Biologic Agents Are Associated with Excessive Weight Gain in Children with Inflammatory Bowel Disease Leonard Haas1•Rachel Chevalier2•Brittny T…. [605506]

ORIGINAL ARTICLE
Biologic Agents Are Associated with Excessive Weight Gain
in Children with Inflammatory Bowel Disease
Leonard Haas1•Rachel Chevalier2•Brittny T. Major3•Felicity Enders3•
Seema Kumar4•Jeanne Tung5
Received: 1 June 2017 / Accepted: 30 August 2017 / Published online: 11 September 2017
/C211Springer Science+Business Media, LLC 2017
Abstract
Background Children with active inflammatory bowel
disease (IBD) are frequently underweight. Anti-tumor
necrosis factor (anti-TNF) agents may induce remission
and restore growth. However, its use in other autoimmune
diseases has been associated with excess weight gain. Our
aim was to examine whether children with IBD could
experience excess weight gain.
Methods A centralized diagnostic index identified pedi-
atric IBD patients evaluated at our institution who received
anti-TNF therapy for at least 1 year between August 1998
and December 2013. Anthropometric data were collected at
time of anti-TNF initiation and annually. Excess weight
gain was defined as DBMI SDS (standard deviation score)
where patients were (1) reclassified from ‘‘normal’’ to
‘‘overweight/obese,’’ (2) ‘‘overweight’’ to ‘‘obese,’’ or (2) a
final BMI SDS [0 and DSDS[0.5.Results During the study period, 268 children received
anti-TNF therapy. Of these, 69 had sufficient follow-up for
a median of 29.3 months. Median age at first anti-TNF
dose was 12.8 years. At baseline, mean weight SDS was
-0.7 (SD 1.4), while mean BMI SDS was -0.6 (1.3).
Using baseline BMI SDS, 11.6% were overweight/obese.
At last follow-up (LFU), however, the mean DBMI SDS
was 0.50 ( p\0.0001). However, 10 (17%) patients had
excess weight gain at LFU; 3 patients were reclassified
from ‘‘normal’’ to ‘‘obese,’’ and 7 had a final BMI SDS [0
andDSDS[0.5.
Conclusions Pediatric patients with IBD may experience
excess weight gain when treated with anti-TNF agents.
Monitoring for this side effect is warranted.
Keywords Infliximab /C1Adalimumab /C1Certolizumab /C1
Pediatric IBD /C1Crohn’s disease /C1Ulcerative colitis
Abbreviations
IBD Inflammatory bowel disease
Anti-TNF Anti-tumor necrosis factor
BMI Body mass index
LFU Last follow-up
SDS Standard deviation score
Introduction
Patients with inflammatory bowel disease (IBD) frequently
experience weight loss due to chronic diarrhea and mal-
absorption. Patients may avoid eating to lessen these
symptoms, exacerbating weight loss [ 1]. Children subse-
quently may develop growth failure [ 2]. Treatment with
anti-tumor necrosis factor agents (anti-TNF) has been
shown to lead to weight gain and a reversal of growthElectronic supplementary material The online version of this
article (doi: 10.1007/s10620-017-4745-1 ) contains supplementary
material, which is available to authorized users.
&Jeanne Tung
[anonimizat]
1Mayo Medical School, Rochester, MN, USA
2Department of Pediatrics, Childrens Mercy Hospital,
Kansas City, MO, USA
3Division of Biomedical Statistics and Informatics, Mayo
Clinic, Rochester, MN, USA
4Division of Pediatric Endocrinology, Mayo Clinic, Rochester,
MN, USA
5Division of Pediatric Gastroenterology and Hepatology,
Mayo Clinic, 200 First Street SW, Rochester, MN 55905,
USA
123Dig Dis Sci (2017) 62:3110–3116
DOI 10.1007/s10620-017-4745-1

failure in children [ 3,4]. It is unclear, however, if patients
may gain excessive weight as a result of anti-TNF therapy.
An average of 5.2 kg weight gain was reported in a ret-
rospective survey of adult Crohn’s patients, and similarfindings have been reported in rheumatoid arthritis, psori-
asis, and psoriatic arthritis [ 5–7].
Due to reports of weight gain in adults and anecdotal
experience in children, we sought to determine if pediatric
patients with IBD experienced excessive weight gain when
exposed to anti-TNF therapy.
