-828
• 133 Sands BE, D’Haens G, Panaccione R. et al. Ozanimod in Patients With Moderate to Severe Ulcerative Colitis Naive to Advanced Therapies. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 2024;
• 134 Sands BE, Schreiber S, Blumenstein I. et al. Clinician’s Guide to Using Ozanimod for the Treatment of Ulcerative Colitis. J Crohns Colitis 2023; 17: 2012-2025
• 135 Peyrin-Biroulet L, Dubinsky MC, Sands BE. et al. Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme. J Crohns Colitis 2024; jjae038
• 136 Sandborn WJ, Vermeire S, Peyrin-Biroulet L. et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. The Lancet 2023; 401: 1159-1171
• 137 Yarur AJ, Chiorean MV, Panés J. et al. Achievement of Clinical, Endoscopic, and Histological Outcomes in Patients with Ulcerative Colitis Treated with Etrasimod, and Association with Faecal Calprotectin and C-reactive Protein: Results From the Phase 2 OASIS Trial. J Crohns Colitis 2024; 18: 885-894
• 138 Balderramo D. Role of the combination of biologics and/or small molecules in the treatment of patients with inflammatory bowel disease. World J Gastroenterol 2022; 28: 6743-6751
• 139 Geem D, Kugathasan S. It Takes Two to Make It Right: Dual Biologic and Small Molecule Therapy for Treatment-Refractory Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27: 1361-1362
• 140 Gallagher J, Rosh JR, Sahn B. The Future of Advanced Therapies for Pediatric Crohn’s Disease. Pediatr Drugs 2023; 25: 621-633
• 141 Wlazło M, Meglicka M, Wiernicka A. et al. Dual Biologic Therapy in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Retrospective Study. Children 2022; 10: 11
• 142 van Rheenen H, van Rheenen PF. Long-Term Efficacy of Anti-Tumor Necrosis Factor Agents in Pediatric Luminal Crohn’s Disease: A Systematic Review of Real-World Evidence Studies. Pediatr Gastroenterol Hepatol Nutr 2020; 23: 121
• 143 Turner D, Ruemmele FM, Orlanski-Meyer E. et al. Management of Paediatric Ulcerative Colitis, Part 2: Acute Severe Colitis; An Evidence-based Consensus Guideline from ECCO and ESPGHAN. J Pediatr Gastroenterol Nutr 2018; 1
• 144 Cheifetz AS, Abreu MT, Afif W. et al. A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease. Am J Gastroenterol 2021; 116: 2014-2025
• 145 Jongsma MME, Winter DA, Huynh HQ. et al. Infliximab in young paediatric IBD patients: it is all about the dosing. Eur J Pediatr 2020; 179: 1935-1944
• 146 Assa A, Matar M, Turner D. et al. Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn’s Disease Compared With Reactive Monitoring. Gastroenterology 2019; 157: 985-996.e2
• 147 Rinawi F, Ricciuto A, Church PC. et al. Association of Early Postinduction Adalimumab Exposure With Subsequent Clinical and Biomarker Remission in Children with Crohn’s Disease. Inflamm Bowel Dis 2021; 27: 1079-1087
• 148 Kantasiripitak W, Wicha SG, Thomas D. et al. A Model-Based Tool for Guiding Infliximab Induction Dosing to Maximize Long-term Deep Remission in Children with Inflammatory Bowel Diseases. J Crohns Colitis 2023; 17: 896-908
• 149 Lawrence S, Faytrouni F, Harris RE. et al. Optimized Infliximab Induction Predicts Better Long-Term Clinical and Biomarker Outcomes Compared to Standard Induction Dosing. J Pediatr Gastroenterol Nutr 2022; 75: 601-607
• 150 Restellini S, Afif W. Update on TDM (Therapeutic Drug Monitoring) with Ustekinumab, Vedolizumab and Tofacitinib in Inflammatory Bowel Disease. J Clin Med 2021; 10: 1242
• 151 Atia O, Shavit-Brunschwig Z, Mould DR. et al. Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study. Lancet Gastroenterol Hepatol 2023; 8: 31-42
• 152 Yerushalmy-Feler A, Pujol-Muncunill G, Martin-de-Carpi J. et al. Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr 2022; 75: 717-723
• 153 Moore H, Dubes L, Fusillo S. et al. Tofacitinib Therapy in Children and Young Adults With Pediatric-onset Medically Refractory Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2021; 73: e57-e62