Journal of Pediatric Gastroenterology and Nutrition, Publish Ahead of Print

DOI : 10.1097/MPG.0000000000002035

Management of paediatric ulcerative colitis, Part 1: ambulatory care- an evidence-based

guideline from ECCO and ESPGHAN

Dan Turner MD PhD1, Frank M. Ruemmele MD PhD2, Esther Orlanski-Meyer MD1,

Anne M. Griffiths MD3, Javier Martin de Carpi MD4, Jiri Bronsky MD PhD5,

Gabor Veres MD PhD6, Marina Aloi MD PhD7, Caterina Strisciuglio MD PhD 8,

Christian P. Braegger MD 9, Amit Assa MD10, Claudio Romano MD11,

Séamus Hussey MB FRCPI 12, Michael Stanton MD13, Mikko Pakarinen MD14,

Lissy de Ridder MD PhD 15, Konstantinos Katsanos MD16, Nick Croft MD PhD17,

Victor Navas-López MD18, David C. Wilson MD19, Sally Lawrence MD20,

Richard K. Russell MD PhD21

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

*ALL AUTHORS CONTRIBUTED EQUALLY

1
Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel;

2
Université Paris Descartes, Sorbonne Paris Cité, APHP, Hôpital Necker Enfants Malades,

Paris, France;

3
The Hospital for Sick Children, University of Toronto, Canada

4
Hospital Sant Joan de Déu, Barcelona, Spain;

5
Department of Paediatrics, University Hospital Motol, Prague, Czech Republic;

6
Ist Dept. of Pediatrics, Semmelweis University, Budapest, Hungary;

7
Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Italy

8
Department of Woman, Child and General and Specialistic Surgery, University of Campania

“Luigi

Vanvitelli”, Napoli, Italy

9
University Children’s Hospital, Zurich, Switzerland

10
Schneider Children's Hospital, Petach Tikva, affiliated to the Sackler Faculty of Medicine, Tel

Aviv University, Israel

11
Pediatric Department, University of Messina, Italy

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

12
National Children’s Research Centre, Royal College of Surgeons of Ireland and University

College Dublin, Ireland;

13
Southampton Children’s Hospital, UK ;

14
Helsinki University Children’s Hospital, Department of Pediatric Surgery, Helsinki, Finland;

15
Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands;

16
University of Ioannina School of Medical Sciences

Ioannina, Greece

17
Barts and the London School of Medicine, Queen Mary University of London, UK;

18
Pediatric Gastroenterology and Nutrition Unit. Hospital Materno. IBIMA. Málaga, Spain

19
Child Life and Health, University of Edinburgh, UK

20
BC Children’s Hospital, University of British Columbia, Vancouver BC, Canada

21
The Royal Hospital for Children, Glasgow, UK;

Funding: European Crohn's and Colitis Organization (ECCO) and the European Society for

Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Conflict of interests

DT- last 3 years received consultation fee, research grant, royalties, or honorarium from Janssen,

Pfizer, Hospital for Sick Children (PUCAI royalties from industry trials), Ferring, AstraZeneca,

Abbvie, Takeda, Ferring, Boehringer Ingelheim, Biogen, Atlantic Health, Shire, Celgene

JMdC-last 3 years received consultation fee, research grant, travel grant, or honorarium from

Abbvie, Abbot, Nestle, MSD, Otsuka, Faes, Nutricia, Fresenius

JB received honoraria, speaker’s fees and/or congress fees from AbbVie, MSD, Nestle, Nutricia

and Biocodex.

GV- received consultation fee from Nestle, Danone and Abbvie.

MA last 3 years received honorarium from AbbVie

FMR received speaker fees from: Schering-Plough, Nestlé, Mead Johnson, Ferring, MSD,

Johnson & Johnson, Centocor, AbbVie; serves as a board member for: SAC:DEVELOP

(Johnson & Johnson), CAPE (ABBVIE), LEA (ABBVIE) and has been invited to MSD France,

Nestlé Nutrition Institute, Nestlé Health Science, Danone, TAKEDA, CELGENE, BIOGEN,

SHIRE, PFIZER, THERAKOS

AA- Received research grant from AbbVie

SH- received a travel bursary from AbbVie

LdR – last 3 years received consultation fee, research grant, or honorarium from ZonMw

(national health institute), Janssen, Pfizer, Mundipharma, Shire and Abbvie

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

KK - Honoraria for consulting services (educational services, scientific articles, participation in

Advisory Boards, clinical trials, other) from the companies as follows AbbVie, ENORASIS,

Ferring, JANNSEN, MSD and Takeda

VNL last 3 years received consultation fee or honorarium from Abbvie, Otsuka and Nestlé

Health Science

SL – last 2 years received honorarium from Janssen

RKR has received speaker’s fees, travel support, or has performed consultancy work with Nestlé

Health Science, AbbVie, Napp, Celltrion, Shire and Janssen.

MS, CS, CB, CR No conflict of interests to declare

EO has received honoraria from Abbvie.

NC research funding for trials, speaker fees and travel for conferences from Takeda, Shire,

Celgene, Roche

MP lectures and congress fees sponsored by Astellas, Baxter and Shire.

AMG consultancy, speakers fees or research support for Abbvie, Celgene, Ferring, Gilead,

Janssen, Pfizer and Takeda.

DCW has received speaker’s fees, travel support, or has performed consultancy work

with Abbvie, Takeda and Falk.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

ABSTRACT

Background: The contemporary management of ambulatory ulcerative colitis (UC) continues to

be challenging with ~20% of children needing a colectomy within childhood years. We thus

aimed to standardize daily treatment of paediatric UC and inflammatory bowel diseases (IBD)-

unclassified through detailed recommendations and practice points.

Methods: These guidelines are a joint effort of the European Crohn's and Colitis Organization

(ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology,

Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence

appraisal using robust methodology was performed before two face-to-face meetings. All 40

included recommendations and 86 practice points, were endorsed by 43 experts in Paediatric

IBD with at least an 88% consensus rate.

Results: These guidelines centre on initial use of mesalamine (including topical), before using

steroids, thiopurines and, for more severe disease, anti-TNF. The use of other emerging therapies

and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision

making based on clinical assessment and the paediatric UC activity index (PUCAI). Advice on

contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic

drug monitoring are presented, as well as other management considerations around pouchitis,

extraintestinal manifestations, nutrition, growth, psychology and transition. A brief section on

disease classification using the PIBD-classes criteria and IBDU is also part of these guidelines.

Conclusion: These guidelines provide a guide to clinicians managing children with UC and

IBDU to provide modern management strategies while maintaining vigilance around appropriate

outcomes and safety issues.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Keywords: Ulcerative Colitis; children, management; guidelines; pediatric ulcerative colitis

activity index (PUCAI); calprotectin; monitoring; treatment; paediatrics; mesalamine,

IBD- unclassified; thiopurines; anti-TNF; vedolizumab

What is known

- The previously published ESPGHAN-ECCO guidelines were published in 2012 and are

updated herein

What is new

- The diagnosis section has been replaced by the IBD-Classes criteria; a discussion of IBD-

U has been added; faecal calprotectin has been given more emphasis; new drugs (e.g.

vedolizumab, golimumab) have been incorporated as off-label medications;

recommendations for therapeutic drug monitoring have been provided; the use of

thrombotic prophylaxis has been revisited; sequential therapy has been newly presented;

a treat to target algorithm has been added and other sections updated.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

INTRODUCTION

Ulcerative colitis (UC) is a disease with a less heterogeneous phenotype than Crohn’s disease

(CD) that still poses many unique challenges. The incidence of paediatric onset UC, which

constitutes roughly 15-20% of all UC, ranges at 1-4/100,000/year in most North American and

European regions (1). It is extensive in 60-80% of all cases, twice as often as in adults (2). Since

disease extent has been consistently associated with disease severity, it is not surprising that

children with UC more often require hospitalization for an acute severe exacerbation (25-30%

over 3-4 years) (3, 4) and more often undergo colectomy for medically refractory disease (up to

30-40% in 10-year follow-up (2, 5), although lower colectomy rates have also been reported (6,

7) (8)). Canadian population-based health administrative data showed no reduction of colectomy

rate from 1994 to 2007 before the widespread use of biologics (9). In addition to more severe

colitis, children also have unique age-related issues, such as growth, pubertal development,

nutrition, and bone mineral density accretion, as well as differing psychosocial needs. Finally,

although mortality in paediatric UC has become rare, a retrospective case collection across

Europe over 6 years nevertheless reported 19 deaths in children with UC mainly due to

infections and cancer (one case of colorectal cancer (CRC)), but including one with toxic

megacolon (10).

The revised Porto criteria (11) proposed explicit guidance for diagnostic workup in paediatric

inflammatory bowel diseases (IBD). Consequently, the Paediatric IBD Porto group of

ESPGHAN published the “PIBD-Classes” criteria that standardized the differentiation of

paediatric IBD into 5 categories: typical UC, atypical UC, IBD-unclassified (IBDU), Crohn’s

colitis and CD (12); the first 3 categories will be covered in these guidelines.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

The PIBD-classes system is based on 23 features which are typical of CD, grouped in 3 classes:

1) those that are totally incompatible with UC and thus should be diagnosed as CD; 2) those that

may be present in UC but rarely (<5%; class 2); and 3) those that may be present in UC

uncommonly (5-10%; class 3). Accumulation of the different features, weighted by the classes,

standardized the diagnosis of PIBD (Figure 1, Table 1). The sensitivity and specificity of the

PIBD-classes to differentiate UC from CD and IBDU was 80% and 84%, and CD from IBDU

and UC 78% and 94%, respectively (12).

The use of the Paris classification is advocated for phenotyping paediatric UC, with E1-E4, A1a-

A2 and S0-S1 denoting disease extent, age of diagnosis and severity, respectively (13).

Additional labels of very-early onset IBD (≤ 6 years of age at diagnosis) and infantile IBD (<2

years of age) may also be added (14).

We aimed to develop guidelines for managing UC in children based on a systematic review of

the literature and a robust consensus process of an international working group composed of

specialists in paediatric IBD from the European Society of Paediatric Gastroenterology,

Hepatology and Nutrition (ESPGHAN) and the European Crohn's and Colitis Organization

(ECCO). We focus on the principles, pitfalls and paediatric considerations related to the

diagnosis and care of children and adolescents with UC. These guidelines supplement those

published for adults (15, 16); similar topics are covered only in brief, referencing the extensive

ECCO review. The paediatric UC guidelines are divided into two parts but should be read as one

manuscript: Part 1: ambulatory UC (updating the previous 2012 ECCO-ESPGHAN guidelines

(17)) and Part 2: Acute severe colitis (ASC; updating the previous 2011 ECCO-ESPGHAN

guidelines (18)).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

In addition to providing an update of new literature, several major topics have changed from the

previous guidelines. The diagnosis section has been replaced by the aforementioned summary

incorporating the IBD-Classes criteria; a discussion of IBD-U has been added briefly; faecal

calprotectin has been given more emphasis; new drugs (e.g. vedolizumab, golimumab and

locally-active steroids) have been incorporated as off-label medications; practical

recommendations for therapeutic drug monitoring have been provided; the use of thrombotic

prophylaxis has been revisited based on predicting variables; sequential therapy has been newly

presented; a treat to target algorithm has been added; and other sections updated and changed.

METHODS

Following an open call in ECCO and the Porto plus the Interest Paediatric IBD groups of

ESPGHAN, 22 international experts in paediatric IBD were selected by the steering committee,

including two paediatric surgeons. A list of 23 questions addressing the management of UC in

children was first developed (composing the subtitles of the current manuscript and the next one

on ASC). Next, a systematic review of the literature was performed centrally by two of the

authors (EOM and CS) with the aid of an experienced librarian searching for all combinations of

UC and paediatrics (Supplemental Table 1, Supplemental Digital Content 1,

http://links.lww.com/MPG/B393). Electronic searches were performed in Oct 2016 using

Medline, Embase, and web of science. Clinical guidelines, systematic reviews, clinical trials,

cohort studies, case-control studies, diagnostic studies, surveys, letters, narrative reviews, case

series, and highly relevant selected abstracts published after 1985 were all utilized if performed

in children. Following elimination of duplicates, 10,096 abstracts were reviewed by EOM for

eligibility. A total of 8,996 abstracts were excluded, mainly for the following reasons: clear

irrelevance to the pre-defined topics, manuscripts published prior to 1985, review manuscripts,

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

manuscripts focusing on CD or on molecular/genetic pathways. Although we aimed to base our

adult literature on the recently updated ECCO UC guidelines (15, 16), salient adult RCTs

identified in the initial search were not excluded for perusal and reference. The decision

regarding questionable eligibility was made by one of the senior authors (DT). Finally, 1100 full

text manuscripts were retrieved and circulated to the relevant subgroups for writing their

sections. Highly relevant manuscripts published after the search date were included individually.

Each of the 23 questions was allocated to a subgroup of two experts for drafting of the first text.

The subgroup's text and recommendations were iterated by email with the steering committee

until refined. The guidelines include both recommendations and practice points that reflect

common practice where evidence is lacking or provide useful technical details, including grading

of evidence according to the Newcastle-Ottawa assessment scales for case-control and cohort

studies (19) and according to the Cochrane Handbook for clinical trials (20) (Supplemental Table

2: tables of evidence with grading, Supplemental Digital Content 2,

http://links.lww.com/MPG/B394). The group then voted on all recommendations and practice

points while adding specific comments using a web-based voting platform. A second round of

electronic voting and revisions was done, including all members of the Paediatric IBD Porto

group of ESPGHAN. In addition, the draft was circulated for comments to ECCO (national

representatives and governing board) and to members of the IBD Interest group of ESPGHAN.

The group met twice face-to-face: during UEGW annual meeting (Barcelona, Oct 2016) before

drafting the initial topics and during ESPGHAN annual meeting (Prague, May 2017) after the

two voting rounds were completed. The meetings were supplemented by an email Delphi process

with the entire group until agreement was reached. In total 43 paediatric IBD experts voted on all

recommendations and practice points: 35 Porto group members (of whom 14 were authors) and 8

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

non- Porto group authors (Supplemental Table 3: names of the 43 voting experts, Supplemental

Digital Content 1, http://links.lww.com/MPG/B393). All statements and practice points were

supported by at least 88% of the group and in most cases reflect almost full consensus.

Recommendations were graded according to Oxford Centre for Evidence-Based Medicine (see

table at https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evidence-2.1.pdf

(21)).

EVALUATION AND PREDICTION

Assessing and predicting disease activity (Figure 2)

Recommendations

1. Disease activity should be monitored at every visit utilizing the PUCAI [EL2] and

treatment should be revisited when PUCAI ≥ 10 points [EL2] (93% agreement)

2. Colonoscopic evaluation is recommended at diagnosis [EL4, adults EL4], before major

therapeutic modifications [EL5, adults EL5], for cancer surveillance [EL5, adults EL3],

and when it is not clear if symptoms are disease-related especially if calprotectin is

elevated [EL5, adults EL5]; it is not routinely indicated during relapses that are not

severe [EL5, adults EL5] (100% agreement)

3. If available, faecal calprotectin should be obtained while in sustained clinical remission

and endoscopic evaluation should be considered when calprotectin is high, as defined

below and in Figure 2 [EL2, adults EL2] (88% agreement)

Practice points:

1. Clinical remission is defined as PUCAI<10 points, mild disease as 10-34 points, moderate

disease 35-64 points and severe disease ≥65 points (Appendix 1). Clinically significant

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 response is defined by a PUCAI change of at least 20 points, or entering remission (95%

agreement).

2. Long-term prognosis is better in patients who achieve complete clinical remission (i.e.

PUCAI<10) during the first 3 months after diagnosis (95% agreement).

3. There is currently no evidence whether measuring calprotectin in a child who is in a

PUCAI-defined remission has an added value for predicting disease course. However,

given the fact that significant endoscopic disease may be present in ~20% of children with

PUCAI<10, it is reasonable to measure calprotectin once sustained clinical remission has

been achieved to verify mucosal healing and select those who require endoscopic

assessment. Other faecal markers (e.g. lactoferrin) may have a comparable diagnostic

value, but less data are published (93% agreement).

4. There is no ideal cut-off value of faecal calprotectin to reflect mucosal inflammation and

predict disease outcome (Tables 2 and 3). Values differ substantially in the different

studies using different reference standards. Cut-off value<100mcg/g usually reflects

remission while >250 mcg/g more accurately predicts mucosal inflammation. The value

that should trigger an endoscopic evaluation or a change in treatment should be thus

individualized based on these values, especially when values increase over time (98%

agreement).

5. An episode of acute severe colitis (i.e. PUCAI ≥ 65) is a risk factor for a more aggressive

disease course and thus this should be incorporated in the management scheme (100%

agreement).

6. Blood tests (CBC, albumin, transaminases, gGT, CRP, and ESR) should be performed

regularly depending on symptoms and therapy and at least every 3 months while on

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 immunosuppressive medications and at least every 6-12 months otherwise. It is a common

practice to include testing for renal function in patients taking mesalamine and annual

urinalysis; however, there is no evidence that this prevents adverse outcomes (98%

agreement).

7. Before treatment modification, it is essential to consider and, if relevant, exclude other

clinical conditions such as non-adherence, irritable bowel syndrome, celiac disease,

medication-related adverse events, and infections (especially C. difficile, which should be

excluded in any acute exacerbation, but also bacterial infections and CMV) (95%

agreement).

8. A standardized endoscopic activity index, including the Mayo endoscopic subscore or

Ulcerative Colitis Endoscopic Index of Severity (UCEIS), should be used during

colonoscopic examinations (95% agreement).

9. Colorectal cancer surveillance by a trained endoscopist is recommended following 8-10

years of disease duration, dictated by risk factors such as disease extent, disease severity

over the course of disease and family history. Surveillance recommendations in children

with PSC can be found in the PSC section. According to the adult guidelines, chromo-

endoscopy with targeted biopsies has been shown to increase dysplasia detection rate. If

not available, random biopsies (quadrantic biopsies every 10 cm) and targeted biopsies of

any visible lesion should be performed using high definition (93% agreement).

In two paediatric inception cohorts, disease severity during the first 3 months after diagnosis and

the occurrence of an episode of ASC were associated with increased risk of refractory disease

(22, 23). Thus, by using constructs of disease severity it is possible to characterize children who

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

are at high risk for a more complicated disease course and to guide management and tight

monitoring.

Endoscopy is the reference standard to evaluate mucosal inflammation. Mayo endoscopic score

of none, mild, moderate or severe (0–3 points) with number of involved colonic segments

(rectum, sigmoid, and descending, transverse, and ascending colon) may be used in paediatric

UC (24). The modified Mayo endoscopic score is an easy to use, non-validated tool, which

combines disease extent with Mayo Endoscopic score (25). The ulcerative colitis endoscopic

index of severity (UCEIS) is a convenient and validated index which includes vascular pattern,

bleeding, and ulcers at the worst part (26, 27). These indices are described in the coming

ESPGHAN Porto group guidelines of endoscopy utilization in IBD (JPGN 2018).

Mucosal healing in UC is associated with a favourable disease outcome in adult patients (28-31).

Nevertheless, clinical remission has been proven to predict long term outcomes in UC, with no

less accuracy than endoscopic evaluation, both in children using the PUCAI (23, 32) and in

adults (33). An adult study showed that UCEIS predicted relapse in 155 patients who were in

clinical remission; however clinical remission was not stringently defined (i.e. partial Mayo

score of 0-1, allowing for streaks of blood for instance) and the number needed to test was high

(34). A post-hoc analysis of the adult ACT trials showed that while endoscopic inflammation

predicted colectomy, this was not the case in the subgroup of patients who were in clinical

remission (28). A PUCAI-defined remission at 3 months following diagnosis predicted 1-year

sustained steroid free remission (AUROC 0.7, 95%CI 0.6-0.8) and colectomy by 2 years

(AUROC 0.75 (0.6-0.89), It was superior to both CRP and ESR (23) and predicted choice of

treatment (35, 36). Furthermore, in the prospective multi-centre PROTECT paediatric cohort

study, failure to achieve clinical remission (PUCAI<10) 4 weeks after discharge of children who

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

required intravenous corticosteroids at disease onset was highly associated with need for

additional medical therapy by week 12 (37).

PUCAI cut-off scores of remission, mild, moderate and severe disease have been validated in

several cohorts (35, 38, 39) and were successfully utilized in the PROTECT study to guide the

choice of initial treatment at disease onset, as outlined in Figure 4 (37). PUCAI at diagnosis was

associated with steroid-free remission rates at week 12 and with long term outcomes (at 54

weeks). However, selected children with moderate disease activity were treated with 5ASA and

not with oral steroids, and on average had similar outcomes at week 12; this supports our

algorithm that 5ASA may be considered also in the lower range of the moderate disease activity

group (Figure 4). The PUCAI correlates well with endoscopic appearance of the colonic mucosa,

showing similar remission rates in multiple studies (38-43). In addition, the correlation of the

PUCAI with Mayo score has been reported to be as high as 0.95 (32, 38, 39). While most

aforementioned studies report a group average, on an individual basis there is a likelihood of

~20% for a significant mucosal inflammation even in the presence of a PUCAI-defined complete

remission (44). Therefore, biomarkers should be used to confirm endoscopic remission in those

who are in sustained clinical remission, particularly in the presence of PSC where the PUCAI

does not correlate well with mucosal inflammation (45) (Figure 2).

Routine laboratory parameters (platelets, CRP, albumin, haemoglobin) are more frequently

normal in UC than in CD during mild to moderate flares (46, 47). In contrast to adult UC, high

sensitivity (hs)-CRP was not suitable to differentiate between remission and relapse in children

with normal standard CRP (48). In paediatric UC, ESR and CRP should be measured at least

initially, since at times only one measure is elevated (49). Initial albumin was the only significant

laboratory test that was predictive for acute severe colitis in one follow-up study (23). Similarly,

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

earlier surgery was necessary in children with initially low serum albumin (HR 6.05, 99% CI

2.15–17.04) in 57 children who ultimately required colectomy (median time to surgery was 3.8

years) (50). In another study elevated white blood cell and low haematocrit measured at

diagnosis were associated with colectomy rate at 3 years (51).

Faecal biomarkers are non-invasive markers of mucosal inflammation, especially histological

activity (52-54). Correlation of calprotectin with clinical disease activity, endoscopic, and

histological indices has been described both in children and adults (52, 55-59) (Table 2). In a

retrospective paediatric study, calprotectin value of 275 mcg/g achieved sensitivity and negative

predictive value of 97% and specificity and positive predictive value of 85% in evaluating

histological activity (60). A few studies have indicated that calprotectin can be useful to predict

relapses in UC patients (56, 61, 62), but its added predictive utility while in clinical remission is

less clear (Table 3).

Roughly 60% of children with UC are pANCA positive at the time of diagnosis (63). pANCA

positivity was not associated with disease activity in one paediatric study (64), or with early

relapse (1 year follow-up) (65). On the other hand, in a recent Porto group multicenter

retrospective study of 801 children with colonic IBD, pANCA predicted the need for biologics in

UC (p=0.026) (63). In an adult UC population pANCA status was associated with higher risk of

pouchitis after colectomy (66).

Data supporting colorectal cancer surveillance recommendations can be found in extensive adult

guidelines (15, 16, 67). Of note, a Swedish nationwide cohort study of paediatric IBD confirmed

that colorectal cancer was almost non-existent during the first five years of follow-up, but

incidence was higher after 10 years of follow-up (68). Interestingly, the incidence of colorectal

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

cancer in the first 20 years of follow-up was considerably lower in childhood-onset inflammatory

bowel disease than in disease with onset at other ages.

MEDICAL MANAGEMENT

5-ASA and enemas

Recommendations

1. Oral 5-ASA compounds are recommended as first-line induction and maintenance

therapy for mild-moderate UC [EL2, adults EL1] (100% agreement)

2. Combined oral and rectal 5-ASA therapy is more effective than oral 5-ASA monotherapy

[EL2, adults EL1] (98% agreement)

3. Rectal monotherapy should be reserved for mild – moderate ulcerative proctitis, an

uncommon paediatric phenotype [EL2, adults EL1] (100% agreement)

4. When rectal therapy is used, 5-ASA is preferred over steroids [EL5, adults EL1] (100%

agreement)

Practice points

1. No mesalamine delivery system has proven clearly superior for induction or maintenance

of remission. Sulfasalazine may be somewhat superior to mesalamine for maintenance of

remission in adult studies but paediatric data are lacking. Only sulfasalazine is available

in liquid formulation and might be also effective for arthritis but it is associated with

more adverse events (100% agreement).

2. Suggested dosing: oral mesalamine 60-80 mg/kg/day to 4.8g daily; rectal mesalamine 25

mg/kg up to 1g daily; sulfasalazine 40-70 mg/kg/day up to 4g daily. Higher rectal doses

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 up to 4g are being used but evidence suggest that it is no more effective than 1g (98%

agreement).

3. Suppositories are useful for limited proctitis, while foam and liquid mesalamine enemas

are also suitable in more extensive colitis (95% agreement).

4. Dosing 5-ASA once-daily can be considered for induction of remission and for

maintenance (95% agreement).

5. Gradual sulfasalazine dose augmentation over 7–14 days may mitigate against dose-

dependent side-effects (see text) (93% agreement).

6. The effective induction dose should be continued also as the maintenance dose. Dose

reduction, within the suggested dose range, may be considered after several months of

sustained remission. Maintenance therapy should be continued in paediatric patients

(93% agreement).

7. Most children with mild-moderate UC will not achieve remission with oral mesalamine

monotherapy alone. Treatment modification should be considered in those who do not

show initial meaningful response within 2-3 weeks of therapy (95% agreement).

8. Acute mesalamine intolerance could present as an exacerbation of the UC, usually within

the first month of treatment. Symptoms resolve within days of cessation. Recurrence on

re-challenge is diagnostic and precludes its future use. Symptoms usually recur also

following rectal administration (100% agreement).

9. Rectal tacrolimus may be considered in patients with ulcerative proctitis who are either

refractory or intolerant to mesalamine and steroids topical therapies (suggested dose

0.07mg/kg/day; maximum dose in adult trials 3mg/day) (88% agreement).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Strong evidence, mostly from adult trials, supports the use of 5-ASA for induction and

maintenance of remission in mild-moderate UC (41, 69-72). In that context, mesalamine induces

remission in 35-55% of children, as defined by the PUCAI (73, 74).

The MUPPIT trial randomised children with mild-moderate UC into once versus twice daily oral

mesalamine (Pentasa®), with comparable outcomes (74). Once daily dosing achieved clinical

response in 25/43 (60%) and remission in 13/43 (30%), compared with 25/40 (63%) and 16/40

(40%), respectively, for the twice daily group. Most responders did so by week 2 and no further

response was seen after week 3. While the groups were statistically comparable, more patients in

the once-daily study arm had pancolitis and were already on immunomodulators. Endoscopic

remission was not assessed and the study was not powered for non-inferiority. Long term studies

of 5-ASA of once daily maintenance in paediatrics are currently ongoing. In another paediatric

RCT, low versus higher dose balsalazide induced remission in 3/35 (9%) versus 4/33 (12%) of

children, respectively (72). Clinical improvement in mild-moderate UC was seen in nearly twice

as many children randomised to sulfasalazine (22/28, 79%) compared to olsalazine (11/28, 39%)

(71).

There are no paediatric maintenance comparative trials of 5-ASA, but only ~ 40% (86/213) of

children treated with 5-ASA within 1 month of diagnosis were in steroid-free remission by one

year in the North American registry (75). Similar data were reported from the prospective Italian

paediatric IBD registry, with 45% of patients in remission at 1 year on 5-ASA therapy alone

(76). EPIMAD data reported that 32% (36/113) of children with UC remained on 5-ASA therapy

without steroids, by maximum follow up (5). In a recent Cochrane analysis of adult trials, the

relative risk of successful induction of clinical and endoscopic remission with 5-ASA was 1.16

(95% CI 1.12 – 1.21) and 1.29 (95% CI 1.16-1.69), respectively (69). No specific 5-ASA

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

compound was superior for inducing remission, although sulfasalazine was statistically superior

to other 5-ASA compounds for maintenance of remission (69, 70, 77, 78).

The pharmacokinetics of 5-ASA are comparable between children and adults (79-81). Adult

trials have shown somewhat greater efficacy of higher induction mesalamine dose in patients

with severe or extensive disease, phenotypes more commonly seen in children (82-84). However,

in a multicentre RCT, 81 children with mild-moderate UC were randomised to high dose (53-

118mg/kg/d) or lower dose (27-71mg/kg/d) delayed release mesalamine with similar PUCAI-

defined remission rates after induction (55% and 56% respectively) (73). While greater

reductions in faecal biomarkers were seen in the higher dose group, this did not reach

significance. This trial enrolled on average children with milder disease which may explain the

higher remission rates compared to other aforementioned paediatric trials.

