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FOCUS ON IBD THROUGH THE AGES

Advances in the medical management


ofpaediatric IBD
Marina Aloi, Federica Nuti, Laura Stronati and Salvatore Cucchiara
Abstract | IBD includes two classic entities, Crohns disease and ulcerative colitis, and a third undetermined
form (IBDU), characterized by a chronic relapsing course resulting in a high rate of morbidity and impaired
quality of life. Children with IBD are vulnerable in terms of growth failure, malnutrition and emotional effects.
The aims of therapy have now transitioned from symptomatic control to the achievement of mucosal healing
and deep remission. This type of therapy has been made possible by the advent of disease-modifying drugs,
such as biologic agents, which are capable of interrupting the inflammatory cascade underlying IBD. Biologic
agents are generally administered in patients who are refractory to conventional therapies. However, there
is growing support that such agents could be used in the initial phases of the disease, typically in paediatric
patients, to interrupt and cease the inflammatory process. Until several years ago, most therapeutic
programmes in paediatric patients with IBD were borrowed from adult trials, whereas paediatric studies were
often retrospectiveand uncontrolled. However, guidelines on therapeutic management of paediatric IBD and
controlled, prospective, randomized trials including children with IBD have now been published. Here, thecurrent
knowledge concerning treatment options for children with IBD are reported. We also highlight the effectiveness
and safety of new therapeutic advances in these paediatric patients.
Aloi, M. etal. Nat. Rev. Gastroenterol. Hepatol. 11, 99108 (2014); published online 20 August 2013; doi:10.1038/nrgastro.2013.158

Introduction

Pediatric
Gastroenterology and
Liver Unit, Department
of Pediatrics, Sapienza
University of Rome,
Viale Regina Elena
324, Rome 00161,
Italy (M. Aloi, F. Nuti,
S.Cucchiara).
Department of
Radiobiology and
Human Health, ENEA
(National Agency
forEnergy, New
Technologies and
Environment), Via
Anguillarese 301,
Rome 00123, Italy
(L.Stronati).
Correspondence to:
S. Cucchiara
salvatore.cucchiara@
uniroma1.it

IBD is characterized by a chronic unremitting course


that places a burden on the patients quality of life and
the health-care system.1 Epidemiological data from the
past 2years indicate that the highest rates of IBD occur
in Western countries, with a paediatric incidence of
~810 cases per 100,000 people per year.2,3 Of all IBD
cases diagnosed per year, ~25% of them are in children
andadolescents.4
Although the disease mechanisms and diagnostic
procedures are similar in paediatric and adult patients,
several aspects of the disorder make children with IBD
a unique population.5,6 Indeed, children with IBD tend
to have a severe form of the disease with a more rapid
evolution than adults.1,7,8 In paediatric ulcerative colitis,
there is a higher prevalence of pancolitis (~7090%) than
proctitis or left-sided colitis. Moreover, isolated colonic
inflammation is more common in young children with
Crohns disease than in adolescents, in whom disease
localization is similar to that observed in adults.9,10
Epidemiological data from the EPIMAD registry showed
that complicated behaviour in Crohns disease is present
at the time of diagnosis in ~30% of children and in 59%
of children at 10-year follow-up.7
Traditional therapeutic aims in paediatric IBD have
focussed on inducing and maintaining remission, promoting growth, improving patient quality of life and
minimizing drug and disease complications. 5 With
Competing interests
The authors declare no competing interests.

the advent of disease-modifying medications, mucosal


healing has emerged as a crucial target that seems to be
tightly associated with a change in disease course.11,12 In
the past couple of years, the concept of deep remission
(encompassing mucosal healing as well as biological and
clinical remission) was introduced as a measure of treatment efficacy;13 the aim of this approach is to prevent
bowel damage and surgery in the short-to-intermediate
term and disability in the long term.14
In this Review, we aim to describe the current knowledge in treatment options for children with IBD, emphasizing the unique aspects of the paediatric condition
in terms of efficacy and safety of medical therapy and
highlighting areas that require future investigation.

Traditional and evolving therapies


The initial management of most children with IBD encompasses the so-called conventional therapiesnamely,
corticosteroids, 5aminosalicylates (5-ASAs), immuno
modulators and nutritional support. The conventional
approach is based on the escalation of drugs, from those
with a better safety profile but a lower efficacy (such as
mesalamine and sulfasalazine) to those with improved
efficacy but a greater risk of adverse effects (including
corticosteroids, immunomodulators, biologic agents
and surgery). This step-up approach has the advantage
of reserving drugs with higher levels of toxicity for those
patients who are in need of more intensive therapy 15
(Figure1). However, conventional therapies do not alter
the development of disease complications or the need for