Methods
Study Design and Population
This retrospective study was approved by the Mayo Clinic
Institutional Review Board. The medical records of allpatients seen in the Division of Pediatric Gastroenterology
and Hepatology were electronically searched to identify
patients with IBD who received anti-TNF therapy betweenAugust 1998 and December 2013. Clinical notes were
searched for the words ‘‘ulcerative colitis’’ or ‘‘pancolitis,’’
‘‘Crohn’s disease,’’ ‘‘indeterminate colitis,’’ ‘‘infliximab’’or ‘‘Remicade,’’ ‘‘adalimumab’’ or ‘‘Humira,’’ and ‘‘cer-
tolizumab’’ or ‘‘Cimzia.’’ Pediatric patients were defined as
those who were less than 18 years of age at the time of firstanti-TNF therapy.
Records were reviewed for demographic information,
duration and extent of disease, length of follow-up, anddates and dosing of anti-TNF therapy. Prior and con-
comitant medications were recorded. We collected
anthropomorphic data at time of anti-TNF initiation, 2, 6,and 12 months, annually, as well as last follow-up (LFU).
Last follow-up was defined as the end of the study period,
discontinuation of anti-TNF therapy, or intestinal surgery.Patients were excluded if they had insufficient data or
follow-up ( \12 months after anti-TNF initiation). If
patients switched anti-TNF agents, we continued to collectanthropometric data if the time interval between agents did
not exceed 3 months. The physician global assessment
(PGA) was used to assess the patient’s disease activity ateach time point.
Anthropometric Data
Weight, height, and body mass index (BMI) were calcu-
lated at each time point, and converted to standard devia-tion scores (SDS) for analyses, based on Centers for
Disease Control 2000 published data [ 8]. These SDS scores
account for differences in the rate of change in weight andBMI based on age and gender. For instance, an appropriateweight gain over 1 year at the 50 %would be 5.4 kg for a
13-year-old boy and 3.5 kg for a 13-year-old girl, but only
3.6 kg for a 16-year-old boy and 1.3 kg for a 16-year-old
girl. Weight and BMI SDS at each time point are reportedas mean with standard deviation. Using Centers for Disease
Control data, underweight was defined as BMI SDS
\-1.645 (corresponding to the 5 %), overweight between
1.036 (85 %) and 1.645 (95 %), and obese SDS [1.645
(95%), respectively. Although an increase in weight or
BMI SDS would be considered a statistically significant
change in weight gain, the definition of excess weight gain
is lacking in the literature. Further, patients who areunderweight and/or growth stunted due to active Crohn’s
disease may start with negative SDS scores and have
appropriately large gains in weight, height, and BMI afterachieving remission. In the absence of an existing defini-
tion for excess weight gain , we chose to describe the
number of patients who by BMI SDS (1) changed from‘‘normal’’ (between -1.645 and 1.036) to ‘‘overweight/
obese’’ ( [1.036), (2) changed from ‘‘overweight’’ ( [1.036)
to ‘‘obese’’ ( [1.645), and (3) had both a final BMI SDS [0
andDSDS[0.5 during the study period.
Statistical AnalysisDescriptive statistics were used, including percentages for
discrete variables, and mean, median, and range for con-tinuous variables. Differences between baseline and last
follow-up SDS were analyzed using a paired ttest. Linear
mixed effects models were used to analyze weight andBMI SDS over time by gender, IBD type, Paris age clas-
sification at baseline, baseline weight and BMI categories
with random effects for subject. Each univariate modelincluded time, the covariate, and the interaction between
time and the covariate. JMP version 10.0 and SAS version
9.3 (Sas Institute Inc. Cary, NC) was used for all analyses,and p\0.05 was considered statistically significant. All
statistical tests were two-sided.
Results
Demographics and Medication Use
Between August 1998 and December 2013, 268 pediatric
patients with IBD evaluated at our institution received anti-
TNF therapy, of whom 69 had at least 1 year of anti-TNF
therapy and follow-up (Supplement 1). The baselinecharacteristics of the cohort are summarized in Table 1.
The median age at time of diagnosis was 12.8 years (range
4.2–17.4), with a median of 7.3 months (range 0–133) fromIBD diagnosis to start of anti-TNF therapy. Median follow-
up of our cohort was 29.3 months (range 12.0–109.2), withDig Dis Sci (2017) 62:3110–3116 3111
123

data available beyond 24 months in 43 patients (62.3%).