Oral mesalamine may be better tolerated than sulfasalazine (relative risk of adverse effects 0.48,

95% CI 0.36-0.63), but the latter is cheaper and remains the only 5-ASA available in liquid

formulation (70, 71). Moreover, except for the uncommon allergic reaction (<0.1%), the vast

majority of events are mild (e.g. headache and gastrointestinal symptoms) (85, 86). Serious

adverse events with 5-ASA treatment are rare and include renal, pancreatic, pulmonary and

cardiac complications (87-93). Withdrawal due to intolerance in adult studies is in the range of 2-

5% (69, 70). Intolerance to 5-ASA medications may mimic a colitis flare, and when clinically

proven by re-challenge, it precludes further use of 5-ASA compounds (94). Regular laboratory

monitoring of full blood count, renal function, and urinalysis, though not supported by evidence,

remains the practice of many clinicians.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Rectal therapy (as suppositories) is indicated for ulcerative proctitis, an infrequent phenotype in

paediatrics (95). In order to allay concerns and ensure optimal compliance, children and their

caregivers require support and reassurance when topical rectal therapies are proposed.

In a paediatric ulcerative proctitis trial, mesalamine suppositories (0.5g daily) were associated

with improved disease activity at 3 and 6 weeks in children with mild-moderate proctitis (95).

Combining oral and rectal 5-ASA therapy improves clinical outcomes (96-98). Remission was

reported in 16/38 children (42%) in a prospective uncontrolled trial of 3 weeks’ rectal

mesalamine in patients unresponsive to oral high dose mesalamine (99). Adult studies with larger

numbers and a higher evidence level have shown that rectal mesalamine foam, gel or liquid

enema formulations have comparable tolerance, safety and outcomes (100-103). Once daily

rectal therapy is as effective as divided daily dosing (104). In adults, daily doses in excess of 1g

of rectal mesalamine do not enhance outcomes including clinical, endoscopic and histological

remission (100, 101). Rectal steroid preparations are useful for patients who are 5-ASA

intolerant. They are superior to placebo in children and adults for inducing remission of proctitis,

but meta-analysis data consistently support the superiority of rectal mesalamine over rectal

steroids (symptomatic remission OR 1.65 [95% CI 1.1-2.45]) (100, 101).

Rectal tacrolimus has been reported in children and adults as a successful third-line treatment of

ulcerative proctitis (105, 106). In a recent double blind placebo-controlled trial, 8/11 adult

patients receiving rectal tacrolimus ointment (1.5mg twice daily) achieved mucosal healing by

week 8, compared with 1/10 receiving placebo (107). Although usually well tolerated, rare

toxicity episodes have been reported (106).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Oral steroids

Recommendations:

1. Oral steroids should be used as second line treatment for mild-moderate UC not

responding to 5-ASA (oral +/- rectal) and may be considered as first line in the higher

end of the moderate disease range [EL3, adults EL1] (100% agreement)

2. Severe UC should normally be treated with intravenous steroids [EL2, adults EL1] (98%

agreement)

3. Second-generation oral steroids with lower systemic effect such as beclomethasone

dipropionate (BDP) [EL2, adults EL1] and budesonide-MMX [EL5, adults EL2; the

evidence for budesonide-MMX is supportive only for left sided colitis] may be

considered in patients with mild disease refractory to 5-ASA prior to oral prednisolone

(93% agreement)

4. Steroids are not recommended for maintaining remission; steroid sparing strategies

should be applied [EL5, adults EL4] (100% agreement)

Practice Points:

1. Regarding recommendation #2, a short trial of oral steroids could be considered in

selected children with severe colitis (i.e. PUCAI≥65) who appear well with normal or

near normal lab values (93% agreement).

2. The recommended daily dose for oral prednisolone/prednisone is 1mg/kg/day (max 40

mg) once daily for 2-3 weeks followed by a tapering period of up to 8-10 weeks (Table 4)

(98% agreement).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 3. Once daily administration of steroids in the morning is as effective as the same dose

given in multiple divided doses (100% agreement).

4. In patients > 30kg the dosing schedule of BDP is 5mg once daily for 4 weeks and for

budesonide-MMX 9 mg for 8 weeks. Dosing for children <30kg has not been established

and no liquid formulation is available. There is no evidence to support tapering of either

drug. While abrupt discontinuation has been practiced in the RCTs, alternate day tapering

over 2-4 weeks has been proposed by some (93% agreement).

5. The term “steroid-dependency” applies to patients who: i) are unable to stop steroids

within three months without recurrent active disease; or ii) have a relapse requiring

steroids within three months of stopping steroids (95% agreement).

6. High glucocorticoid dose and long duration of the therapy (more than 3 months) has been

associated with adrenal suppression (AS) (i.e. present after gradual weaning off) in 20%

of children with IBD (98% agreement).

7. If symptoms of adrenal suppression (e.g. weakness/fatigue, malaise, nausea, vomiting,

diarrhoea, headache, arthralgia and abdominal pain) are present while weaning steroids,

adrenal insufficiency should be excluded by first testing cortisol level at 08:00 AM prior

to drug intake, and, if abnormal, consult with a paediatric endocrinologist (93%

agreement).

Studies of oral steroids for treating children with active UC report short term (1-3 months)

remission rates of 50-64% (108-110); at one year 49-61% had prolonged response, 14-49% were

steroid- dependent and 5-29% required surgery (5, 7, 108, 110). Mucosal healing lags behind

clinical improvement; in a non-randomised study after 8 weeks of steroids or 5-ASA, 87% had

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

clinical remission, 40% endoscopic remission and 15% histological remission with no significant

difference in outcomes between the two therapies (111).

Steroid dependency has been reported to be higher in children than in adults (45% vs. 8%

respectively) (7). Strategies to avoid steroid dependency include optimization of 5-ASA,

adjuvant therapy with enemas, and escalation to thiopurines or biologics.

Second-generation topical steroids have a more favourable safety profile and may be considered

before systemic steroids in selected patients (112). BDP uses gastro-resistant film coatings to

target delivery to the distal small intestine and the colon. Studies in adults demonstrate the

effectiveness of BDP compared with both prednisolone and mesalamine (15, 113). A RCT of 30

children (weight >30kg) with mild-to-moderate UC showed that oral BDP, 5mg/day for 4 weeks,

was well tolerated and more effective than 5-ASA in achieving both clinical remission (80% vs

33%, p<0.025) and endoscopic remission (73% vs 27%, p< 0.025), respectively (41).

A Cochrane systematic review of older selective release budesonide in adults showed that it was

less likely to induce remission than mesalamine (RR 0.72, 95% CI 0.57 to 0.91) with no benefit

over placebo (RR 1.41, 95%- CI 0.59 3.39) (114). Budesonide-MMX is a novel oral formulation

designed to extend release of the drug to the colon. Two adult trials showed significant benefit in

the ITT population (combined left sided and extensive) but sub-analysis based upon disease

extent was only significant for left sided disease (115, 116). Indeed, in a recent case-series of 16

children, 15 of whom with pancolitis, budesonide-MMX showed minimal clinical effectiveness

(117). Another recent RCT in adult UC refractory to 5ASA showed superiority over placebo but

with a disappointing 6% effect size difference; no subgroup analysis of disease extent was

performed (118).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Children with UC may have more steroid-related complications, including osteopenia, acne,

glaucoma, and cataracts, than adults even when adjusted for weight (119). Even low steroid

doses (0.1–0.4 mg/kg/ day) can suppress growth (120). The ECCO statement in adults suggests

supplementation with vitamin D while on steroid therapy (121), but we could not find clear

evidence to support supplementing vitamin D in those who are not deficient and receiving

standard-duration course of steroids. AS may present with non-specific symptoms (including

abdominal pain, malaise, weakness/fatigue, nausea, diarrhoea, headache, fever, arthralgia) or

rarely adrenal crisis (hypotension, lethargy, decreased consciousness/coma, hyponatraemia,

hypoglycemia, seizures) (122). There are no published consensus guidelines that advise who

should be screened for AS. In one recent review, it was recommended to screen patients who

received steroids for >3 weeks and after gradual weaning have persistent symptoms that may be

attributable to AS (123). The range of 8AM morning cortisol value at which AS is confirmed

varies between studies. In one recent review a value of <100 nmol/l was used while >500 nmol/L

virtually excluded AS (124). Another manuscript suggested that <85 nmol/l should be used to

diagnose AS (123). In a study of consecutive children with IBD about to stop steroids (i.e. on

physiological doses of oral steroids meaning 5-10 mg daily prednisolone) 20% had biochemical

AS using a value <69 nmol/l and of these half had an undetectable cortisol (125). Higher

glucocorticoid dose and longer duration of the therapy were associated with increased risk (125).

In the only study of children with IBD no–one on treatment for less than 3 months had

biochemically confirmed AS (present after gradually weaning to physiological doses of steroids)

(125-127).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Immunomodulators

Recommendations

1. Thiopurines are recommended for maintaining remission in children who are corticosteroid-

dependent or relapsing frequently (≥2 relapses per year) despite optimal 5-ASA treatment as

well as in 5-ASA intolerant patients [EL3, adults EL1]; thiopurines should be considered

following discharge from acute severe colitis episode [EL4, adults EL3] (98% agreement)

2. Thiopurines should not be used for induction of remission in paediatric UC patients [EL5,

adults EL2] (100% agreement)

3. Measuring thiopurine metabolites is recommended in patients with incomplete response on a

stable thiopurine dosage, in patients who present with leukopenia or elevated transaminases,

or if poor compliance is suspected [EL2, adults EL2] (95% agreement)

Practice points

1. Thiopurines may be somewhat more effective than 5-ASA for maintaining remission in

UC, but considering their safety profile, they should generally be reserved as second line

therapy after 5-ASA has failed (93% agreement).

2. Determination of TPMT genotype or phenotype (i.e. TPMT activity) is encouraged to

identify patients at greater risk of profound myelosuppression. Dose should be reduced in

heterozygous patients or in those with low activity. Thiopurines should not be used in

children homozygous mutants for TPMT or those with very low TPMT activity as

defined at each laboratory (93% agreement).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

3. Regular monitoring of blood counts and liver enzymes is recommended in all cases every

1-2 weeks during the first month then every month up to 3 months followed by every 3

months thereafter. (100% agreement).

4. Families should be instructed to use sun protection with the use of thiopurines and other

immunosuppressive drugs (100% agreement).

5. Given its excellent safety profile, it is reasonable to continue 5-ASA with thiopurines, at

least initially, despite lack of evidence. 5-ASA inhibits the enzyme TPMT thus increasing

the active metabolite 6-TGN (88% agreement).

6. The maximal therapeutic effect of thiopurines may not be evident until 10-12 weeks of

treatment (98% agreement).

7. Thiopurine dose should be approximately 2-2.5mg/kg of azathioprine and 1-1.5mg/kg of

mercaptopurine, in a single daily dose in patients with a normal TPMT. Measuring

thiopurine metabolites may assist in further dose adjustments and reduce adverse events

while considering 6-TGN level of 235-450 pmol/8X108 RBCs and 6MMP<6700

pmol/8X108 RBCs as optimal (note that cutoff values may vary between methods (128))

(95% agreement).

8. Patients who show gastrointestinal intolerance or flu-like reaction to one thiopurine

compound may tolerate lower doses or a "switch" to another thiopurine (azathioprine to

6-mercaptopurine and vice versa). Limited data suggest that splitting the daily dose into

two, may alleviate gastrointestinal and hepatic toxicity in patients who have hyperactive

TPMT activity (95% agreement).

9. Thiopurines should be discontinued in clinically significant myelosuppression or

pancreatitis. Reintroduction of thiopurines after leukopenia (but not usually pancreatitis)

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 can be considered at a lower dose after carefully assessing the risks and benefits and after

measuring thiopurine metabolites and/or TPMT (95% agreement).

10. Change in treatment should be considered in patients with active disease despite adequate

6-TGN level after at least 12 weeks of thiopurine treatment. (98% agreement).

11. Concomitant use of allopurinol) 50 mg once daily in patients<30 kg and 100 mg once

daily is patients≥30 kg, maximum 5mg/kg) with reduced dose of azathioprine (to

approximately 25-30% of initial dose), may provide a valid therapeutic option in cases of

hyperactive TPMT resulting in high 6-MMP (often associated with elevated

transaminases) and low 6-TGN, in suitably experienced units. Children must be closely

monitored given the increased risk of toxicity (95% agreement).

12. Benefits of withdrawal should be carefully weighed against an increased risk of relapse.

Thiopurine withdrawal could be considered in patients in sustained clinical remission

following long-term treatment (at least 1 year) after ensuring complete mucosal healing

and preferably also histological remission. In the case of thiopurine withdrawal, 5-ASA

treatment may assist in maintaining remission (particularly in patients naïve to 5-ASA)

(91% agreement).

13. Methotrexate might rarely be considered in UC patients who fail to respond or are

intolerant to thiopurines, when other alternatives are not possible or available (91%

agreement).

14. Oral tacrolimus (FK-506) may be considered in selected outpatient UC children as

another option to steroids for bridging to thiopurines or vedolizumab (given the longer

time to onset of action). At initiation, high target serum trough level (10–15 ng/mL)

should be achieved with a gradual titration to lower trough levels (5-10 and eventually 2-

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 5ng/mL) in-order to avoid serious adverse events. Selected patients may benefit from a

long-term, low-dose treatment (i.e. drug level target of 2ng/mL) but careful consideration

of the potential toxicity should be taken as well as noting the limited supportive evidence

(93% agreement).

The efficacy of thiopurines (azathioprine and 6-mercaptopurine) was evaluated systematically

for both induction and maintenance of remission in adult UC patients. Meta-analyses of adult

data concluded that azathioprine is not more effective than placebo for induction of remission but

is superior to placebo in preventing relapse (129-131). In a recent prospective cohort study,

sustained clinical benefit was achieved in 60% of 255 adult UC patients receiving azathioprine

following 5-ASA failure, at a median follow-up of 30 months (132).

Prospective paediatric studies reported steroid-free remission rates of 49% at 1 year (133) and

72% at 2 years (134) in thiopurine treated children with no difference in either clinical or

endoscopic end-points between early or late initiation of treatment. A few retrospective studies

(135-138) in children supported the benefit of thiopurines in maintaining remission and steroid

sparing with a median time to achieve steady state of thiopurine levels of 55 days (139). Cox

proportional hazard modelling of retrospective data from 1175 incident children and young

adults, did not demonstrate a benefit to early thiopurine use in reducing the risk of colectomy

(140).

Despite one negative small adult study (141), it is not unreasonable to combine 5-ASA with

thiopurines given the excellent safety profile of the former and its possible additive effect,

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

including chemoprotection. 5-ASA may partially inhibit TMPT activity and therefore may

increase 6-TGN levels (142, 143).

Most adult studies used doses of 2.5 mg/kg for azathioprine and 1.5 mg/kg for 6-MP. However,

there was no clear dose–response effect for azathioprine, implying that low dose azathioprine

(1.5mg/kg) may not be inferior to standard dose (144). Children younger than 6 years may

require higher doses of azathioprine per body weight with doses of up to 3mg/kg day (145, 146).

The relative risk of serious adverse events with thiopurines was found to be 2.82 in a Cochrane

meta-analysis of adult data (130). Thiopurine withdrawal rate due to adverse events in large

paediatric cohorts was 18% (147) and 30% (148). Dose-independent adverse reactions include

fever, pancreatitis, rash, arthralgias, nausea, vomiting and diarrhea, while dose-dependent

toxicities included leukopenia (up to 5%), thrombocytopenia, infections and hepatitis (149, 150).

A meta-analysis of studies of 6-MP found that it was tolerated in 68% of 455 adult patients who

were azathioprine-intolerant, lending support to switching between these drugs in cases of

specific dose independent adverse events (151). Switching in the case of pancreatitis has

traditionally not been recommended but some recent case series have challenged this notion

(151).

A meta-analysis (25,728 IBD patient-years) demonstrated that patients younger than 30 years

have a high relative risk for non-Hodgkin's lymphoma (SIR = 6.99) with younger men at the

highest risk but the absolute risk is much higher in the elderly. The absolute risk is estimated at 1

in 4000–5000 patients younger than 30 years (152). Hepatosplenic T-cell lymphoma (HSTCL) is

a very rare but fatal complication of thiopurine therapy. Of over 40 reported cases of IBD-related

HSTCL, almost all received thiopurines, with or without anti-TNF; there are only extremely rare

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

and anecdotal case reports of children with HSTCL who were treated solely with anti-TNF (153,

154).

TPMT assay (either phenotype or genotype) can be used before initiation of thiopurines to

identify some of the patients who are at risk for dose-dependent myelosuppression, and in whom

this drug should either not be used (if homozygous for variant alleles or have very low TPMT

activity) or administered at lower dosage (if heterozygous for variant alleles or having low

TPMT activity). TPMT testing does not, however, replace the need for mandatory monitoring of

complete blood cell count especially during initiation of treatment. In an adult study (155), a

significantly smaller proportion of carriers of a TPMT variant with adjusted dose developed

hematologic adverse events (RR=0.11). In a paediatric study, 7 of 46 (15%) carriers of at least

one variant allele or low/intermediate TPMT activity developed myelosuppression compared to

0/62 in the wild type/high activity group (156). In contrast, a study of 72 children showed no

association between TPMT polymorphisms and the occurrence of thiopurine-related adverse

events (157).

In the case of hyperactive TPMT resulting in high 6-MMP and low 6-TGN, concomitant use of

allopurinol with reduced dose of azathioprine may provide a valid therapeutic option (158, 159)

but needs to be used with caution. Adequate dose reduction and repeated monitoring of CBC and

6-TGN/6-MMP is essential to avoid myelosuppression related side effects. In adult trials,

allopurinol was used at 100 mg once daily (158, 160) whereas in the few paediatric case series

lower doses (50 mg or 75 mg once daily) were used in younger children (159, 161).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Therapeutic drug monitoring, namely measurement of thiopurine metabolites, specifically 6-

TGN and 6-methylmercaptopurine ribonucleotides (6-MMP) levels, has been implemented as a

means of optimizing efficacy and avoiding myelosuppression. In a meta-analysis which included

1026 IBD children (162), higher 6-TGN concentrations were not consistently associated with

leukopenia, while marginally associated with greater likelihood of clinical remission. High 6-

MMP levels correlated with hepatotoxicity, and low thiopurine metabolite levels with non-

compliance. In a retrospective study including 86 IBD children, 6-TGN levels of >250 pmol per

8x108 red blood cells correlated with a higher response rate (OR= 4.14) (163). The association

between both bone marrow toxicity and clinical response with 6-TGN levels was demonstrated

in prospective adult studies (164, 165) as well as several retrospective paediatric cohort studies

(163, 166, 167). Dose adjustment following measurement of metabolites was reported to increase

disease remission rate (168). Children with IBD were shown to experience fewer exacerbations

when thiopurine metabolites were measured (169). In a study of 78 IBD children, 6-TGN level

above 405 pmol/8X108 RBCs was the only predictor for azathioprine resistance (OR 10.8)

implying that patients with active disease and adequate 6-TGN level should receive alternative

therapies (170).

Thiopurine withdrawal after attaining sustained remission is controversial. In a retrospective

study of 127 UC patients in remission, ~one third relapsed within 12 months following

withdrawal, and two-thirds within 5 years (171). Moderate/severe relapse rate of 26% at 2 years

was observed in 108 UC patients who withdrew treatment following prolonged thiopurine

treatment (172).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Cochrane meta-analyses of methotrexate (MTX) for induction (2 RCTs, 101 patients) (173) or

maintenance (3 RCTs, 165 patients) (174) of remission in adult UC concluded that there is no

evidence supporting the use of MTX for either induction or maintenance of remission in UC.

Nevertheless, this conclusion relies on low quality evidence. In the METEOR double-blind,

placebo-controlled trial of 111 steroid-dependent UC adults, steroid-free remission at week 16

was not statistically different than placebo (32% vs. 20%, respectively; p>0.05) though clinical

remission did differ (42% vs. 24%, respectively; p=0.04) (175). In a retrospective study of 32

UC children unresponsive or intolerant to thiopurines, response/remission was achieved in 72%,

63% and 50% of patients treated with parenteral MTX at 3, 6 and 12 months respectively (176).

Tacrolimus has been studied in ambulatory UC patients (177). An RCT comparing high target

trough level of tacrolimus (10–15 ng/mL) vs. low trough level (5–10 ng/mL) vs. placebo in adult

moderate to severe UC patients who were hospitalized for the study, reported a significantly

higher response rate in the high trough group (68% vs. 38% vs. 10%, respectively) (178). A

retrospective cohort study of 25 ambulatory moderate to severe adult UC patients reported 52%

clinical improvement and 44% clinical remission at 6 months (179). Three small retrospective

paediatric studies, including 18 steroid refractory/dependent UC patients (180), 10 (181) and 8

(182) steroid resistant patients treated with tacrolimus, reported 50% to 95% response rate;

however colectomy was eventually performed in most patients during the follow-up period. In a

subgroup analysis, steroid dependent patients had a significantly higher long-term colectomy free

rate when compared with steroid refractory patients (78% vs. 0%) (180).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Biologics

Recommendations:

1. Infliximab should be considered in chronically active or steroid-dependent UC,

uncontrolled by 5-ASA and thiopurines, for both induction and maintenance of remission

[EL2, adults EL1] (100% agreement)

2. Adalimumab [EL4, adults EL4] or golimumab [EL4, adults EL3] could be considered in

those who initially respond but then lose response or are intolerant to infliximab, based

on serum levels and antibodies (Figure 3) (95% agreement)

3. Adalimumab and golimumab have no role in patients with primary non-response to

infliximab [EL4, adults EL4] (93% agreement)

4. Vedolizumab should be considered in chronically active or steroid-dependent patients as

second line biologic therapy after anti-TNF failure [EL4, adults EL2] (95% agreement)

Practice points:

1. Screening for latent tuberculosis with combination of patient history, chest X-ray, tuberculin

skin test or interferon-gamma release assays (quantiferon) is essential before initiating

anti-TNF. The quantiferon test is preferred in patients under immunosuppressive therapy

and in BCG immunized patients. Screening for hepatitis B and C viruses, varicella zoster

virus, and HIV when appropriate, is also recommended if not done recently (95%

agreement).

2. In ambulatory patients with UC, infliximab should be administered initially at 5mg/kg/dose

(at weeks 0, 2 and 6 followed by 5 mg/kg every 8 weeks for maintenance). Higher initial

dosing should be considered in children with low body weight (<30kg) or high BMI, and

in the presence of higher inflammatory burden and hypoalbuminemia. Target trough

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 levels post induction (week 14) and subsequent doses are reported in different studies as

>4-5µg/ml. Rapid infusion (over 1 hour) seems as safe and effective as traditional slower

infusions, if the induction doses were well tolerated and dose is stable (98% agreement).

3. Infliximab is recommended to be used preferably in combination with an immunomodulator

(IMM) (with the most evidence in UC being thiopurines) in order to reduce the likelihood

of developing antibodies to infliximab (ATI) and in thiopurine-naïve patients to enhance

effectiveness. Discontinuation of the IMM may be considered after 6 months, especially

in boys, preferably after ensuring trough IFX level>5µg/ml, since levels may decrease

after stopping IMM (98% agreement).

4. The utility of combination adalimumab, golimumab and vedolizumab with thiopurines is

more controversial and they are most commonly prescribed as monotherapy in children

(100% agreement).

5. Golimumab recommended doses for induction are 200mg at week 0 followed by 100mg at

week 2 for those weighing ≥45kg. Children with lower weight should be dosed based on

body surface area (BSA) (115 and 60mg/m2 at weeks 0 and 2). Maintenance doses q4w

are 60mg/m2 if weight <45kg and 100 mg if weight ≥45kg. Target trough levels during

maintenance are >2 mcg/ml (100% agreement).

6. Extrapolating from paediatric Crohn’s disease, adalimumab should be started at 160mg,

followed by 80mg after two weeks and then 40mg every other week in adolescents with

weight >40kg. Optimal dosing in younger children has not been well defined, but BSA-

based dosing could be considered taking as a base an adult BSA of 1.73m2 (i.e. induction

with 92 mg/m2 followed by 46mg/m2 followed by 23mg/m2 every other week for

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 maintenance). Adalimumab target levels during maintenance are reported in different

studies as >5-8µg/ml (100% agreement).

7. Measurement of drug levels and anti-drug antibody levels following induction (i.e. at the

week 14 infusion for infliximab and at 8-10 week for adalimumab) can assist in

optimizing treatment. Measuring drug levels is also useful in the assessment of

unsatisfactory response to anti-TNF to guide dose escalation or a switch to another

biologic (see text) (98% agreement).

8. Standard vedolizumab dosing in adults has been adapted in paediatric studies (5mg/kg up to

300 mg per dose at weeks 0, 2, 6 followed by every 8 weeks thereafter). For those

weighing <30kg, higher dose per kg is required, but BSA-based calculation may be

preferred (i.e. 177mg/m2). The effect of vedolizumab in UC has been described to occur

by week 6 of treatment, but complete response may not be apparent until week 14.

Shortening of interval between infusions to 4 weekly may be required during

maintenance in partial responders (93% agreement).

9. In patients with persistent symptomatic distal inflammation despite adequate optimal anti-

TNF treatment, addition of rectal therapies (preferably 5-ASA) could be beneficial (98%

agreement).

A Cochrane systematic review of 7 adult UC trials concluded that infliximab is effective in

inducing clinical remission, promoting mucosal healing, and reducing the need for colectomy in

patients with active UC (183). Combination therapy with infliximab and azathioprine was shown

to be superior in the SUCCESS trial in adult UC to monotherapy with azathioprine or infliximab

alone, while there was no superiority of IFX monotherapy over azathioprine (184).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

In the paediatric UC controlled trial (i.e. the T-72 study), 45 of 60 (75%) ambulatory children

with moderate-severe UC responded to a standard induction protocol of infliximab (185). Both

clinical remission (PUCAI<10 points) and complete mucosal healing (Mayo endoscopic

subscore=0) were achieved in 33% at week 8. Dose escalation to 10mg/kg was required in 44%

of the patients in the maintenance phase.

Different studies in children have shown a pooled long-term success rate of infliximab in UC of

64% (186), and a corticosteroid-free remission of 38% and 21% at 12 and 24 months,

respectively, with a likelihood of avoiding colectomy at 2 years of 61% (187). A relationship

between the increased use of anti-TNF agents and the reduction of surgery risk for UC children

has also been suggested (188).

Adalimumab has shown efficacy and safety for induction and maintenance in the adult moderate-

to-severe active UC. In the adult ULTRA-1 trial, clinical remission was obtained in 18.5% of

patients in the 160/80mg group, 10% in the 80/40mg group and 9.2% in the placebo group (189).

In the ULTRA-2 trial, overall rates of clinical remission for active drug at week 52 were 17.3%,

with better results among anti–TNF naïve patients (22%) as compared to those anti-TNF

experienced (10.2%) (190). A network meta-analysis of 5 RCTs in moderate to severe adult UC

suggested that while infliximab is more effective than adalimumab in the induction of remission,

response and mucosal healing, both are comparable in efficacy at 52 weeks of maintenance

treatment (191). Another meta-analysis showed superiority of infliximab over adalimumab in

inducing and maintaining endoscopic healing in UC (192). In a propensity score adjusted

analysis, a study of 419 adults with UC found no difference in the effectiveness of these agents,

but the adalimumab group was relatively small (193).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

In a retrospective cohort study of 188 children, Vahabnezhad et al showed that 60% of UC

children who discontinued infliximab were commenced on adalimumab, with 83% of these

remaining on adalimumab at last follow-up (194). In another retrospective study, 55% of UC

children switched to adalimumab after infliximab failure, achieved and maintained clinical

remission at a median of 25 months while 36% underwent colectomy (195). There are no

published data on adalimumab in UC children naïve to anti-TNF.

A second subcutaneously administered, fully human anti-TNF agent, golimumab, has been

studied in placebo-controlled trials among anti-TNF naïve adults with moderately-severely active

UC in the PURSUIT-SC (196) for induction, and PURSUIT-M (197) for maintenance.

Golimumab use in paediatric UC was studied in an open-label pharmacokinetic study of 35

children with moderate-severe UC (198, 199). Doses given subcutaneously at weeks 0 and 2

were 90mg/ m2 and 45mg/m2 for children weighing <45kg and 200mg followed by 100mg for

those weighing ≥45kg. Maintenance doses of 45mg/m2 if weight <45kg and 100mg if weight

≥45kg were given every 4 weeks. Among week 6 Mayo clinical responders (60%) who

continued to receive q4w golimumab maintenance, 57% were in PUCAI remission at week 14.