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Key points
Paediatric IBD often presents with a more severe phenotype and course than
the adult-onset disease
Current therapeutic goals for paediatric IBD have evolved from symptomatic
control towards the achievement of mucosal healing and deep remission
Advances in our understanding of the immunobiology of IBD have led to the
discovery of biologic agents; using biologic agents as disease-modifying drugs
in early IBD might induce disease stabilization and limit its progression
The aggressive nature and the evolution of IBD in childhood and its consequent
metabolic effects make biologic agents an attractive option for many paediatric
patients with IBD
Widely agreed data indicate that biologic agents in paediatric IBD facilitate
mucosal healing and improve growth and quality of life by achieving steroidsparing remission
Improved understanding of the mechanisms of paediatric IBD will lead to a
recognition of which patients might most benefit from early use of biologic agents

Nutritional
support

Surgery
Biologic agents

Step-up
approach

Top-down
approach
Immunomodulators
(AZA or 6-MP or MTX)

Prednisone or budesonide

5-ASA or sulfasalazine

Figure 1 | Therapeutic pyramid for paediatric IBD. Step-up


approach: from mild to stronger and more toxic therapies.
Top-down approach: early aggressive treatment with
immunomodulators and biologic agents. Abbreviations:
5-ASA, 5-aminosalicylate; 6-MP, 6mercaptopurine; AZA,
azathioprine; MTX, methotrexate.

surgery. Hence, paediatric gastroenterologists are moving


toward an early aggressive approach, with the aim of
changing the natural history of the disease.16 Unfortunately,
to date, no defined criteria exist from which a clinician can
decide with a high degree of confidence which patients will
benefit from this approach.7,9 Identifying the genetic, lab
oratory or clinical criteria for predicting which paediatric
patients will have a disabling disease course is a challenge
in current paediatric IBDresearch.

5-Aminosalicylates
Although several paediatric gastroenterologists commonly use 5ASAs in the management of paediatric
IBD, only a few, small, randomized controlled trials
(RCTs) have evaluated their efficacy in children with
ulcerative colitis,1719 with very poor data in Crohns
disease.20 Studies in adults demonstrated that 5ASAs are
effective at high doses to induce remission of mild-tomoderate ulcerative colitis.21 5ASAs are generally used
100 | FEBRUARY 2014 | VOLUME 11

in children with ulcerative colitis, primarily based on the


above results and guidelines from the European Crohns
and Colitis Organisation (ECCO) and the European
Society for Paediatric Gastroenterology, Hepatology and
Nutrition guidelines (ESPGHAN).22 These guidelines
recommend oral 5ASA regimens as a first-line induction therapy for mildly to moderately active paediatric
ulcerative colitis and for the maintenance of remission.23
However, a high percentage of newly diagnosed children
present with extensive and moderate-to-severe disease23
and require a combination of drugs for inducing and
maintaining remission. In these patients, 5ASAs are
combined with corticosteroids or more aggressive drugs
to obtain disease remission.
5ASAs have various delivery systems that target specific parts of the bowel; thus, knowledge of disease distribution is important. Generally, these drugs are well
tolerated, with few adverse effects, and continue to be
used by paediatric gastroenterologists in the management of ulcerative colitis, despite the lack of evidence. On
the other hand, 5-ASAs should not be used in paediatric
Crohns disease owing to the lack of any evidence of
efficacy. Indeed, a multicentre RCT demonstrated the
absence of effectiveness of 5ASAs in the maintenance of
remission in 60 children with Crohns disease.20

Nutritional therapy
Exclusive enteral nutrition (EEN), which consists of different formulas (namely, elemental, semi-elemental and
polymeric), is the primary therapy used for inducing
and maintaining remission in Crohns disease, as a supplement for improving growth, as well as replenishing micronutrient deficiency.24 The main difference
between these formulas is the degree of protein hydroly
sis: elemental formulas consist primarily of amino
acids whereas semi-elemental and polymeric comprise
partially or extensively hydrolysed proteins. However,
although EEN has received favourable acceptance as a
therapeutic agent in several parts of the world (mainly
Europe and Canada), it is not widely used in other countries (such as the USA). EEN also seems to be less effective in Crohns disease colitis24 and can be difficult to
administer for long periods of time.25
Despite several small paediatric studies that suggest
the effectiveness of EEN in active Crohns disease,2631
aCochrane review in 2007 reported that corticosteroids
are significantly more effective in achieving remission
than EEN (OR 0.35, 95% CI 0.320.58).32 A previous
meta-analysis of paediatric studies published in 1998
included five trials with a total of 147 children who
received EEN and concluded that EEN and cortico
steroids were of equal efficacy in treating children with
active Crohns disease.33 Thus, the benefits of EEN might
differ between paediatric and adult populations 32,34
(Table1). Moreover, several studies have suggested
that EEN might be able to achieve mucosal healing in
children. Borrelli etal.31 in a prospective, controlled,
open-label trial evaluated 37 children who were randomly allocated to receive a 10-week course of either
oral polymeric diet or oral methylprednisolone. Clinical

