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off-label as a second-line biological therapy in refractory pediatric UC. An early
report by Noe et al. evaluated the short-term response of adalimumab in pediatric
IBD; three patients with UC who had failed infliximab were included in this retro-
spective, two of whom responded to adalimumab based on decreased LCAI score,
and the third patient required colectomy for refractory disease [ 30 ]. A slightly larger
retrospective review of 11 pediatric patients with UC treated with adalimumab after
loss of response or intolerance to infliximab showed similar outcomes with 55% of
patients achieving clinical remission at 6 months and through follow-up (mean
duration of therapy 21.5 months) [ 39 ]. Four patients did require colectomy for
refractory disease, and the median time to colectomy was 7 months after initiation
of adalimumab therapy. A prospective multicenter randomized double-blind
placebo- controlled study evaluating the efficacy and safety of adalimumab in pedi-
atric patients with moderate to severe UC is ongoing (ClinicalTrials.gov identifier:
NCT02065557) and will hopefully shed more light on the role of adalimumab in
this complicated disease. Overall adalimumab appears to have significant efficacy
in pediatric IBD, and based on a single-center study of utilization trends from 2007
to 2012 of anti-TNF in adults and children with inflammatory bowel disease, there
has been a rise in the use of this medication; however, infliximab remains the domi-
nant anti-TNF therapy, particularly in the pediatric population [ 40 ].
Anti-TNF Therapy Impact on Growth and Bone Health
Growth impairment is a common extraintestinal manifestation of pediatric IBD,
particularly in CD. Decrease in height velocity has been reported in pediatric CD
prior to diagnosis, and up to 60% of children will have a decrease in height percen-
tiles during their disease course [ 41 – 43 ]. The etiology of growth impairment is mul-
tifactorial. Prior to diagnosis, patients may have malnutrition from decreased intake,
possibly related to anorexia induced by increased circulating TNF-α, increased
losses, and increased metabolic demands from inflammation; additionally, inflam-
matory cytokines, specifically TNF-α, interleukin 1, and interleukin 6, directly
impact the growth hormone axis [ 43 – 46 ]. This combination of factors leads to
decreased circulating insulin-like growth factor 1 (IGF-1) and growth impairment.
After diagnosis, the use of corticosteroids may further impact growth by inhibition
of IGF-1. Restoration and promotion of normal linear growth in pediatric patients
are important therapeutic goals.
Multiple studies, including REACH and IMAgINE 1, have reported beneficial
effects of anti-TNF in restoring growth by improving height velocity. Walters et al.
retrospectively evaluated linear growth in 32 patients with active CD, mostly (59%)
in early puberty (Tanner I–III). In the analysis of all patients, height velocity
increased from a mean of −0.51 to +2.4 after 12 months of therapy [ 47 ]. Height
velocity improvement was dependent on pubertal stage, with improvement seen in
patients in early puberty compared to no improvement in patients near the end of
puberty (Tanner IV–V). Patients in early puberty who achieved complete
S. Patel and J. Strople