Complete mucosal healing at week 6 was achieved in 23%, slightly higher than reported in the

adult trials. While the PK data of the entire paediatric cohort were comparable with those

previously reported in the golimumab adult trials, drug levels in the subgroup of children

weighing <45kg were numerically lower than those ≥45kg. This likely stems from the under-

dosing of the former group. The equivalent dosing of 200mg in adults and adolescents would

translate to 115mg/m2 in BSA (considering 200mg/1.73m2) followed by 60mg/m2 for

maintenance. Given the lower drug levels in the paediatric study, these higher doses should be

considered in practice.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

In general, response to anti-TNF medication can occur as early as 1–4 weeks and peaks by week

12-16 of treatment (200) (189) (190). During induction, trough level of ≥15ug/ml at week 6 best

predicted likelihood of short-term mucosal healing (area under the ROC of 0.69) (201).

Recommended optimal levels for infliximab during maintenance therapy for improved clinical

outcomes has been defined as >4µg/ml (202, 203) (204), for adalimumab >5µg/ml (205, 206)

and for golimumab >1.4µg/ml (207). However, for mucosal healing, adult studies from both UC

(208, 209) and CD (209, 210) suggested that higher adalimumab level ≥7.1-9.4 μg/ml may be

more appropriate. Similarly, infliximab trough levels >5µg/ml were associated with mucosal

healing in adult IBD (209) and with a decreased risk for loss of response when withdrawing

concomitant immunomodulators (211). The American Gastroenterological Association (AGA)

guidelines thus recommends using higher cut-off values of ≥5ug/ml for infliximab and

≥7.5ug/ml for adalimumab (212).

Drug and antibody levels should dictate the course of action in patients with secondary loss of

response (213) (Figure 3). Ongoing symptoms despite adequate drug levels, mandates switching

therapy “out of class”. High antibodies titre predicts failure of dose intensification (213) (Figure

3).

Factors predicting lower drug levels (and thus possibly dictating higher dosing) include higher

body mass index (214), low body weight <30kg (215-217), male gender (218), high

inflammatory burden (extent and severity of disease) (219), hypoalbuminemia (220), the

presence of anti-drug antibodies, and the absence of a concomitant immunomodulator (221, 222)

(184) (223).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Safety issues of anti-TNF include acute infusion reactions (within 4 hours of infusion), delayed

hypersensitivity reactions (beyond 4 hours and up to 14 days), serious and opportunistic

infections (224), and a potential risk of skin cancer; evidence to date does not indicate that anti-

TNF is associated with lymphoma if prescribed as mono-therapy, but a recent study challenges

this concept (225). Psoriasis has been well documented as an adverse class effect of anti-TNF,

but it is usually mild and controllable in the majority of patients with topical therapy (226). Other

very rare adverse events, such as demyelination events and optic neuritis, have been reported

(227).

There is no clear evidence that pre-medication with any drug prevents the development of acute

infusion reaction (228, 229). A self-reporting system in the USA with more than 5000

documented patients calculated a rate of infusion reactions of 3% (1.1% immediate and 1.7%

delayed) in IBD-treated patients (230).

Required infectious screening prior to initiation of anti-TNF treatment includes testing for HBV,

HCV, HIV, VZV, and tuberculosis according to local prevalence and national recommendations

(231). The risk of reactivation of other viruses (e.g. CMV, EBV) is not clear. A recent systematic

review and meta-analysis including 49 RCT comprising >14,000 patients treated with biologics

(anti-TNF, natalizumab, and vedolizumab) concluded that their use has a moderate risk of any

infection (OR 1.19 (95%CI 1.1-1.29)) and a significant risk of opportunistic infections in IBD

(OR 1.90 (1.21-3.01)) (232). In another study, the estimated risk of severe infections in IBD

patients treated with anti-TNF has been reported as 2.2% (233). Concomitant

immunosuppressant treatment, particularly steroids, is an additional risk for opportunistic and

other infections. Surprisingly, the meta-analysis found a reduced risk of serious infections (OR

0.56 (0.35-0.9)) and no increased risk of malignancies (OR 0.9 (0.54-1.5)), but for the latter

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

outcome the data were insufficient in terms of exposure and follow-up period (232). Studies

report conflicting results regarding the risk of anti-TNF and the risk for melanoma and non-

melanoma skin cancer (234, 235).

DEVELOP is a prospective post-marketing industry-initiated safety registry for paediatric IBD,

which includes both patients exposed and never exposed to infliximab (236). In 5766 patients

(29% UC; 24,543 patient years follow-up; median 4.5 years per patient follow-up) there were 15

malignancy events (13 exposed to thiopurines (10 with infliximab; 3 thiopurine only); 1 only to

infliximab; 1 to neither biologics nor thiopurines). Comparison with rates from the SEER

database of healthy controls indicated a standardized incidence rate (SIR) for neoplasia 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

(SIR 1.49, 95% CI 0.04-8.28). Five children in total experienced hemophagocytic lymphocytic

histiocytosis (HLH), 4 with primary EBV infection, one with CMV infection, and all during

thiopurine monotherapy.

Vedolizumab is a humanized anti-α4β7 integrin that downregulates intestinal inflammation by

specifically inhibiting intestinal T-lymphocyte migration into the tissue. In the adult GEMINI-1

study in UC, 47% of patients responded to 2-dose induction (300 mg per dose) by week 6 and

were re-randomized to continued vedolizumab 300 mg intravenously (q 4 weekly vs q 8 weekly

vs placebo). The 52 week remission rates among initial week 6 responders were 42% (q8w) and

45% (q4w) (237), regardless of the prior anti-TNF exposure status (238) (239). This is supported

by pharmacokinetic data demonstrating significant correlation between higher vedolizumab drug

levels and clinical response in IBD patients.(240-242)

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Experience with vedolizumab in paediatric UC is currently limited to small retrospective cohorts,

almost all with prior anti-TNF failure. The 14 week remission rates were 37% (n=41 definition

of remission included steroid-free and utilized ITT rates) (243), 40% (n=5; (244)), and 76%

(n=22 (245)). The 22 week corresponding remission rates in the three studies were 34%, 40%,

and 71%, respectively.

There is no evidence that combination therapy with IMM is superior over sole vedolizumab

treatment based on limited data from adults (246) and children (243).

Limited safety data are reported for vedolizumab in children. Conrad et al reported 29 adverse

events in children including upper respiratory tract infections, nausea, fatigue, headaches,

nasopharyngitis, skin infections and sinusitis (244). Pruritus, infusion reaction and

nasopharyngitis (one each) was also reported by the Paediatric IBD Porto group of ESPGHAN

(243).

In a recent network meta-analysis in adults, infliximab, adalimumab, golimumab and

vedolizumab were all superior to placebo for maintenance of remission and response, however

superiority of one agent over another could not be clearly established (247). Similar non

superiority was shown between infliximab and adalimumab in UC (193). However, another

indirect meta-analysis showed superiority of infliximab over adalimumab; the difference reached

statistical significance only at week 8 (OR for mucosal healing was 0.46 (95CI% 0.25-0.84) in

favour of infliximab at week 8 and 0.5 (0.23-1.11) at week 52) (191).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Other interventions

Recommendations:

1. Granulocyte/monocyte apheresis should not be routinely used in paediatric UC [EL4,

adult EL2] (100% agreement)

2. Faecal microbiota transplantation (FMT) should not be routinely used in paediatric UC

[EL4, adult EL1] (100% agreement)

3. Antibiotics should not be routinely used for induction or maintenance of remission of

paediatric UC [EL5, adult EL2] (100% agreement)

4. Probiotic agents (e.g. VSL#3, E. coli Nissle 917) may be considered in mild UC as an

adjuvant therapy or in those intolerant to 5-ASA [EL2, adult EL2] (100% agreement)

5. Curcumin may be considered as an add-on therapy for inducing and maintaining clinical

remission of mild-to-moderate UC [EL4, adult EL1] (91% agreement)

6. Germinated barley foodstuff, omega-3, aloe vera, herbal medicine and intravenous

immunoglobulin, are not recommended as primary treatment [EL5, adult EL2] (98%

agreement)

Practice points:

1. If apheresis is considered, then the most commonly utilized scheme involves one

session/week of granulocyte/monocyte apheresis for 5–10 consecutive weeks (93%

agreement).

2. VSL#3 dosing may be seen in Table 5. E. coli Nissle 1917 strain is prescribed as

200mg/day in adults and adolescents. No dosing recommendation is available for young

children (98% agreement).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 3. Neither the formulation nor dosage of curcumin (the active ingredient of tumeric/curcum)

are established for children but evidence suggests that it can be safely used up to 4g/day

for induction and up to 2g/day during maintenance. The induction dosing of an ongoing

paediatric trial is as follows: (all doses are daily, prescribed as two divided doses): 4g for

children over 30 kg, 3g for 20-30 kg and 2g for those under 20 kg (safety has not been

established in infants). Doses may be halved for maintenance treatment (98%

agreement).

Apheresis acts by an extracorporeal removal of leukocytes and other cells of the immune system

(granulocytes, granulocyte/monocyte) through an adsorptive system of cellulose acetate beads

(Adacolumn®, Otsuka Pharmaceuticals), or a polyester fibre filter (Cellsorba®, Asahi Medical

Company). Overall, paediatric data suggest a possible clinical efficacy of apheresis in children

with both steroid-dependent and resistant UC, with reported response rates ranging between 60

and 85%, although they are mainly small case series or cohort studies (248-253). Data in adults

are conflicting, with some observational and randomized clinical trials suggesting benefit (254-

259), others, among them a large randomized, double-blind clinical trial evaluating active versus

sham apheresis, showing no efficacy (260). A systematic review published in 2010 reported that,

although there may be some efficacy in specific settings, concerns about methodological quality

of identified studies prevent a rigorous meta-analysis and definitive conclusions (261).

FMT is based on the transfer of stool from a healthy donor, with a presumed healthy diverse

microbiome, to a patient. Related or unrelated donors can be used, and they must undergo an

accurate clinical and laboratory screening before the procedure. Some studies have used

specifically-prepared fresh stools, although frozen stools seem to have the same efficacy and

safety (262), with delivery both to the upper gastrointestinal tract through nasogastric tube or to

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

the lower GI tract through colonoscopy or serial enemas. A few case series on the efficacy of

FMT in paediatric UC have been published, reporting inconclusive results (263-265). The largest

paediatric series (9 children with UC) showed a 33% clinical remission (PUCAI<10) with serial

enemas (263). One small paediatric study reported no clinical improvement after FMT delivered

via nasogastric tube (264). Overall, the safety profile appears acceptable, although mild-to-

moderate side effects were common, and a case of transitory systemic reaction (profuse

sweating, vomiting, paleness, tachycardia and fever) has been reported (266). There may be a

theoretical risk pertaining the transfer of an adult microbiome to a child, particularly very young

with a developing microbiome, to quickening of immune aging and developing immune-related

consequences (267). Rapid weight gain and the development of autoimmune disease have been

reported after FMT in adults and in animal models (268, 269) (270).

Two small RCT in adults with active UC reported different results: one showed clinical and

endoscopic benefit of FMT administered via enema compared to sham (271); the other reported

no difference between FMT using healthy donors or autologous faeces administered via naso-

duodenal tube, although the limited number of patients and the route of administration may have

impacted on these results (272). Interestingly, patients who responded to FMT from a healthy

donor restored their altered microbiota toward the healthy donor composition, while non-

responders had no changes. Recently, the results of a third large, randomized, placebo-controlled

trial in active UC resistant to conventional treatment have been reported (273). Eighty-one adults

with UC were randomized to receive a single FMT or placebo colonoscopic infusion on day 1,

followed by FMT or placebo enemas 5 days per week for 8 weeks. Each active enema was

derived from 3-7 unrelated donors. Steroid-free clinical remission with endoscopic response was

achieved in 11/41 (27%) patients receiving FMT compared to 3/40 (8%) patients receiving

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

placebo (p = 0.02). Microbial diversity increased and persisted after FMT while Fusobacterium

spp was associated with lack of remission. Although FMT is gaining increased enthusiasm, the

ideal donor and method of administration should be first determined before this can be

incorporated outside the research setting.

Probiotics have been evaluated for induction and maintenance of remission in UC. One

paediatric and three adult trials found E. coli Nissle 1917 to be as successful as mesalamine in

maintaining remission (274-277). The dosage used in all these studies, including the paediatric

one, is 200 mg/day (100 mg contains 25 × 109 viable E. coli bacteria), administered as capsules.

A recent systematic review and meta-analysis suggests that E. coli Nissle is equivalent to

mesalamine to prevent relapse, while its efficacy is comparable to placebo in the induction of

remission (278). However, a previous Cochrane systematic review highlighted several

methodological limitations in the maintenance studies, preventing any conclusion (279).

A small randomized, placebo-controlled trial of 29 children treated with 5-ASA reported that the

combination of VSL#3 in conjunction with concomitant steroid induction and mesalamine

maintenance treatment was superior to placebo in inducing and maintaining 1-year remission

(280). A small open-label study in 18 children with mild-moderate UC evaluated the efficacy of

VSL#3 added to standard treatment with 56% remission rate (281). Overall, adult data suggest a

therapeutic benefit of VSL#3 in the maintenance of remission, supported by a systematic review

(282). Studies on VSL#3 in IBD patients were performed on the original formulation containing

8 bacterial strains (Lactobacillus paracasei DSM 24733, Lactobacillus plantarum DSM 24730,

Lactobacillus acidophilus DSM 24735, Lactobacillus delbrueckii subspecies bulgaricus DSM

24734, Bifidobacterium longum DSM 24736, Bifidobacterium infantis DSM 24737,

Bifidobacterium breve DSM 24732, and Streptococcus thermophilus DSM 24731). Changing the

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

manufacturing processes by different manufacturers may not have the same clinical efficacy and

safety. Scarce published data report varying content of live/dead bacteria in various VSL#3

products and differences in effect on intestinal epithelial cell status (283, 284). However, more

studies are needed to confirm these data and no changes in the recommendations are warranted at

this stage. One randomized paediatric trial showed that rectal enemas of Lactobacillus reuteri

ATCC 55730, added to oral mesalamine, were superior to placebo for inducing remission in left-

sided UC (285).

Antibiotics have been evaluated as a therapy for UC both in the induction of remission and to

prevent disease relapses as shown in two systematic reviews and meta-analyses (286, 287). Both

included 9 RCTs and concluded that antibiotics may improve outcomes in UC, but further

studies are required to confirm this benefit since the included trials were very heterogeneous in

their methodology and the type of drug intervention. The use of antibiotics in treating paediatric

UC outside the research setting awaits further trials.

Recently, a small case series on the tolerability of curcumin added to standard therapy in

paediatric IBD has been published, reporting an acceptable tolerability and a possible signal of

benefit (288). Two placebo-controlled trials conducted in adults suggested the possible efficacy

of curcumin in achieving and maintaining sustained clinical remission (289, 290). Moreover,

endoscopic remission was observed in 38% (8/22) patients treated with curcumin, compared with

0% (0/16) in the placebo group (290). A recent randomized, placebo-controlled, pilot study

reported efficacy of topical curcumin as enema, added to oral mesalamine, compared to placebo,

in 45 adults with mild-moderate proctitis/proctosigmoiditis (291).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Systematic review of complementary and alternative medicine treatments in IBD, including aloe-

vera, andrographis paniculata, artemisia absinthium, barley foodstuff, boswellia serrata,

cannabis, evening primrose oil, Myrrhinil intest®, plantago ovata, silymarin, sophora, tormentil,

wheatgrass-juice and wormwood reported a possible benefit of some interventions, although,

given the small number of trials and their heterogeneous methodological quality, no definite

conclusions could be drawn (292, 293). Of note, oral aloe- vera has been evaluated in a double-

blind, randomized, placebo-controlled trial as an adjuvant therapy in 44 adults with mild-to-

moderate UC (294). Higher remission and response rates with improvement of the histological

score were reported in the aloe-vera group. These encouraging but preliminary findings await

confirmation before aloe-vera can be recommended for clinical practice.

Other complementary therapies, including germinated barley foodstuff and herbal medicine have

been studied in adult case series or prospective cohorts. Because of sample size, study design,

concomitant therapies and methodological limitations, these agents cannot currently be

recommended for treating paediatric UC (292, 293, 295).

A systematic review and a meta-analysis reported no efficacy of omega-3 supplement for

maintaining remission in UC (295-297). Recently, a retrospective individual cohort study of 24

adults with IBD suggested efficacy and safety of intravenous immunoglobulin (IVIG) in the

short-term management, when standard therapies are contraindicated (298). However, there are

no RCTs on its role both in adults and children.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

IBD-unclassified (IBD-U)

Recommendation

10. Treatment of IBD-U patients should broadly follow that of UC patients of a similar disease

severity [EL4, adult EL5] (98% agreement)

Practice points

1. A diagnosis of IBD-U should only be made after a full assessment including

ileocolonoscopy, gastroscopy and small bowel imaging (100% agreement).

2. A lower threshold for disease reassessment should be adopted in patients with IBD-U

prior to treatment change (95% agreement).

3. Although not validated for this indication, it is reasonable to use the PUCAI score to

assess disease activity also in IBD-U given the similarity of IBD-U, clinically, to UC

(98% agreement).

4. A multi-item algorithm should be used to standardize the diagnosis of IBD-U (Figure 1;

Table 1) (98% agreement).

5. While ASCA+/ANCA- profile is more suggestive of CD, and ASCA-/ANCA+ of UC,

their diagnostic accuracy is too low to be used in isolation in the setup of IBD-U (98%

agreement).

Patients with IBD-U represent approximately 5-10% of paediatric IBD without a decline in

incidence over time despite improved diagnostic measures. The rate is even higher in very early

onset IBD. Complete examination is important, however, and the proportion of patients with

IBD-U is reduced if a full diagnostic work up is performed (299). IBD-U is not a

misclassification but rather a true overlap diagnosis within the spectrum of phenotypes between

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

UC and Crohn's colitis (12). Historically, patients with IBD-U have often been poorly classified

with no specific guidance available for detailed diagnostic criteria. The PIBD-Classes criteria

were validated on a large multicentre dataset of 749 patients with colonic IBD from the

Paediatric IBD Porto group of ESPGHAN (12). A diagnostic algorithm combining 23 features of

different weightings (grouped in class 1,2 and 3 features) (Table 1) may differentiate between

patients with UC, atypical UC, IBD-U, Crohn’s colitis and ileal/ileocolonic Crohn’s disease

(Figure 1)(12).

Given the rarity of IBD-U and the hitherto lack of standardized diagnosis, there are very few

studies which have been able to collect treatment information on significant numbers of patients.

The aforementioned retrospective study from the Porto group of ESPGHAN utilized the data of

537 children with colonic IBD, including 260 IBD-U, to explore common treatment schemes and

to compare the treatment outcomes (300). This study demonstrated that treatment for IBD-U and

UC were broadly similar with the most common treatment used initially being 5-ASA. The use

of steroids was lower than in UC; thiopurines and infliximab use was broadly similar to patients

with UC and lower than for patients with Crohn’s disease. Rates of surgery were lower than in

Crohn’s disease and UC and the disease was more likely to be mild at follow up compared to the

other IBD subtypes, despite the similar use of medications as in UC. This suggests that treatment

can follow that of UC initially with a 5-ASA regimen.

SURGICAL CONSIDERATIONS (related to both Part 1 and 2 of these guidelines)

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

The surgeon’s perspective

Recommendations:

1. Elective colectomy should be considered in children with active, or steroid-dependent, UC

despite optimized medical therapy, and in those with colonic dysplasia [EL4, adult EL3]

(98% agreement)

2. Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA; J pouch) and a

covering loop-ileostomy is the recommended elective surgery for paediatric UC [EL3,

adult EL3] (93% agreement)

3. Three stage procedure (subtotal colectomy with ileostomy first) is recommended for

patients with acute severe colitis, treated with high-dose steroids or recent anti-TNF

therapy, severe malnutrition, or IBD-U; however, the final choice of the surgical approach

should be individualized [EL4, adult EL3] (98% agreement)

4. A minimally invasive laparoscopic approach is recommended in children as there are

equivalent outcomes to open surgery both for urgent and elective cases and possibly

superior outcomes regarding fertility in girls [EL4, adult EL3] (100% agreement)

5. Pouch surgery for children with UC should be performed by experienced paediatric or

adult surgeons in high volume centres performing at least 10 pouches per year (100%

agreement)

Practice points

1. Crohn's disease must be excluded before the time of surgery, through a diagnostic work-up

including ileocolonoscopy, gastroscopy and small bowel imaging, prior to colectomy, as

clinical status allows (100% agreement).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

2. Functional outcomes and surgical complications are comparable after hand-sewn and stapled

IPAA. The length of remaining anorectal mucosa between the dentate line and the

anastomosis should not exceed 2cm, regardless of anastomotic technique (100%

agreement).

3. IPAA without a covering loop ileostomy (i.e. one stage procedure) may be considered in

selected children with mild disease and good nutritional status without anti-TNF or steroid

treatment, provided that no technical difficulties or anastomotic tension occur during surgery;

however, the final choice of the surgical approach should be individualized (98%

agreement).

4. There is no published evidence on whether postponing pouch surgery after subtotal

colectomy, for example until after puberty, influences long-term outcomes after IPAA. If

pouch surgery is delayed, a strategy to maintain the rectal stump free of inflammation should

be discussed, based on topical treatment (100% agreement).

5. The role of ileo-rectal anastomosis (IRA) remains controversial. It may be offered to selected

female patients, who are particularly concerned about the risk of reduced fertility associated

with IPAA. Information on higher failure rate and the need for life-long cancer surveillance

should be provided (98% agreement).

6. Treatment with steroids (prednisolone >0.25 mg/kg/day or >20 mg/day) is associated with an

increased risk of surgical complications, whereas thiopurines and calcineurin inhibitors are

not. There are insufficient data regarding vedolizumab. Anti-TNF increases the risk in

Crohn’s disease and according to the precautious principal, colectomy should be preferably

performed 4-6 weeks after the last infliximab infusion if it can be safely postponed (93%

agreement).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Surgery for paediatric UC may require up to 3 staged procedures – first stage, subtotal colectomy

with end-ileostomy; second stage, restorative procto-colectomy with ileal pouch-anal

anastomosis or ileo-rectal anastomosis (with or without covering ileostomy); third stage, closure

of the covering ileostomy. The decision concerning the best combination of procedures is

dictated by the clinical status of the patient. Restorative procto-colectomy and IPAA/IRA with

covering ileostomy can be performed as a combined first stage for most ‘ambulatory’ elective

UC cases. The covering ileostomy is reversed several months later after confirmed healing of the

pouch (301-305). Three-stage surgery (subtotal colectomy and ileostomy first) is recommended

for ASC, for example where the pre-operative PUCAI is >45, or in those on high-dose pre-

operative steroids (prednisolone >0.20mg/kg/day) (36, 303). Although single stage restorative

procto-colectomy IPAA without a covering ileostomy was not associated with increased

anastomotic complications in some retrospective paediatric series (302, 306-308), this cannot be

recommended before more studies are available given the retrospective design of the studies and

the inherent confounding by indication bias.

Emergency surgery for ASC is an initial subtotal colectomy (leaving a rectal stump) with end-

ileostomy formation only. Creation of IPAA/IRA should be deferred until the clinical status of

the patient has normalized, followed by stoma closure as the third stage. Laparoscopic

colectomy/ileostomy for both ASC and ambulatory UC is safe and feasible in experienced hands

also in children (36, 309). The PUCAI has been reported in a retrospective analysis to be a useful

tool when considering 1 vs. 2 vs. 3 stage procedures for paediatric UC (36).

As significant complication rates are reported after colectomy for both ASC and ambulatory UC

in children, in particular infectious and thromboembolic events (8, 310), peri-operative antibiotic

and thromboembolism prophylaxis should be routine. The rectal stump can be fashioned as a

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

mucous fistula (open or within the subcutaneous tissue) if there is significant proctitis. A more

commonly used alternative is to close the rectal stump within the abdomen and place a

temporary trans-anal drain (311). Length of hospital stay, short-term surgical complications and

functional outcomes seem similar after open and laparoscopic procedures (302, 312-314).

Steroid treatment, hypoalbuminemia and malnutrition are also associated with increased surgical

complication rates (315). In ASC, children are likely to have been on recent steroid therapy and

may be in a relatively poor nutritional state, but surgery when needed should not be delayed to

correct this. Thiopurine and calcineurin inhibitors were not associated with postoperative

surgical complications (315-317), while current retrospective paediatric data on anti-TNF

regimens are controversial (315, 316, 318). Meta-analysis of adult data shows an increased risk

of surgical complications in patients who had been on pre-operative anti-TNF therapy in CD but

not in UC (319, 320).

According to a meta-analysis of five paediatric studies (306 patients), straight ileo-anal

anastomosis (SIAA) was associated with a higher failure rate (15% vs 8%) and perianal sepsis

(20% vs 10%), as well as a higher stooling frequency as compared with a J-pouch ileo-anal

anastomosis (JPAA) (321). A more recent multicenter study, including 112 children with SIAA,

and 91 with JPAA, reported comparable postoperative complication rates (322). Both day-time

and night-time stooling frequency were higher after SIAA, although the difference became less

apparent by two years (mean 24-hours stooling frequency 8.4 vs 6.2 at two years). This

difference may still be clinically important, because quality of life in children after restorative

proctocolectomy is inversely associated with stooling frequency (304).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

JPAA, on the other hand, carries a risk of pouchitis, which clearly exceeds the incidence of

enteritis following SIAA (49% vs 24%, OR 4.5; see henceforth detailed chapter on the pouch)

(322). Surgical complications and functional outcomes are comparable after hand-sewn or

stapled J-pouch anastomosis. For example, in one series, stool frequency was 4/day after both

techniques (301, 323, 324). However, a common complication of stapled IAA is an undesirably

long rectal stump with excessive remaining anorectal mucosa above the dentate line (> 2 cm).

Chronic inflammation of the rectal mucosal remnant, is called ‘cuffitis’ and discussed further

below. One study reported a lower rate of small bowel obstruction during four post-operative

years after laparoscopic IPAA compared to open procedures (312), while no difference was

found in another (302).

In those undergoing IPAA, the diagnosis of UC may change to CD; ~15% in adult series (301,

304, 305, 325) and 11 of 128 children (9%) in a recent multi-center paediatric study from the

Paediatric IBD Porto group of ESPGHAN (326, 327). Three-stage IPAA has been used to avoid

these complications in children with IBD-U. However, histology of a colectomy specimen or

pre-operative diagnosis of IBD-U poorly predicts the long-term outcomes of IPAA in adults with

UC (328, 329). In most studies the incidence of pouchitis and post-operative diagnosis of CD is

similar after IPAA in patients with UC and IBD-U (323). There is no published evidence on

whether postponing pouch surgery after subtotal colectomy for an extended period of time

influences the rate of complications or long-term outcome after IPAA. Overall, results from

paediatric series of IPAA in terms of later pouch abandonment (<15% at median 10 to 20 years

follow-up) are similar to adult reports, albeit with shorter length of follow-up in most series (302,

304, 330). A multicenter, retrospective study from the Paediatric IBD Porto Group of ESPGHAN

included 129 children who underwent IPAA, showed an increased rate of surgical complications

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

in children undergoing colectomy under the age of 10 years but there was no difference in

complications rate whether the pouch surgery was delayed or not (326).

While IPAA has been shown to reduce female fecundity and fertility in adult studies, most used

the non-stringent definition of inability to become pregnant within 1-year of intent (324, 325).

This should be discussed with female patients and their family before any surgical procedures.

IPAA surgery decreases fertility rate by 52% among women with IBD aged 15-44 years (325).

Laparoscopic IPAA, as is increasingly performed, may ameliorate the risk of subfertility due to

reduced adhesion formation, pelvic scarring and Fallopian tube obstruction (331-333). In one

adult series, spontaneous pregnancy rate was higher after laparoscopic IPAA (70%) compared to

open IPAA (39%, p=0.023) among 50 women who attempted to conceive (328). Fertility is also

much better preserved after IRA (302). Fecundity remained similar to the general population

after IRA, but dropped to 54% after IPAA among women with familial adenomatous polyposis

(329). In a recent follow-up study of 343 adults with UC, 10-year and 20-year IRA failure rate

was 27% and 40% respectively (330). Secondary proctectomy was required for refractory

proctitis (66%), dysplasia (11%) and for cancer (10%) (334). At the end of the follow-up, 18%

had undergone secondary IPAA and 13% had permanent ileostomy. Although faecal continence

and stooling frequency is better preserved after IRA compared to IPAA, most patients require

anti-inflammatory medication and urgency rate is higher, while quality of life similar to that after

IPAA (330).