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FOCUS ON IBD THROUGH THE AGES


Table 1 | Prospective trials on enteral therapy in paediatric Crohns disease
Study

Trial duration
(weeks)

Response to EEN
(no.of patients)

Response to steroids
(no. of patients)

Relative risk (95% CI)

Seidman etal.26 (1991)

8 of 10

5 of 9

1.20 (0.423.46)

Seidman etal.27 (1993)

26 of 34

31 of 34

0.84 (0.501.41)

Thomas etal.

(1993)

12 of 12

12 of 12

1.0 (0.452.22)

Ruuska etal.29 (1994)

9 of 10

8 of 9

1.01 (0.392.62)

Sanderson etal.30 (1987)

8 of 9

7 of 8

1.02 (0.372.80)

Borrelli etal.

10

15 of 19

12 of 18

1.38 (0.603.12)

28

31

(2006)

Abbreviation: EEN, enteral nutritional therapy.

remission and mucosal healing, the latter being assessed


through endoscopy and histology at weeks0 and 10, were
the primary efficacy outcomes. At week10, both endoscopic and histological scores markedly decreased in the
polymeric group when compared with the corticosteroid
group (74% versus 33%).31 Previously, Fell etal.,35 in an
uncontrolled study, demonstrated clinical and histological remission at 8weeks in >70% of 29 children who
received a polymeric diet alone, with a dramatic downregulation of potent proinflammatory cytokines, such as
IL1, IFN and IL8 at the mucosal level. In 2013, the
long-term effect of EEN on the anthropometry and nutritional status of 109 children with IBD was reported after
a 2year follow-up. Sustained improvements in weight
and BMI, but not in height zscore, were demonstrated.36
Several theories explain the mechanisms of action of
EEN. The most advanced theory is through the alteration
of the gut microbiota;37,38 other possible mechanisms
include bowel rest (through the reduction in antigenic
load, decreased gut metabolic activity and motility)39 and
both direct and indirect immunoregulatory effects.40 The
main drawback of EEN is poor compliance. Most parents
are reluctant to give their children total enteral nutrition
for 68weeks as required. Moreover, not all children are
able to consume adequate formula volume by mouth and,
thus, might require the insertion of nasogastric tubes.

Corticosteroids
Conventional corticosteroids are commonly used for the
induction of remission in moderate-to-severe Crohns
disease and ulcerative colitis. However, corticosteroids
are ineffective in healing the inflamed mucosa4143 and
have several adverse effects (listed in Supplementary
Box1 online); thus, patients are generally rapidly weaned
from corticosteroids after induction of remission.
Budesonide, an oral steroid preparation that is released
in the distal ileum and proximal colon, can be considered
for use in patients with Crohns disease limited to those
areas.44 Budesonide has fewer systemic adverse effects
than prednisone, but it is not without adverse effects as
its rapid withdrawal can lead to adrenal insufficiency.45
Rectal steroid enemas are available and can be used to
treat ulcerative proctitis and sigmoid disease without
systemic effects. Beclometasone dipropionate (BDP)
is released in the colon and several adult studies have
demonstrated its efficacy in ulcerative colitis and colonic
Crohns disease.46 A paediatric trial in 2010 comparing

the efficacy of oral BDP with mesalamine in 30 children


with mild-to-moderate ulcerative colitis showed that
BDP had a better and more rapid efficacy in inducing
clinical and endoscopic remission than mesalamine, with
a good tolerability profile.47

Immunomodulators
Thiopurines (azathioprine and its metabolite
6mercaptopurine) are effective maintenance agents in
both Crohns disease and ulcerative colitis.48,49 These drugs
have a slow onset of action, so are not used for inducing
remission. However, they are often started in conjunction
with corticosteroids in moderate-to-severe disease and
can decrease the duration of corticosteroid use. In the
only paediatric prospective, multicentre, double-blind,
placebo-controlled trial, 55 children newly diagnosed with
moderate-to-severe Crohns disease were randomly allocated to receive either prednisone with 6mercaptopurine
or prednisone with placebo to induce remission. No differences between the two groups were seen at 1month
and 3months (remission was 89% in both groups); at the
18-month follow-up, 91% of the children who received
6mercaptopurine continued to be in remission versus
only 53% who received placebo.48 This trial, along with
other uncontrolled paediatric reports,50,51 has led most
paediatric gastroenterologists to commonly use thio
purines in children with Crohns disease. Intriguingly,
clinical trials in adults demonstrated a markedly lower
efficacy of azathioprine and 6mercaptopurine to maintain
remission5153 than that reported in the study of Markowitz
etal.48 These varying results raise several issues, such as
a particular sensitivity of paediatric patients to thio
purines, and the effect of the early introduction of azathio
prine or 6mercaptopurine in the course of the disease.
Interestingly, in routine clinical practice, only 60% of
children who are treated with thiopurines are in remission
1year after beginning therapy,54 irrespective of whether
the therapy was begun within the first 3months after diagnosis or thereafter. No other prospective controlled studies
on the efficacy of thiopurines in paediatric Crohns disease
have been performed since then. No similar studies have
been conducted in paediatric ulcerative colitis; however,
several retrospective reports have demonstrated the effectiveness of thiopurines in corticosteroid-dependent or
corticosteroid-refractory ulcerative colitis.49,55
Methotrexate has a more rapid onset of action
than thiopurines and is often used as a second-line