The majority of patients had Crohn’s disease (85.5%), with
a predominantly ileocolonic (83.1%) distribution and
inflammatory phenotype. However, 12 patients (20.3%)had penetrating disease. Of the 8 patients with ulcerative
colitis, 5 (62.5%) had pancolitis at initiation of anti-TNF
therapy.
The type of anti-TNF used, concomitant medications,
and baseline serology are shown in Table 2. Infliximab
(IFX) was the most common anti-TNF therapy used for 63(92.6%) of patients, while 32 (46.4%) received adali-
mumab, and 8 (11.6%) received certolizumab. During the
study period, 26 (37.7%) switched to a second drug, while4 (5.8%) received all three anti-TNF agents. Escalation of
therapy (dose or frequency) was instituted for 39 (61.9%)
patients, with an average of 1.8 changes (range 0–4).Concomitant immunomodulation was used in 25 (36.2%)
patients. Use of corticosteroids at baseline, 24 months, and
LFU was 68.1, 6.3, and 5.8%, respectively. Within2 months of anti-TNF initiation, 21 (31%) achieved andTable 1 Demographic
characteristics of pediatric
patients who received anti-TNF
agents ( n=69)Male, n(%) 37/69 (53.6%)
Race, n(%)
Caucasian 61/69 (88.4%)Black 4/69 (5.8%)
Asian/Pacific Islander 2/69 (2.9%)
Other/unknown 2/69 (2.9%)
Median age at diagnosis (years) (range) 12.8 (4.2–17.4)
\10 years, n(%) 16 (23.1%)
10–15 years, n(%) 46 (66.7%)
[16 years, n(%) 7 (10.1%)
Duration of disease at start of anti-TNF, months (range) 7.3 (0–133)Type of inflammatory bowel disease, n(%)
Crohn’s disease 59/69 (85.5%)Ulcerative colitis 8/69 (11.6%)Indeterminate 2/69 (2.8%)
Crohn’s disease distribution (Paris classification), n(%)
L1 Small intestine 10/59 (16.9%)L2 Colon 6/59 (10.2%)L3 Small intestine and colon 49/59 (83.1%)
L4a Isolated upper disease 24/59 (40.7%)
B1 Inflammatory 50/59 (72.3%)B2 Stricturing 6/59 (10.2%)B3 Penetrating 12/59 (20.3%)B2B3 Penetrating and stricturing 1/59 (2.7%)P Perianal disease 12/59 (20.3%)
Ulcerative colitis disease distribution, n(%)
Proctitis or left-sided 2/8 (2.5%)Extensive 1/8 (12.5%)
Pancolitis 5/8 (62.5%)
Anti-TNF anti-tumor necrosis factor, IFX infliximab
Table 2 Initial anti-TNF therapy, concomitant medications, and
baseline serology
Infliximab, n(%) 63/69 (91.3%)
Adalimumab, n(%) 32/69 (46.4%)
Certolizumab, n(%) 8/69 (11.6%)
Corticosteroids (IV) 4/69 (5.67%)
Corticosteroids (oral) 52/69 (75.4%)Mesalamine 16/69 (23.2%)Azathioprine 13/69 (18.8%)Methotrexate 12/69 (17.4%)Median hemoglobin (g/dL) (IQR) ( n=54) 12 (3.2–14.7)
Median albumin (g/dL) (IQR) ( n=35) 3.7 (2.5–4.6)
Median C-reactive protein (mg/L) (IQR) ( n=50) 8.9 (0–65.9)
Anti-TNF anti-tumor necrosis factor, IVintravenous3112 Dig Dis Sci (2017) 62:3110–3116
123

sustained clinical remission through the remaining study
period. Twenty-three (33.3%) patients discontinued all
anti-TNF therapy during the study period; 11 (16.1%) due
to side effects, 5 (7.2%) switched to an immunomodulator,and 6 (5.9%) required surgery.