Data from the Porto group of ESPGHAN suggest that the experience of the surgeon is associated

with the likelihood of development of chronic pouchitis; (15%) in surgeons with >10

surgeries/year vs (41%) in surgeons with <10/year, p=0.013 (327). This is in line with a large

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

study from the UK showing the pouch outcome was superior if done in centres performing at

least 9-10 procedures annually (335).

Pouchitis and cuffitis

Recommendations:

1. Pouchoscopy with mucosal biopsies should be performed at the first suspected episode of

pouchitis [EL3, adult EL3] (95% agreement)

2. A 14 day course of ciprofloxacin and/or metronidazole is recommended as first-line

therapy for pouchitis while the former may be more effective [EL5, adult EL1] (100%

agreement)

3. Combined metronidazole and ciprofloxacin or oral/topical budesonide can be used in

persistent cases [EL5, adult EL2] (98% agreement)

4. In recurrent and/or chronic pouchitis, VSL#3 is recommended for maintaining remission

[EL5, adult EL1] (98% agreement)

5. Topical mesalamine is recommended for treating cuffitis [EL 5, adult EL4] (100%

agreement)

Practice Points:

1. A clinically useful categorization of pouchitis is "antibiotic-responsive" (i.e. infrequent

episodes (<4/year) each with a rapid response to a 2-week course of a single antibiotic,

"antibiotic-dependent" (i.e. frequent episodes (>4/year) or persistent symptoms which

require long-term antibiotic therapy to maintain remission) and "antibiotic-refractory"

(i.e. failure to respond to a 4-week course of antibiotics, necessitating an alternative

therapy of 4 weeks or longer). Duration of pouchitis can be categorized as acute (<4

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 weeks) or chronic (≥4 weeks) and frequency may be described as infrequent, relapsing,

or continuous (100% agreement).

2. In chronic, recurrent or refractory pouchitis-like symptoms, other diagnoses, such as

cuffitis, missed Crohn’s disease, anastomotic ulcer, irritable pouch syndrome, infectious

pouchitis and anastomotic stenosis, should be excluded (100% agreement).

3. Faecal calprotectin may be used to assess pouch inflammation to minimize repeated

pouchoscopies in recurrent pouchitis and to monitor response to treatment. Calprotectin

>300ug/g is suggestive of pouchitis while lower levels do not preclude pouchitis (57%

sensitivity, 92% specificity) (95% agreement).

4. The common antibiotic dosing strategies for pouchitis are ciprofloxacin (30 mg/kg/day up

to 1 gr/day in 2 divided doses) and/or metronidazole (20–30 mg/kg/day in 3 divided

doses up to 1.5gr/day) for 14 days (98% agreement).

5. VSL#3 can be used once daily at an age or weight-dependent dose (Table 5). (95%

agreement).

6. VSL#3 may be also effective for preventing the first episode of pouchitis, but this is not

justified since many children will never develop pouchitis (100% agreement).

7. Thiopurines may be considered in refractory pouchitis, not responding to antibiotic

therapy or in the presence of budesonide dependence, despite the lack of good evidence.

The effectiveness of infliximab for this indication has been demonstrated only in adult

case series with a response rate of ~50% (98% agreement).

Pouchitis, a non-specific and idiopathic inflammation of the ileal reservoir, is the most common

complication of IPAA, occurring in 24% to 67% of paediatric UC patients (301, 302, 304, 322,

325, 336-339). A recent multicenter, retrospective cohort study from the Paediatric IBD Porto

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Group of ESPGHAN included 129 children who underwent IPAA (93% UC and 7% IBDU) and

showed that 86 children (67%) developed pouchitis during follow-up (327). In 33 (26%) the

pouchitis was chronic, 10 of whom (8%) had Crohn's-like disease of the pouch. Median time

from pouch formation to the first episode of pouchitis was 10.5 months (IQR 6-22); in 54% of

cases the first episode occurred within one year. In an older cohort of 399 UC children with a

mean age of 18+3years at colectomy, 121 (36%) had at least one episode of acute pouchitis, and

29 (9%) pouch failure (302). Pouch type, age and operative technique had no impact on whether

patients developed pouchitis.

Symptoms and severity of pouchitis vary, but typically include increased stool frequency and

urgency, tenesmus, incontinence, abdominal pain, and rectal bleeding (340). Cuffitis, residual

rectal cuff inflammation, may cause symptoms similar to those of pouchitis, especially bleeding.

The cuff is the remaining rectal mucosa between the dentate line and the anastomosis after

restorative procto-colectomy. Symptoms of pouch dysfunction in patients with IPAA may be

caused by conditions other than pouchitis, including CD of the pouch, anastomotic ulcer or

stenosis. In children, the occurrence of terminal ileitis, or “pre-pouch ileitis,” has also been

reported (341), and does not necessarily confirm the diagnosis of CD if it involves only mild

inflammation in a short segment. Other differential diagnoses include ischemia and, rarely,

infections such as CMV and C. difficile. A diagnosis of irritable pouch syndrome is suspected

when symptoms are present without endoscopic inflammation (342). Thus, endoscopic and

histological evaluation of the pouch should be performed at the first episode of pouchitis and

periodically thereafter.

Endoscopic features of pouchitis may include hyperemia, diminished vascular pattern, friability,

hemorrhage, and ulcers. Abnormalities may be focal or diffuse, and unlike in UC, they may be

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

discontinuous. Often, they are more severe in the distal compared to the proximal pouch (343-

345). Mucosal biopsies typically demonstrate partial to complete villous blunting with crypt

hyperplasia and increased mononuclear inflammatory cells and eosinophils in the lamina propria,

crypt abscesses, and ulcerations. Mucosal biopsies should be obtained from the pouch and from

the afferent ileal loop, but not from the staple line, as erosions and/or ulcers along the staple line

do not necessarily indicate pouchitis (346).

Two main scoring systems exist for the diagnosis of pouchitis but their utility in clinical practice

is limited as they await further validation to associate the scores with clinical outcomes (347,

348). The Pouchitis Disease Activity Index (PDAI) evaluates symptoms, endoscopic findings

and histological patterns in a composite score, with a score of >7 indicating pouchitis (349). The

Pouchitis Activity Score (PAS) incorporates similar elements to the PDAI and a score >13 is

suggestive of pouchitis (350). A modified PDAI (mPDAI), omits the histology component (351).

Several variables may predict the risk of pouchitis. A small paediatric study reported that the

only predictive factor associated with risk of pouchitis was a higher PUCAI score at the time of

diagnosis (339). As discussed above, data suggest that the surgeon’s experience is associated

with risk for pouchitis (327). Chronic pouchitis was also associated with Ashkenazi Jewish

ethnicity, while any-pouchitis was associated with age at diagnosis and longer disease duration.

Several adult studies have reported an increased incidence of pouchitis in patients with a younger

age at onset, backwash ileitis, PSC, extensive colonic disease, positive pANCA, preoperative

steroid use, being a non-smoker, and carriage of genetic polymorphisms in NOD2/CARD15,

which is more prevalent in Ashkenazi Jews (66, 352-360).

The probiotic mixture VSL#3 was effective in maintaining remission in adult patients with

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

chronic pouchitis as shown in two double-blind placebo-controlled trials from Italy (361, 362)

Results regarding the effectiveness of VSL#3 in preventing pouchitis are more controversial

(363, 364).

Antibiotic treatment is considered first-line treatment for pouchitis. However, only small

placebo-controlled trials have been conducted to support this practice and none in children (365,

366). Ciprofloxacin may be slightly more effective than metronidazole, with fewer adverse

events. Shen et al. have shown the superiority of ciprofloxacin over metronidazole in inducing

remission (367). In antibiotic-refractory pouchitis, Gionchetti et al used oral budesonide for 8

weeks and achieved remission in 75% of 20 patients (368) (369). A case-series of 28 patients

with refractory pouchitis were treated with infliximab of whom 88% responded after 10 weeks,

and 56% after a median follow-up of 20 months (370); other case series also support the use of

infliximab in refractory pouchitis (371, 372) as well as adalimumab (373) and alicaforsen (an

inhibitor of intercellular adhesion molecule-1) enemas (374).

In an open study, topical treatment with metronidazole induced clinical improvement within a

few days without systemic side-effects and with a decrease in concentrations of anaerobic

bacteria (375). Furthermore, uncontrolled studies have suggested that 5-ASA either as

suppositories or enemas may help in the treatment of pouchitis (376).

OTHER MANAGEMENT CONSIDERATIONS

Extraintestinal manifestations (EIM)

Recommendations

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 1. Treatment of peripheral arthritis should be directed at inducing remission of the luminal

disease [EL4, adult EL3]; sulfasalazine should be considered as first line treatment for

peripheral arthritis, followed by anti-TNF [EL4, adult EL2] (93% agreement)

2. Transaminases and γGT should be monitored at least annually in all UC patients, to

screen for PSC and autoimmune hepatitis [EL4, adult EL4] (100% agreement)

3. Chronic elevation of liver enzymes in the presence of cholestasis, should be investigated

with ultrasound followed by MR-cholangiopancreatography (MRCP), in addition to liver

biopsy when indicated (see practice point); endoscopic retrograde

cholangiopancreatography (ERCP) is recommended for therapeutic interventions [EL3,

adult EL3] (95% agreement)

4. Patients with PSC and IBD are at increased risk for colorectal carcinoma (CRC) and thus

annual or bi-annual surveillance colonoscopy should be initiated from the time of PSC

diagnosis. However, since CRC is extremely rare under the age of 12 years even in the

presence of PSC, in pre-pubertal children surveillance could be deferred dictated by

individual risk factors (disease duration, family history, severity of the disease over time

and disease extent) (95% agreement).

Practice points

1. Acute peripheral arthritis affecting the large joints, is usually associated with active IBD

and thus treatment should be directed to the gut (98% agreement).

2. The diagnosis of axial spondylo-arthritis or sacro-ileitis is based on typical clinical signs

such as progressive low back pain, gluteal and thigh pain combined with radiological

abnormalities (most often MRI). Treating sacro-ileitis requires close collaboration with a

rheumatologist (100% agreement).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 3. If required for the treatment of articular inflammation, NSAID might be used for a short

course and at low doses to minimize the risk of aggravating IBD (98% agreement).

4. Since some degree of autoimmune hepatits/overlap syndrome is not uncommon in

children with PSC, a low threshold should be practiced when considering a liver biopsy

in this setup (95% agreement).

5. No medication has been proven to reduce the time from PSC diagnosis to liver transplant

or the development of cholangiocarcinoma. The benefit of ursodeoxycholic acid remains

questionable, and if used, doses should be preferably low (10-15mg/kg/d). Alternatively,

oral vancomycin may be considered (usual total daily dose 35mg/kg (maximum 1500mg)

divided into 3 times daily), for 12 weeks but long term data are lacking (95%

agreement).

6. PSC is a significant risk factor for cholangiocarcinoma also during childhood. Serial

CA19.9 and liver ultrasound/MRCP testing may thus be considered every 1-2 years to

screen for cholangiocarcinoma but there is no paediatric evidence to support this practice

(95% agreement).

We would like to refer the reader to comprehensive ECCO guidelines on EIM and highlight here

only pertinent points common in children (377). Some EIM are associated with intestinal disease

activity (i.e. erythema nodosum, peripheral arthritis), whereas others occur independently (i.e.

pyoderma gangrenosum, uveitis, ankylosing spondylitis, and PSC) (378). Data from two

paediatric registries in the USA (379, 380) and one in Europe (378) indicate that one or more

EIMs are present at diagnosis in 6-17% % of children with UC, especially those older than 5

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

years, with an increase to almost 50% with disease evolution (381) (382, 383) (384), and more

so with extensive colitis (380).

Joint disease in IBD may be axial (sacro-ileitis or ankylosing spondylitis), causing lower back

pain or peripheral arthritis, which is usually acute and self-limiting, seronegative and not

deforming. In children, the prevalence of arthritis seems to be twice as high as in adults, (379)

with a clear female predominance. There are some concerns about aggravating the bowel disease

by using NSAIDs, however, the risk seems to be low if prescribed for a short course and at low

doses (385). The sulfapyridine component of sulfasalazine has an anti-inflammatory effect on

both the colonic mucosa and the joints (386). MTX is the cornerstone disease-modifying anti-

rheumatic drug in juvenile arthritis (387) but anti-TNF regimes have emerged in the last two

decades (388).

PSC is three times more likely to occur in UC compared to CD (380), and is associated with

older age in children (380). PSC may precede the onset of IBD by years but may occur even after

colectomy. The prevalence of PSC in paediatric IBD is 1.6% at 10 years after diagnosis (379),

but higher at 3% (389) if systematic screening tests are performed. In a recent multicentre report

of 781 children with PSC (4,277 person-years of follow-up), overall event-free survival was 70%

at 5 years and 53% at 10 years but PSC-IBD was associated with a favourable prognosis;

cholangiocarcinoma occurred in 1% (390).

Being non-invasive, MRCP is the most appropriate imaging modality for diagnosing PSC in

children. A pattern of irregular bile ducts, with zones of narrowing and dilatation is characteristic

of PSC (391). PSC may progress to liver cirrhosis, ultimately necessitating liver transplantation.

Patients with PSC and UC have a greater risk of malignancies such as colorectal cancer and

cholangiocarcinoma (8–30% of UC patients with long standing PSC) (392, 393). A recent study

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

on the cancer and mortality in children in Europe has demonstrated several cases associated with

PSC (10), but CRC in UC children younger than 12 years is extremely rare. PSC is associated

with more extensive disease and thus have greater cancer risk (393) but also with milder disease

course. The higher colectomy rate in these patients is secondary to dysplasia and CRC. In adults

with PSC, ursodeoxycholic acid is reported to improve abnormal liver tests (394) and to reduce

the risk of CRC (395), although this has not been shown by all (396, 397). No therapy has been

shown to reduce time to liver transplantation, cholangiocarcinoma or death (396, 398, 399).

Recent recommendations for adult patients suggest ursodeoxycholic acid at a dose of 10-

15mg/kg/day and warn against high dose treatment (>20mg/kg/d), which may increase mortality

(396, 397, 400).

Oral vancomycin may be considered for 12 weeks as it has been shown to reduce and even

normalize serum liver enzymes and gGT (401-407). Both vancomycin and metronidazole have

been efficacious in recent small studies, however, only patients in the vancomycin groups

reached the primary endpoint, and with fewer adverse effects (405). Oral vancomycin

retreatment when needed has been associated with a rise in T regulatory cells (Treg) and

normalization of liver function tests (408).

Older age at PSC diagnosis increases the risk of colonic neoplasia (409). Targeted biopsies

aimed at abnormal areas identified by newer colonoscopic techniques (chromoendoscopy,

confocal microendoscopy) should be preferred (410). The optimal follow up method is still

debatable (411).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Nutrition, growth and bone health

Practice points:

1. High intake of red or processed meat, protein, alcoholic beverages, sulfur, and sulfates

have been associated with disease exacerbations. However, due to the lack of solid

evidence, exclusion diets should not be used to induce or maintain remission in paediatric

UC, and could lead to nutritional deficiencies (100% agreement).

2. DEXA (corrected for height and possibly bone age to produce age- and sex-matched z

scores (412)) should be considered in high risk patients such as those with severe disease,

prolonged malnutrition, amenorrhea, delayed puberty and/or steroid dependency (98%

agreement).

3. Promoting mucosal healing, adequate nutrition, weight-bearing exercise, avoiding

smoking and steroid-sparing strategies should be employed to facilitate bone health. The

rare use of bisphosphonates should be reserved to those with pathological fractures, in

consultation with a paediatric bone specialist (100% agreement).

4. Growth impairment is rare in children with UC who are not steroid-dependent. Therefore,

Crohn's colitis or primary growth hormone deficiency should be considered when

significant growth impairment is present (100% agreement).

5. Vitamin D should be supplemented if 25-OH vitamin D is less than 50 nmol/l, regardless

of steroid use (93% agreement).

6. There are different strategies in treating vitamin D deficiency in addition to daily

treatment (>2000 IU/day). A commonly applied strategy is to prescribe a “loading dose”

(50,000 IU of vitamin D3 orally once weekly for 2-3 months, or 3 times weekly for 1

month). Single high-dose oral vitamin D3 300,000 to 500,000 IU (i.e. stoss dosing) has

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 been reported (413) to be effective and safe (98% agreement).

While nutritional deficiencies can develop quickly during periods of active UC (414), normal

growth is maintained in >95% of children with UC who are not steroid dependent (415) (416,

417). A more detailed review of all nutritional issues in children with IBD can be found in the

recently published guideline from the Paediatric IBD Porto group of ESPGHAN (418). Patients

with active UC often reduce fiber in their diets without supportive evidence. Corn and corn

products, nuts, milk and bran were avoided by more than 20% of UC patients (419). However,

soluble fiber is the best way to generate short-chain fatty acids such as butyrate, which has anti-

inflammatory effects (420). In addition, many UC patients avoided tomato, dairy products,

chocolate, wheat, tomato sauces and fruit juice (419), but there is no nutritional intervention

clearly supported in UC and the reader is referred to an excellent recent summary on the topic

(420).

Peak bone mass attained during adolescence, is the most important determinant of lifelong

skeletal health. Some osteopenia is present in up to 22% of UC children (421) but severe

osteopenia is only present in 3% to 6% in UC, as compared with 12%-18% in CD (422-424).

Nutritional status seems to have a greater impact on bone status than corticosteroid therapy

(425). Children with IBD are at particularly risk for vitamin D deficiency, but this was not found

to be directly associated with osteopenia (426). Nonetheless vitamin D deficiency should be

treated especially in children with decreased bone mineral density. A recent meta-analysis

showed that low vitamin D is associated with a more active disease (427). Age-appropriate

nutrition support, weight-bearing exercise, and adequate disease control using steroid-sparing

strategies (412, 423, 428) have been suggested as means to improve bone formation but without

supportive evidence. Indeed, a prospective study that followed 58 children with CD for two years

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

did not show significant improvement in bone mineral density despite increased height z-score

and reduced disease activity (423).

The most important determinant of treating osteopenia, besides avoiding steroids, is efficient

treatment aiming at mucosal healing since osteopenia may typically be a consequence of pro-

inflammatory cytokines (429). Indeed, interventions that lead to mucosal healing such as anti-

TNF therapy and exclusive enteral nutrition showed rapid improvement of serum bone markers

in children with CD (430-433) (434). Bisphosphonates are effective to improve bone mineral

density in IBD but paediatric use should be reserved for extreme circumstances, typically when

pathological fractures are present, an uncommon situation in UC.

Psychosocial support, adherence to therapy and transitional care

Recommendations:

1. Adolescents should be included in transition to adult care programs which can be adapted

according to the local organisation of the paediatric and adult facilities [EL4] (100%

agreement)

Practice points:

1. Paediatric IBD centres should offer psychological support according to local resources

(100% agreement).

2. Adherence should be regularly evaluated by patient interviews, drug monitoring (e.g.

serum drug level), and prescription refill rates (100% agreement).

3. Adherence may be improved by providing comprehensive information regarding the

prescribed medication, keeping the pill burden as low as possible, using single daily

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 dosage when possible, utilizing electronic reminders and providing pill boxes (100%

agreement).

Several systematic reviews concluded that adolescents with IBD, especially boys, have reduced

health-related quality of life (HRQOL), including anxiety, depression, social problems, and low

self-esteem (435-438). The altered quality of life of children with IBD can affect the entire

family, who often lack the appropriate strategies to deal with this complicated reality (439). The

rate of depression may be as high as 25% and it is often under-recognized both by parents and

health care professionals. Anxiety and depression appear to be risk factors for early recurrence of

the disease and adversely affect the disease course but may also commonly be a reactive

response to active disease (440). Cognitive behavioral therapy has been shown to be especially

effective in improving depressive symptoms and functioning in children with IBD (441).

Non-adherence in IBD is reported in 50-66% of children (435, 442), especially during

adolescence. Paediatric-specific barriers include fear of adverse events of medication, feeling

that the disease is inactive, belief that the medication is not working, more than one daily

medication, forgetting, interfering with other activities, difficulty in swallowing pills (443), lack

of motivation, and parent-child conflict (444).

Transition is defined as the planned move of adolescents and young adults with long-term

physical conditions from child-centred to adult-orientated health. The optimal timing of

transition from paediatric to adult management of UC has to be decided on an individual basis by

a joint team of paediatric and adult gastroenterologists (445). Several suggestions for transition

programs have been published, but none has been formally evaluated (446). The transition period

usually starts from the age of 14-18 years depending on the development of the patient and

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

availability of qualified paediatric and adult gastroenterologists. The time of transition should be

individually adapted according to the psychosocial readiness. Whenever feasible, at least one

joint clinic with both the paediatric and the adult gastroenterologist is recommended during the

transition process. The adolescent should be encouraged to assume increasing responsibility for

treatment and to visit the clinic room at least once without being accompanied by the parents.

The ECCO topical review on transition to adult care addresses in detail all aspects related to the

steps to be followed during transition (447).

Very early onset IBD presenting as colitis

Practice Points

1. In infants younger than 2 years, allergic colitis, immunological disorders and monogenic

forms of colitis should be excluded (100% agreement).

2. Unusual disease evolution, history of recurrent infections, hemophagocytic

lymphohistiocytosis (HLH), and non-response to multiple IBD medications might

indicate an underlying genetic defect which should prompt genetic and/or immunological

analyses at any age during childhood (Table 6) (100% agreement).

The colitis phenotype is the most common in the VEOIBD group (6 years of age and younger)

(448), and even Crohn's disease frequently resembles UC. Therefore, the term IBD-U rather than

UC might be more appropriate in this earlier age group, reported in 34% and even 71% of very

young children (449, 450). The differential diagnostic spectrum for this age group is challenging

(450, 451) since the colitis might be caused by various immunological disorders: classical

immune defects (such as combined immune-deficiencies), subtle immune defects or defects of

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

the regulation of immune responses due to a monogenetic disorder including defects in IL10-

signaling, XIAP deficiency, defective neutrophil function and many others (Table 6) (451). Since

no specific biological test confirms allergic colitis, only a successful trial of elimination diet is

useful diagnostically (452) and might be proposed according to the clinical context especially in

those younger than 1 year.

A large percentage of children with IBD developing prior to age 6 years present with relatively

typical colitis, including mild disease which can be easily managed with 5-ASA (453).

However, many monogenic forms of VEOIBD may initially appear as typical polygenic IBD but

then prove resistant to standard therapy (450, 451). Over 50 different monogenetic defects

causing an IBD-like disorder have been described. A complete review of the genetic workup of

VEOIBD and treatments is beyond the scope of these guidelines and the reader is referred to a

previous comprehensive review (451). Briefly, appearance of perianal disease with skin

folliculitis during the first few months of life is a strong indicator of a defect in the IL10 axis

(454-456). Repeated bacterial and fungal infections orientate towards defective neutrophil

functions, (e.g. chronic granulomatous disease (CGD) (457, 458)). Recurrent skin infections, and

EBV or CMV-induced hemophagoctic lymphohistiocytosis (HLH) may indicate the presence of

XIAP-defect (459). This X-linked defect can affect boys and in rare cases also girls (460). The

presence of multiple intestinal atresia, or evidence of increased rate of epithelial cell apoptosis on

small bowel biopsy may hint toward TTC7A, especially when observed in the presence of low

IgG levels, T and B cell lymphopenia and mild reduction in NK cells (461-463). Woollen, fragile

hair and facial abnormalities (small chin, broad flat nasal bridge and prominent forehead),

immune defects, liver disease and colitis (referred to as trichohepatoenteric syndrome or

phenotypic diarrhoea) may be due to mutation in SCIVL2 (464) or TTC37 (465). If signs of

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

autoimmunity are associated with intestinal inflammation with high rates of epithelial cell

apoptosis, IPEX-syndrome or IPEX-like disorders should be considered (466-469).

If the molecular defect is caused by a mutation affecting predominantly immunological cells

(e.g. IL10 signalling defects, XIAP and CGD), hematopoietic stem cell transplantation may be

curative (455, 470) (460) (454). Inhibition with IL1-antagonists might be a way to stabilize

patients with IL10 signalling defects while awaiting HSCT, but more confirmation is required

before this can be utilized in clinical practice (471). Early HSCT improves life expectancy of

IL10 deficient patients since they are at risk for developing lymphoma (472). HSCT is not

always the ultimate treatment option, as shown in patients with TTC7A mutations, which involve

the epithelial gut barrier rather than immunological cells. This highlights the importance of a

rapid and precise molecular diagnosis in children with colitis starting early in life.

SYNTHESIS AND SUMMARY (Figures 2 and 4)

The Part 1, ambulatory paediatric UC consensus process, yielded 40 formal recommendations

and 86 practice points along with practical tables, based on systematic review of the literature.

Guidance for the management of paediatric UC is summarized in algorithms to be used in

conjunction with reading this document (Figures 2 and 4). The goal of treatment in active UC

should be complete clinical remission (PUCAI<10 points), and usually this can be assessed

without the need for endoscopic verification. However, ~20% of children in clinical remission

can still have endoscopic inflammation, and thus calprotectin may aid in selecting those who

require endoscopic evaluation to ensure mucosal healing has been achieved. The choice of

treatment in adults is a factor of both the disease severity and disease extent (15, 16), but since

limited distal disease is uncommon in children, paediatric treatment strategy mainly depends on

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

disease severity. Mesalamine regimes are considered first-line for inducing and maintaining

remission of mild to moderate UC. Non response to oral mesalamine may be treated with the

addition of mesalamine enemas and/or switching to locally active steroids, budesonide-MMX

only in left sided colitis. In ambulatory children with moderate to severe UC, or in those with

mild to moderate disease, who have failed optimized mesalamine therapy, oral steroids should be

used, but only as induction agents. If the patient does not clearly respond to oral steroids within

1-2 weeks, consider admission for intravenous corticosteroids (see Part 2 of these guidelines). In

refractory non-severe cases, an alternative to admission may include outpatient treatment with

infliximab (especially in those who failed thiopurines and mesalamine); in selected patients, oral

tacrolimus may be considered.

Patients who received intravenous corticosteroids should be usually weaned to thiopurines.

Almost all children with UC must be treated with a maintenance therapy indefinitely. Anti-TNF

is indicated for non-response to corticosteroids, and in loss of response or intolerance to

mesalamine and thiopurines. Patients needing anti-TNF induction should continue this therapy

and if thiopurine-naïve, may be subsequently stepped down to thiopurines after a period of 6-12

months of deep remission. Golimumab or adalimumab should be considered in secondary loss of

response to infliximab due to antibodies formation. Vedolizumab is a valid option in primary

non-response to anti-TNF, in secondary loss of response in the presence of adequate drug level,

and in anti-TNF related adverse events, such as refractory psoriasis. Endoscopic evaluation is

recommended before any significant treatment change. Finally, colectomy is always a viable

option which must be discussed whenever treatment escalation is considered.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

These clinical management guidelines were developed to assist practitioners at all levels of

health care, while recognizing that each patient is unique. The recommendations may, thus, be

subject to local practice patterns, and serve merely as a general framework for the management

of UC in children. The development of the guidelines should now be followed by dissemination

of the information to clinical practice.

DISCLAIMER

ESPGHAN is not responsible for the practices of physicians and provides guidelines and

position papers as indicators of best practice only. Diagnosis and treatment is at the discretion of

physicians.

QUALIFYING STATEMENT and ACKNOWLEDGMENT

Please refer to the end of Part 2 of these guidelines

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

REFERENCES

1 Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory

bowel disease: a systematic review of international trends. Inflamm Bowel Dis

2011;17:423-39.

2 Van Limbergen J, Russell RK, Drummond HE, et al. Definition of phenotypic

characteristics of childhood-onset inflammatory bowel disease. Gastroenterology

2008;135:1114-22.

3 Turner D, Walsh CM, Benchimol EI, et al. Severe paediatric ulcerative colitis: incidence,

outcomes and optimal timing for second-line therapy. Gut 2008;57:331-8.

4 Dinesen LC, Walsh AJ, Protic MN, et al. The pattern and outcome of acute severe colitis.

J Crohns Colitis 2010;4(4):431-7.

5 Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of

pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol

2009;104(8):2080-8.

6 Langholz E, Munkholm P, Krasilnikoff PA, et al. Inflammatory bowel diseases with

onset in childhood. Clinical features, morbidity, and mortality in a regional cohort. Scand

J Gastroenterol 1997;32(2):139-47.

7 Jakobsen C, Bartek J, Wewer V, et al. Differences in phenotype and disease course in

adult and paediatric inflammatory bowel disease--a population-based study. Aliment

Pharmacol Ther 2011;34(10):1217-24.