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immunomodulator in paediatric patients with Crohns
disease who do not respond to or are intolerant to thiopurines, or in those who have articular involvement.56
Methotrexate is proven to be efficacious in inducing and
maintaining remission in adults with Crohns disease.57
No controlled trials have evaluated its use in paediatric Crohns disease, but retrospective and uncontrolled
reports have shown good remission rates in patients who
fail or are intolerant to thiopurines. 56 Few retrospective, uncontrolled studies have reported on the efficacy
of methotrexate in adult and paediatric patients with
ulcerative colitis, so its use is not based on evidence.58,59
Concerns regarding opportunistic infections and
malignancy give physicians, patients and families reason
to pause whenever immunomodulator use is discussed,
particularly because of the risk of EpsteinBarr virus
(EBV)-associated lymphoproliferation in previously
seronegative patients who start thiopurines secondary to primary infection with EBV.60 Supplementary
Boxes2 and 3 online list the primary adverse effects of
thiopurines and methotrexate.

Biologic agents and Crohns disease


Infliximab
Anti-TNF agents have been used in paediatric patients
with IBD since the 1990s. Infliximab, a chimeric monoclonal antibody against TNF, was approved for paediatric use in 2006 after the REACH study. 61 This study
showed a 63.5% response rate and 55.8% remission rate
at 1year, respectively, in 52patients receiving maintenance therapy with infliximab (5mg/kg every 8weeks)
after a standard induction treatment at 0, 2 and 6weeks.
Concomitant treatment with immunomodulators was
a necessary criterion to enter the study. Furthermore,
this study demonstrated that the maintenance therapy
every 8weeks was superior to every 12weeks, confirming previous data in adults.61 This trial was subsequently
followed by an open-label extension evaluation enrolling
all of the patients who completed treatment until week46
in the first study.62 This cohort of 60 patients continued
infliximab up to an additional 3years of therapy. Efficacy
was evaluated using physician global assessment;
~5068% of patients had no disease, and 8393% had
no or mild disease up to the time of maximal follow-up.62
The primary limitation of this study was the low number
of patients who continued treatment up to 3years (eight
patients). Subsequently, infliximab has been shown to
achieve and maintain remission up to 1year in paediatric
uncontrolled studies, whereas other reports have showed
its efficacy in achieving a response longer than a year that
ranged from 5080%.6366
Infliximab has also been proven to be more effective in
obtaining mucosal healing than immunomodulators.67,68
Only a few paediatric studies have evaluated mucosal
healing as a therapeutic outcome. Endoscopic activity
was evaluated after an induction regimen of infliximab
in a paediatric cohort of 18 patients with Crohns disease,
showing that the Crohns Disease Endoscopic Index of
Severity (CDEIS) and the histological score were markedly reduced at the time of follow-up. 69 Moreover, a
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paediatric study in a Polish population aiming to assess


the efficacy of infliximab induction therapy on mucosal
healing showed complete mucosal healing in 18 of the 66
patients in the study 10weeks after initiation of therapy.
The clinical response was reported in 78% of the patients;
33% of the patients were in clinical remission.70

