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Drug therapy
Original article
Anti-TNF therapy for paediatric IBD: the Scottish national experience
  1. F L Cameron1,
  2. M L Wilson1,
  3. N Basheer1,
  4. A Jamison2,
  5. P McGrogan3,
  6. W M Bisset4,
  7. P M Gillett5,
  8. R K Russell3,
  9. D C Wilson1,5
  1. 1Child Life and Health, University of Edinburgh, Edinburgh, UK
  2. 2University of Glasgow, Glasgow, UK
  3. 3Department of Paediatric Gastroenterology, Royal Hospital for Sick Children, Glasgow, UK
  4. 4Department of Paediatric Gastroenterology, Royal Aberdeen Children's Hospital, Aberdeen, UK
  5. 5Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK
  1. Correspondence to Dr David C Wilson, Department of Paediatric Gastroenterology and Nutrition, Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, 20 Sylvan Place, Edinburgh EH9 1UW, UK; d.c.wilson{at}ed.ac.uk

Abstract

Background and aims Biological agents are being increasingly used in the UK for paediatric-onset inflammatory bowel disease (PIBD) despite limited evidence and safety concerns. We evaluated effectiveness and safety in the clinical setting, highlighting drug cost pressures, using our national Scottish PIBD biological registry.

Methods Complete usage of the biological agents, infliximab (IFX) and adalimumab (ADA) for treatment of PIBD (in those aged <18 years) from 1 January 2000 to 30 September 2010 was collated from all treatments administered within the Scottish Paediatric Gastroenterology, Hepatology and Nutrition (PGHAN) national managed service network (all regional PGHAN centres and paediatric units within their associated district general hospitals).

Results 132 children had biological therapy; 24 required both agents; 114 had Crohn's disease (CD), 16 had ulcerative colitis (UC) and 2 had IBD Unclassified (IBDU). 127 children received IFX to induce remission; 61 entered remission, 49 had partial response and 17 had no response. 72 were given maintenance IFX and 23 required dose escalation. 18 had infusion reactions and 27 had adverse events (infections/other adverse events). 29 had ADA to induce remission (28 CD and 1 UC), 24 after IFX; 10 entered remission, 12 had partial response and 7 had no response. All had maintenance; 19 required dose escalation. 12 children overall required hospitalisation due to drug toxicity. No deaths occurred with either IFX or ADA.

Conclusions Complete accrual of the Scottish nationwide ‘real-life’ experience demonstrates moderate effectiveness of anti tumour necrosis factor agents in severe PIBD but duration of effect is limited; significant financial issues (drug cost—need for dose escalation and/or multiple biological usage) and safety issues exist.

  • Gastroenterology
  • Therapeutics
  • Paediatric Practice

https://doi.org/10.1136/archdischild-2013-305812

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    What is already known on this topic?

    • Anti tumour necrosis factor (TNF) biologicals are effective in the induction and maintenance of remission in paediatric Crohn's disease and for induction of remission in paediatric ulcerative colitis.

    • Anti-TNF biological usage is increasing in the UK and worldwide.

    • Side effects are seen in 15% cases, but most are not serious.

    What this study adds?

    • In a population-based nationwide study with accrual of all patients with inflammatory bowel disease (IBD) (Crohn's disease, ulcerative colitis and IBD unclassified (IBDU)), infliximab (IFX) induced remission in 48% of patients.

    • A significant number of patients require dose escalation (32% and 66% on maintenance IFX and adalimumab) and/or 2nd biological usage (18%), which together have significant drug cost implications.

    • 9% of patients with paediatric-onset IBD exposed to antiTNF biologicals required hospitalisation in this 11-year Scottish population-based cohort study.