8 Ashton JJ, Versteegh HP, Batra A, et al. Colectomy in pediatric ulcerative colitis: A

single center experience of indications, outcomes, and complications. J Pediatr Surg

2016;51(2):277-81.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

9 Benchimol EI, Guttmann A, To T, et al. Changes to surgical and hospitalization rates of

pediatric inflammatory bowel disease in Ontario, Canada (1994-2007). Inflamm Bowel

Dis 2011;17(10):2153-61.

10 de Ridder L, Turner D, Wilson DC, et al. Malignancy and mortality in pediatric patients

with inflammatory bowel disease: a multinational study from the porto pediatric IBD

group. Inflamm Bowel Dis 2014;20(2):291-300.

11 Levine A, Koletzko S, Turner D, et al. The ESPGHAN Revised Porto Criteria for the

Diagnosis of Inflammatory Bowel Disease in Children and Adolescents. J Pediatr

Gastroenterol Nutr 2014;58(6):795-806.

12 Birimberg-Schwartz L, Zucker DM, Akriv A, et al. Development and validation of

diagnostic criteria for IBD subtypes with an emphasis on IBD-Unclassified in children: a

multicenter study from the Pediatric IBD Porto group of ESPGHAN. J Crohns Colitis

2017.

13 Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal

classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel

Dis 2011;17(6):1314-21.

14 Turner D, Muise AM Very Early Onset IBD: How Very Different 'on Average'? J Crohns

Colitis 2017;11(5):517-18.

15 Harbord M, Eliakim R, Bettenworth D, et al. Third European Evidence-based Consensus

on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management. J

Crohns Colitis 2017.

16 Magro F, Gionchetti P, Eliakim R, et al. Third European Evidence-based Consensus on

Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch

Disorders. J Crohns Colitis 2017;11(6):649-70.

17 Turner D, Levine A, Escher JC, et al. Management of pediatric ulcerative colitis: joint

ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol

Nutr 2012;55(3):340-61.

18 Turner D, Travis SP, Griffiths AM, et al. Consensus for managing acute severe ulcerative

colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and

the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol 2011;106(4):574-88.

19 Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing

the quality of nonrandomised studies in meta-analyses.

2013:http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

20 Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of

Interventions. The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd.;

2011:www.cochrane-handbook.org.

21 OCEBM Levels of Evidence Working Group. The Oxford Levels of Evidence 2. Oxford

Centre for Evidence-Based Medicine:http://www.cebm.net/index.aspx?o=5653.

22 Aloi M, D'Arcangelo G, Pofi F, et al. Presenting features and disease course of pediatric

ulcerative colitis. J Crohns Colitis 2013;7(11):e509-15.

23 Schechter A, Griffiths C, Gana JC, et al. Early endoscopic, laboratory and clinical

predictors of poor disease course in paediatric ulcerative colitis. Gut 2015;64(4):580-8.

24 Schroeder KW, Tremaine WJ, Ilstrup DM Coated oral 5-aminosalicylic acid therapy for

mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med

1987;317(26):1625-9.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

25 Lobaton T, Bessissow T, De Hertogh G, et al. The Modified Mayo Endoscopic Score

(MMES): A New Index for the Assessment of Extension and Severity of Endoscopic

Activity in Ulcerative Colitis Patients. J Crohns Colitis 2015;9(10):846-52.

26 Travis SP, Schnell D, Krzeski P, et al. Developing an instrument to assess the endoscopic

severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity

(UCEIS). Gut 2012;61(4):535-42.

27 Travis SP, Schnell D, Krzeski P, et al. Reliability and initial validation of the ulcerative

colitis endoscopic index of severity. Gastroenterology 2013;145(5):987-95.

28 Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is

associated with improved long-term clinical outcomes in ulcerative colitis.

Gastroenterology 2011;141(4):1194-201.

29 Gustavsson A, Järnerot G, Hertervig E, et al. Clinical trial: colectomy after rescue

therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled

infliximab study. Aliment Pharmacol Ther 2010;32(8):984-89.

30 Froslie KF, Jahnsen J, Moum BA, et al. Mucosal Healing in inflammatory bowel disease:

results from a Norwegian population-based cohort. Gastroenterology 2007;133(412-22.

31 Solberg IC, Lygren I, Jahnsen J, et al. Clinical course during the first 10 years of

ulcerative colitis: results from a population-based inception cohort (IBSEN Study). Scand

J Gastroenterol 2009;44(4):431-40.

32 Turner D, Griffiths AM, Veerman G, et al. Endoscopic and clinical variables that predict

sustained remission in children with ulcerative colitis treated with infliximab. Clin

Gastroenterol Hepatol 2013;11(11):1460-5.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

33 Reinish W Association between Week Eight Mayo Subscores and Hospitalization Rates

in Adalimumab-treated Patients with Ulcerative Colitis from ULTRA 1 and ULTRA 2.

Am J Gastroenterol 2013;108(Suppl 1s):S506.

34 Arai M, Naganuma M, Sugimoto S, et al. The Ulcerative Colitis Endoscopic Index of

Severity is Useful to Predict Medium- to Long-Term Prognosis in Ulcerative Colitis

Patients with Clinical Remission. J Crohns Colitis 2016;10(11):1303-09.

35 Turner D, Hyams J, Markowitz J, et al. Appraisal of the pediatric ulcerative colitis

activity index (PUCAI). Inflamm Bowel Dis 2009;15(8):1218-23.

36 Gray FL, Turner CG, Zurakowski D, et al. Predictive value of the Pediatric Ulcerative

Colitis Activity Index in the surgical management of ulcerative colitis. J Pediatr Surg

2013;48(7):1540-5.

37 Hyams JS, Davis S, Mack DR, et al. Factors associated with early outcomes following

standardised therapy in children with ulcerative colitis (PROTECT): a multicentre

inception cohort study. Lancet Gastroenterol Hepatol 2017;2(12):855-68.

38 Turner D, Seow CH, Greenberg GR, et al. A systematic prospective comparison of

noninvasive disease activity indices in ulcerative colitis. Clin Gastroenterol Hepatol

2009;7(10):1081-8.

39 Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a

pediatric ulcerative colitis activity index: a prospective multicenter study.

Gastroenterology 2007;133(2):423-32.

40 Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with

infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol

Hepatol 2012;10(4):391-99 e1.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

41 Romano C, Famiani A, Comito D, et al. Oral beclomethasone dipropionate in pediatric

active ulcerative colitis: a comparison trial with mesalazine. J Pediatr Gastroenterol Nutr

2010;50(4):385-9.

42 Turner D, Veereman G, Hyams J, et al. Similarity of clinical outcomes and Golimumab

pharmacokinetics in adult and pediatric patients with moderate to severe UC. J Pediatr

Gastroenterol Nutr 2016;62(Suppl 1.):G-P 150.

43 Wiernicka A, Szymanska S, Cielecka-Kuszyk J, et al. Histological healing after

infliximab induction therapy in children with ulcerative colitis. World J Gastroenterol

2015;21(37):10654-61.

44 Kerur B, Litman HJ, Stern JB, et al. Correlation of endoscopic disease severity with

pediatric ulcerative colitis activity index score in children and young adults with

ulcerative colitis. World J Gastroenterol 2017;23(18):3322-29.

45 Ricciuto A, Carman N, Fish J, et al. Symptoms underestimate endoscopic activity in

PSC-IBD

J Ped Gastroenterol Nutr 2017;65(Supplement 2):S104.

46 Mack DR, Langton C, Markowitz J, et al. Laboratory values for children with newly

diagnosed inflammatory bowel disease. Pediatrics 2007;119(6):1113-9.

47 Weinstein TA, Levine M, Pettei MJ, et al. Age and family history at presentation of

pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2003;37(5):609-13.

48 Sidoroff M, Karikoski R, Raivio T, et al. High-sensitivity C-reactive protein in paediatric

inflammatory bowel disease. World J Gastroenterol 2010;16(23):2901-06.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

49 Turner D, Mack DR, Hyams J, et al. C-reactive protein (CRP), erythrocyte sedimentation

rate (ESR) or both? A systematic evaluation in pediatric ulcerative colitis. J Crohns

Colitis 2011;5(5):423-9.

50 Kelley-Quon LI, Jen HC, Ziring DA, et al. Predictors of proctocolectomy in children with

ulcerative colitis. J Pediatr Gastroenterol Nutr 2012;55(5):534-40.

51 Moore JC, Thompson K, Lafleur B, et al. Clinical variables as prognostic tools in

pediatric-onset ulcerative colitis: a retrospective cohort study. Inflamm Bowel Dis

2011;17(1):15-21.

52 Canani RB, Terrin G, Rapacciuolo L, et al. Faecal calprotectin as reliable non-invasive

marker to assess the severity of mucosal inflammation in children with inflammatory

bowel disease. Dig Liver Dis 2008;40(7):547-53.

53 Borkowska A, Liberek A, Luczak G, et al. Fecal lactoferrin, a marker of intestinal

inflammation in children with inflammatory bowel disease. Acta Biochim Pol

2015;62(3):541-5.

54 Fagerberg UL, Loof L, Lindholm J, et al. Fecal calprotectin: a quantitative marker of

colonic inflammation in children with inflammatory bowel disease. J Pediatr

Gastroenterol Nutr 2007;45(4):414-20.

55 Schoepfer AM, Beglinger C, Straumann A, et al. Ulcerative colitis: correlation of the

Rachmilewitz endoscopic activity index with fecal calprotectin, clinical activity, C-

reactive protein, and blood leukocytes. Inflamm Bowel Dis 2009;15(12):1851-8.

56 Tibble JA, Sigthorsson G, Bridger S, et al. Surrogate markers of intestinal inflammation

are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology

2000;119(1):15-22.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

57 Roszak D, Galecka M, Cichy W, et al. Determination of faecal inflammatory marker

concentration as a noninvasive method of evaluation of pathological activity in children

with inflammatory bowel diseases. Adv Med Sci 2015;60(2):246-52.

58 Komraus M, Wos H, Wiecek S, et al. Usefulness of faecal calprotectin measurement in

children with various types of inflammatory bowel disease. Mediators Inflamm

2012;2012(608249.

59 Ashorn S, Honkanen T, Kolho KL, et al. Fecal calprotectin levels and serological

responses to microbial antigens among children and adolescents with inflammatory

bowel disease. Inflamm Bowel Dis 2009;15(2):199-205.

60 Diamanti A, Colistro F, Basso MS, et al. Clinical role of calprotectin assay in

determining histological relapses in children affected by inflammatory bowel diseases.

Inflamm Bowel Dis 2008;14(9):1229-35.

61 Yamamoto T, Shiraki M, Bamba T, et al. Fecal calprotectin and lactoferrin as predictors

of relapse in patients with quiescent ulcerative colitis during maintenance therapy. Int J

Colorectal Dis 2014;29(4):485-91.

62 Sipponen T, Kolho KL Faecal calprotectin in children with clinically quiescent

inflammatory bowel disease. Scand J Gastroenterol 2010;45(7-8):872-7.

63 Birimberg-Schwartz L, Wilson DC, Kolho KL, et al. pANCA and ASCA in Children

with IBD-Unclassified, Crohn's Colitis, and Ulcerative Colitis-A Longitudinal Report

from the IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2016;22(8):1908-14.

64 Zholudev A, Zurakowski D, Young W, et al. Serologic testing with ANCA, ASCA, and

anti-OmpC in children and young adults with Crohn's disease and ulcerative colitis:

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 diagnostic value and correlation with disease phenotype. Am J Gastroenterol

2004;99(11):2235-41.

65 Miele E, Pascarella F, Quaglietta L, et al. Altered intestinal permeability is predictive of

early relapse in children with steroid-responsive ulcerative colitis. Aliment Pharmacol

Ther 2007;25(8):933-9.

66 Fleshner PR, Vasiliauskas EA, Kam LY, et al. High level perinuclear antineutrophil

cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts

the development of chronic pouchitis after ileal pouch-anal anastomosis. Gut

2001;49(5):671-7.

67 Laine L, Kaltenbach T, Barkun A, et al. SCENIC international consensus statement on

surveillance and management of dysplasia in inflammatory bowel disease. Gastrointest

Endosc 2015;81(3):489-501 e26.

68 Olen O, Askling J, Sachs MC, et al. Childhood onset inflammatory bowel disease and

risk of cancer: a Swedish nationwide cohort study 1964-2014. BMJ 2017;358(j3951.

69 Wang Y, Parker CE, Bhanji T, et al. Oral 5-aminosalicylic acid for induction of remission

in ulcerative colitis. Cochrane Database Syst Rev 2016;4(CD000543.

70 Wang Y, Parker CE, Feagan BG, et al. Oral 5-aminosalicylic acid for maintenance of

remission in ulcerative colitis. Cochrane Database Syst Rev 20165):CD000544.

71 Ferry GD, Kirschner BS, Grand RJ, et al. Olsalazine versus sulfasalazine in mild to

moderate childhood ulcerative colitis: results of the Pediatric Gastroenterology

Collaborative Research Group Clinical Trial. J Pediatr Gastroenterol Nutr 1993;17(1):32-

8.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

72 Quiros JA, Heyman MB, Pohl JF, et al. Safety, efficacy, and pharmacokinetics of

balsalazide in pediatric patients with mild-to-moderate active ulcerative colitis: results of

a randomized, double-blind study. J Pediatr Gastroenterol Nutr 2009;49(5):571-9.

73 Winter HS, Krzeski P, Heyman MB, et al. High- and low-dose oral delayed-release

mesalamine in children with mild-to-moderately active ulcerative colitis. J Pediatr

Gastroenterol Nutr 2014;59(6):767-72.

74 Turner D, Yerushalmi B, Kori M, et al. Once- Versus Twice-daily Mesalazine to Induce

Remission in Paediatric Ulcerative Colitis: A Randomised Controlled Trial. J Crohns

Colitis 2016.

75 Zeisler B, Lerer T, Markowitz J, et al. Outcome following aminosalicylate therapy in

children newly diagnosed as having ulcerative colitis. J Pediatr Gastroenterol Nutr

2013;56(1):12-8.

76 Nuti F, Tringali G, Miele E, et al. Aminosalicylates and pediatric UC: Use and efficacy at

one year from diagnosis, results from the pediatric IBD Italian Registry. Digestive and

Liver Disease;47(e262.

77 Nikfar S, Rahimi R, Rezaie A, et al. A meta-analysis of the efficacy of sulfasalazine in

comparison with 5-aminosalicylates in the induction of improvement and maintenance of

remission in patients with ulcerative colitis. Dig Dis Sci 2009;54(6):1157-70.

78 Feagan BG, Chande N, MacDonald JK Are there any differences in the efficacy and

safety of different formulations of Oral 5-ASA used for induction and maintenance of

remission in ulcerative colitis? evidence from cochrane reviews. Inflamm Bowel Dis

2013;19(9):2031-40.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

79 Cuffari C, Pierce D, Korczowski B, et al. Randomized clinical trial: pharmacokinetics

and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis. Drug

Des Devel Ther 2016;10(593-607.

80 Wiersma H, Escher JC, Dilger K, et al. Pharmacokinetics of mesalazine pellets in

children with inflammatory bowel disease. Inflamm Bowel Dis 2004;10(5):626-31.

81 Christensen LA, Fallingborg J, Jacobsen BA, et al. Bioavailability of 5-aminosalicyclic

acid from slow release 5-aminosalicyclic acid drug and sulfasalazine in normal children.

Dig Dis Sci 1993;38(10):1831-6.

82 Hanauer SB, Sandborn WJ, Dallaire C, et al. Delayed-release oral mesalamine 4.8 g/day

(800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to

moderately active ulcerative colitis: The ASCEND I trial. Can J Gastroenterol

2007;21(12):827-34.

83 Sandborn WJ, Regula J, Feagan BG, et al. Delayed-release oral mesalamine 4.8 g/day

(800-mg tablet) is effective for patients with moderately active ulcerative colitis.

Gastroenterology 2009;137(6):1934-43 e1-3.

84 Lichtenstein GR, Ramsey D, Rubin DT Randomised clinical trial: delayed-release oral

mesalazine 4.8 g/day vs. 2.4 g/day in endoscopic mucosal healing--ASCEND I and II

combined analysis. Aliment Pharmacol Ther 2011;33(6):672-78.

85 Buurman D, J,, De Monchy JG, Schellekens RC, et al. Ulcerative colitis patients with an

inflammatory response upon mesalazine cannot be desensitized: a randomized study.

Scand J Gastroenterol 2015;50(4):399-405.

86 Gonzalo MA, Alcalde MM, García JM, et al. Desensitization after fever induced by

mesalazine. Allergy 1999;54(11):1224-25.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

87 Heap GA, So K, Weedon M, et al. Clinical Features and HLA Association of 5-

Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease. J

Crohns Colitis 2016;10(2):149-58.

88 Arend LJ, Springate JE Interstitial nephritis from mesalazine: case report and literature

review. Pediatr Nephrol 2004;19(5):550-3.

89 Co ML, Gorospe EC Pediatric case of mesalazine-induced interstitial nephritis with

literature review. Pediatr Int 2013;55(3):385-7.

90 Rosenbaum J, Alex G, Roberts H, et al. Drug rash with eosinophilia and systemic

symptoms secondary to sulfasalazine. J Paediatr Child Health 2010;46(4):193-6.

91 Kohli R, Melin-Aldana H, Sentongo TA Mesalamine-induced pneumonitis during

therapy for chronic inflammatory bowel disease: a pediatric case report. J Pediatr

Gastroenterol Nutr 2005;41(4):479-82.

92 Sentongo TA, Piccoli DA Recurrent pericarditis due to mesalamine hypersensitivity: a

pediatric case report and review of the literature. J Pediatr Gastroenterol Nutr

1998;27(3):344-7.

93 Nair AG, Cross RR Mesalamine-induced myopericarditis in a paediatric patient with

Crohn's disease. Cardiol Young 2015;25(4):783-6.

94 Iofel E, Chawla A, Daum F, et al. Mesalamine intolerance mimics symptoms of active

inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002;34(1):73-6.

95 Heyman MB, Kierkus J, Spenard J, et al. Efficacy and safety of mesalamine suppositories

for treatment of ulcerative proctitis in children and adolescents. Inflamm Bowel Dis

2010;16(11):1931-9.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

96 Probert CS, Dignass AU, Lindgren S, et al. Combined oral and rectal mesalazine for the

treatment of mild-to-moderately active ulcerative colitis: rapid symptom resolution and

improvements in quality of life. J Crohns Colitis 2014;8(3):200-7.

97 Marteau P, Probert CS, Lindgren S, et al. Combined oral and enema treatment with

Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive

mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled

study. Gut 2005;54(7):960-5.

98 Connolly MP, Poole CD, Currie CJ, et al. Quality of life improvements attributed to

combination therapy with oral and topical mesalazine in mild-to-moderately active

ulcerative colitis. Digestion 2009;80(4):241-6.

99 Levine A, Yerushalmi B, Kori M, et al. Mesalamine Enemas for Induction of Remission

in Oral Mesalamine-refractory Pediatric Ulcerative Colitis: A Prospective Cohort Study.

J Crohns Colitis 2017;11(8):970-74.

100 Marshall JK, Thabane M, Steinhart AH, et al. Rectal 5-aminosalicylic acid for

maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev

2012;11(CD004118.

101 Marshall JK, Thabane M, Steinhart AH, et al. Rectal 5-aminosalicylic acid for induction

of remission in ulcerative colitis. Cochrane Database of Systematic Reviews (Online)

20101):CD004115-CD15.

102 Cohen RD, Dalal SR Systematic Review: Rectal Therapies for the Treatment of Distal

Forms of Ulcerative Colitis. Inflamm Bowel Dis 2015;21(7):1719-36.

103 Watanabe M, Nishino H, Sameshima Y, et al. Randomised clinical trial: evaluation of the

efficacy of mesalazine (mesalamine) suppositories in patients with ulcerative colitis and

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 active rectal inflammation -- a placebo-controlled study. Aliment Pharmacol Ther

2013;38(3):264-73.

104 Lamet M A multicenter, randomized study to evaluate the efficacy and safety of

mesalamine suppositories 1 g at bedtime and 500 mg Twice daily in patients with active

mild-to-moderate ulcerative proctitis. Digestive Diseases and Sciences 2011;56(2):513-

22.

105 Lawrance IC, Copeland TS Rectal tacrolimus in the treatment of resistant ulcerative

proctitis. Aliment Pharmacol Ther 2008;28(10):1214-20.

106 Lee CH, Tasker N, La Hei E, et al. Raised tacrolimus level and acute renal injury

associated with acute gastroenteritis in a child receiving local rectal tacrolimus. Clin J

Gastroenterol 2014;7(3):238-42.

107 Lawrance IC, Baird A, Lightower D, et al. Efficacy of Rectal Tacrolimus for Induction

Therapy in Patients With Resistant Ulcerative Proctitis. Clin Gastroenterol Hepatol

2017;15(8):1248-55.

108 Tung J, Loftus EV, Jr., Freese DK, et al. A population-based study of the frequency of

corticosteroid resistance and dependence in pediatric patients with Crohn's disease and

ulcerative colitis. Inflamm Bowel Dis 2006;12(12):1093-100.

109 Cakir M, Ozgenc F, Yusekkaya HA, et al. Steroid response in moderate to severe

pediatric ulcerative colitis: a single center's experience. World J Pediatr 2011;7(1):50-3.

110 Hyams J, Markowitz J, Lerer T, et al. The natural history of corticosteroid therapy for

ulcerative colitis in children. Clin Gastroenterol Hepatol 2006;4(9):1118-23.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

111 Beattie RM, Nicholls SW, Domizio P, et al. Endoscopic assessment of the colonic

response to corticosteroids in children with ulcerative colitis. J Pediatr Gastroenterol Nutr

1996;22(4):373-9.

112 Dignass A, Eliakim R, Magro F, et al. Second European evidence-based consensus on the

diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns

Colitis 2012;6(10):965-90.

113 Campieri M, Adamo S, Valpiani D, et al. Oral beclometasone dipropionate in the

treatment of extensive and left-sided active ulcerative colitis: a multicentre randomised

study. Aliment Pharmacol Ther 2003;17(12):1471-80.

114 Sherlock ME, Seow CH, Steinhart AH, et al. Oral budesonide for induction of remission

in ulcerative colitis. Cochrane Database of Systematic Reviews (Online)

201010):CD007698-CD98.

115 Travis SP, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-

to-moderate ulcerative colitis: results from the randomised CORE II study. Gut

2014;63(3):433-41.

116 Sandborn WJ, Danese S, D'Haens G, et al. Induction of clinical and colonoscopic

remission of mild-to-moderate ulcerative colitis with budesonide MMX 9 mg: pooled

analysis of two phase 3 studies. Aliment Pharmacol Ther 2015;41(5):409-18.

117 Karolewska-Bochenek K, Dziekiewicz M, Banaszkiewicz A Budesonide MMX in

pediatric patients with ulcerative colitis. J Crohns Colitis 2017:In press.

118 Rubin DT, Cohen RD, Sandborn WJ, et al. Budesonide Multi-Matrix Is Efficacious for

Mesalamine-Refractory, Mild to Moderate Ulcerative Colitis: A Randomized, Placebo-

Controlled Trial. J Crohns Colitis 2017.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

119 Uchida K, Araki T, Toiyama Y, et al. Preoperative steroid-related complications in

Japanese pediatric patients with ulcerative colitis. Dis Colon Rectum 2006;49(1):74-9.

120 Sidoroff M, Kolho KL Glucocorticoids in pediatric inflammatory bowel disease. Scand J

Gastroenterol 2012;47(7):745-50.

121 Gomollon F, Dignass A, Annese V, et al. 3rd European Evidence-based Consensus on the

Diagnosis and Management of Crohn's Disease 2016: Part 1: Diagnosis and Medical

Management. J Crohns Colitis 2017;11(1):3-25.

122 Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of

the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol

2013;9(1):30.

123 Ahmet A, Kim H, Spier S Adrenal suppression: A practical guide to the screening and

management of this under-recognized complication of inhaled corticosteroid therapy.

Allergy Asthma Clin Immunol 2011;7(13.

124 Charmandari E, Nicolaides NC, Chrousos GP Adrenal insufficiency. Lancet

2014;383(9935):2152-67.

125 Sidoroff M, Kolho KL Screening for adrenal suppression in children with inflammatory

bowel disease discontinuing glucocorticoid therapy. BMC Gastroenterol 2014;14(51.

126 Sidoroff M, Kolho KL Glucocorticoid sensitivity in inflammatory bowel disease. Ann

Med 2012;44(6):578-87.

127 Quax RA, Manenschijn L, Koper JW, et al. Glucocorticoid sensitivity in health and

disease. Nat Rev Endocrinol 2013;9(11):670-86.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

128 Shipkova M, Armstrong VW, Wieland E, et al. Differences in nucleotide hydrolysis

contribute to the differences between erythrocyte 6-thioguanine nucleotide concentrations

determined by two widely used methods. Clin Chem 2003;49(2):260-8.

129 Gisbert JP, Linares PM, McNicholl AG, et al. Meta-analysis: the efficacy of azathioprine

and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther 2009;30(2):126-37.

130 Timmer A, Patton PH, Chande N, et al. Azathioprine and 6-mercaptopurine for

maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev

20165):CD000478.

131 Khan KJ, Dubinsky MC, Ford AC, et al. Efficacy of immunosuppressive therapy for

inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol

2011;106(4):630-42.

132 Sood R, Ansari S, Clark T, et al. Long-term efficacy and safety of azathioprine in

ulcerative colitis. J Crohns Colitis 2015;9(2):191-7.

133 Hyams JS, Lerer T, Mack D, et al. Outcome following thiopurine use in children with

ulcerative colitis: a prospective multicenter registry study. Am J Gastroenterol

2011;106(5):981-7.

134 Aloi M, D'Arcangelo G, Bramuzzo M, et al. Effect of Early Versus Late Azathioprine

Therapy in Pediatric Ulcerative Colitis. Inflamm Bowel Dis 2016;22(7):1647-54.

135 Barabino A, Torrente F, Ventura A, et al. Azathioprine in paediatric inflammatory bowel

disease: an Italian multicentre survey. Aliment Pharmacol Ther 2002;16(6):1125-30.

136 Kader HA, Mascarenhas MR, Piccoli DA, et al. Experiences with 6-mercaptopurine and

azathioprine therapy in pediatric patients with severe ulcerative colitis. J Pediatr

Gastroenterol Nutr 1999;28(1):54-8.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

137 Verhave M, Winter HS, Grand RJ Azathioprine in the treatment of children with

inflammatory bowel disease. J Pediatr 1990;117(5):809-14.

138 Tajiri H, Tomomasa T, Yoden A, et al. Efficacy and safety of azathioprine and 6-

mercaptopurine in Japanese pediatric patients with ulcerative colitis: a survey of the

Japanese Society for Pediatric Inflammatory Bowel Disease. Digestion 2008;77(3-

4):150-4.

139 Pozler O, Chladek J, Maly J, et al. Steady-state of azathioprine during initiation treatment

of pediatric inflammatory bowel disease. J Crohns Colitis 2010;4(6):623-8.

140 Chhaya V, Pollok RC, Cecil E, et al. Impact of early thiopurines on surgery in 2770

children and young people diagnosed with inflammatory bowel disease: a national

population-based study. Aliment Pharmacol Ther 2015;42(8):990-9.

141 Mantzaris GJ, Sfakianakis M, Archavlis E, et al. A prospective randomized observer-

blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the

maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol

2004;99(6):1122-8.

142 Szumlanski CL, Weinshilboum RM Sulphasalazine inhibition of thiopurine

methyltransferase: possible mechanism for interaction with 6-mercaptopurine and

azathioprine. Br J Clin Pharmacol 1995;39(4):456-9.

143 Andrews JM, Travis SP, Gibson PR, et al. Systematic review: does concurrent therapy

with 5-ASA and immunomodulators in inflammatory bowel disease improve outcomes?

Aliment Pharmacol Ther 2009;29(5):459-69.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

144 Luan ZJ, Li Y, Zhao XY, et al. Treatment efficacy and safety of low-dose azathioprine in

chronic active ulcerative colitis patients: A meta-analysis and systemic review. J Dig Dis

2016;17(10):652-59.

145 Grossman AB, Noble AJ, Mamula P, et al. Increased dosing requirements for 6-

mercaptopurine and azathioprine in inflammatory bowel disease patients six years and

younger. Inflamm Bowel Dis 2008;14(6):750-5.

146 Stocco G, Martelossi S, Arrigo S, et al. Multicentric Case-Control Study on Azathioprine

Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease.

Inflamm Bowel Dis 2017;23(4):628-34.