Weight and BMI SDS of Overall CohortFigure 1shows box plots of weight and BMI SDS over
time of the overall cohort. (SDS scores of weight and BMI
at baseline, 12, 24 months, and LFU are shown in Sup-
plement 2.). At 24 months, weight and BMI data wereavailable for 32 and 30 patients, respectively. At initiation
of anti-TNF therapy, the mean weight SDS was -0.65 (SD
1.4), while the mean BMI SDS was -0.59 (SD 1.3). At
baseline, 15 (21.7%) patients were underweight (weight
SDS\-1.645), while 6 (8.7%) were overweight with a
weight SDS [1.036. Using baseline BMI SDS, the per-
centages for underweight and overweight/obese patients
were 15.9 and 11.6%, respectively. At 24 months after
anti-TNF initiation, the mean weight SDS and BMI SDS at24 months was -0.09 (1.1), and -0.09 (0.9), respectively.
At LFU, the mean weight SDS and BMI SDS was -0.10
(1.4) and -0.09 (1.3), respectively. After 24 months of
biologic therapy, the average Dweight SDS and DBMI SDS
were not significant compared to baseline. At LFU, how-
ever, the mean Dweight SDS was 0.56 ( p\0.0001), while
DBMI SDS was 0.50 ( p\0.0001).Change in Weight Categories Over Time
Table 3outlines the weight categories using BMI SDS
from baseline to LFU. Patients who were ‘‘underweight’’ at
baseline either remained underweight or normalized. Of the58 patients who were of ‘‘normal,’’ ‘‘overweight,’’ or
‘‘obese’’ at baseline, 10 (17%) gained excess weight using
our criteria. Of the 50 patients who were initially ‘‘normal’’weight at baseline, 3 were ‘‘overweight/obese’’ at follow-
up. An additional 5 had a final SDS [0.5 and DSDS[0.5.
Of the 4 patients who were ‘‘obese’’ at baseline, 2 had aDSDS[0.5. The 8 patients with a baseline BMI SDS
[1.036 (‘‘obese’’) remained so at LFU. The median fol-
low-up time in this subset of patients was 31.5 months(range 13.6–108). We examined the potential contribution
of corticosteroids to excess weight gain. Nine children had
no exposure to corticosteroids for at least 12 months priorto LFU, while 1 child had no exposure for at least
6 months. Patients who were underweight at baseline
gained weight faster than patients who were of normalweight or obese ( p=0.02), likely reflecting improvements
in disease activity (Supplement 3).
A larger percentage of patients with ulcerative colitis
were overweight by weight SDS (25 vs. 5.1%) and BMI
SDS (25 vs. 8.5%) than Crohn’s disease at baseline. At
LFU, patients with Crohn’s disease had statistically sig-nificant weight gain, with a mean weight DSDS of 0.57
(SD 0.8) and DBMI SDS of 0.52 (SD 0.8) ( p\0.0001)
(Supplement 2). Although no difference in weight gain
Fig. 1 Weight and BMI SDS
over time in pediatric patientstreated with anti-TNF therapy. oand?indicate outliers and the
mean of the weight and BMI
SDS scores, respectivelyDig Dis Sci (2017) 62:3110–3116 3113
123

over time was observed by IBD type at 24 months
(p=0.18), slower gains in weight SDS were observed in
patients with Crohn’s disease compared to ulcerative colitis
(-0.01, 95% CI -0.02, -0.006, p=0.0002) (Supplement
3).
At baseline, more females were overweight by both
weight (12.5 vs. 4.5%) and BMI SDS (15.6 vs. 8.1%) than
males. While both genders experienced significant increa-
ses in both weight and BMI SDS at LFU (Supplement 2),we did not observe a difference between genders over time.
However, younger patients ( \10 years) experienced faster
weight gain than older patients at 24 months ( p=0.02)
and LFU ( p\0.001).
We did not detect differences in need for dose increases
based on baseline weight categories. Disease activity dur-ing the course of the study period (sustained remission
within 2 months of starting anti-TNF agent or flares during
the study period) was not associated with significantchanges in weight or BMI gain.
Discussion
To our knowledge, this is the first study to investigatewhether anti-TNF therapy is associated with excessive
weight gain in children with IBD. In our cohort of 69
patients, 10 patients gained excess weight by BMI SDS,including 3 patients who were of ‘‘normal’’ weight at
baseline but were ‘‘obese’’ at LFU. Those who were
overweight at baseline remained in this category. We did
not detect differences in weight gain by gender or IBD
type.