    Introduction

    Inflammatory bowel disease (IBD) comprises Crohn’s disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBDU). Paediatric-onset IBD (PIBD) is a lifelong disorder, more extensive at diagnosis, followed by more dynamic early progression than adult-onset IBD.1 Scotland has the highest PIBD incidence rate in the UK, and incidence continues to rise.2 ,3

    Usage of biological therapy in PIBD is increasing worldwide with infliximab (IFX) (Remicade, MSD) and adalimumab (ADA) (Humira, Abbvie) licensed for PIBD use in the UK. Despite widespread usage, no complete nationwide data exist as the UK PIBD audit, a national report on biological therapy, had incomplete reporting both within and among UK PIBD centres.4 Safety concerns regarding biologicals include infusion reactions, reactivation of latent tuberculosis, infections, neurological sequelae including demyelination5 ,6 and cancer—notably, the rare but usually fatal hepatosplenic T-cell lymphoma.7

    IFX, the first tumour necrosis factor-alpha (TNF-α) antagonist8 gained UK licences for adult and paediatric CD in 2002 and 2010, respectively,9 ,10 having been used off-licence from the late 1990s11 prior to randomised controlled trials (RCTs) in PIBD12–14 given available high-quality evidence for IFX use in adult IBD.15 ,16 ADA, a humanised anti-TNFα, effectively induces and maintains remission in adult CD and UC.17–21 Efficacy was confirmed by RCT in paediatric CD in 201222 with prior widespread off-licence experience reported via UK audit;23 ADA was licensed for UK paediatric CD use in 2013.

    The aim of this Scottish nationwide cohort study over the first decade of biological usage was to evaluate effectiveness, safety and drug cost pressures.

    Methods

    Data was gathered from the three regional Paediatric Gastroenterology, Hepatology and Nutrition (PGHAN)-shared care networks (west, southeast and north of Scotland,) involving all four tertiary PGHAN centres (Glasgow, Edinburgh, Dundee and Aberdeen) and all paediatric units in district general hospitals, which form a Scottish PGHAN-managed service network, covering all patients with PIBD in paediatric services. The Scottish population on 30 June 2010 was 5 222 100, with 1 037 839 (19.9%) aged <18 years (http://www.gro-scotland.gov.uk/statistics/theme/population/estimates/mid-year/archive/2010/tables.html).

    Patients—All patients with PIBD within paediatric services were included if aged <18 years at start of biological therapy from 1 January 2000 to 30 September 2010, with 10 weeks minimum follow-up. Patients were identified using PGHAN department-held records and databases (prospective and/or retrospective), pharmacy lists, nurse practitioner records and case-note review. We excluded patients whose main reason for biological therapy was not primarily IBD (eg, arthritis or uveitis).

    Drug administration—IFX induction dosing was 5 mg/kg at 0, 2 and 6 weeks. Prior to 2006, some received episodic IFX dosing (as required, unscheduled) following induction. Maintenance IFX was 5 mg/kg administered 8-weekly; dose escalation (increased dose and/or shortened frequency of dosing) and de-escalation occurred. ADA induction comprised two doses (160 mg/80 mg, 80 mg/40 mg, 40/20 mg or 24 mg/m2) followed by fortnightly maintenance dosing (80 mg, 40 mg, 20 mg or 24 mg/m2); dose escalation and de-escalation occurred.

    Data collection and ethics—Not all centres maintained prospective databases, so data was collected periodically via proforma and entered on the Scottish PIBD biological registry database (held in the University of Edinburgh). All entries were reviewed for accuracy and completeness by the senior investigator (DCW). Demographic information included disease phenotype;24 biological schedule and regimen (induction only; induction-episodic; induction-episodic-maintenance; induction-maintenance); medications (including steroids, thiopurines and methotrexate) and surgery before, at and after biological start. Response to treatment by IFX/ADA was divided into steroid-free remission, remission, partial response, loss of response and no response. Physician global assessment (PGA) was assessed through history, clinical examination, anthropometry and laboratory values after induction treatment. Remission was defined as improvement to inactive disease,25 partial response as improved symptoms, but continuing disease activity, and loss of response where initial remission required later surgery or anti-TNF withdrawal during maintenance, and switch to another medication, including second anti-TNF agent.26 The Paediatric Ulcerative Colitis Activity Index and the Paediatric Crohn's Disease Activity Index were recorded at defined timepoints in some;27 ,28 PGA was collected and defined as remission, mild and moderate/severe disease activity for all.