147 Fuentes D, Torrente F, Keady S, et al. High-dose azathioprine in children with

inflammatory bowel disease. Aliment Pharmacol Ther 2003;17(7):913-21.

148 Kirschner BS Safety of azathioprine and 6-mercaptopurine in pediatric patients with

inflammatory bowel disease. Gastroenterology 1998;115(4):813-21.

149 Sandborn WJ A review of immune modifier therapy for inflammatory bowel disease:

azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol

1996;91(3):423-33.

150 Connell WR, Kamm MA, Ritchie JK, et al. Bone marrow toxicity caused by azathioprine

in inflammatory bowel disease: 27 years of experience. Gut 1993;34(8):1081-5.

151 Kennedy NA, Rhatigan E, Arnott ID, et al. A trial of mercaptopurine is a safe strategy in

patients with inflammatory bowel disease intolerant to azathioprine: an observational

study, systematic review and meta-analysis. Aliment Pharmacol Ther 2013;38(10):1255-

66.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

152 Kotlyar DS, Lewis JD, Beaugerie L, et al. Risk of lymphoma in patients with

inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-

analysis. Clin Gastroenterol Hepatol 2015;13(5):847-58 e4; quiz e48-50.

153 Subramaniam K, D'Rozario J, Pavli P Lymphoma and other lymphoproliferative

disorders in inflammatory bowel disease: a review. J Gastroenterol Hepatol

2013;28(1):24-30.

154 Yabe M, Medeiros LJ, Daneshbod Y, et al. Hepatosplenic T-cell lymphoma arising in

patients with immunodysregulatory disorders: a study of 7 patients who did not receive

tumor necrosis factor-alpha inhibitor therapy and literature review. Ann Diagn Pathol

2017;26(16-22.

155 Coenen MJ, de Jong DJ, van Marrewijk CJ, et al. Identification of Patients With Variants

in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine

Treatment of Inflammatory Bowel Disease. Gastroenterology 2015;149(4):907-17 e7.

156 Gazouli M, Pachoula I, Panayotou I, et al. Thiopurine methyltransferase genotype and

thiopurine S-methyltransferase activity in Greek children with inflammatory bowel

disease. Ann Gastroenterol 2012;25(3):249-53.

157 De Ridder L, Van Dieren JM, Van Deventer HJ, et al. Pharmacogenetics of thiopurine

therapy in paediatric IBD patients. Aliment Pharmacol Ther 2006;23(8):1137-41.

158 Gerich ME, Quiros JA, Marcin JP, et al. A prospective evaluation of the impact of

allopurinol in pediatric and adult IBD patients with preferential metabolism of 6-

mercaptopurine to 6-methylmercaptopurine. J Crohns Colitis 2010;4(5):546-52.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

159 Rahhal RM, Bishop WP Initial clinical experience with allopurinol-thiopurine

combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis

2008;14(12):1678-82.

160 Pavlidis P, Stamoulos P, Abdulrehman A, et al. Long-term Safety and Efficacy of Low-

dose Azathioprine and Allopurinol Cotherapy in Inflammatory Bowel Disease: A Large

Observational Study. Inflamm Bowel Dis 2016;22(7):1639-46.

161 Ihekweazu FD, Kellermayer R Allopurinol: a Useful Adjunct to Thiopurine Therapy for

Pediatric Ulcerative Colitis in the Biologic Era. J Pediatr Gastroenterol Nutr 2014.

162 Konidari A, Anagnostopoulos A, Bonnett LJ, et al. Thiopurine monitoring in children

with inflammatory bowel disease: a systematic review. Br J Clin Pharmacol

2014;78(3):467-76.

163 Nguyen TV, Vu DH, Nguyen TM, et al. Exploring associations of 6-thioguanine

nucleotide levels and other predictive factors with therapeutic response to azathioprine in

pediatric patients with IBD using multilevel analysis. Inflamm Bowel Dis

2013;19(11):2404-10.

164 Hanai H, Iida T, Takeuchi K, et al. Thiopurine maintenance therapy for ulcerative colitis:

the clinical significance of monitoring 6-thioguanine nucleotide. Inflamm Bowel Dis

2010;16(8):1376-81.

165 Wong DR, Coenen MJ, Vermeulen SH, et al. Early Assessment of Thiopurine

Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in

Inflammatory Bowel Disease. J Crohns Colitis 2017;11(2):175-84.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

166 Lee MN, Kang B, Choi SY, et al. Relationship between azathioprine dosage, 6-

thioguanine nucleotide levels, and therapeutic response in pediatric patients with IBD

treated with azathioprine. Inflamm Bowel Dis 2015;21(5):1054-62.

167 Ooi CY, Bohane TD, Lee D, et al. Thiopurine metabolite monitoring in paediatric

inflammatory bowel disease. Aliment Pharmacol Ther 2007;25(8):941-7.

168 Gupta P, Gokhale R, Kirschner BS 6-mercaptopurine metabolite levels in children with

inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2001;33(4):450-4.

169 Banerjee S, Bishop WP Evolution of thiopurine use in pediatric inflammatory bowel

disease in an academic center. J Pediatr Gastroenterol Nutr 2006;43(3):324-30.

170 Nguyen TV, Nguyen TM, Lachaux A, et al. Usefulness of thiopurine metabolites in

predicting azathioprine resistance in pediatric IBD patients. J Clin Pharmacol

2013;53(9):900-8.

171 Cassinotti A, Actis GC, Duca P, et al. Maintenance treatment with azathioprine in

ulcerative colitis: outcome and predictive factors after drug withdrawal. Am J

Gastroenterol 2009;104(11):2760-7.

172 Kennedy NA, Kalla R, Warner B, et al. Thiopurine withdrawal during sustained clinical

remission in inflammatory bowel disease: relapse and recapture rates, with predictive

factors in 237 patients. Aliment Pharmacol Ther 2014;40(11-12):1313-23.

173 Chande N, Wang Y, MacDonald JK, et al. Methotrexate for induction of remission in

ulcerative colitis. Cochrane Database Syst Rev 20148):CD006618.

174 Wang Y, MacDonald JK, Vandermeer B, et al. Methotrexate for maintenance of

remission in ulcerative colitis. Cochrane Database Syst Rev 20158):CD007560.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

175 Carbonnel F, Colombel JF, Filippi J, et al. Methotrexate Is Not Superior to Placebo for

Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a

Larger Proportion of Patients With Ulcerative Colitis. Gastroenterology

2016;150(2):380-8 e4.

176 Aloi M, Di Nardo G, Conte F, et al. Methotrexate in paediatric ulcerative colitis: a

retrospective survey at a single tertiary referral centre. Aliment Pharmacol Ther

2010;32(8):1017-22.

177 Baumgart DC, Macdonald JK, Feagan B Tacrolimus (FK506) for induction of remission

in refractory ulcerative colitis. Cochrane Database Syst Rev 20083):CD007216.

178 Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral

tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006;55(9):1255-62.

179 Landy J, Wahed M, Peake ST, et al. Oral tacrolimus as maintenance therapy for

refractory ulcerative colitis--an analysis of outcomes in two London tertiary centres. J

Crohns Colitis 2013;7(11):e516-21.

180 Ziring DA, Wu SS, Mow WS, et al. Oral tacrolimus for steroid-dependent and steroid-

resistant ulcerative colitis in children. J Pediatr Gastroenterol Nutr 2007;45(3):306-11.

181 Navas-Lopez VM, Blasco Alonso J, Serrano Nieto MJ, et al. Oral tacrolimus for pediatric

steroid-resistant ulcerative colitis. J Crohns Colitis 2014;8(1):64-9.

182 Truffinet O, Martinez-Vinson C, Guerriero E, et al. Tacrolimus Exerts Only a Transient

Effectiveness in Refractory Pediatric Crohn Disease: a Case Series. J Pediatr

Gastroenterol Nutr 2017;64(5):721-25.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

183 Lawson MM, Thomas AG, Akobeng AK Tumour necrosis factor alpha blocking agents

for induction of remission in ulcerative colitis. Cochrane Database Syst Rev

2006;3(CD005112.

184 Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and

azathioprine is superior to monotherapy with either agent in ulcerative colitis.

Gastroenterology 2014;146(2):392-400 e3.

185 Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with

infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol

Hepatol 2012;10(4):391-9 e1.

186 Turner D, Griffiths AM Acute severe ulcerative colitis in children: a systematic review.

Inflamm Bowel Dis 2011;17(1):440-9.

187 Hyams JS, Lerer T, Griffiths A, et al. Outcome following infliximab therapy in children

with ulcerative colitis. Am J Gastroenterol 2010;105(6):1430-6.

188 Larsen MD, Qvist N, Nielsen J, et al. Use of Anti-TNFalpha Agents and Time to First-

time Surgery in Paediatric Patients with Ulcerative Colitis and Crohn's Disease. J Crohns

Colitis 2016;10(6):650-6.

189 Reinisch W, Sandborn WJ, 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(6):780-87.

190 Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains

clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology

2012;142(2):257-65 e1-3.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

191 Thorlund K, Druyts E, Mills EJ, et al. Adalimumab versus infliximab for the treatment of

moderate to severe ulcerative colitis in adult patients naive to anti-TNF therapy: An

indirect treatment comparison meta-analysis. J Crohns Colitis 2014;8(7):571-81.

192 Cholapranee A, Hazlewood GS, Kaplan GG, et al. Systematic review with meta-analysis:

comparative efficacy of biologics for induction and maintenance of mucosal healing in

Crohn's disease and ulcerative colitis controlled trials. Aliment Pharmacol Ther

2017;45(10):1291-302.

193 Ananthakrishnan AN, Cagan A, Cai T, et al. Comparative Effectiveness of Infliximab

and Adalimumab in Crohn's Disease and Ulcerative Colitis. Inflamm Bowel Dis

2016;22(4):880-5.

194 Vahabnezhad E, Rabizadeh S, Dubinsky MC A 10-year, single tertiary care center

experience on the durability of infliximab in pediatric inflammatory bowel disease.

Inflamm Bowel Dis 2014;20(4):606-13.

195 Volonaki E, Mutalib M, Kiparissi F, et al. Adalimumab as a second-line biological

therapy in children with refractory ulcerative colitis. Eur J Gastroenterol Hepatol

2015;27(12):1425-8.

196 Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical

response and remission in patients with moderate-to-severe ulcerative colitis.

Gastroenterology 2014;146(1):85-95; quiz e14-5.

197 Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical

response in patients with moderate-to-severe ulcerative colitis. Gastroenterology

2014;146(1):96-109 e1.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

198 Turner D, Veereman G, Hyams J, et al. A multicentre open-label study assessing

pharmacokinetics, efficacy, and safety of subcutaneous golimumab in paediatric patients

with moderately-severely active Ulcerative Colitis. J Crohns Colitis 2016;10(suppl

1):S364-S65.

199 Hyams JS, Chan D, Adedokun OJ, et al. Subcutaneous Golimumab in Pediatric

Ulcerative Colitis: Pharmacokinetics and Clinical Benefit. Inflamm Bowel Dis

2017;23(12):2227-37.

200 Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance

therapy for ulcerative colitis. N Engl J Med 2005;353(23):2462-76.

201 Papamichael K, Van Stappen T, Vande Casteele N, et al. Infliximab Concentration

Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing

in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol 2016;14(4):543-9.

202 Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration

of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology

2014;147(6):1296-307.e5.

203 Imaeda H, Bamba S, Takahashi K, et al. Relationship between serum infliximab trough

levels and endoscopic activities in patients with Crohn's disease under scheduled

maintenance treatment. J Gastroenterol 2014;49(4):674-82.

204 Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction serum infliximab trough level

and decrease of C-reactive protein level are associated with durable sustained response to

infliximab: a retrospective analysis of the ACCENT I trial. Gut 2014;63(11):1721-7.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

205 Roblin X, Marotte H, Rinaudo M, et al. Association between pharmacokinetics of

adalimumab and mucosal healing in patients with inflammatory bowel diseases. Clin

Gastroenterol Hepatol 2014;12(1):80-84.e2.

206 Mazor Y, Almog R, Kopylov U, et al. Adalimumab drug and antibody levels as

predictors of clinical and laboratory response in patients with Crohn's disease. Aliment

Pharmacol Ther 2014;40(6):620-8.

207 Adedokun OJ, Xu Z, Marano CW, et al. Pharmacokinetics and Exposure-response

Relationship of Golimumab in Patients with Moderately-to-Severely Active Ulcerative

Colitis: Results from Phase 2/3 PURSUIT Induction and Maintenance Studies. J Crohns

Colitis 2017;11(1):35-46.

208 Papamichael K, Baert F, Tops S, et al. Post-Induction Adalimumab Concentration is

Associated with Short-Term Mucosal Healing in Patients with Ulcerative Colitis. J

Crohns Colitis 2017;11(1):53-59.

209 Ungar B, Levy I, Yavne Y, et al. Optimizing Anti-TNF-alpha Therapy: Serum Levels of

Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With

Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2016;14(4):550-57 e2.

210 Zittan E, Kabakchiev B, Milgrom R, et al. Higher Adalimumab Drug Levels are

Associated with Mucosal Healing in Patients with Crohn's Disease. J Crohns Colitis

2016;10(5):510-5.

211 Drobne D, Bossuyt P, Breynaert C, et al. Withdrawal of immunomodulators after co-

treatment does not reduce trough level of infliximab in patients with Crohn's disease. Clin

Gastroenterol Hepatol 2015;13(3):514-21.e4.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

212 Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association

Institute Guideline on Therapeutic Drug Monitoring in Inflammatory Bowel Disease.

Gastroenterology 2017;153(3):827-34.

213 Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are

associated with outcome of interventions after loss of response to infliximab or

adalimumab. Clin Gastroenterol Hepatol 2015;13(3):522-30.e2.

214 Klaasen R, Wijbrandts CA, Gerlag DM, et al. Body mass index and clinical response to

infliximab in rheumatoid arthritis. Arthritis Rheum 2011;63(2):359-64.

215 Feber J, Al-Matrafi J, Farhadi E, et al. Prednisone dosing per body weight or body

surface area in children with nephrotic syndrome: is it equivalent? Pediatr Nephrol

2009;24(5):1027-31.

216 Kelsen JR, Grossman AB, Pauly-Hubbard H, et al. Infliximab therapy in pediatric

patients 7 years of age and younger. J Pediatr Gastroenterol Nutr 2014;59(6):758-62.

217 Adedokun OJ, Xu Z, Padgett L, et al. Pharmacokinetics of Infliximab in Children with

Moderate-to-Severe Ulcerative Colitis: Results from a Randomized, Multicenter, Open-

label, Phase 3 Study. Inflamm Bowel Dis 2013;19(13):2753-62.

218 Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of

infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol 2009;65(12):1211-28.

219 Ordas I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory

bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther

2012;91(4):635-46.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

220 Fasanmade AA, Adedokun OJ, Olson A, et al. Serum albumin concentration: a predictive

factor of infliximab pharmacokinetics and clinical response in patients with ulcerative

colitis. Int J Clin Pharmacol Ther 2010;48(5):297-308.

221 Gecse KB, Vegh Z, Lakatos PL Optimizing biological therapy in Crohn's disease. Expert

Rev Gastroenterol Hepatol 2016;10(1):37-45.

222 Ungar B, Mazor Y, Weisshof R, et al. Induction infliximab levels among patients with

acute severe ulcerative colitis compared with patients with moderately severe ulcerative

colitis. Aliment Pharmacol Ther 2016;43(12):1293-9.

223 Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and

shorten half-life in inflammatory bowel disease: a population pharmacokinetic study.

Inflamm Bowel Dis 2014;20(12):2247-59.

224 Nanau RM, Cohen LE, Neuman MG Risk of infections of biological therapies with

accent on inflammatory bowel disease. J Pharm Pharm Sci 2014;17(4):485-531.

225 Lemaitre M, Kirchgesner J, Rudnichi A, et al. Association Between Use of Thiopurines

or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma

in Patients With Inflammatory Bowel Disease. JAMA 2017;318(17):1679-86.

226 Eickstaedt JB, Killpack L, Tung J, et al. Psoriasis and Psoriasiform Eruptions in Pediatric

Patients with Inflammatory Bowel Disease Treated with Anti-Tumor Necrosis Factor

Alpha Agents. Pediatr Dermatol 2017;34(3):253-60.

227 Alexandre B, Vandermeeren Y, Dewit O, et al. Optic Neuritis Associated or Not with

TNF Antagonists in Patients with Inflammatory Bowel Disease. J Crohns Colitis

2016;10(5):541-8.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

228 Jacobstein DA, Markowitz JE, Kirschner BS, et al. Premedication and infusion reactions

with infliximab: results from a pediatric inflammatory bowel disease consortium.

Inflamm Bowel Dis 2005;11(5):442-6.

229 Lahdenne P, Wikström AM, Aalto K, et al. Prevention of acute adverse events related to

infliximab infusions in pediatric patients. Arthritis Care Res (Hoboken) 2010;62(6):785-

90.

230 Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients

with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J

Gastroenterol 2012;107(9):1409-22.

231 Andersen NN, Jess T Risk of infections associated with biological treatment in

inflammatory bowel disease. World J Gastroenterol 2014;20(43):16014-9.

232 Bonovas S, Fiorino G, Allocca M, et al. Biologic Therapies and Risk of Infection and

Malignancy in Patients With Inflammatory Bowel Disease: A Systematic Review and

Network Meta-analysis. Clin Gastroenterol Hepatol 2016;14(10):1385-97.e10.

233 Lawrance IC, Radford-Smith GL, Bampton PA, et al. Serious infections in patients with

inflammatory bowel disease receiving anti-tumor-necrosis-factor-alpha therapy: an

Australian and New Zealand experience. J Gastroenterol Hepatol 2010;25(11):1732-8.

234 Raaschou P, Simard JF, Holmqvist M, et al. Rheumatoid arthritis, anti-tumour necrosis

factor therapy, and risk of malignant melanoma: nationwide population based prospective

cohort study from Sweden. Bmj 2013;346(f1939.

235 Mercer LK, Askling J, Raaschou P, et al. Risk of invasive melanoma in patients with

rheumatoid arthritis treated with biologics: results from a collaborative project of 11

European biologic registers. Ann Rheum Dis 2017;76(2):386-91.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

236 Hyams JS, Dubinsky MC, Baldassano RN, et al. Infliximab Is Not Associated With

Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric

Patients With Inflammatory Bowel Disease. Gastroenterology 2017;152(8):1901-14 e3.

237 Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance

therapy for ulcerative colitis. N Engl J Med 2013;369(8):699-710.

238 Feagan BG, Rubin DT, Danese S, et al. Efficacy of Vedolizumab Induction and

Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure

to Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol 2017;15(2):229-39.e5.

239 Bickston SJ, Behm BW, Tsoulis DJ, et al. Vedolizumab for induction and maintenance of

remission in ulcerative colitis. Cochrane Database Syst Rev 20148):Cd007571.

240 Yarur A, Bruss A, Jain A, et al. Higher vedolizumab levels are associated with deep

remission in patients with Crohn's disease and ulcerative colitis on maintenance therapy

with vedolizumab. Abstract - European Crohn's and Colitis Organisation 2017 Annual

Meeting 2017:DOP020.

241 Schulze H, Esters P, Hartmann F, et al. A prospective cohort study to assess the relevance

of Vedolizumab drug level monitoring in IBD patients Abstract - European Crohn's and

Colitis Organisation 2017 Annual Meeting 2017P521).

242 Williet N, Paul S, Del Tedesco E, et al. Serum vedolizumab assay at week 6 predicts

sustained clinical remission and lack of recourse to optimisation in inflammatory bowel

disease. ECCO annual meeting 2016:Abst P632.

243 Ledder O, Assa A, Levine A, et al. Vedolizumab in pediatric inflammatory bowel

disease: a retrospective multi-center experience from the Paediatric IBD Porto group of

ESPGHAN. J Crohns Colitis 2017.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

244 Conrad MA, Stein RE, Maxwell EC, et al. Vedolizumab Therapy in Severe Pediatric

Inflammatory Bowel Disease. Inflamm Bowel Dis 2016;22(10):2425-31.

245 Singh N, Rabizadeh S, Jossen J, et al. Multi-Center Experience of Vedolizumab

Effectiveness in Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis

2016;22(9):2121-6.

246 Shelton E, Allegretti JR, Stevens B, et al. Efficacy of Vedolizumab as Induction Therapy

in Refractory IBD Patients: A Multicenter Cohort. Inflamm Bowel Dis

2015;21(12):2879-85.

247 Danese S, Fiorino G, Peyrin-Biroulet L, et al. Biological agents for moderately to

severely active ulcerative colitis: a systematic review and network meta-analysis. Ann

Intern Med 2014;160(10):704-11.

248 Ikeda H, Ishimaru Y, Takayasu H, et al. Efficacy of granulocyte apheresis in pediatric

patients with ulcerative colitis: a pilot study. J Pediatr Gastroenterol Nutr

2006;43(5):592-6.

249 Martin de Carpi J, Vilar P, Prieto G, et al. Safety and efficacy of granulocyte and

monocyte adsorption apheresis in paediatric inflammatory bowel disease: a prospective

pilot study. J Pediatr Gastroenterol Nutr 2008;46(4):386-91.

250 Ruuska T, Wewer V, Lindgren F, et al. Granulocyte-monocyte adsorptive apheresis in

pediatric inflammatory bowel disease: results, practical issues, safety, and future

perspectives. Inflamm Bowel Dis 2009;15(7):1049-54.

251 Tanaka T, Okanobu H, Kuga Y, et al. Clinical and endoscopic features of responders and

non-responders to adsorptive leucocytapheresis: a report based on 120 patients with

active ulcerative colitis. Gastroenterol Clin Biol 2010;34(12):687-95.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

252 Tomomasa T, Kobayashi A, Kaneko H, et al. Granulocyte adsorptive apheresis for

pediatric patients with ulcerative colitis. Dig Dis Sci 2003;48(4):750-4.

253 Tomomasa T, Tajiri H, Kagimoto S, et al. Leukocytapheresis in pediatric patients with

ulcerative colitis. J Pediatr Gastroenterol Nutr 2011;53(1):34-9.

254 WJ. S. Preliminary data on the use of apheresis ininflammatory bowel disease. Inflamm

Bowel Dis; 2006:S15-21.

255 Dignass AU EA, Kilander A, Pukitis A, Rhodes JM, Vavricka, S. Clinical trial: five or

ten cycles of granulocyte-monocyteapheresis show equivalent efficacy and safety in

ulcerative colitis. Aliment Pharmacol Ther; 2010:1286–95.

256 Kruis W, Dignass A, Steinhagen-Thiessen E, et al. Open label trial of granulocyte

apheresis suggests therapeutic efficacy in chronically activesteroid refractory ulcerative

colitis. World J Gastroenterol 2005;11(44):7001–6.

257 Sawada K KK, Suzuki Y, Bamba T, Munakata A, Hibi T, et al. Leukocytapheresis in

ulcerative colitis: results of a multicenter double-blind prospective case–control study

with sham apheresis as placebo treatment Am J Gastroenterol; 2005:1362–9.

258 Sawada K MT, Shimoyama T, Satomi M, Sawada T, Nagawa H, et al. Multicenter

randomized controlled trial for the treatment of ulcerative colitis with a

leukocytapheresis column. Curr Pharm Des; 2003:307–21.

259 Yokoyama Y, Matsuoka K, Kobayashi T, et al. A large-scale, prospective, observational

study of leukocytapheresis for ulcerative colitis: treatment outcomes of 847 patients in

clinical practice. J Crohns Colitis 2014;8(9):981-91.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

260 Sands BE, Katz S, Wolf DC, et al. A randomised, double-blind, sham-controlled study of

granulocyte/monocyte apheresis for moderate to severe Crohn's disease. Gut

2013;62(9):1288-94.

261 Thanaraj S, Hamlin PJ, Ford AC Systematic review: granulocyte/monocyte adsorptive

apheresis for ulcerative colitis. Aliment Pharmacol Ther 2010;32(11-12):1297-306.

262 Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal ficrobiota fransplantation and

clinical resolution of diarrhea in patients with recurrent clostridium difficile infection: a

randomized clinical trial. JAMA 2016;315(2):142-9.

263 Kunde S, Pham A, Bonczyk S, et al. Safety, tolerability, and clinical response after fecal

transplantation in children and young adults with ulcerative colitis. J Pediatr

Gastroenterol Nutr 2013;56(6):597-601.

264 Suskind DL, Singh N, Nielson H, et al. Fecal microbial transplant via nasogastric tube for

active pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2015;60(1):27-9.

265 Kellermayer R, Nagy-Szakal D, Harris RA, et al. Serial fecal microbiota transplantation

alters mucosal gene expression in pediatric ulcerative colitis. Am J Gastroenterol

2015;110(4):604-6.

266 Vandenplas Y, Veereman G, van der Werff Ten Bosch J, et al. Fecal Microbial

Transplantation in Early-Onset Colitis: Caution Advised. J Pediatr Gastroenterol Nutr

2015;61(3):e12-4.

267 Hourigan SK, Oliva-Hemker M Fecal microbiota transplantation in children: a brief

review. Pediatr Res 2016;80(1):2-6.

268 Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with

increased capacity for energy harvest. Nature 2006;444(7122):027–31.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

269 Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal

microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol

2012;107(7):1079-87.

270 Alang N, Kelly CR Weight gain after fecal microbiota transplantation. Open Forum

Infect Dis 2015;2(1):ofv004.

271 Moayyedi P, Surette MG, Kim PT, et al. Fecal Microbiota Transplantation Induces

Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial.

Gastroenterology 2015;149(1):102-09.e6.

272 Rossen NG, Fuentes S, van der Spek MJ, et al. Findings From a Randomized Controlled

Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology

2015;149(1):110-18.e4.

273 Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota

transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet

2017;389(10075):1218-28.

274 Henker J, Muller S, Laass MW, et al. Probiotic Escherichia coli Nissle 1917 (EcN) for

successful remission maintenance of ulcerative colitis in children and adolescents: an

open-label pilot study. Z Gastroenterol 2008;46(9):874-5.

275 Kruis W, Schutz E, Fric P, et al. Double-blind comparison of an oral Escherichia coli

preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment

Pharmacol Ther 1997;11(5):853-8.

276 Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the

probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut

2004;53(11):1617-23.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

277 Rembacken BJ, Snelling AM, Hawkey PM, et al. Non-pathogenic Escherichia coli versus

mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet

1999;354(9179):635-39.

278 Losurdo G, Iannone A, Contaldo A, et al. Escherichia coli Nissle 1917 in Ulcerative

Colitis Treatment: Systematic Review and Meta-analysis. J Gastrointestin Liver Dis

2015;24(4):499-505.

279 Naidoo K, Gordon M, Fagbemi AO, et al. Probiotics for maintenance of remission in

ulcerative colitis. Cochrane Database Syst Rev 2011;12(CD007443.

280 Miele E, Pascarella F, Giannetti E, et al. Effect of a probiotic preparation (VSL#3) on

induction and maintenance of remission in children with ulcerative colitis. Am J

Gastroenterol 2009;104(2):437-43.

281 Huynh HQ, deBruyn J, Guan L, et al. Probiotic preparation VSL#3 induces remission in

children with mild to moderate acute ulcerative colitis: a pilot study. Inflamm Bowel Dis

2009;15(5):760-8.

282 Mardini HE, Grigorian AY Probiotic mix VSL#3 is effective adjunctive therapy for mild

to moderately active ulcerative colitis: a meta-analysis. Inflamm Bowel Dis

2014;20(9):1562-7.

283 Cinque B, La Torre C, Lombardi F, et al. VSL#3 probiotic differently influences IEC-6

intestinal epithelial cell status and function. J Cell Physiol 2017.

284 Cinque B, La Torre C, Lombardi F, et al. Production Conditions Affect the In Vitro Anti-

Tumoral Effects of a High Concentration Multi-Strain Probiotic Preparation. PLoS One

2016;11(9):e0163216.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

285 Oliva S, Di Nardo G, Ferrari F, et al. Randomised clinical trial: the effectiveness of

Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative

colitis. Aliment Pharmacol Ther 2012;35(3):327-34.

286 Khan KJ, Ullman TA, Ford AC, et al. Antibiotic therapy in inflammatory bowel disease:

a systematic review and meta-analysis. Am J Gastroenterol 2011;106(4):661-73.

287 Wang SL, Wang ZR, Yang CQ Meta-analysis of broad-spectrum antibiotic therapy in

patients with active inflammatory bowel disease. Exp Ther Med 2012;4(6):1051-56.

288 Suskind DL, Wahbeh G, Burpee T, et al. Tolerability of curcumin in pediatric

inflammatory bowel disease: a forced-dose titration study. J Pediatr Gastroenterol Nutr

2013;56(3):277-9.

