173symptomatic remission also had more substantial improvement in linear growth
compared to those who only had a partial clinical response. A second small retro-
spective study of 36 children treated with adalimumab demonstrated comparable
results with 42% of the cohort demonstrating catch-up growth [ 48 ]. Again, improve-
ment in height standard deviation score was seen only in patients in early puberty
and was more likely in those patients who had achieved remission. A larger retro-
spective review of 121 pediatric patients receiving anti-TNF therapy (93 on inflix-
imab, 28 on adalimumab, 93% CD) had similar findings, with disease status
(remission) and early pubertal stage predicting improvement in linear growth [ 49 ].
One of the primary outcomes in the REACH study was assessment of change in
height from baseline to week 54 [ 8 ]. In patients with a delay in bone age of at least
1 year, there was significant improvement in height Z-scores at both 30 and 54 week,
with a mean improvement in Z-scores of 0.3 and 0.5, respectively. Although not a
primary outcome, significant improvement from baseline to week 26 and week
56 in height velocity Z-scores was also observed in both the low-dose and high-dose
adalimumab groups in the IMAgINE 1 study [ 36 ]. The improvement in linear
growth appears to be durable; in one study of 195 patients who received infliximab,
patients who were in tanner stage 1 and 2 at induction continue to have increase in
height Z-score for up to 4 years post initiation of therapy [ 49 ]. Anti-TNF therapy
does lead to decreased use of corticosteroid effect; however, the corticosteroid
“sparing effect” is not the sole reason for growth restoration as improvement in
height velocity is seen in both children who do and do not receive corticosteroid
therapy [ 48 , 50 ]. A decrease in inflammatory cytokines that directly impact the
growth hormone axis likely plays a role in restoration of growth. Anti-TNF therapy
is associated with increase in sex hormones (testosterone and estradiol) at 10 weeks
and 12 months post initiation across all tanner stages, and in a small study of adult
patients with CD, infliximab therapy led to an increase in IGF-1 levels to a level
comparable with controls, suggesting possible reversal of growth hormone resis-
tance seen in active disease [ 51 , 52 ]. Together, these hormonal changes may lead to
improvement in linear growth and progression through puberty in pediatric patients.
Decreased bone mineral density (BMD) is prevalent in pediatric IBD and has
been reported in 43% of patients with CD and 39% with UC [ 53 ]. Although malnu-
trition, pubertal delay, decreased weight-bearing activities due to illness, and corti-
costeroid exposure are contributing factors, inflammation also impacts bone health.
As a result, children may not attain and/or maintain their peak bone mass, which
may impact future skeletal health. Improvement in bone health and vitamin D
homeostasis has been observed with anti-TNF therapy. In the REACH study, 112
patients had markers of bone metabolism including bone-specific alkaline phospha-
tase (BSAP) and N-terminal propeptide of type I collagen (P1NP), products of
osteoblast activity, collected at baseline and at 10 weeks [ 54 ]. BSAP and P1NP
were negatively associated with baseline PCDAI, and both of these biomarkers of
bone formation increased during the 10-week interval. The authors hypothesized
that improvement in these markers was due to reversal of TNF-α effects on bone
growth, decreased corticosteroid exposure, and improvement in linear growth.
Griffin et al. evaluated improvement in bone density and structure by tibia
11 Biologic Therapy in Pediatric Inflammatory Bowel Disease