    Data were collected at study end (31 December 2010; transition to adult services; emigration from Scotland). Acute infusion reactions occurred during or within one hour of infusion stopping. All serious adverse events (resulting in hospitalisation during or within 90 days of stopping treatment, prolonged hospitalisation, life-threatening or death) and adverse events, which investigators thought possibly related to biological therapy, were recorded.

    Steroid dependency was defined as inability to wean steroids despite continuous therapy/rapid recommencement after weaning within 16 weeks; steroid resistance as no clinical effect despite high doses. Thiopurine (azathioprine or mercaptopurine) and methotrexate intolerance occurred when reproducible symptoms (eg, headache, nausea, fatigue) led to discontinuation. Thiopurine and methotrexate resistance were defined as lack of clinical response despite 16 weeks of therapy; loss of response was when initial remission was lost despite possible dose escalation.

    Statistics

    Descriptive statistics were median (range) for non-parametric continuous results and number (%) for categories. Twelve-month CD remission rate was compared with duration of illness and immunomodulator use at baseline by χ2 analysis, significance defined as p<0.05 using SPSS V.19 IBM.

    Results

    All patients with IBD receiving anti-TNF agents (IFX and ADA)

    One hundred and thirty-two patients with PIBD were given biologicals from 1 January 2000 to 30 September 2010: 127 patients IFX and 29 ADA (tables 1⇓⇓–4); 24 patients received ADA post-IFX and 5 as initial therapy. Fifty-five were female, 114 had CD, 16 had UC and two had IBDU. IBD was diagnosed at 11.3 (2.7–17.2) years, and first biological received at 2.5 (0.02–11.4) years postdiagnosis at 13.9 (5.9–17.6) years. Prior to corticosteroids, thiopurine and methotrexate had been received by 114, 108 and 44 patients, respectively.

    View this table:
    Table 1

    Baseline characteristics of 127 patients requiring infliximab (IFX); results are expressed as median (range)

    View this table:
    Table 2

    Response to infliximab (IFX) postinduction and surgical procedures

    View this table:
    Table 3

    Adalimumab (ADA) in inflammatory bowel disease (IBD): Baseline characteristics of patients with IBD on ADA

    View this table:
    Table 4

    Response and outcome postinduction to adalimumab (ADA) and surgical procedures

    Details of all patients receiving IFX

    One hundred and twenty-seven children commenced IFX at 14.0 (5.96–17.6) years, 2.51 (0.02–11.4) years postdiagnosis at 11.2 (2.72–17.2) years; 51 were female (table 1). They received 5 (1–22) doses over 1.92 (0.21–6.77) years of follow-up, a cumulative national total of 803 doses over 291 patient-years follow-up. Prior corticosteroids, thiopurine and methotrexate had been received by 109, 106 and 39, respectively. Postinduction, 61 were in remission, 49 had partial response and 17 had no response (table 2). Nine patients with CD started episodic dosing in 2000–2005 (last episodic dose 2007); 1 had maintenance therapy. Seventy-two commenced maintenance IFX and 12 more entered remission, so overall, 73 gained remission after 3 (1–9) doses.

    Safety (table 5, see online supplementary table S1)—Eighteen (all CD) had 19 acute infusion reactions. There were 17 infections, serious with hospital admission (2–21 days) in six. Ten patients required hospitalisation—one with a severe lupus-like reaction who needed intensive care.