Adalimumab
Among the other anti-TNF agents, adalimumab, a fully
humanized monoclonal antibody that is primarily used
as a second-line biologic therapy for infliximab failures
or nonresponders, is now also considered to be the antiTNF antagonist of choice in paediatric Crohns disease.7175
A 41% remission rate at 1year has been reported. 74
Furthermore, a multicentre, RCT in 2012 evaluated the
efficacy and safety of two adalimumab double-blind
maintenance dosing regimens in paediatric patients
with moderate-to-severe disease Crohns disease. 75
Adalimumab led to remission rates of 38.7% and 33.3%
at weeks 26 and 52, respectively, in the high-dose group
(40mg in patients weighing >40kg and 20mg in patients
weighing <40kg given every other week). These results
were numerically, but not statistically significantly,
higher than those in the low-dose group (20mg in
patients weighing >40kg and 10mg in patients weighing <40kg given every other week). Dividing patients
according to previous exposure to infliximab, the rates of
clinical response and remission at week26 were greater
in infliximab-naive patients than those previously
exposed. At week52, the trends remained the same.75
Although the study was not powered to assess the differences between patients who were naive or non-naive
to infliximab, the former were more likely to achieve
clinical remission or response than patients who had
been previously exposed, with efficacy rates similar
to the REACH population.75 It is conceivable that this
difference could be a result of a change in the mucosal
cytokine profile in patients who fail a first anti-TNF
treatment. Table2 lists the prospective trials on the
efficacy of biologic agents in paediatric Crohns disease.
Other anti-TNF agents
No paediatric data exist for certolizumab pegol. In the
only existing paediatric trial on natalizumab, a humanized IgG4 monoclonal antibody anti-4 integrin subunit,
Hyams etal.76 evaluated safety and efficacy in adolescents with moderate-to-severe Crohns disease. The
study treated 38 patients who received three doses of
natalizumab at 0, 4 and 8weeks. The PCDAI (Pediatric
Crohns Disease Activity Index) was used for evaluation
and indicated response and remission rates of 55% and
29%, respectively. This study was performed before the
first cases of progressive multifocal leukoencephalopathy
were reported in adults; this severe adverse event remains
the primary concern against extensive use of this therapy.
Overview of use of biologic agents
The appearance of biologic agents in the therapeutic
armamentarium for IBD has generated widespread
anticipation with regard to their capability of changing

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Table 2 | Efficacy results of main prospective trials on biologic therapy in paediatric Crohns disease
Trial

No. of
patients

Primary efficacy
endpoint

Treatment

Results
Response

Remission

Hyams
etal.62
(2011)
(REACH)

112

PCDAI at 10 and
54weeks

Infliximab 5mg/kg at 0, 2 and 6weeks


Randomly allocated to receive infliximab every
8 or 12weeks
Treatment with immunomodulators was a
requirement to enter the study

Every 8weeks: 65.5%


Every 12weeks: 33.3%

Every 8weeks: 55.8%


Every 12weeks: 23.5%

Hyams
etal.64
(2009)

202

PGA at 1, 2 and 3years


of follow-up in patients
who had at least 1year
of follow-up after
induction

Infliximab maintenance therapy


Episodic switched to maintenance therapy
Use of immunomodulators permitted

1year: 64%
2years: 70%
3years: 83%

1year: 26%
2years: 44%
3years: 33%

Viola
etal.72
(2009)

23

PCDAI at 2, 4, 12, 24
and 48weeks

Adalimumab
Weight 40kg
Induction: 160mg then 80mg after 2weeks
Maintenance: 80mg every other week
Use of immunomodulators permitted

2weeks: 87%
4weeks: 88%
12weeks: 70%
24weeks: 86%
48weeks: 91%

2weeks: 36.3%
4weeks: 60.8%
12weeks: 30.5%
24weeks: 50.0%
48weeks: 65.2%

Week26
Infliximab experience
High dose: 59.1%
Low dose: 48.4%
Infliximab naive
High dose: 68.6%
Low dose: 63.0%

Week26
Infliximab experience
High dose: 38.7%
Low dose: 28.4%
Infliximab naive:
High dose: 56.9%
Low dose: 35.2%

Week 52
Infliximab experience
High dose: 41.9%
Low dose: 28.4%
Infliximab naive:
High dose: 54.9%
Low dose: 33.3%

Week52
Infliximab experience
High dose: 33.3%
Low dose: 23.2%
Infliximab naive:
High dose: 45.1%
Low dose: 27.8%

Adalimumab
Weight 40kg
Induction: 80mg followed by 40mg after 2weeks
Maintenance: 40mg every other week
Use of immunomodulators permitted
Hyams
etal.75
(2012)
(IMAGINE)

188

PCDAI at 26 and
52weeks

Adalimumab
Weight 40kg (high dose)
Induction: 160mg then 80mg after 2weeks
Maintenance: 40mg or 20mg every other week
Use of immunomodulators permitted
Adalimumab
Weight 40kg (low dose)
Induction: 80mg then 40mg after 2weeks
Maintenance: 20mg or 10mg every other week
Use of immunomodulators permitted

Abbreviations: PCDAI, Pediatric Crohns Disease Activity Index; PGA, Physician Global Assessment.