The prevalence of overweight/obese pediatric patients
with IBD varies across studies. In our study, 11.6% were
overweight/obese at baseline using BMI SDS. Data from
the ImproveCareNow registry reported that 20% of CDpatients were overweight or obese at time of study entry,
while inception data from the Pediatric IBD collaborative
and the Wisconsin cohort reported 9 and 10%, respectively.These inception cohorts reported 20 and 34% overweight/
obese prevalence in their UC patients [ 4,6].
Studies of anti-TNF weight gain in patients with IBD are
scant. Although Issa et al. reported an average weight gain
of 5.3 kg over 24 months in adults with IBD treated with
infliximab, the ImproveCareNow IBD registry observed asmall but nonsignificant association in pediatric patients
who were overweight/obese and concomitant infliximab
use [ 5,9]. Studies in the adult rheumatology and derma-
tology literature suggest significant weight gains ranging
from 2.2 to 4.8 kg. Brown et al.’s retrospective study of
patients with rheumatoid arthritis treated with anti-TNFagents found that although 64.8% gained an average of
4.6 kg over 24 months, 32.1% lost an average of 4.36 kg.
In contrast to our findings, higher BMI at baseline wasTable 3 BMI SDS at last follow-up by initial weight categories, n=69
Baseline weight category
n(%)Weight category at LFU At LFU, BMI SDS [0.5 and DSDS[0.5
Underweight
n=11 (15.9%)Underweight
n=4n/a
Normal
n=7
Normal weightn=50 (72.5%)Underweight n=1 n/a
Normaln=46n=5 -0.75 to 0.56 ( D1.31)
0.01 to 0.81 ( D0.80)
-0.30 to 0.92 ( D1.21)
0 to 1.01 ( D1.01)
-0.42 to 1.06 ( D1.48)
Obesen=3n=3 -1.44 to 1.31 ( D2.75)
0.98 to 1.74 ( D0.76)
-1.54 to 2.16 ( D3.7)
Overweightn=4 (5.8%)Overweight
n=4–
Obese
n=4 (5.8%)Overweight
n=1n/a
Obese
n=3n=2 1.74 to 2.38 ( D
0.63)
1.22 to 2.42 ( D1.20)3114 Dig Dis Sci (2017) 62:3110–3116
123

negatively associated with weight gain [ 6]. In a large open-
label study of 106 patients with spondyloarthropathy trea-
ted with infliximab or etanercept, an average weight gains
of 2.2 kg occurred within 24 months [ 10]. Renzo et al. [ 7]
reported similar findings in their study of infliximab and
etanercept in adult patients with psoriasis (2.2 kg) and
psoriatic arthritis (1.63 kg) in only 24 weeks. Florin et al.reported incremental weight gain over time in 35 patients
with psoriasis treated with infliximab—2.5 kg at
12 months and 4.8 kg at 24 months. As in our cohort,
changes were greater in patients who were of normal
weight at baseline than those who were overweight/obese[11]. Only one study has examined other autoimmune
conditions treated with anti-TNF therapy in the pediatric
population; Shafferman et al. [ 12] reported a statistically
significant increase of BMI SDS score of 0.15 in pediatric
patients with juvenile idiopathic arthritis, although this was
not statistically different from increases in a cohort notexposed to anti-TNF therapy.
The mechanism of excess weight gain (beyond nor-
malization of weight and/or growth) caused by anti-TNFtherapy is not fully understood. TNF-alpha is known to
cause cachexia, which in addition to weight loss, is asso-
ciated with muscle and adipose wasting and anorexia. Anti-TNF therapy may not only reverse anorexia, but contribute
to an ongoing increase in appetite through effects on
ghrelin, leptin, and adiponectin [ 13]. Ghrelin is an orexi-
genic hormone produced by the stomach and intestine in
response to hunger, leading to increased food intake [ 14].
Studies in patients with active rheumatoid arthritis havedemonstrated low levels in active disease and increased
serum levels after anti-TNF treatment [ 13,15]. In contrast,
leptin is an anorexic peptide hormone produced by adipo-cytes, which can alter food intake and subsequently body
weight and fat stores through its action on the hypothala-
mus [ 16]. Leptin levels have been shown to be decreased in
children with IBD, but the effect of anti-TNF therapy on
levels has been variable [ 17–20].