    View this table:
    Table 5

    Toxicity while on infliximab requiring hospitalisation

    IFX use in CD—One hundred and nine patients with CD commenced IFX (table 1). Forty-eight had perianal disease, 50 had growth delay and 30 pubertal delay. Table 2 shows postinduction outcome; 61% were weaned off steroids and five discontinued IFX for allergic response/adverse event.

    Sixty-five progressed to maintenance IFX; five more attained remission, so totally, 56 gained remission after 3 (1–9) doses. Ten (15%) stopped IFX in remission as a ‘long drug holiday’; five were withdrawn after IFX bridge to remission with planned conversion to immunomodulator monotherapy, four were withdrawn after a lengthy remission (treatment goals achieved) and one was withdrawn after planned bridge to surgery. Twenty-six (40%) subsequently discontinued IFX after a median of 0.83 (0.3–2.8) years—15 for loss of response (only 10 having a trial of drug optimisation), 7 primary non-response despite starting maintenance as a partial responder and 2 each after severe allergic or adverse events. Twenty-nine (45%) patients remained on IFX after 0.92 (0.21–4.2) years at study end; 18 were in remission, with 26 on coimmunosuppression.

    Twenty-two required dose escalation; 15 had shortened infusion schedule—shortest frequencies of 7 weeks (n=7), 6 weeks (6), 5 weeks (1) and 4 weeks (1). Fourteen subsequently discontinued—11 loss of response, 2 primary non-response and 1 planned withdrawal. Three had lengthened schedule to 12 weeks, with one each having sustained remission, then a long drug holiday, continuing at study end, and reversion to 8-weekly. Fifteen had increased dose: 8 increased dose and frequency and 7 increased dose alone. Maximum doses were 10 mg/kg (n=11), 7 mg/kg (2) and 6.5 mg/kg (2). Forty-one patients underwent surgery either pre-IFX or post-IFX (table 2).

    Eighty-five had a 12-month follow-up, with no significant difference between 12-month remission and baseline coimmunomodulation (p=0.16); 34/78 with and 5/7 without baseline immunomodulation were in remission. There was no significant association between 12-month remission rate between 45 who had CD duration ≥2 years at first IFX versus 20 with disease duration <2 years (p=0.47), with 19/45 and 20/40 in remission.

    IFX use in UC—Sixteen patients with UC received IFX, 9 progressing to surgery (table 2), 1 had IFX as a bridge to immunosuppression. Seven had maintenance IFX: 1 continuing IFX in remission and 6 discontinuing (1 primary non-response after partial response, 2 loss of response (1 dose increase to 10 mg/kg) and 3 planned withdrawals in sustained remission) by study end.

    IFX use in IBDU—Two patients required IFX for acute severe colitis (tables 1 and 2): one a failed attempt to prevent colectomy and the other a non-responder after IFX bridge to azathioprine, but subsequent prolonged remission on azathioprine monotherapy; neither had maintenance.

    Details of all patients requiring ADA

    Twenty-nine patients aged 13.8 (6.8–17.2) years received ADA, diagnosed at 10.9 (4.9–14.9) years; 28 had CD and 1 UC, 17 were male (table 3). Twenty-four had previously received IFX. One family of a child with moderate–severe UC and prior IFX loss of response refused colectomy, so received ADA (tables 3 and 4) with colectomy after primary non-response despite dose escalation (dose and frequency). All had maintenance, receiving 29 (8–93) doses over 1.15 (0.24–2.6) years follow-up, a cumulative national total of 964 doses over 44.9 patient-years follow-up.

    Safety (table 6)—Nine had adverse effects, minor, except for two hospitalisations (1 perianal abscess, 1 Clostridium difficile infection).