the course of the disease. Unfortunately, strong data confirming such expectations are lacking. On the basis of
data from adult trials and uncontrolled paediatric data
that suggest a better outcome in patients with a shorter
disease history,7779 a new therapeutic scheme referred to
as top-down therapy has been introduced. In this setting,
more aggressive treatments, such as biologic agents and
immunomodulators, are used as first-line therapy, but
the effectiveness of this approach in altering disease
course has not yet been established (Figure1). Data
from adult cohorts that support a top-down approach
have just become available; the documentation highlights
that early treatment with an anti-TNF agent seems to be
more effective than the classic step-up approach in specific cohorts.77 A Korean group has analysed the effect
of the introduction of infliximab as a first-line therapy
against the conventional treatment schedule in two small
retrospective studies in paediatric Crohns disease. The
authors concluded that a top-down approach is more
effective than conventional treatment in inducing and
maintaining remission in up to 2years of follow-up.8081
Yet, the small number of patients enrolled in the study
and the retrospective nature should be borne in mind
when these data are interpreted.

Epidemiological data have shown that a high proportion of patients present with a mild disease course, 82
leading to the risk of overtreating a large percentage of
patients. Prognostic biomarkers, indicative of a more
disabling disease course, could ensure the correct therapeutic approach is selected at the time of diagnosis and
are warranted.8386
Protracted follow-up programmes in children with IBD
have become of pivotal importance, both for efficacy and
safety purposes, especially regarding the concerns about
opportunistic infections and malignancies. The description of a rare but frequently fatal non-Hodgkin lymph
oma, hepatosplenic Tcell lymphoma, in young patients
treated with a combination therapy of thiopurines and
anti-TNF antibodies8789 has increased these safety warnings. Indeed, this finding has modified the attitude
towards therapy for paediatric IBD from a combined use
of immunomodulators and biologic agents to biologic
monotherapy; certain data in adults, however, reported
that the former schedule was more effective in patients
who were naive to both therapies.90 Supplementary Box4
highlights the primary adverse effects of biologic therapy.
Of crucial importance for the management of paedi
atric patients with IBD using biologic agents is the exit

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strategymore specifically, when and in whom to cease
therapy, and the determination of drug trough levels and
antibodies against infliximab or adalimumab during
follow-up visits. With respect to the first point, no RCTs
have evaluated the relapse rates in patients maintaining or stopping anti-TNF therapy in adult or paediatric
IBD populations. A prospective study assessed the risk
of relapse after infliximab therapy withdrawal in 115
adults with Crohns disease who had been treated for
at least 1year with infliximab and immunomodulators
and had been in steroid-free remission for the previous 6months. The overall relapse rate after infliximab
withdrawal was 43.9% at 1year and 52.2% at 2years and
was associated with many factors: corticosteroid use
612months before baseline; no previous surgical resection; male sex; haemoglobin levels 14.5g/l; leukocyte
count >6109; CDEIS >0; high sensitivity; C-reactive
protein level 5mg/l; infliximab trough level 2mg/l;
and faecal calprotectin level 300g/g. The presence of
six or more of these factors was associated with 100%
risk of relapse within 1year after treatment withdrawal,
whereas patients in the low-risk group (with no more
than three risk factors) had a 06% risk.91
As for the second point, the chimeric nature of inflixi
mab is the primary source of its immunogenicity for
humans, which is characterized by the occurrence
of anti-drug antibodies (ADA). ADA are thought to
interfere with the pharmacodynamics and pharmaco
kinetics of the compound. Adalimumab, although fully
humanized, similarly elicits the formation of ADA that
are also correlated with reduced drug levels and loss
of response.9298 The true incidence of ADA formation
against infliximab in Crohns disease remains unclear.
For episodic infliximab, the incidence is 3661%,
whereas it is substantially reduced to 518% by maintenance schedules.9295 The incidence of ADA during
maintenance therapy with adalimumab in adult populations is estimated to be 2.83.7%.96,97 Paediatric data
on immunogenicity are available from the REACH trial
(ADA to infliximab reported at 2.9%) and IMAGINE
trial (ADA to adalimumab reported at 3.3%).61,75 Overall,
a critical observation of data from the adult studies make
it unlikely that a loss of response and the occurrence of
infusion reactions are principally a result of ADA formation to either infliximab or adalimumab. A more
relevant measure of immunogenicity to infliximab or
adalimumab is likely to be circulating drug concentration, which could guide therapeutic decisions in the case
of primary nonresponse or secondary loss of response to
biologic therapies.98
In summary, biologic therapies are now routinely
used in paediatric Crohns disease and have the capacity to achieve and maintain remission in the short-tointermediate term. There is no clear support for an
extensive top-down approach; however, in the case of
a complicated disease from the time of diagnosis, biologic therapies seem to be the most promising approach.
No clear indications have shown when to cease therapy,
especially in paediatric patients. In a very select cohort
of patients in deep clinical, endoscopic and serological
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remission, the possibility of ceasing therapy might be


considered. When there is a loss of response, it is prob
ably more useful to monitor drug trough levels than
ADA to guide further therapeutic strategies.

