REVIEW

URRENT
C
OPINION

Adjunctive treatment to antitumor necrosis factor in

pediatric patients with refractory Crohns disease
Imad Absah a,b and Michael Stephens a,b

Purpose of review
The use of antitumor necrosis factor (anti-TNF) agents to treat Crohns disease in children has become quite
common over the past decade. There are incomplete data to guide the clinician in choosing whether
adjunctive therapy should be added to optimize response to these drugs.
Recent findings
Addition of immunomodulators such as thiopurines or possibly methotrexate can increase anti-TNF drug
levels, reduce the risk of antidrug antibodies, and improve response. This is tempered by the reports of
younger patients developing hepato-splenic T-cell lymphoma while taking thiopurines with and without
concomitant anti-TNF medications. The available data are reviewed including recent pediatric reports.
Summary
The addition of immunomodulators to anti-TNF therapies can optimize their performance. Careful discussion
of the risks and side-effects must be undertaken when considering this approach. Additional knowledge is
required to stratify which children with inflammatory bowel disease need this approach, and/or who are at
risk for significant complications.
Keywords
antitumor necrosis factor, azathioprine, Crohns disease, mercaptopurine, methotrexate, thiopurine

INTRODUCTION
Pediatric inflammatory bowel diseases (IBDs) are
chronic, incurable, and immune-mediated gastrointestinal disorders involving 1.4 million patients in
the United States. Up to 20% of the IBD cases present
during childhood and adolescence [1]. The prevalence of Crohns disease is more common than
ulcerative colitis in children with IBD [2].
Recent epidemiologic studies suggested an
increase in pediatric Crohns disease incidence over
the last few years [3,4]. Pediatric onset IBD (Crohns
specifically) tends to be more aggressive and have a
more complicated clinical course in comparison to
adult onset IBD [5,6]. Children with IBD typically
present with moderate-to-severe disease activity,
with more than 30% presenting with extensive
disease [7,8]. The differences between adult and
pediatric IBD demonstrate that early onset disease
is a more severe phenotype. This would also suggest
that the ideal treatment strategy in a child should
not be the application of approaches validated in
adults and simply dose adjusted for a smaller
patient.
Until the late 1990s, treatment options for
pediatric patients with Crohns disease were limited
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to corticosteroids, exclusive enteral nutrition,

immunomodulators including thiopurines and
methotrexate (MTX), and surgery. Infliximab was
the first anti-tumor necrosis factor (anti-TNF) biologic approved for adults with Crohns disease in
1998. Off label use in pediatric patients quickly
followed [9]. Food and Drug Administration approval for pediatric use was issued in 2006. Pediatric
studies have shown that anti-TNFa can induce
remission in up to 88% of children with moderate-to-severe Crohns disease [10]. Which children
should receive anti-TNF therapy and the timing of
its introduction remain important sources of controversy. Early introduction of anti-TNF therapy
may be most appropriate in specific situations such
a
Division of Gastroenterology and Hepatology and bDivision of Pediatric
Gastroenterology and Hepatology at Mayo Clinic, Rochester, Minnesota,
USA

Correspondence to Imad Absah, MD, Assistant Professor of Pediatrics,

College of Medicine, Division of Pediatric Gastroenterology and
Hepatology, 200 First Street SW, Rochester, MN 55901, USA.
Tel: +1 507 266 0114; e-mail: absah.imad@mayo.edu
Curr Opin Pediatr 2013, 25:624628
DOI:10.1097/MOP.0b013e328364df22
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Adjunctive therapy Absah and Stephens

KEY POINTS
 Combining immunomodulators with anti-TNF agents
can optimize response for Crohns disease.
 Adjunctive therapy can prevent development of ADAs
and increase anti-TNF drug levels.
 Aggressive lymphomas have been observed in patients
taking thiopurines in combination with anti-TNF agents.

as failure to thrive, short stature (particularly in

peri-pubertal patients), fistulizing or stricturing
disease, and small bowel Crohns disease [11]. It is
important to recognize that, despite at least a decade
of widespread use of anti-TNF in children, the rate of
surgical resection in Crohns disease has remained
stable [12,13].
Recent data demonstrated that up to 50% of
pediatric Crohns patients will lose response to
infliximab (IFX) by 5 years [14 ]. Gisbert and Panes
[15] calculated the annual risk for loss of infliximab
response to be 13% per patient-year. Strategies to
minimize an individuals risk for loss of response are
even more important in children who have a disease
duration horizon extending for many decades.
Adjunctive therapy represents one approach to
reduce immunogenicity against anti-TNF agents
and to presumably extend the durability of
response. Another rationale for combining antiTNF medications with other therapies is to optimize
disease control in partial responders. We will review
the available literature that can guide the clinician
in making decisions about adjunctive therapy to
anti-TNF agents in children.
&