    View this table:
    Table 6

    Adverse events to adalimumab (ADA)

    ADA use in CD—Ten gained remission postinduction (table 4) and 14/18 on maintenance after 0.35 (0.10–0.65) years, totalling 24 achieving remission. Eighteen required dose escalation—3 increased dosage to 80 mg and 15 increased to weekly dosing (2/15 increased frequency and dose), with seven reversing escalation. Six discontinued ADA after 0.96 (0.31–1.5) years: 2 primary non-response, 3 loss of response and 1 planned withdrawal. Twenty-two continued ADA after 1.28 (0.30–2.6) years at study end and 17 in remission (13 on coimmunosuppression). Eight of 11 (73%) patients with CD with primary IFX non-response gained remission on second biological compared with 11 of 12 (92%) with loss of IFX response. Twelve patients underwent surgery (table 4).

    Twenty were followed-up at 12 months, with no significant difference between 12-month remission (n=11) and baseline coimmunomodulation (n=15) (p=0.79): 8/15 with and 3/5 without baseline immunomodulation in remission. There was no significant association between 12-month remission rate between 15 who had CD duration ≥2 years at first ADA versus 5 with disease duration <2 years (p=0.22), with 7/15 and 4/5 in remission.

    Discussion

    Effectiveness, safety and cost-relevant data are vital when monoclonal antibodies are introduced for common, chronic and currently incurable diseases of childhood/adult life; IBD is an excellent exemplar. Pivotal RCTs are vital evidence of efficacy, but often may not reflect evolving ‘real-life’ clinical practice, so comprehensive outcome data from treatment registries help inform service design, delineate cost pressures and provide effectiveness and safety information for policy makers, clinicians, patients and families. Unlike other publications, we included patients of all PIBD subtypes and both IFX and ADA usage, fully reflecting current clinical practice. This is the only large UK population-based (region of UK or one of the four UK nations) study of biological therapy in PIBD. The only other full national PIBD biological experiences reported have been from Denmark29 and The Netherlands,30 both on IFX usage in CD alone. The largest population-based regional studies are from Northern France and Toronto, Canada, again only IFX for CD.31 ,32

    Effectiveness—IFX and ADA were moderately effective in inducing remission during ‘real-life’ usage, with remission rates of 48% and 36% for IFX (10–12 weeks) and ADA (4 weeks), respectively; 57% and 75% in total gained remission after medians of three IFX and two ADA doses. Although our CD postinduction rates of 48% with IFX and 36% of ADA are low when compared with published rates of 34%–85%8 and 61%–70%,23–25 respectively, our 12-month CD remission rates of 40% for IFX and 45% for ADA compare with published rates of 25%–83%8 and 41%–49%.23–25 A worrying result is the lack of durable response for many on CD maintenance IFX therapy; 40% discontinued for primary non-response/loss of response/adverse effects after a median of 0.83 years. Reasons for lower effectiveness from our multicentre 11-year nationwide study with full accrual compared with some published literature, include that anti-TNF may have been used more liberally in some centres (thus, better effectiveness rates) than real-life UK practice, where local prescribing restraints and national advice led to a clear top-up policy in everyday practice, only progressing to biologicals if all other therapies failed or became inappropriate. Ability to dose-escalate (immediately increasing drug cost) to reverse loss of response has previously been difficult in many UK centres compared with others worldwide—dose optimisation to prevent complete loss of response was used in 50% of patients with CD treated with IFX in Toronto from 2000 to 2011.32 Most studies arise from single academic centres, rather than population-based, therefore, are subject to referral biases, potentially treating more patients of severe disease, or having more liberal anti-TNF strategies. Our retrospective study contains data from 2000 onwards, reflecting how IFX/ADA were first used, with only some Scottish centres early adopters of strategies now seen as routine for biological therapy (eg, maintenance rather than episodic IFX dosing in 2000–2005, induction dosing followed by some maintenance treatment when bridging to immunosuppression, strong evidence of prolonged ‘deep remission’ on biological prior to planned treatment withdrawal and dose optimisation to rescue loss of response).