Biologic agents in ulcerative colitis


According to joint ECCO and ESPGHAN guidelines
on the management of paediatric ulcerative colitis, in
addition to patients with acute severe ulcerative colitis
(ASC) who need a second-line therapy, another candidate for infliximab is a child with persistently active
disease, uncontrolled or dependent on corticosteroids
despite concomitant immunomodulators, and for whom
colectomy is advisable.21 Although studies in adults
with moderate-to-severe ulcerative colitis have shown
that infliximab is useful in promoting and maintaining remission, few data exist in children with chronic
refractory ulcerative colitis undergoing treatment with
biologicagents.99
A group consensus in adults with ulcerative colitis who
are unresponsive to conventional treatment revealed
that infliximab effectively induces clinical remission,
promoting mucosal healing and decreasing the need
for surgery.100 ACT1 and ACT2 were the first RCTs to
evaluate infliximab for the induction and maintenance of
remission in adults with moderate-to-severe active ulcerative colitis.101 When compared with placebo, patients on
infliximab had a markedly higher clinical response at
weeks8, 30, and 54, as well as a reduced risk of colectomy,
which was associated with mucosal healing at week8.
A multicentre phaseIII open-label, parallel group
RCT has prospectively assessed the efficacy and safety
of infliximab in 60 children with active moderate-tosevere ulcerative colitis despite therapy with cortico
steroids and immunomodulators.102 At week8, clinical
response was reached in 73.3% of patients, whereas clinical remission was observed in 40.0% of the patients. At
week54, clinical remission was achieved in more patients
who received the drug every 8weeks than those who
did every 12weeks (38.1% versus 18.2%), whereas the
rate of serious adverse events and infections was similar
in the two arms. At week8, mucosal healing was documented in >two-thirds of patients, but endoscopy was
optional at week54. No difference was observed in any
efficacy endpoints in patients who received concomitant immunomodulators compared with those who
receivedmonotherapy.
In a previous observational multicentre study by the
Paediatric Inflammatory Bowel Disease Collaborative
Research Group Registry, 52 children with active ulcerative colitis (87% with pancolitis, 63% corticosteroidrefractory and 35% corticosteroid-dependent) received
infliximab for a median period of 8months from
thetime of diagnosis.103 The concomitant therapy atthe
beginning of infliximab treatment included cortico
steroids (87%), thiopurines (63%), and 5ASAs (51%).
Corticosteroid-free inactive disease was reached in
38% and 21% of the patients at 1 and 2years, respectively, whereas 61% did not need a colectomy at 2years.
Previous studies in children with ulcerative colitis that

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FOCUS ON IBD THROUGH THE AGES


were retrospective and with small sample sizes, dem
onstrated the effectiveness of infliximab in inducing
remission, both in the chronic refractory disease and
the acute phases of the disease.104109
Interestingly, to obtain information on dosing practice
of infliximab in ulcerative colitis treatment, a survey of
paediatric gastroenterologists has shown that the attitude toward using high doses of infliximab (10mg/kg)
to obtain remission is more common than generally
thought, both in academic institutions and hospitalbased practices.110 Thus, the need for more standardized
guidelines on the use of dose escalation of biologic agents
seems to be warranted.

Acute severe ulcerative colitis


Severe flare-ups of ulcerative colitis are a medical emergency, and hospitalization is recommended if patients
have a severe, systemic impairment, bowel dilatation,
spontaneous abdominal pain unrelated to bowel movements, marked anaemia or hypoalbuminaemia. 111
Although acute conditions in Crohns disease are primarily a result of complications, such as occlusion or
haemorrhage, ASC is a life-threatening condition with
a high rate of clinical deterioration and colectomy.112
Approximately 2840% of paediatric patients with ulcerative colitis have at least one acute severe episode during
their disease course. 113 A consensus statement from
ECCO and ESPGHAN has provided a useful guide for
managing ASC in children.114 To assess disease severity,
a validated scoring tool, the Paediatric Ulcerative Colitis
Activity Index (PUCAI), has proven to be useful.115
Intravenous corticosteroids are the first-line therapy
(methylprednisolone 11.5mg/kg per day, up to
60mg daily). Stool cultures for enteric pathogens and
Clostridium difficile toxins are recommended, as is
plain abdominal radiography at baseline to detect bowel
d ilatation. 116 If the PUCAI score on day3 is >45, a
second-line therapy is considered with surgical consul
tation and screening for tuberculosis, if biologic therapy
is planned. A sigmoidoscopy is suggested to exclude
cytomegalovirus infection and granulomatous inflammation.114 On day5, patients with a PUCAI score of >65
should undergo a second-line therapy. The second-line
therapy includes biologic agents, calcineurin inhibitors,
primarily ciclosporin and, as a minor option, tacro
limus.117 Although a parallel, open-label, RCT in adults
with ASC has shown that ciclosporin was not more efficacious than infliximab,118 there are no comparative prospective trials between these two agents in children. In
a review of the medical management of ASC in adults,
both infliximab and ciclosporin have been proven to be
effective as rescue medical therapies in ASC.119
Several practical points are helpful in selecting the
most appropriate drug. Ciclosporin or tacrolimus are
generally given as a bridge to thiopurine maintenance
treatment and stopped as the thiopurine becomes active
(34months). If patients have previously failed thio
purine or exhibited biochemical and clinical features
associated with calcineurin toxicity (hypomagnesaemia,
hypocholesterolaemia, hypoglycaemia and hypertension,