289 Hanai H IT, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative colitis:

randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol

Hepatol 2006;4:1502-6

290 Lang A, Salomon N, Wu JC, et al. Curcumin in Combination With Mesalamine Induces

Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized

Controlled Trial. Clin Gastroenterol Hepatol 2015;13(8):1444-9.e1.

291 Singla V, Pratap Mouli V, Garg SK, et al. Induction with NCB-02 (curcumin) enema for

mild-to-moderate distal ulcerative colitis - a randomized, placebo-controlled, pilot study.

J Crohns Colitis 2014;8(3):208-14.

292 Langhorst J, Wulfert H, Lauche R, et al. Systematic review of complementary and

alternative medicine treatments in inflammatory bowel diseases. J Crohn Colitis

2015;9(1):86-106.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

293 Ng SC, Lam YT, Tsoi KK, et al. Systematic review: the efficacy of herbal therapy in

inflammatory bowel disease. Aliment Pharmacol Ther 2013;38(8):854-63.

294 Langmead L, Feakins RM, Goldthorpe S, et al. Randomized, double-blind, placebo-

controlled trial of oral aloe vera gel for active ulcerative colitis. Aliment Pharmacol Ther

2004;19(7):739-47.

295 Cabré E, Mañosa M, Gassull MA Omega-3 fatty acids and inflammatory bowel diseases -

a systematic review. Br J Nutr 2012;107(Suppl 2):S240-52.

296 Turner D, Shah PS, Steinhart AH, et al. Maintenance of remission in inflammatory bowel

disease using omega-3 fatty acids (fish oil): a systematic review and meta-analyses.

Inflamm Bowel Dis 2011;17(1):336-45.

297 Turner D, Steinhart AH, Griffiths AM Omega 3 fatty acids (fish oil) for maintenance of

remission in ulcerative colitis. Cochrane Database Syst Rev 20073):CD006443.

298 Merkley SA, Beaulieu DB, Horst S, et al. Use of intravenous immunoglobulin for

patients with inflammatory bowel disease with contraindications or who are unresponsive

to conventional treatments. Inflamm Bowel Dis 2015;21(8):1854-9.

299 Winter DA, Karolewska-Bochenek K, Lazowska-Przeorek I, et al. Pediatric IBD-

unclassified Is Less Common than Previously Reported; Results of an 8-Year Audit of

the EUROKIDS Registry. Inflamm Bowel Dis 2015;21(9):2145-53.

300 Aloi M, Birimberg-Schwartz L, Buderus S, et al. Treatment Options and Outcomes of

Pediatric IBDU Compared with Other IBD Subtypes: A Retrospective Multicenter Study

from the IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2016;22(6):1378-83.

301 Polites SF, Potter DD, Moir CR, et al. Long-term outcomes of ileal pouch-anal

anastomosis for pediatric chronic ulcerative colitis. J Pediatr Surg 2015;50(10):1625-9.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

302 Ozdemir Y, Kiran RP, Erem HH, et al. Functional outcomes and complications after

restorative proctocolectomy and ileal pouch anal anastomosis in the pediatric population.

J Am Coll Surg 2014;218(3):328-35.

303 Lillehei CW, Leichtner A, Bousvaros A, et al. Restorative proctocolectomy and ileal

pouch-anal anastomosis in children. Dis Colon Rectum 2009;52(9):1645-9.

304 Pakarinen MP, Natunen J, Ashorn M, et al. Long-term outcomes of restorative

proctocolectomy in children with ulcerative colitis. Pediatrics 2009;123(5):1377-82.

305 Mortellaro VE, Green J, Islam S, et al. Occurrence of Crohn's disease in children after

total colectomy for ulcerative colitis. J Surg Res 2011;170(1):38-40.

306 Gray BW, Drongowski RA, Hirschl RB, et al. Restorative proctocolectomy without

diverting ileostomy in children with ulcerative colitis. J Pediatr Surg 2012;47(1):204-8.

307 Dolgin SE, Shlasko E, Gorfine S, et al. Restorative proctocolectomy in children with

ulcerative colitis utilizing rectal mucosectomy with or without diverting ileostomy. J

Pediatr Surg 1999;34(5):837-9; discussion 39-40.

308 Ryan DP, Doody DP Restorative proctocolectomy with and without protective ileostomy

in a pediatric population. J Pediatr Surg 2011;46(1):200-3.

309 Marceau C, Alves A, Ouaissi M, et al. Laparoscopic subtotal colectomy for acute or

severe colitis complicating inflammatory bowel disease: a case-matched study in 88

patients. Surgery 2007;141(5):640.

310 Lazzerini M, Bramuzzo M, Maschio M, et al. Thromboembolism in pediatric

inflammatory bowel disease: systematic review. Inflamm Bowel Dis 2011;17(10):2174-

83.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

311 Carter FM, McLeod RS, Cohen Z Subtotal colectomy for ulcerative colitis: complications

related to the rectal remnant. Dis Colon Rectum 1991;34(11):1005-09.

312 Linden BC, Bairdain S, Zurakowski D, et al. Comparison of laparoscopic-assisted and

open total proctocolectomy and ileal pouch anal anastomosis in children and adolescents.

J Pediatr Surg 2013;48(7):1546-50.

313 Diamond IR, Gerstle JT, Kim PC, et al. Outcomes after laparoscopic surgery in children

with inflammatory bowel disease. Surg Endosc 2010;24(11):2796-802.

314 Pini-Prato A, Faticato MG, Barabino A, et al. Minimally invasive surgery for paediatric

inflammatory bowel disease: Personal experience and literature review. World J

Gastroenterol 2015;21(40):11312-20.

315 Markel TA, Lou DC, Pfefferkorn M, et al. Steroids and poor nutrition are associated with

infectious wound complications in children undergoing first stage procedures for

ulcerative colitis. Surgery 2008;144(4):540-45.

316 Schaufler C, Lerer T, Campbell B, et al. Preoperative immunosuppression is not

associated with increased postoperative complications following colectomy in children

with colitis. J Pediatr Gastroenterol Nutr 2012;55(4):421-4.

317 Hait EJ, Bousvaros A, Schuman M, et al. Pouch outcomes among children with

ulcerative colitis treated with calcineurin inhibitors before ileal pouch anal anastomosis

surgery. J Pediatr Surg 2007;42(1):31-5.

318 Kennedy R, Potter DD, Moir C, et al. Pediatric chronic ulcerative colitis: does infliximab

increase post-ileal pouch anal anastomosis complications? J Pediatr Surg 2012;47(1):199-

203.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

319 Billioud V, Ford AC, Tedesco ED, et al. Preoperative use of anti-TNF therapy and

postoperative complications in inflammatory bowel diseases: a meta-analysis. J Crohns

Colitis 2013;7(11):853-67.

320 Narula N, Charleton D, Marshall JK Meta-analysis: peri-operative anti-TNFalpha

treatment and post-operative complications in patients with inflammatory bowel disease.

Aliment Pharmacol Ther 2013;37(11):1057-64.

321 Tilney HS, Constantinides V, Ioannides AS, et al. Pouch-anal anastomosis vs straight

ileoanal anastomosis in pediatric patients: a meta-analysis. J Pediatr Surg

2006;41(11):1799-808.

322 Seetharamaiah R, West BT, Ignash SJ, et al. Outcomes in pediatric patients undergoing

straight vs J pouch ileoanal anastomosis: a multicenter analysis. J Pediatr Surg

2009;44(7):1410-7.

323 Davis C, Alexander F, Lavery I, et al. Results of mucosal proctectomy versus extrarectal

dissection for ulcerative colitis and familial polyposis in children and young adults. J

Pediatr Surg 1994;29(2):305-9.

324 Luukkonen P, Jarvinen H Stapled vs hand-sutured ileoanal anastomosis in restorative

proctocolectomy. A prospective, randomized study. Arch Surg 1993;128(4):437-40.

325 Shannon A, Eng K, Kay M, et al. Long-term follow up of ileal pouch anal anastomosis in

a large cohort of pediatric and young adult patients with ulcerative colitis. J Pediatr Surg

2016;51(7):1181-6.

326 Orlanski-Meyer E, Topf-Olivestone C, Shtayer E, et al. Short and long-term surgical

outcomes and Pouch function following proctocolectomy and pouch formation in

Paediatric UC: A multicentre-retrospective cohort study from the Porto IBD working

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 group of ESPGHAN. ESPGHAN annual meeting, Prague, May 12th 2017:Abstr G-P-

308.

327 Orlanski-Meyer E, Topf-Olivestone C, Ledder O, et al. Pouchitis in paediatric UC: A

multicentre longitudinal cohort study from the Porto IBD working group of ESPGHAN.

ESPGHAN annual meeting, Prague, May 12th 2017:Abstr G-O-038.

328 Nasseri Y, Melmed G, Wang HL, et al. Rigorous histopathological assessment of the

colectomy specimen in patients with inflammatory bowel disease unclassified does not

predict outcome after ileal pouch-anal anastomosis. Am J Gastroenterol 2010;105(1):155-

61.

329 Murrell ZA, Melmed GY, Ippoliti A, et al. A prospective evaluation of the long-term

outcome of ileal pouch-anal anastomosis in patients with inflammatory bowel disease-

unclassified and indeterminate colitis. Dis Colon Rectum 2009;52(5):872-8.

330 Myrelid P, Oresland T A reappraisal of the ileo-rectal anastomosis in ulcerative colitis. J

Crohns Colitis 2015;9(6):433-8.

331 Hull TL, Joyce MR, Geisler DP, et al. Adhesions after laparoscopic and open ileal pouch-

anal anastomosis surgery for ulcerative colitis. Br J Surg 2012;99(2):270-5.

332 Bartels SA, D'Hoore A, Cuesta MA, et al. Significantly increased pregnancy rates after

laparoscopic restorative proctocolectomy: a cross-sectional study. Ann Surg

2012;256(6):1045-8.

333 Beyer-Berjot L, Maggiori L, Birnbaum D, et al. A total laparoscopic approach reduces

the infertility rate after ileal pouch-anal anastomosis: a 2-center study. Ann Surg

2013;258(2):275-82.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

334 Uzzan M, Cosnes J, Amiot A, et al. Long-term follow-up after ileorectal anastomosis for

ulcerative colitis: A GETAID/GETAID chirurgie multicenter retrospective cohort of 343

Patients. Ann Surg 2016.

335 Burns EM, Bottle A, Aylin P, et al. Volume analysis of outcome following restorative

proctocolectomy. Br J Surg 2011;98(3):408-17.

336 Koivusalo A, Pakarinen MP, Rintala RJ Surgical complications in relation to functional

outcomes after ileoanal anastomosis in pediatric patients with ulcerative colitis. J Pediatr

Surg 2007;42(2):290-5.

337 Patton D, Gupta N, Wojcicki JM, et al. Postoperative outcome of colectomy for pediatric

patients with ulcerative colitis. J Pediatr Gastroenterol Nutr 2010;51(2):151-4.

338 Knod JL, Holder M, Cortez AR, et al. Surgical outcomes, bowel habits and quality of life

in young patients after ileoanal anastomosis for ulcerative colitis. J Pediatr Surg

2016;51(8):1246-50.

339 Dharmaraj R, Dasgupta M, Simpson P, et al. Predictors of Pouchitis After Ileal Pouch-

Anal Anastomosis in Children. J Pediatr Gastroenterol Nutr 2016;63(4):e58-62.

340 Perrault J Pouchitis in Children: Therapeutic Options. Curr Treat Options Gastroenterol

2002;5(5):389-97.

341 Slatter C, Girgis S, Huynh H, et al. Pre-pouch ileitis after colectomy in paediatric

ulcerative colitis. Acta Paediatr 2008;97(3):381-3.

342 Shen B, Achkar JP, Lashner BA, et al. Irritable pouch syndrome: a new category of

diagnosis for symptomatic patients with ileal pouch-anal anastomosis. Am J

Gastroenterol 2002;97(4):972-7.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

343 Goldstein NS, Sanford WW, Bodzin JH Crohn's-like complications in patients with

ulcerative colitis after total proctocolectomy and ileal pouch-anal anastomosis. Am J Surg

Pathol 1997;21(11):1343-53.

344 Setti Carraro PG, Talbot IC, Nicholls JR Patterns of distribution of endoscopic and

histological changes in the ileal reservoir after restorative proctocolectomy for ulcerative

colitis. A long-term follow-up study. Int J Colorectal Dis 1998;13(2):103-7.

345 Warren BF, Shepherd NA The role of pathology in pelvic ileal reservoir surgery. Int J

Colorectal Dis 1992;7(2):68-75.

346 Pemberton JH The problem with pouchitis. Gastroenterology 1993;104(4):1209-11.

347 Ben-Bassat O, Tyler AD, Xu W, et al. Ileal pouch symptoms do not correlate with

inflammation of the pouch. Clin Gastroenterol Hepatol 2014;12(5):831-37 e2.

348 Shen B, Achkar JP, Lashner BA, et al. Endoscopic and histologic evaluation together

with symptom assessment are required to diagnose pouchitis. Gastroenterology

2001;121(2):261-7.

349 Sandborn WJ, Tremaine WJ, Batts KP, et al. Pouchitis after ileal pouch-anal anastomosis:

a Pouchitis Disease Activity Index. Mayo Clin Proc 1994;69(5):409-15.

350 Heuschen UA, Autschbach F, Allemeyer EH, et al. Long-term follow-up after ileoanal

pouch procedure: algorithm for diagnosis, classification, and management of pouchitis.

Dis Colon Rectum 2001;44(4):487-99.

351 Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a

simplified approach to the diagnosis of pouchitis. Dis Colon Rectum 2003;46(6):748-53.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

352 Abdelrazeq AS, Kandiyil N, Botterill ID, et al. Predictors for acute and chronic pouchitis

following restorative proctocolectomy for ulcerative colitis. Colorectal Dis

2008;10(8):805-13.

353 Hata K, Watanabe T, Shinozaki M, et al. Patients with extraintestinal manifestations have

a higher risk of developing pouchitis in ulcerative colitis: multivariate analysis. Scand J

Gastroenterol 2003;38(10):1055-8.

354 Sandborn WJ, Landers CJ, Tremaine WJ, et al. Antineutrophil cytoplasmic antibody

correlates with chronic pouchitis after ileal pouch-anal anastomosis. Am J Gastroenterol

1995;90(5):740-7.

355 Lipman JM, Kiran RP, Shen B, et al. Perioperative factors during ileal pouch-anal

anastomosis predict pouchitis. Dis Colon Rectum 2011;54(3):311-7.

356 Merrett MN, Mortensen N, Kettlewell M, et al. Smoking may prevent pouchitis in

patients with restorative proctocolectomy for ulcerative colitis. Gut 1996;38(3):362-4.

357 Carter MJ, Di Giovine FS, Cox A, et al. The interleukin 1 receptor antagonist gene allele

2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis.

Gastroenterology 2001;121(4):805-11.

358 Meier CB, Hegazi RA, Aisenberg J, et al. Innate immune receptor genetic

polymorphisms in pouchitis: is CARD15 a susceptibility factor? Inflamm Bowel Dis

2005;11(11):965-71.

359 Tyler AD, Milgrom R, Xu W, et al. Antimicrobial antibodies are associated with a

Crohn's disease-like phenotype after ileal pouch-anal anastomosis. Clin Gastroenterol

Hepatol 2012;10(5):507-12 e1.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

360 Wu XR, Ashburn J, Remzi FH, et al. Male Gender Is Associated with a High Risk for

Chronic Antibiotic-Refractory Pouchitis and Ileal Pouch Anastomotic Sinus. J

Gastrointest Surg 2016;20(3):631-9.

361 Mimura T, Rizzello F, Helwig U, et al. Once daily high dose probiotic therapy (VSL#3)

for maintaining remission in recurrent or refractory pouchitis. Gut 2004;53(1):108-14.

362 Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment

in patients with chronic pouchitis: a double-blind, placebo-controlled trial.

Gastroenterology 2000;119(2):305-9.

363 Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic

therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003;124(5):1202-9.

364 Pronio A, Montesani C, Butteroni C, et al. Probiotic administration in patients with ileal

pouch-anal anastomosis for ulcerative colitis is associated with expansion of mucosal

regulatory cells. Inflamm Bowel Dis 2008;14(5):662-8.

365 Pineton de Chambrun GP, Torres J, Darfeuille-Michaud A, et al. The role of

anti(myco)bacterial interventions in the management of IBD: is there evidence at all? Dig

Dis 2012;30(4):358-67.

366 Holubar SD, Cima RR, Sandborn WJ, et al. Treatment and prevention of pouchitis after

ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database Syst Rev

20106):CD001176.

367 Shen B, Achkar JP, Lashner BA, et al. A randomized clinical trial of ciprofloxacin and

metronidazole to treat acute pouchitis. Inflamm Bowel Dis 2001;7(4):301-5.

368 Gionchetti P, Rizzello F, Poggioli G, et al. Oral budesonide in the treatment of chronic

refractory pouchitis. Aliment Pharmacol Ther 2007;25(10):1231-6.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

369 Biancone L, Michetti P, Travis S, et al. European evidence-based Consensus on the

management of ulcerative colitis: Special situations. J Crohns Colitis 2008;2(1):63-92.

370 Ferrante M, D'Haens G, Dewit O, et al. Efficacy of infliximab in refractory pouchitis and

Crohn's disease-related complications of the pouch: a Belgian case series. Inflamm

Bowel Dis 2010;16(2):243-9.

371 Barreiro-de Acosta M, Garcia-Bosch O, Souto R, et al. Efficacy of infliximab rescue

therapy in patients with chronic refractory pouchitis: a multicenter study. Inflamm Bowel

Dis 2012;18(5):812-7.

372 Calabrese C, Gionchetti P, Rizzello F, et al. Short-term treatment with infliximab in

chronic refractory pouchitis and ileitis. Aliment Pharmacol Ther 2008;27(9):759-64.

373 Barreiro-de Acosta M, Garcia-Bosch O, Gordillo J, et al. Efficacy of adalimumab rescue

therapy in patients with chronic refractory pouchitis previously treated with infliximab: a

case series. Eur J Gastroenterol Hepatol 2012;24(7):756-8.

374 Greuter T, Biedermann L, Rogler G, et al. Alicaforsen, an antisense inhibitor of ICAM-1,

as treatment for chronic refractory pouchitis after proctocolectomy: A case series. United

European Gastroenterol J 2016;4(1):97-104.

375 Nygaard K, Bergan T, Bjorneklett A, et al. Topical metronidazole treatment in pouchitis.

Scand J Gastroenterol 1994;29(5):462-7.

376 Miglioli M, Barbara L, Di Febo G, et al. Topical administration of 5-aminosalicylic acid:

a therapeutic proposal for the treatment of pouchitis. N Engl J Med 1989;320(4):257.

377 Harbord M, Annese V, Vavricka SR, et al. The First European Evidence-based

Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease. J Crohns

Colitis 2016;10(3):239-54.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

378 Aloi M, Cucchiara S Extradigestive manifestations of IBD in pediatrics. Eur Rev Med

Pharmacol Sci 2009;13 Suppl 1(23-32.

379 Jose FA, Garnett EA, Vittinghoff E, et al. Development of extraintestinal manifestations

in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis

2009;15(1):63-8.

380 Dotson JL, Hyams JS, Markowitz J, et al. Extraintestinal manifestations of pediatric

inflammatory bowel disease and their relation to disease type and severity. J Pediatr

Gastroenterol Nutr 2010;51(2):140-5.

381 Hyams JS Extraintestinal manifestations of inflammatory bowel disease in children. J

Pediatr Gastroenterol Nutr 1994;19(1):7-21.

382 Hyams JS Crohn's disease in children. Pediatr Clin North Am 1996;43(1):255-77.

383 Winesett M Inflammatory bowel disease in children and adolescents. Pediatr Ann

1997;26(4):227-34.

384 Mamula P, Markowitz JE, Baldassano RN Inflammatory bowel disease in early

childhood and adolescence: special considerations. Gastroenterol Clin North Am

2003;32(3):967-95.

385 Bonner GF, Fakhri A, Vennamaneni SR A long-term cohort study of nonsteroidal anti-

inflammatory drug use and disease activity in outpatients with inflammatory bowel

disease. Inflamm Bowel Dis 2004;10(6):751-7.

386 Orchard TR, Jewell, D.P. . Conditions of the eyes and joints associated with

inflammatory bowel disease. In: S. R. Targan, Shanahan, F., Karp, L.C. ed. Inflammatory

bowel disease: translating basic science into clinical practice. Chichester, UK: John

Wiley & Sons Ltd; 2010:553-61.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

387 van Dijkhuizen EH, Wulffraat NM Prediction of methotrexate efficacy and adverse

events in patients with juvenile idiopathic arthritis: a systematic literature review. Pediatr

Rheumatol Online J 2014;12(51.

388 Horneff G Update on biologicals for treatment of juvenile idiopathic arthritis. Expert

Opin Biol Ther 2013;13(3):361-76.

389 Ponsioen CY Diagnosis, Differential Diagnosis, and Epidemiology of Primary Sclerosing

Cholangitis. Dig Dis 2015;33 Suppl 2(134-9.

390 Deneau MR, El-Matary W, Valentino PL, et al. The natural history of primary sclerosing

cholangitis in 781 children: A multicenter, international collaboration. Hepatology

2017;66(2):518-27.

391 Charatcharoenwitthaya P, Lindor KD Primary sclerosing cholangitis: diagnosis and

management. Curr Gastroenterol Rep 2006;8(1):75-82.

392 Broome U, Lofberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative

colitis: evidence for increased neoplastic potential. Hepatology 1995;22(5):1404-8.

393 Fevery J, Henckaerts L, Van Oirbeek R, et al. Malignancies and mortality in 200 patients

with primary sclerosering cholangitis: a long-term single-centre study. Liver Int

2012;32(2):214-22.

394 Cullen SN, Chapman RW The medical management of primary sclerosing cholangitis.

Semin Liver Dis 2006;26(1):52-61.

395 Singh S, Khanna S, Pardi DS, et al. Effect of ursodeoxycholic acid use on the risk of

colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory

bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis

2013;19(8):1631-8.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

396 Pardi DS, Loftus EV, Jr., Kremers WK, et al. Ursodeoxycholic acid as a

chemopreventive agent in patients with ulcerative colitis and primary sclerosing

cholangitis. Gastroenterology 2003;124(4):889-93.

397 Eaton JE, Silveira MG, Pardi DS, et al. High-dose ursodeoxycholic acid is associated

with the development of colorectal neoplasia in patients with ulcerative colitis and

primary sclerosing cholangitis. Am J Gastroenterol 2011;106(9):1638-45.

398 Lindor KD Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing

Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med 1997;336(10):691-5.

399 Sjoqvist U, Tribukait B, Ost A, et al. Ursodeoxycholic acid treatment in IBD-patients

with colorectal dysplasia and/or DNA-aneuploidy: a prospective, double-blind,

randomized controlled pilot study. Anticancer Res 2004;24(5B):3121-7.

400 Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the

treatment of primary sclerosing cholangitis. Hepatology 2009;50(3):808-14.

401 Rahimpour S, Nasiri-Toosi M, Khalili H, et al. A Triple Blinded, Randomized, Placebo-

Controlled Clinical Trial to Evaluate the Efficacy and Safety of Oral Vancomycin in

Primary Sclerosing Cholangitis: a Pilot Study. J Gastrointestin Liver Dis 2016;25(4):457-

64.

402 Buness C, Lindor KD, Miloh T Oral Vancomycin Therapy in a Child with Primary

Sclerosing Cholangitis and Severe Ulcerative Colitis. Pediatr Gastroenterol Hepatol Nutr

2016;19(3):210-13.

403 Ali AH, Carey EJ, Lindor KD Current research on the treatment of primary sclerosing

cholangitis. Intractable Rare Dis Res 2015;4(1):1-6.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

404 Davies YK, Tsay CJ, Caccamo DV, et al. Successful treatment of recurrent primary

sclerosing cholangitis after orthotopic liver transplantation with oral vancomycin. Case

Rep Transplant 2013;2013(314292.

405 Tabibian JH, Weeding E, Jorgensen RA, et al. Randomised clinical trial: vancomycin or

metronidazole in patients with primary sclerosing cholangitis - a pilot study. Aliment

Pharmacol Ther 2013;37(6):604-12.

406 Lindor KD New treatment strategies for primary sclerosing cholangitis. Dig Dis

2011;29(1):113-6.

407 Mieli-Vergani G, Vergani D Unique features of primary sclerosing cholangitis in

children. Curr Opin Gastroenterol 2010;26(3):265-8.

408 Abarbanel DN, Seki SM, Davies Y, et al. Immunomodulatory effect of vancomycin on

Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. J Clin

Immunol 2013;33(2):397-406.

409 Navaneethan U, Kochhar G, Venkatesh PG, et al. Duration and severity of primary

sclerosing cholangitis is not associated with risk of neoplastic changes in the colon in

patients with ulcerative colitis. Gastrointest Endosc 2012;75(5):1045-54 e1.

410 Dyson JK, Rutter MD Colorectal cancer in inflammatory bowel disease: what is the real

magnitude of the risk? World J Gastroenterol 2012;18(29):3839-48.

411 Mooiweer E, van der Meulen-de Jong AE, Ponsioen CY, et al. Chromoendoscopy for

Surveillance in Inflammatory Bowel Disease Does Not Increase Neoplasia Detection

Compared With Conventional Colonoscopy With Random Biopsies: Results From a

Large Retrospective Study. Am J Gastroenterol 2015;110(7):1014-21.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

412 Pappa H, Thayu M, Sylvester F, et al. Skeletal health of children and adolescents with

inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011;53(1):11-25.

413 Shepherd D, Day AS, Leach ST, et al. Single High-Dose Oral Vitamin D3 Therapy

(Stoss): A Solution to Vitamin D Deficiency in Children With Inflammatory Bowel

Disease? J Pediatr Gastroenterol Nutr 2015;61(4):411-4.

414 Rocha R, Santana GO, Almeida N, et al. Analysis of fat and muscle mass in patients with

inflammatory bowel disease during remission and active phase. Br J Nutr

2009;101(5):676-9.

415 Sawczenko A, Sandhu BK Presenting features of inflammatory bowel disease in Great

Britain and Ireland. Arch Dis Child 2003;88(11):995-1000.

416 Markowitz J, Grancher K, Rosa J, et al. Growth failure in pediatric inflammatory bowel

disease. J Pediatr Gastroenterol Nutr 1993;16(4):373-80.

417 Turunen P, Ashorn M, Auvinen A, et al. Long-term health outcomes in pediatric

inflammatory bowel disease: a population-based study. Inflamm Bowel Dis

2009;15(1):56-62.

418 Miele E, Shamir R, Aloi M, et al. Nutrition in Paediatric Inflammatory Bowel Disease: A

Position Paper on Behalf of The Porto IBD Group of ESPGHAN. J Pediatr Gastroenterol

Nutr 2018.

419 Green TJ, Issenman RM, Jacobson K Patients' diets and preferences in a pediatric

population with inflammatory bowel disease. Can J Gastroenterol 1998;12(8):544-9.

420 Lewis JD, Abreu MT Diet as a Trigger or Therapy for Inflammatory Bowel Diseases.

Gastroenterology 2017;152(2):398-414 e6.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

421 Ahmed SF, Horrocks IA, Patterson T, et al. Bone mineral assessment by dual energy X-

ray absorptiometry in children with inflammatory bowel disease: evaluation by age or

bone area. J Pediatr Gastroenterol Nutr 2004;38(3):276-80.

422 Gokhale R, Favus MJ, Karrison T, et al. Bone mineral density assessment in children

with inflammatory bowel disease. Gastroenterology 1998;114(5):902-11.

423 Sylvester FA, Wyzga N, Hyams JS, et al. Natural history of bone metabolism and bone

mineral density in children with inflammatory bowel disease. Inflamm Bowel Dis

2007;13(1):42-50.

424 Walther F, Fusch C, Radke M, et al. Osteoporosis in pediatric patients suffering from

chronic inflammatory bowel disease with and without steroid treatment. J Pediatr

Gastroenterol Nutr 2006;43(1):42-51.

425 Bak-Drabik K, Adamczyk P, Chobot A, et al. Bone status assessed by quantitative

ultrasound in children with inflammatory bowel disease: a comparison with DXA. Expert

Rev Gastroenterol Hepatol 2016;10(11):1305-12.

426 Pappa HM, Gordon CM, Saslowsky TM, et al. Vitamin D status in children and young

adults with inflammatory bowel disease. Pediatrics 2006;118(5):1950-61.

427 Lu C, Yang J, Yu W, et al. Association between 25(OH)D Level, Ultraviolet Exposure,

Geographical Location, and Inflammatory Bowel Disease Activity: A Systematic Review

and Meta-Analysis. PLoS One 2015;10(7):e0132036.