    Cost pressures—34% of Scottish CD on maintenance IFX required dose intensification, effective in 41%. In trials or cohort studies using 8-weekly infusions, dose intensification was 11%–50%.12 ,31–33 Sixty six per cent of Scottish patients with ADA required dose escalation compared with 25% seen in the RESEAT25 study and 35% in the UK/Irish audit.23 Within 132 PIBD cases, 18% required second biological, all ADA post-IFX. Significant cost implications on pharmacy budgets exist, with many patients requiring dose escalation and/or a second biological agent; the counter-argument is that dose optimisation prevents complete loss of response, improves patient quality of life, reduces expensive endoscopic/radiological reassessments and prevents hospitalisation—all much harder cost pressures to identify as they will not be captured as single budget items.

    Safety—Neither deaths nor malignancy occurred. IFX infusion reactions occurred in 17%, with 15% in multiple pooled studies.8 Serious infections occurred in 3% of cases, similar to pooled studies at 3.3%;8 11 (9%) required hospitalisation due to IFX toxicity. ADA was well tolerated, with 2 (7%) hospitalised for toxicity but mostly minor side effects, although serious infections of 3% were noted in other studies.8

    We demonstrate that biologicals are moderately effective in PIBD management, but many have limited duration of effect. We confirm known safety signals without new types of adverse effect or deaths and highlight drug cost issues. With limitations in durable effectiveness, new classes of biological agents are urgently required for children intolerant or completely losing response to anti-TNF. Study weaknesses include inability to enumerate those aged <18 years managed with biologicals in adult services, plus retrospective data accrual in one network. Full evaluation of the role of biologicals in PIBD requires prospective registries with accrual of all patients receiving all these agents.

    Acknowledgments

    We are grateful for the help and support provided by all the clinical teams within the Scottish Paediatric Gastroenterology, Hepatology and Nutrition national managed clinical network, and in particular, wish to thank Karen Fraser, Pam Rogers, Dr Gamal Mahdi, Karen McIntyre, Dr David Goudie, Rae Urquhart and Carol Cameron.