This excess weight gain seen with anti-TNF therapy
may have clinical consequences. First, it is our anecdotal
experience that patients and their families brought up their
concerns about the weight gain and appearance. Secondly,there may be subsequent failure to achieve or maintain
clinical response to anti-TNF therapy. Obesity has been
associated with increased levels of the pro-inflammatoryadipokines leptin, resistin, and visfatin, as well as
decreased levels of the anti-inflammatory adiponectin [ 21].
A recent meta-analysis of anti-TNF therapy in adults withautoimmune diseases showed an OR 2.16 risk of failing to
achieve clinical response or remission in obese patients,
regardless of fixed or weight-based dosing [ 22]. The
ImproveCareNow registry observed higher rates of IBD-
related surgery in children who were overweight or obese[9]. While we did not observe a correlation between
overweight/obesity and disease activity, our sample size
may be too small to observe a difference, and this was not a
primary aim of our study.
In our cohort, patients \10 years of age had the most
weight gain during our study period. This may reflect the
faster growth velocity seen in early puberty and/or greaterimpact of anti-TNF agents seen in this population. We did
not observe a difference in the proportion of patients with
excess weight gain between patients \10 vs. C10 years of
age, but this is likely due to sample size. Walters et al. [ 23]
observed that infliximab only improved the height velocityin pediatric Crohn’s when used in children in early puberty
compared to late puberty. Children \10 years of age would
be Tanner 1-II, while 10–15 years of age may span thespectrum of pubertal staging. At our center, we do not
routinely record pubertal staging; thus, our analysis was
confined to Paris age classification. Additional studies witha larger cohort may help clarify whether anti-TNF effects
on weight would also vary by pubertal staging.
There are several limitations to our study. Although 268
patients received anti-TNF therapy during our study period,
we analyzed 69 patients with at least 1 year of follow-up
anthropometric data. As a tertiary care center, somepatients who switched care to our center had already ini-
tiated anti-TNF therapy without baseline anthropometric
data available. In addition, it is our practice to coordinateinfliximab infusions with local institutions or home infu-
sions when feasible for the convenience of our patients.
Although monitoring serology is obtained and results faxedto us at the time of infusions, we typically do not receive
anthropometric data. Patients who received adalimumab
therapy at home may not have been seen close to thetimepoints we set for our study protocol. The majority of
our patients used corticosteroids at some point during the
study period, and the retrospective nature of the studyprecluded adjusting for duration and dosing. While these
could have confounded our study, the minority of patients
were using corticosteroids at 24 months (6.3%) and LFU(5.8%). Further, those who gained excess weight by our
criteria had not been exposed to corticosteroids for at least
6 months. Lastly, our cohort was largely Caucasian andcentered in the Midwest United States, so our results may
not be generalizable to other ethnicities and regions.
Our study demonstrates that some pediatric patients with
IBD may experience excessive weight gain when treated
with anti-TNF agents. Those who are of ‘‘normal’’ or
‘‘overweight’’ by BMI SDS seem to be at greater risk.Additional larger studies are needed to verify this associ-
ation. Monitoring for this side effect and appropriate
counseling regarding lifestyle modifications are warranted.Dig Dis Sci (2017) 62:3110–3116 3115
123

Acknowledgments The authors thank Kevin Chevalier for assisting
in statistical analysis.
Author’s contribution LH contributed to the acquisition and anal-
ysis of data, and writing of the manuscript. RC contributed to thedesign, data acquisition, and writing of the manuscript. BM con-tributed to the statistical analysis and interpretation of data. FE con-
tributed to the design, analysis, and interpretation of data. SK
contributed to the conception and design, interpretation of data, andwriting of the manuscript. JT contributed to the conception anddesign, analysis and interpretation of data, and writing of the manu-
script. All the authors have approved the final version for publication
and agree to be accountable for this work.
Compliance with ethical standards
Conflict of interest None.
References
1. Gerasimidis K, McGrogan P, Edwards CA. The aetiology and
impact of malnutrition in paediatric inflammatory bowel disease.
J Hum Nutr Diet . 2011;24:313–326.
2. Vadan R, Gheorghe LS, Constantinescu A, et al. The prevalence
of malnutrition and the evolution of nutritional status in patients
with moderate to severe forms of Crohn’s disease treated with
Infliximab. Clin Nutr . 2011;30:86–91.
3. Borrelli O, Bascietto C, Viola F, et al. Infliximab heals intestinal
inflammatory lesions and restores growth in children with
Crohn’s disease. Dig Liver Dis . 2004;36:342–347.