428 Werkstetter KJ, Pozza SB, Filipiak-Pittroff B, et al. Long-term development of bone

geometry and muscle in pediatric inflammatory bowel disease. Am J Gastroenterol

2011;106(5):988-98.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

429 Hyams JS, Wyzga N, Kreutzer DL, et al. Alterations in bone metabolism in children with

inflammatory bowel disease: an in vitro study. J Pediatr Gastroenterol Nutr

1997;24(3):289-95.

430 Franchimont N, Putzeys V, Collette J, et al. Rapid improvement of bone metabolism after

infliximab treatment in Crohn's disease. Aliment Pharmacol Ther 2004;20(6):607-14.

431 Thayu M, Leonard MB, Hyams JS, et al. Improvement in biomarkers of bone formation

during infliximab therapy in pediatric Crohn's disease: results of the REACH study. Clin

Gastroenterol Hepatol 2008;6(12):1378-84.

432 Ryan BM, Russel MG, Schurgers L, et al. Effect of antitumour necrosis factor-alpha

therapy on bone turnover in patients with active Crohn's disease: a prospective study.

Aliment Pharmacol Ther 2004;20(8):851-7.

433 Miheller P, Muzes G, Racz K, et al. Changes of OPG and RANKL concentrations in

Crohn's disease after infliximab therapy. Inflamm Bowel Dis 2007;13(11):1379-84.

434 Whitten KE, Leach ST, Bohane TD, et al. Effect of exclusive enteral nutrition on bone

turnover in children with Crohn's disease. J Gastroenterol 2010;45(4):399-405.

435 Greenley RN, Stephens M, Doughty A, et al. Barriers to adherence among adolescents

with inflammatory bowel disease. Inflamm Bowel Dis 2010;16(1):36-41.

436 Greenley RN, Hommel KA, Nebel J, et al. A meta-analytic review of the psychosocial

adjustment of youth with inflammatory bowel disease. J Pediatr Psychol 2011;35(8):857-

69.

437 Timmer A, Preiss JC, Motschall E, et al. Psychological interventions for treatment of

inflammatory bowel disease. Cochrane Database of Systematic Reviews (Online)

20112):CD006913-CD13.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

438 Ross SC, Strachan J, Russell RK, et al. Psychosocial functioning and health-related

quality of life in paediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr

2011;53(5):480-8.

439 Engstrom I Parental distress and social interaction in families with children with

inflammatory bowel disease. J Am Acad Child Adolesc Psychiatry 1991;30(6):904-12.

440 Mittermaier C, Dejaco C, Waldhoer T, et al. Impact of depressive mood on relapse in

patients with inflammatory bowel disease: a prospective 18-month follow-up study.

Psychosom Med 2004;66(1):79-84.

441 Rufo PA, Denson LA, Sylvester FA, et al. Health supervision in the management of

children and adolescents with IBD: NASPGHAN recommendations. J Pediatr

Gastroenterol Nutr 2012;55(1):93-108.

442 Hommel KA, Denson LA, Baldassano RN Oral medication adherence and disease

severity in pediatric inflammatory bowel disease. Eur J Gastroenterol Hepatol

2011;23(3):250-4.

443 Hommel KA, Baldassano RN Brief report: Barriers to treatment adherence in pediatric

inflammatory bowel disease. J Pediatr Psychol 2010;35(9):1005-10.

444 Reed-Knight B, Lewis JD, Blount RL Association of disease, adolescent, and family

factors with medication adherence in pediatric inflammatory bowel disease. J Pediatr

Psychol 2011;36(3):308-17.

445 Ruemmele FM, Turner D Differences in the management of pediatric and adult onset

ulcerative colitis--lessons from the joint ECCO and ESPGHAN consensus guidelines for

the management of pediatric ulcerative colitis. J Crohns Colitis 2014;8(1):1-4.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

446 Goodhand J, Hedin CR, Croft NM, et al. Adolescents with IBD: the importance of

structured transition care. J Crohns Colitis 2011;5(6):509-19.

447 van Rheenen PF, Aloi M, Biron IA, et al. European Crohn's and Colitis Organisation

Topical Review on Transitional Care in Inflammatory Bowel Disease. J Crohns Colitis

2017;11(9):1032-38.

448 Oliva-Hemker M, Hutfless S, Al Kazzi ES, et al. Clinical Presentation and Five-Year

Therapeutic Management of Very Early-Onset Inflammatory Bowel Disease in a Large

North American Cohort. J Pediatr 2015;167(3):527-32 e1-3.

449 Prenzel F, Uhlig HH Frequency of indeterminate colitis in children and adults with IBD -

a metaanalysis. J Crohns Colitis 2009;3(4):277-81.

450 Kammermeier J, Dziubak R, Pescarin M, et al. Phenotypic and Genotypic

Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years. J

Crohns Colitis 2017;11(1):60-69.

451 Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very

early onset inflammatory bowel disease. Gastroenterology 2014;147(5):990-1007 e3.

452 Koletzko S, Niggemann B, Arato A, et al. Diagnostic approach and management of

cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical

guidelines. J Pediatr Gastroenterol Nutr 2012;55(2):221-9.

453 Benchimol EI, Mack DR, Nguyen GC, et al. Incidence, outcomes, and health services

burden of very early onset inflammatory bowel disease. Gastroenterology

2014;147(4):803-13 e7; quiz e14-5.

454 Begue B, Verdier J, Rieux-Laucat F, et al. Defective IL10 signaling defining a subgroup

of patients with inflammatory bowel disease. Am J Gastroenterol 2011;106(8):1544-55.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

455 Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations

affecting the interleukin-10 receptor. N Engl J Med 2009;361(21):2033-45.

456 Glocker EO, Frede N, Perro M, et al. Infant colitis--it's in the genes. Lancet

2010;376(9748):1272.

457 Damen GM, van Krieken JH, Hoppenreijs E, et al. Overlap, common features, and

essential differences in pediatric granulomatous inflammatory bowel disease. J Pediatr

Gastroenterol Nutr 2010;51(6):690-7.

458 Dhillon SS, Fattouh R, Elkadri A, et al. Variants in nicotinamide adenine dinucleotide

phosphate oxidase complex components determine susceptibility to very early onset

inflammatory bowel disease. Gastroenterology 2014;147(3):680-89 e2.

459 Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences

of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency)

versus type 2 (XLP-2/XIAP deficiency). Blood 2011;117(5):1522-9.

460 Aguilar C, Lenoir C, Lambert N, et al. Characterization of Crohn disease in X-linked

inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy

Clin Immunol 2014.

461 Lemoine R, Pachlopnik-Schmid J, Farin HF, et al. Immune deficiency-related

enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat

domain 7A deficiency. J Allergy Clin Immunol 2014;134(6):1354-64.

462 Bigorgne AE, Farin HF, Lemoine R, et al. TTC7A mutations disrupt intestinal epithelial

apicobasal polarity. J Clin Invest 2013;124(1):328-37.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

463 Fernandez I, Patey N, Marchand V, et al. Multiple intestinal atresia with combined

immune deficiency related to TTC7A defect is a multiorgan pathology: study of a

French-Canadian-based cohort. Medicine (Baltimore) 2014;93(29):e327.

464 Fabre A, Charroux B, Martinez-Vinson C, et al. SKIV2L mutations cause syndromic

diarrhea, or trichohepatoenteric syndrome. Am J Hum Genet 2012;90(4):689-92.

465 Fabre A, Martinez-Vinson C, Roquelaure B, et al. Novel mutations in TTC37 associated

with tricho-hepato-enteric syndrome. Hum Mutat 2011;32(3):277-81.

466 Torgerson TR, Linane A, Moes N, et al. Severe food allergy as a variant of IPEX

syndrome caused by a deletion in a noncoding region of the FOXP3 gene.

Gastroenterology 2007;132(5):1705-17.

467 Moes N, Rieux-Laucat F, Begue B, et al. Reduced expression of FOXP3 and regulatory

T-cell function in severe forms of early-onset autoimmune enteropathy. Gastroenterology

2010;139(3):770-8.

468 Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy

and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet

2001;27(1):18-20.

469 Baud O, Goulet O, Canioni D, et al. Treatment of the immune dysregulation,

polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow

transplantation. N Engl J Med 2001;344(23):1758-62.

470 Engelhardt KR, Shah N, Faizura-Yeop I, et al. Clinical outcome in IL-10- and IL-10

receptor-deficient patients with or without hematopoietic stem cell transplantation. J

Allergy Clin Immunol 2013;131(3):825-30.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

471 Shouval DS, Biswas A, Goettel JA, et al. Interleukin-10 receptor signaling in innate

immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage

function. Immunity 2014;40(5):706-19.

472 Neven B, Mamessier E, Bruneau J, et al. A Mendelian predisposition to B cell lymphoma

caused by IL-10R deficiency. Blood 2013;122(23):3713-22.

473 D'Haens G, Ferrante M, Vermeire S, et al. Fecal calprotectin is a surrogate marker for

endoscopic lesions in inflammatory bowel disease. Inflamm Bowel Dis

2012;18(12):2218-24.

474 Schoepfer AM, Beglinger C, Straumann A, et al. Fecal calprotectin more accurately

reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive

protein, platelets, hemoglobin, and blood leukocytes. Inflamm Bowel Dis

2013;19(2):332-41.

475 Scaioli E, Scagliarini M, Cardamone C, et al. Clinical application of faecal calprotectin in

ulcerative colitis patients. Eur J Gastroenterol Hepatol 2015;27(12):1418-24.

476 Dranga M, Mihai C, Drug V, et al. A rapid test for assessing disease activity in ulcerative

colitis. Turk J Gastroenterol 2016;27(2):149-55.

477 Langhorst J, Elsenbruch S, Koelzer J, et al. Noninvasive markers in the assessment of

intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin,

calprotectin, and PMN-elastase, CRP, and clinical indices. Am J Gastroenterol

2008;103(1):162-9.

478 Falvey JD, Hoskin T, Meijer B, et al. Disease activity assessment in IBD: clinical indices

and biomarkers fail to predict endoscopic remission. Inflamm Bowel Dis 2015;21(4):824-

31.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

479 Guardiola J, Lobatón T, Rodríguez-Alonso L, et al. Fecal level of calprotectin identifies

histologic inflammation in patients with ulcerative colitis in clinical and endoscopic

remission. Clin Gastroenterol Hepatol 2014;12(11):1865-70.

480 Lin W, Wong J, Tung C, et al. Fecal calprotectin correlated with endoscopic remission

for Asian inflammatory bowel disease patients. World J Gastroenterol

2015;21(48):13566-73.

481 Lobaton T, Rodriguez-Moranta F, Lopez A, et al. A new rapid quantitative test for fecal

calprotectin predicts endoscopic activity in ulcerative colitis. Inflamm Bowel Dis

2013;19(5):1034-42.

482 Samant H, Desai D, Abraham P, et al. Fecal calprotectin and its correlation with

inflammatory markers and endoscopy in patients from India with inflammatory bowel

disease. Indian J Gastroenterol 2015;34(6):431-35.

483 Xiang JY, Ouyang Q, Li GD, et al. Clinical value of fecal calprotectin in determining

disease activity of ulcerative colitis. World J Gastroenterol 2008;14(1):53-7.

484 Nancey S, Boschetti G, Moussata D, et al. Neopterin is a novel reliable fecal marker as

accurate as calprotectin for predicting endoscopic disease activity in patients with

inflammatory bowel diseases. Inflamm Bowel Dis 2013;19(5):1043-52.

485 Takashima S, Kato J, Hiraoka S, et al. Evaluation of Mucosal Healing in Ulcerative

Colitis by Fecal Calprotectin Vs. Fecal Immunochemical Test. Am J Gastroenterol

2015;110(6):873-80.

486 Sandborn WJ, Panés J, Zhang H, et al. Correlation Between Concentrations of Fecal

Calprotectin and Outcomes of Patients With Ulcerative Colitis in a Phase 2 Trial.

Gastroenterology 2016;150(1):96-102.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

487 Kolho KL, Sipponen T The long-term outcome of anti-tumor necrosis factor-alpha

therapy related to fecal calprotectin values during induction therapy in pediatric

inflammatory bowel disease. Scand J Gastroenterol 2014;49(4):434-41.

488 De Vos M, Louis EJ, Jahnsen J, et al. Consecutive fecal calprotectin measurements to

predict relapse in patients with ulcerative colitis receiving infliximab maintenance

therapy. Inflamm Bowel Dis 2013;19(10):2111-7.

489 Gisbert JP, Bermejo F, Perez-Calle JL, et al. Fecal calprotectin and lactoferrin for the

prediction of inflammatory bowel disease relapse. Inflamm Bowel Dis 2009;15(8):1190-

8.

490 Ho GT, Lee HM, Brydon G, et al. Fecal calprotectin predicts the clinical course of acute

severe ulcerative colitis. Am J Gastroenterol 2009;104(3):673-8.

491 Lasson A, Simren M, Stotzer PO, et al. Fecal calprotectin levels predict the clinical

course in patients with new onset of ulcerative colitis. Inflamm Bowel Dis

2013;19(3):576-81.

492 Costa F, Mumolo MG, Ceccarelli L, et al. Calprotectin is a stronger predictive marker of

relapse in ulcerative colitis than in Crohn's disease. Gut 2005;54(3):364-8.

493 D'Inca R, Dal Pont E, Di Leo V, et al. Can calprotectin predict relapse risk in

inflammatory bowel disease? Am J Gastroenterol 2008;103(8):2007-14.

494 Garcia-Sanchez V, Iglesias-Flores E, Gonzalez R, et al. Does fecal calprotectin predict

relapse in patients with Crohn's disease and ulcerative colitis? J Crohns Colitis

2010;4(2):144-52.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

495 Hosseini SV, Jafari P, Taghavi SA, et al. Fecal Calprotectin is an Accurate Tool and

Correlated to Seo Index in Prediction of Relapse in Iranian Patients With Ulcerative

Colitis. Iranian Red Crescent Medical Journal 2015;17(2):e22796.

496 Jauregui-Amezaga A, Lopez-Ceron M, Aceituno M, et al. Accuracy of advanced

endoscopy and fecal calprotectin for prediction of relapse in ulcerative colitis: a

prospective study. Inflamm Bowel Dis 2014;20(7):1187-93.

497 Ferreiro-Iglesias R, Barreiro-de Acosta M, Otero Santiago M, et al. Fecal Calprotectin as

Predictor of Relapse in Patients With Inflammatory Bowel Disease Under Maintenance

Infliximab Therapy. J Clin Gastroenterol 2016;50(2):147-51.

498 Tursi A, Elisei W, Picchio M, et al. Accuracy of rapid fecal calprotectin test in

monitoring inflammatory bowel diseases under treatment with TNFα antagonists. Dig Dis

Sci 2015;60(5):1406-13.

499 Theede K, Holck S, Ibsen P, et al. Fecal Calprotectin Predicts Relapse and Histological

Mucosal Healing in Ulcerative Colitis. Inflamm Bowel Dis 2016;22(5):1042-8.

500 Frin A, Filippi J, Boschetti G, et al. Accuracies of fecal calprotectin, lactoferrin, M2-

pyruvate kinase, neopterin and zonulin to predict the response to infliximab in ulcerative

colitis. Dig Liver Dis 2017;49(1):11-16.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Figure 1: Classificattion algorithm
m into paediiatric IBD suubclasses baased on the ““PIBD-classees”

features of
o Table 1

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Figure 2: Algorithm for monitoring paediatric UC during the maintenance phase

Footnote:

1
Assessments earlier than 3 months are usually required and in any significant disease or

deterioration, early intervention is required

2
The decision whether to escalate therapy based on a Mayo-0 or 1 endoscopic findings should be

individualized such as based on the current treatment (e.g. it is easier to increase mesalamine

dose or add rectal therapy than starting thiopurines), symptoms and extent (short Mayo 1

segment may be closely monitored whereas extensive disease may require escalation)

3
Proceeding to colonoscopy should preferably be based on at least two independent

measurements of calprotectin

4
Obtaining calprotectin may be delayed to 4-6 months since histological remission lags after

macroscopic improvement.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Figure 3: Practical in
nterpretation
n of drug lev
vels and antibbodies for innfliximab annd adalimum
mab

Footnotee:

Differentt countries use

u different measuring kits
k with diffferent cut-offf values; abssolute drug aand

antibodiees levels should be adaptted accordin

ngly

1
Some studies (and th
he AGA reco
ommendatio
on in adults ((212)) suggeest that higheer levels for

infliximaab (>5μg/ml)) and adalim

mumab (>8μg
g/ml) shouldd be the goal (see text)

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 4 Summary flowchart off managing paediatric UC
Figure 4:

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Table 1: PIBD-classes features (to be used in the PIBD-classes algorithm (Figure 1))

Q Feature

Clas 1 At least one well-formed granuloma anywhere in the GI tract, remote from
s1 ruptured crypt

2 At least one of deep ulcerations, cobblestoning or stenosis anywhere in the small

bowel or UGI tract (excluding stomach)1

3 Fistulizing disease (internal or perianal)

4 Large inflamed perianal skin tags

5 Thickened jejunal or ileal bowel loops on radiology or other evidence of

significant small bowel inflammation on capsule endoscopy not compatible with
backwash ileitis

6 Any ileal inflammation in the presence of normal cecum (i.e. incompatible with
backwash ileitis)2

Clas 7 Macroscopically and microscopically normal appearing skip lesions in untreated

s2 patients (excluding rectal sparing and cecal patch)

8 Complete (macroscopic and microscopic) rectal sparing

9 Macroscopically normal colon in between inflamed mucosa but with microscopic

inflammation (i.e. relative patchiness)

1 Significant growth delay (height velocity< minus 2 SD), not explained by other
0 causes (e.g. celiac disease, prolonged steroid treatment or growth hormone
deficiency)

1 Transmural inflammation of the colon in the absence of severe colitis

1

1 Small and not deep ulcers (including aphthous ulcerations), anywhere in the small
2 bowel, duodenal and esophageal (excluding stomach and colon) not explained by
other causes (e.g. H. pylori, NSAIDS and celiac disease)3

1 Multiple (≥5) small and not deep ulcers (including aphthous ulcerations), in the
3 stomach or colon (on the background of normal mucosa), not explained by other
causes (e.g. H. pylori and NSAIDS)

1 Ileitis, otherwise compatible with backwash ileitis, but in the presence of only
4 mild inflammation in the cecum

1 Positive ASCA in the presence of negative pANCA

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 5

1 Reverse gradient of mucosal inflammation (proximal >distal (except rectal

6 sparing))

1 Severe scalloping of the stomach or duodenum, not explained by other causes (e.g.
7 celiac disease and H. pylori)

1 Deep ulcerations (at least one) or severe cobblestoning of stomach not explained
8 by other causes (e.g. H. pylori, NSAIDS and celiac disease)

Clas 1 Focal chronic duodenitis on histology

s3 9

2 Focal active colitis on histology in more than one biopsy

0

2 Several (<5) aphthous ulcerations in the colon or in the stomach

1

2 Non bloody diarrhoea

2

2 Focal enhanced gastritis on histology

3

Footnote:
1
Deep ulcerations or severe cobblestoning of stomach score as item #18; if there are ulcerations
in the duodenum or oesophagus which are small and not deep score as item #12
2
If cecum with mild inflammation score as item #14
3
If ulcers are deep score as item #2
4
Backwash ileitis: a short segment of non-stenotic erythema or edema in the presence of
pancolitis including the ileocecal valve, without granulomata or deep ulcers

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Table 2: The utility of different cut-off values of faecal calprotectin to predict endoscopic
disease in UC (selected references)

Study Cut- Reference standard Sen Spe PP NP

design off s c V V

Paediatric

Diamanti n=41 275 Histology 94 95 94 95

(60)
retrospecti
ve

Adult

D’Haens n=39 250 Endoscopic Mayo>0 71 100 100 47

(473)
prospectiv Endoscopic Mayo>1 86 78 82 82
e

Schoepfe n=228 57 Modified Baron≥2 91 90

r (474)
prospectiv 50 Modified Baron≥2 92 86
e

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Scaioli n=121 110 Endoscopic Mayo>0 98 90 93 98
(475)
prospectiv 270 Endoscopic Mayo>1 88 88 88 93
e

Dranga n=103 15 Endoscopic Mayo>0 98 76 96 46

(476)
prospectiv
e

Langhors n=42 48 Endoscopy total score>1 81 72

t (477)
prospectiv
e

Falvey n=65 125 Baron score>1 74 80 85 67

(478)
prospectiv
e

Guardiol n=59 155 Endoscopic Mayo=0-1 and 89 71 54 89

a (479) activity on histology
prospectiv
e

Lin (480) n=52 191 UCEIS < 3 88 75

prospectiv
e

Lobatón n=123 250 Endoscopic Mayo=0-1 73 89 86 79

(481)
prospectiv 160 Endoscopic Mayo=0 66 85
e

Samant n=32 800 Endoscopic Mayo>1 96 71

(482)
retrospecti
ve

Xiang n=66 50 Sutherland criteria>2 91 79

(483)
prospectiv
e

Nancey n=55 250 Rachmilewitz≤2 91 87 87 91

(484)
prospectiv 100 100 53 85 100
e

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Takashi n=92 250 Endoscopic Mayo=0 82 62 61 83
ma
(485) prospectiv 200 77 72 67 81
e
369 Endoscopic Mayo=0-1 86 63 79 74

250 70 66 76 59

Sandborn n=194 150 Mayo score ≤2, with no subscore 68 79 57 86

(486) >1
prospectiv
e Endoscopic Mayo=0 79 75 39 94

Endoscopic Mayo=0-1 85 54

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Table 3: Cut-off values of faecal calprotectin in prediction poor outcome in UC (selected
references)

Study Samplin Reference Cut-off Follo Sen Spe PP NP

design g time outcome w-up s c V V

Paediatric

Kolho n=18 1 year

(487)
retro

Adults

De Vos n=113 Clinical Relapse: change >300 52 93 58 - -

(488) remissio in therapy or wks
pro n with endoscopic
inflixima Mayo>2
b

Gisbert n=74 Clinical Remission <150 12 31 91 - -

(489) remissio mo
pro n for 6 <167 69 74 - -
mo

Ho 90 Acute Colectomy >1922 24 97 - -

(490) severe
pro colitis >431 96 20 - -

Lasson n=69 At Mayo score<3 <169 12 64 70 80 51

(491) diagnosis mo
pro
<262 24 51 81 85 45
mo

<262 36 52 85 88 45
mo

Costa n=41 Clinical Remission <150 12 89 82 81 90

(492) remissio mo
pro n for 1- (UCAI<5)
12mo

D’Inca n=97 Remissio Remission <130 12 70 70 - -

(493) n mo
pro (Edwards and
Truelove

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 score<3)

Garcia- n=69 Clinical Remission <120 12 81 63 49 88

Sanchez remissio mo
(494) pro n for ≥3 (modified
mo Truelove and
Witts<11)

Yamam n=80 Clinical Relapse by the <170 12 76 76 - -

oto (61) remissio DAI mo
pro n for ≥3
mo

Hossein n=157 Clinical Seo index>220 >341 12 80 89 - -

i (495) remissio mo
pro n for ≥3 or need for
mo therapy change

Jauregu n=70 Partial Endoscopic >100 12 64 53 67 88

i- Mayo>0 mo
Amezag pro Mayo≤1
a (496) >250 12 78 45 85 88
mo

Ferreir n=20 Clinical Clinical relapse >198 2 mo 100 81 48 100

o- remissio by the partial
Iglesias pro n for ≥6 Mayo
(497) mo with
inflixima
b

Tursi n=20 Before Active disease >15 12 66 56 18 92

(498) starting by the DAI mo
pro biologics
Endoscopic >15 12 47 87 90 37
Mayo= 2-3 mo

Theede n=70 Clinical Relapse >321 6 mo 63 86 46 92

(499) remissio requiring
pro n therapy change
>321 12 46 86 46 86
mo

Frin n=31 2 wks Response (by the <800 14 wk 82 69 78 85

(500) after Mayo score)
pro starting
inflixima
b

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 14 wks Sustained <146 54 wk 90 72 86 80
after remission (by
starting the partial Mayo
inflixima score) without
b IFX dose
intensification or
other treatments

Ulcerative Colitis Activity Index, UCAI; Disease Activity Index, DAI; IFX, infliximab; wk,
week; mo, months; FU, follow-up; Retro, retrospective; Pro, prospective

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

TABLE 4. Steroids tapering schedule (doses are in mg/day prednisone equivalent): The goal is
to discontinue steroids by week 10.

Week Week Week Week Week Week Week Week Week Week
1 2 3 4 5 6 7 8 9 10
60 50 40 35 30 25 20 15 10 5
50 45 40 35 30 25 20 15 10 5
45 40 40 35 30 25 20 15 10 5
40 40 40 35 30 25 20 15 10 5
35 35 35 30 25 20 15 15 10 5
30 30 30 25 20 15 15 10 10 5
25 25 25 20 20 15 15 10 5 5
20 20 20 15 15 12.5 10 7.5 5 2.5
15 15 15 12.5 10 10 7.5 7.5 5 2.5

Footnote:
Avoid steroid dependency by timely escalation of maintenance therapy when needed. The risk
for exacerbation is smaller with prednisone doses >20 mg, but the risk for adverse events is then
higher thus a more rapid tapering to ≤20mg is desired. Shortening each stage from 7 to 5 days or
any other tapering modification may be considered individually since many factors come into
play when weaning off steroids. Consider the possibility of adrenal insufficiency, even many
months after tapering off steroids.

First 2 to 3 weeks: start prednisone at 1 mg/kg up to 40 mg once daily (after discharge from
acute severe colitis admission, the dose may be as high as 60 mg/day; see part 2 of these
guidelines). If there is no significant improvement (i.e. PUCAI decrease of <20 points) after 7 to
14 days, or an increase in PUCAI ≥20 points at any time, then escalate treatment after excluding
other causes for steroid-refractory disease (see text and Figure 2, 4).

After the first 2 to 3 weeks: PUCAI 15 to 30: consider keeping the dose stable (while
prolonging the total course by 1 week); PUCAI>35, increase steroids to the dose of the previous
1 to 2 steps for 1 week and then re-start weaning more slowly; PUCAI > 60 or increase in
PUCAI by ≥20 points at any time, escalate treatment.

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Table 5. Paediatric VSL#3 dosing (by Miele et al, 29)

Age, years Weight, Kg Daily/dose, bacteria/day)

4-6 17–23 1 sachet (450 billion)
7-9 24–33 2 sachets (900 billion)
11-14 34–53 3 sachets (1350 billion)
15-17 54–66 4 sachets (1800 billion)

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Table 6: Diagnostic work-up of VEO-IBD to be adapted according to the clinical presentation
(see text)

Basic Immune work-up Examples

Complete Blood Count Neutropenia, lymphocytopenia,

thrombocytopenia

Lymphocyte Subset T-/B-cell defects, regulatory T cell

defects (FOXP3, CD25)

IgG-A-M-E SCID, CVID, B cell defects,

Agammaglobulinaemia, Hyper-
IgM/hyper-IgE syndrome

oxidative burst CGD

functional tests IL10-axis (LPS-IL10 stimulation)

XIAP-nod-axis (MDP stimulation)
Apoptosis tests (XIAP)

Genetic testing

Candidate gene approach Suspected defect or confirmation of

identified defect

Gene Panel Unclear diagnosis

Whole Exome Sequencing Research protocol for search of new

mutations

Whole Genome Sequencing Research protocol for search of new

mutations

SCID-severe combined immunodeficiency, CVID-common variable immunodeficiency, CGD-

chronic granulomatous disease, IL-interleukin, XIAP-X-linked inhibitor of apoptosis protein

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

APPENDICES

Appendix 1: The Pediatric Ulcerative Colitis Activity Index (PUCAI)

ITEM POINTS

1. Abdominal pain:

No pain 0
Pain can be ignored 5
Pain cannot be ignored 10

2. Rectal bleeding

None 0
Small amount only, in less than 50% of stools 10
Small amount with most stools 20
Large amount (>50% of the stool content) 30

3. Stool consistency of most stools

Formed 0
Partially formed 5
Completely unformed 10

4. Number of stools per 24 hours

0-2 0
3-5 5
6-8 10
>8 15

5. Nocturnal stools (any episode causing wakening)

No 0
Yes 10

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

 6. Activity level

No limitation of activity 0
Occasional limitation of activity 5
Severe restricted activity 10

SUM OF PUCAI (0-85)

For User’s guide and cutoff values for response, remission, mild, moderate and severe disease
activity, refer to the original study (39).

Copyright © ESPGHAN and NASPGHAN. All rights reserved.