neurological abnormalities), infliximab should be


the preferred therapy.119,120 The sequential therapy of
calcineurin inhibitors and infliximab and vice versa is
discouraged owing to the risk of toxicity and severe infections, as well as increased surgical morbidity and mortality. Nevertheless, a case series examining adults indicated
that the sequential administration of ciclosporin or
tacrolimus followed by infliximab, or vice versa, can lead
to a successful response in ~2545% of patients.121123
Retrospective studies in paediatric patients receiving
ciclosporin have shown a short-termcolectomy-freerate
of 6087%, whereas the longterm co lectomy-free
rateincreased from 0% to 72%.124128
The response rate to oral tacrolimus seems to be lower
than that to ciclosporin, although the former shows a
better safety profile and bioavailability.116,124 Of note,
very few controlled studies have been conducted on
the use of tacrolimus in children with severe ulcerative
colitis.129131 No strict criteria define failure of secondline therapy; however, it is generally recommended to
continue treatment for at least 1week for ciclosporin
and up to 2weeks for tacrolimus or infliximab before
defining failure.114 Unlike ciclosporin, infliximab can be
continued as long-term maintenance therapy,99 with the
latter being commonly chosen as rescue therapy. No data
are available for thiopurine-naive patients who respond
to infliximab as to whether the latter should be given as
monotherapy or as a bridge to thiopurine maintenance;
this choice is influenced by local clinical practice and
personal attitude.132

New horizons and perspectives


The past few years have seen an enormous progress in the
knowledge of the mechanisms underlying pathogenesis
of IBD, resulting in the implementation of agents minimizing or counteracting specific steps along the inflammatory cascade leading to the disease.133 The majority
of current data are related to anti-TNF agents that have
achieved treatment goals such as mucosal healing and
reduced need for hospitalization and surgeries. However,
research is ongoing to generate drugs that target other
pathways, such as the IL-23T-helper17 axis, JAKSTAT
signalling pathway, adhesions molecules, chemokine
antagonists and cytokine blockers.134141 Furthermore,
cell-based therapy from the perspective of immune
education and regulation is being considered for IBD
therapy. 142 Nevertheless, owing to the complexityof
IBD pathogenesis and the lack of full reproducibility ofhuman disease by mouse models, not all offered
biologic treatments have been successful.135
The management of IBD by paediatric gastroentero
logists is now moving from symptomatic control to
achievement of mucosal healing and deep remission with
the use of specific biologic agents.142 It is widely agreed
that paediatric IBD often displays an aggressive phenotype with serious complications such as malnutrition,
growth delay and severe impairment of quality of life.
Moreover, according to epidemiological reports, progression of paediatric disease to a complicated course
is more rapid and frequent than previously thought.1,79

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY


2014 Macmillan Publishers Limited. All rights reserved

VOLUME 11 | FEBRUARY 2014 | 105

REVIEWS
Awareness that early use of disease-modifying agents,
such as biologic agents, can alter the disease course and
limit its progression through a profound inhibition of the
inflammatory process underlying IBD is growing.
The most pressing issue in the management of
paediatric IBD will be the identification of patients with
an expected complicated course (that is, those who are
candidates for an early aggressive therapy), by adapting the therapeutic decisions to the specific condition
of each patient.144 We are probably nearing a phase in
which patients with IBD will be exhaustively evaluated
by investigating their genetic background, serological
markers, endoscopic and imaging features, and perhaps
by studying the cytokine profile in the gut mucosa.
This personalized approach will define a patient profile
that could predict disease course and help to select the
correcttherapy.145

Conclusions
IBD has been traditionally viewed as a chronic disorder,
consisting of two distinct entities, Crohns disease and
ulcerative colitis, and an undetermined form (IBDU),
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2.

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concept is developing in the identification of different
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therapeutic protocols for both adults and children with
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