    References

    1. ↵
      1. Van Limbergen J,
      2. Russell RK,
      3. Drummond HE, et al
      . Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008;135:1114–22. doi:10.1053/j.gastro.2008.06.081
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Henderson P,
      2. Hansen R,
      3. Cameron FL, et al
      . Rising incidence of pediatric inflammatory bowel disease in Scotland. Inflamm Bowel Dis 2011;18:999–1005. doi:10.1002/ibd.21797
      OpenUrlPubMed
    3. ↵
      1. Sawczenko A,
      2. Sandhu BK
      . Presenting features of inflammatory bowel disease in Great Britain and Ireland. Br Med J 2003;88:995–1000.
      OpenUrl
    4. ↵
      Physicians RCo. Biological therapies audit sub group. National clinical audit report of biological therapies. Paediatric national report. UK IBD audit. London: Royal College of Physicians, 2013.
    5. ↵
      1. Zamvar V,
      2. Sugarman ID,
      3. Tawfik RF, et al
      . Posterior reversible encephalopathy syndrome following infliximab infusion. J Pediatr Gastroenterol Nutr 2009;48:102–5. doi:10.1097/MPG.0b013e31818aedb4
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Haddock R,
      2. Garrick V,
      3. Horrocks I, et al
      . A case of posterior reversible encephalopathy syndrome in a child with Crohn's disease treated with Infliximab. J Crohn's Colitis 2011;5:623–7. doi:10.1016/j.crohns.2011.06.011
      OpenUrlAbstract/FREE Full Text
    7. ↵
      1. Mackey AC,
      2. Green L,
      3. Liang L, et al
      . Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007;44:265–7. doi:10.1097/MPG.0b013e31802f6424
      OpenUrlCrossRefPubMed
    8. ↵
      1. de Bie CI,
      2. Escher JC,
      3. de Ridder L
      . Antitumor necrosis factor treatment for pediatric inflammatory bowel disease. Inflamm Bowel Dis 2012;18:985–1002. doi:10.1002/ibd.21871
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      National Institute for Clinical E. Guidance on the use of infliximab for Crohn's disease. NICE 2002(1):40.
    10. ↵
      Nice. Infliximab (review) and adalimumab for the treatment of Crohn's disease. NICE technology appraisal guidance 187 2010.
    11. ↵
      1. Wilson DC,
      2. Thomas AG,
      3. Croft NM, et al
      . Systematic review of the evidence base for the medical treatment of paediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2010;50:S14–34. doi:10.1097/MPG.0b013e3181c92caa
      OpenUrlCrossRefPubMed
    12. ↵
      1. Hyams J,
      2. Crandall W,
      3. Kugathasan S, et al
      . Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology 2007;132:863–73. doi:10.1053/j.gastro.2006.12.003
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Hyams J,
      2. Damaraju L,
      3. Blank M, et al
      . Induction and maintenance therapy with infliximab for children with moderate-to-severe ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:391–9. doi:10.1016/j.cgh.2011.11.026
      OpenUrlCrossRefPubMed
    14. ↵
      1. Ruemmele FM,
      2. Lachaux A,
      3. Cézard JP, et al
      . Efficacy of infliximab in pediatric Crohn's disease: a randomized multicenter open-label trial comparing scheduled to on demand maintenance therapy. Inflamm Bowel Dis 2009;15:388–94. doi:10.1002/ibd.20788
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Rutgeerts P,
      2. Sandborn WJ,
      3. Feagan BG, et al
      . Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76. doi:10.1056/NEJMoa050516
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Hanauer SB,
      2. Feagan BG,
      3. Lichtenstein GR, et al
      . Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9. doi:10.1016/S0140-6736(02)08512-4
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      1. Hanauer SB,
      2. Sandborn WJ,
      3. Rutgeerts P, et al
      . Human anti–tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I Trial. Gastroenterology 2006;130:323–33. doi:10.1053/j.gastro.2005.11.030
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Reinisch W,
      2. Sandborn WJ,
      3. Hommes DW, et al
      . Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011;60:780–7. doi:10.1136/gut.2010.221127
      OpenUrlAbstract/FREE Full Text
    19. ↵
      1. Sandborn WJ,
      2. Rutgeerts P,
      3. Enns R, et al
      . Adalimumab induction therapy for Crohn disease previously treated with infliximab a randomized trial. Ann Intern Med 2007;146:829–38. doi:10.7326/0003-4819-146-12-200706190-00159
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Colombel JF,
      2. Sandborn WJ,
      3. Rutgeerts P, et al
      . Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007;132:52–65. doi:10.1053/j.gastro.2006.11.041
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. McDermott E,
      2. Murphy S,
      3. Keegan D, et al
      . Efficacy of adalimumab as a long term maintenance therapy in ulcerative colitis. J Crohn's Colitis 2013;7:150–3. doi:10.1016/j.crohns.2012.03.016
      OpenUrlAbstract/FREE Full Text
    22. ↵
      1. Hyams JS,
      2. Griffiths A,
      3. Markowitz J, et al
      . Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. Gastroenterology 2012;143:365–74. e2. doi:10.1053/j.gastro.2012.04.046
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Russell RK,
      2. Wilson ML,
      3. Loganathan S, et al
      . A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease. Aliment Pharmacol Ther 2011;33:946–53. doi:10.1111/j.1365-2036.2011.04603.x
      OpenUrlCrossRefPubMed
    24. ↵
      1. Silverberg MS,
      2. Satsangi J,
      3. Ahmad T, et al
      . Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005;19(Suppl A):5–36.
      OpenUrlPubMed
    25. ↵
      1. Rosh JR,
      2. Lerer T,
      3. Markowitz J, et al
      . Retrospective Evaluation of the Safety and Effect of Adalimumab Therapy (RESEAT) in pediatric Crohn's disease. Am J Gastroenterol 2009;104:3042–9. doi:10.1038/ajg.2009.493
      OpenUrlCrossRefPubMed
    26. ↵
      1. De Bie CI,
      2. Hummel TZ,
      3. Kindermann A, et al
      . The duration of effect of infliximab maintenance treatment in paediatric Crohn's disease is limited. Aliment Pharmacol Ther 2011;33:243–50. doi:10.1111/j.1365-2036.2010.04507.x
      OpenUrlCrossRefPubMed
    27. ↵
      1. Hyams JS,
      2. Ferry GD,
      3. Mandel FS, et al
      . Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr 1991;12:439–47.
      OpenUrlPubMedWeb of Science
    28. ↵
      1. Turner D,
      2. Otley AR,
      3. Mack D, et al
      . Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007;133:423–32. doi:10.1053/j.gastro.2007.05.029
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Wewer V,
      2. Riis L,
      3. Vind I, et al
      . Infliximab dependency in a national cohort of children with Crohn's disease. J Pediatr Gastroenterol Nutr 2006;42:40–5. doi:10.1097/01.mpg.0000189137.06151.33
      OpenUrlCrossRefPubMed
    30. ↵
      1. de Ridder L,
      2. Benninga MA,
      3. Taminiau JAJM, et al
      . Infliximab use in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007;45:3–14. doi:10.1097/MPG.0b013e31803e171c
      OpenUrlCrossRefPubMed
    31. ↵
      1. Crombé V,
      2. Salleron J,
      3. Savoye G, et al
      . Long-term outcome of treatment with infliximab in pediatric-onset Crohn's disease: a population-based study. Inflamm Bowel Dis 2011;17:2144–52. doi:10.1002/ibd.21615
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Church PC,
      2. Guan J,
      3. Walters TD, et al
      . Infliximab maintains durable response and facilitates catch-up growth in luminal pediatric Crohn's disease. Inflamm Bowel Dis 2014;20:1177–86. doi:10.1097/MIB.0000000000000083
      OpenUrlCrossRefPubMed
    33. ↵
      1. Assa A,
      2. Hartman C,
      3. Weiss B, et al
      . Long-term outcome of tumor necrosis factor alpha antagonist's treatment in pediatric Crohn's disease. J Crohn's Colitis 2013;7:369–76. doi:10.1016/j.crohns.2012.03.006
      OpenUrlAbstract/FREE Full Text