DRUG DISPOSITION OF BIOLOGIC

THERAPIES
The pharmacokinetic and pharmacodynamic
behavior of monoclonal antibodies (large protein
base molecules) can be very different from that
of more conventional small molecule drugs. The
classical determinants of absorption, distribution,
metabolism, and elimination are not necessarily
involved, and these processes are mediated by very
different mechanisms. A detailed discussion of these
factors is beyond the scope of this work and is well
reviewed elsewhere [16 ]. Briefly, some of the
unique factors that can affect drug bioavailability
include antidrug antibodies (ADAs), high-baseline
TNFa levels (increased clearance through target
binding), and low albumin (associated with
increased clearance, presumably through rapid
enteral protein losses). Mechanisms of degradation
and elimination of monoclonal antibodies are not
&&

well understood but are felt to be through proteolytic catabolism after receptor-mediated endocytosis
in the reticuloendothelial system. Detectable trough
concentrations of IFX are associated with improved
response and when it is given regularly as opposed to
episodically. Episodic treatment is also associated
with a higher risk of ADAs [17]. Adjunctive therapeutic strategies for anti-TNF agents generally aim to
reduce the formation of ADAs, or reduce clearance
of the drug through immunomodulatory effects
on elimination processes. Because many of these
adjunctive therapies are effective against Crohns
disease in their own right, combination therapy
may be synergistic.

CORTICOSTEROIDS
Historically, steroids have been used in Crohns
disease patients to induce remission or treat disease
exacerbation. Although this approach may establish
rapid clinical improvement, it does not effectively
maintain remission in adult or pediatric Crohns
disease patients [18,19]. In addition to the lack of
long-term clinical efficacy, chronic steroid therapy
involves unwanted metabolic consequences in
children.
A potentially useful role for corticosteroids in
Crohns disease is the adjunctive use with antiTNFa. Corticosteroids decrease the formation of
antibodies to infliximab (ATI) that adversely affects
IFX pharmacokinetics. A study by Farrell et al. [20]
suggested that intravenous hydrocortisone premedication significantly reduces ATI levels but does not
eliminate ATI formation or infusion reactions. As is
the case with all strategies to reduce ATI formation,
important data are lacking to allow intelligent translation to clinical care. Some pediatric centers routinely premedicate all patients receiving infliximab.
Current thinking encourages minimization of
steroid exposure for children with IBD, and others
do not employ this approach or only premedicate
certain patients (e.g., those who have had an infusion reaction). Unfortunately, there are no data to
allow stratification of patients to identify those at
higher risk of ATI.

THIOPURINES
Combination therapy using anti-TNFa with a thiopurine reduces the risk of ADA, increases anti-TNFa
levels, and has superior efficacy to monotherapy. At
least two studies have demonstrated that patients
who receive concomitant immunosuppression with
episodic use of IFX have a lower incidence of ADAs
[21,22]. This has also been demonstrated in patients
receiving regularly scheduled infusions [23]. The

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Gastroenterology and nutrition

Study of Biologic and Immunomodulator Naive

Patients in Crohns Disease trial randomized IFX
and thiopurine naive patients to azathioprine,
IFX, or combination therapy with both. The group
that received combination therapy had a lower rate
of ADAs and superior treatment response [24].
Similar results were noted when combining newer
anti-TNFa medications such as certolizumab and
adalimumab with thiopurines [25,26].
The superior efficacy and reduced ATI formation
have made combination therapy more attractive. By
design, the largest prospective study of IFX for
pediatric Crohns disease included concomitant
immunomodulators (thiopurine or MTX) [10].
Beginning around 2004, multiple reports arose of
invasive hepatosplenic T-cell lymphoma in patients
taking thiopurines in combination with anti-TNFa
[27]. Subsequent surveillance has revealed
additional cases in patients receiving thiopurine
monotherapy [28]. This has impacted the practice
patterns of many pediatric gastroenterologists, as
the vast majority of patients who developed this
aggressive lymphoma were men and under the age
of 35. Another important safety consideration is
the increased risk for opportunistic infections and
overall lymphomas and leukemias in IBD patients
receiving concomitant therapy [29]. It should be
noted that this observed risk of serious infection
was seen mostly in older and sicker patients. When
considering combination therapy, the potential
risks must be balanced against the benefit for an
individual patient and frankly discussed.

