177observed in thiopurine-exposed patients, adding to the growing evidence that this
class of medications may be the main risk factor for this significant complication
of immunosuppressive therapy.
Other Biologic Therapies in Pediatric IBD
Although pediatric IBD patients generally respond well to anti-TNF therapy, based
on current data, 30–40% of IBD patients are primary nonresponders, and still more
discontinue therapy with time due to loss of response or intolerance to these thera-
pies. Several biologic agents have been developed that target other mechanisms of
inflammation, including integrins and IL12/IL23 pathway. Natalizumab, a human-
ized monoclonal IgG4 antibody against α4 integrin, inhibits migration of lympho-
cytes to both the central nervous system and gastrointestinal tract; natalizumab was
the first anti-integrin used for treatment of Crohn’s disease. Experience in pediatric
Crohn’s disease has been limited due to concerns regarding the development of
progressive multifocal leukoencephalopathy from reactivation of the JC virus that
has been reported with this therapy. Early experience in pediatrics showed potential,
with one phase 2 single-arm open-label study demonstrating early efficacy in mod-
erately to severely active pediatric Crohn’s disease [ 71 ]. Thirty-eight adolescent
patients received three intravenous infusions of natalizumab 3 mg/kg at 0, 4, and
8 weeks (32 per protocol), and although safety/tolerability was the primary study
objective, clinical efficacy was evaluated through week 12. Mean PCDAI signifi-
cantly decreased from baseline at all assessments, with the most significant decrease
occurring at 10 weeks; at this time point, 55% of patients had clinical response
(decrease in PCDAI by at least 15 points from baseline), and 29% were in clinical
remission (PCDAI <10). Thirty-two patients (84%) reported adverse events, most
commonly headaches (10%), CD exacerbation (9%), and fever (8%). Eight patients
(21%) developed a serious adverse event most related to hospitalization for compli-
cations or symptoms related to CD. Overall the medication was well tolerated and
no significant safety events were reported through week 32. A second small retro-
spective single-center study evaluated maintenance of natalizumab (300 mg every
4 week) in nine patients who had failed one or more anti-TNF therapies [ 72 ]. By
week 10, 50% (4 of 8) of patients were in remission, and remission was maintained
at the time of last follow-up (20–52 weeks), and three of five patients were able to
taper off prednisone therapy. No serious adverse events or serious infections were
observed during this study; however, the median treatment duration was relatively
short at 8.25 months (range 3.5–35), and all patients were transitioned to vedoli-
zumab once this therapy received FDA approval in 2014. Although this data is
promising, safety concerns have limited ongoing use in the pediatric population.
Vedolizumab is a humanized monoclonal IgG1 antibody to α 4 β7 integrin, which
selectively inhibits T-lymphocyte adhesion to mucosal addressin cell adhesion mol-
ecule- 1 (MAdCAM-1) mitigating the concerns of PML from inhibition of CNS
T-cell trafficking. Given the favorable safety profile, this medication has become the
11 Biologic Therapy in Pediatric Inflammatory Bowel Disease