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    • Supplementary Data

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    Footnotes

    • Contributors FLC, NB, AJ and DCW collected the data. DCW reviewed the proformas from all centres for completeness and sense checking. MLW and FLC entered data onto a spreadsheet, then FLC performed analysis including statistical analysis. FLC and DCW prepared the manuscript, and all other authors contributed to the review of the manuscript and adaption for publication. DCW is the guarantor of the publication.

    • Funding FLC is generously funded by a CICRA Research Training Fellowship. This work was supported by the GI-Nutrition Research fund, University of Edinburgh, and the Catherine MacEwen Foundation, Glasgow, and by CICRA. MLW and RKR are principal and coinvestigators for PICTS (Paediatric IBD Cohort and Treatment Study) funded by the Medical Research Council (G0800675). RKR is supported by a NRS Career Research Fellowship.

    • Competing interests FLC has received speaker's fees from MSD. MLW is partly supported by an investigator-initiated grant award from MSD. WMB has received consultation fees from MSD. RKR has received consultation fees, speaker's fees, meeting attendance support or research support from MSD, Ferring, Janssen—Cilag, Dr Falk and Nestle. DCW has received consultation fees, speaker's fees, meeting attendance support or research support from MSD, Dr Falk, Ferring, Pfizer and Nestle. PM has received consultation fees, speaker fees, meeting attendance support or research support from MSD, Dr Falk, Ferring and Nestle. PMG, NB and AJ have no conflicting interests.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Any data requests to Professor DC Wilson, lead for Scottish PIBD biologicals registry.

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