era of anti-TNFa agents on pediatric patients with

Crohns disease. One retrospective study looking
specifically at the concomitant use of MTX and
anti-TNFa in refractory cases of Crohns disease
reported a 50% clinical remission rate after a few
weeks of adding MTX to the current anti-TNFa
medication (IFX or adalimumab). Average followup for these patients was 14 months. All the responders remained in clinical remission without any
serious adverse events (i.e., bone marrow suppression, pneumonitis, and serious infections) [35]. In a
recent retrospective Canadian study of a large
cohort of pediatric patients treated with MTX, a
small number of these patients received MTX as
an adjunctive therapy to IFX. Although overall
long-term remission rates were low, the subgroup
of patients with colonic Crohns disease appeared
particularly responsive to MTX [36]. Importantly, a
recent randomized trial suggested that concomitant
use of IFX and MTX was no more effective than IFX
alone in Crohns disease patients requiring treatment with prednisone [37].
Main adverse effects of MTX include bone
marrow suppression and liver toxicity. Monitoring
of complete blood count and liver function tests
regularly is recommended. In cases with persistently
abnormal liver function tests of unknown cause,
MTX should be discontinued. Contraceptive
measures should always be used when prescribing
MTX to a female patient of child-bearing age, and it
is contraindicated in pregnancy due to embryo
toxicity [38].

METHOTREXATE

CONCLUSION

Although the precise mechanism of MTX as an

immune modulator is unclear, its role as a folate
antagonist that inhibits DNA and protein synthesis,
resulting in lymphocyte apoptosis, is defined [30].
Data from rheumatology literature suggest that concomitant use of MTX and anti-TNFa medications is
more effective in treating severe refractory cases of
rheumatoid arthritis (RA) and arthritis-induced
chronic anemia [31]. Whether the response is
because of a reduced immunogenicity against
anti-TNFa agents or through the addition of differently acting immune-modulators like MTX is
unclear. Most of the gastroenterology literature
about the use of MTX in treating pediatric patients
with Crohns disease is relevant to children failing
thiopurine treatment or corticosteroid dependency.
These pediatric data are mostly small retrospective
reports suggesting that MTX can induce clinical
remission by 4270% for patients with active disease despite thiopurine treatment [3234]. Several
recent reports examined the efficacy of MTX in the

The decision to add an adjuvant therapy to an antiTNF agent when treating a pediatric patient with
refractory Crohns disease should be a mutual
decision between the clinician and family following
a complete discussion of the potential risks and
benefits. Careful attention must be paid to ensure
the patient would not benefit from other interventions (e.g., surgical resection of a distal ileal stricture).
Although there is growing consensus in favor of
combination therapy among adult IBD thought leaders when looking at the overall adult experience [39 ],
the safety issues reported in young men have created
more confusion for the pediatric gastroenterologist.
Although some routinely combine anti-TNF agents
and immunomodulators, others do so only in
selected patients (e.g., patients who have developed
ATI and are starting a second anti-TNF agent, or
patients with a partial response despite dose optimization of their anti-TNF drug) or not at all. Safety
profiles may also drive the choice of concomitant
agent (thiopurines for girls but MTX for boys).

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Adjunctive therapy Absah and Stephens

The question remains whether MTX is a reasonable and/or safer alternative to thiopurines in this
situation. The data from patients with RA as well as
much of the IBD data are encouraging. Vermeire
et al. [22] showed equivalent benefit in reducing the
risk of ATI in patients taking either MTX or a thiopurine in combination with IFX. Unfortunately, the
lack of improved response reported by Feagan et al.
[37] raises doubts. That a therapeutic effect of a
treatment strategy is helpful in one immune-mediated disorder but not in another is not without
precedent (e.g., etanercept).
Currently, there are no means to stratify which
patients are most likely to benefit (or experience
harm) from combination therapy. In children, several large multicenter studies are seeking to identify
biomarkers that predict disease behavior. The RISK
study is following a large inception cohort of children with Crohns disease prospectively to identify
genetic, immunologic, and environmental factors
associated with severe disease behavior. The Predicting Response to Standardized Pediatric Colitis
Therapy study was recently launched in children
with ulcerative colitis. Although identifying children who are at a higher risk of disease complications is important, it will also be important to
demonstrate that an intervention such as the early
introduction of anti-TNF therapy (with or without
adjunctive medications) alters the natural history of
the disease. Interest is also focusing on identifying
other agents that can synergize with anti-TNF
agents, with a recent study combining adalimumab
and ciprofloxacin for perianal fistulizing Crohns
disease [40].
Acknowledgements
None.
Conflicts of interest
Dr Stephens has received research support from the
following industrial entities: Prometheus Laboratories,
Abbott Laboratories, Schwarz Biosciences, Janssen Biotech, Astra-Zeneca.
Dr Absah has no conflicts of interest.

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