4. Hyams J, Crandall W, Kugathasan S, et al. Induction and main-
tenance infliximab therapy for the treatment of moderate-to-
severe Crohn’s disease in children. Gastroenterology .
2007;132:863–873.
5. Issa M, Weber L, Shidham S, et al. Infliximab significantly
increases proportion of overweight/obese Crohn’s disease
patients receiving longterm maintenance therapy. Gastroen-
terology . 2006;130:A209.
6. Brown RA, Spina D, Butt S, et al. Long-term effects of anti-
tumour necrosis factor therapy on weight in patients with
rheumatoid arthritis. Clin Rheumatol . 2012;31:455–461.
7. Renzo LD, Saraceno R, Schipani C, et al. Prospective assessment
of body weight and body composition changes in patients withpsoriasis receiving anti-TNF-alpha treatment. Dermatol Ther .
2011;24:446–451.
8. Kuczmarski RJ, Ogden CL, Guo SS, et al. CDC growth charts for
the United States: methods and development. Vital Health Stat .
2000;11:1–190.9. Long MD, Crandall WV, Leibowitz IH, et al. Prevalence and
epidemiology of overweight and obesity in children with inflam-
matory bowel disease. Inflamm Bowel Dis . 2011;17:2162–2168.
10. Briot K, Gossec L, Kolta S, et al. Prospective assessment of body
weight, body composition, and bone density changes in patients
with spondyloarthropathy receiving anti-tumor necrosis factor-alpha treatment. J Rheumatol . 2008;35:855–861.
11. Florin V, Cottencin AC, Delaporte E, et al. Body weight incre-
ment in patients treated with infliximab for plaque psoriasis. J
Eur Acad Dermatol Venereol . 2013;27:e186–e190.
12. Shafferman A, Fontaine KR, Cron RQ, et al. Changes in body
mass index in children with juvenile idiopathic arthritis treated
with tumor necrosis factor inhibitors. J Rheumatol .
2014;41:113–118.
13. Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, et al. Anti-
tumour necrosis factor alpha therapy modulates ghrelin in
patients with severe rheumatoid arthritis. Ann Rheum Dis .
2008;67:1644–1646.
14. Kalra SP, Bagnasco M, Otukonyong EE, et al. Rhythmic, recip-
rocal ghrelin and leptin signaling: new insight in the development
of obesity. Regul Pept . 2003;111:1–11.
15. Otero M, Nogueiras R, Lago F, et al. Chronic inflammation
modulates ghrelin levels in humans and rats. Rheumatology .
2004;43:306–310.
16. Roubos EW, Dahmen M, Kozicz T, et al. Leptin and the
hypothalamo-pituitary-adrenal stress axis. Gen Comp Endocrinol .
2012;177:28–36.
17. Aurangzeb B, Leach ST, Lemberg DA, et al. Assessment of
nutritional status and serum leptin in children with inflammatorybowel disease. J Pediatr Gastroenterol Nutr . 2011;52:536–541.
18. Fawcett RL, Waechter AS, Williams LB, et al. Tumor necrosis
factor-alpha inhibits leptin production in subcutaneous andomental adipocytes from morbidly obese humans. J Clin Endo-
crinol Metab . 2000;85:530–535.
19. Franchimont D, Roland S, Gustot T, et al. Impact of infliximab on
serum leptin levels in patients with Crohn’s disease. J Clin
Endocrinol Metab . 2005;90:3510–3516.
20. Karmiris K, Koutroubakis IE, Xidakis C, et al. The effect of
infliximab on circulating levels of leptin, adiponectin and resistin
in patients with inflammatory bowel disease.
Eur J Gastroenterol
Hepatol . 2007;19:789–794.
21. Versini M, Jeandel PY, Rosenthal E, et al. Obesity in autoim-
mune diseases: not a passive bystander. Autoimmun Rev .
2014;13:981–1000.
22. Singh S, Facciorusso A, Singh AG, et al. Obesity is associated
with inferior response to anti-TNF therapy in immune-mediated
inflammatory diseases: a systematic review and meta-analysis.Gastroenterology . 2017;152:S154.
23. Walters TD, Gilman AR, Griffiths AM. Linear growth improves
during infliximab therapy in children with chronically active
severe Crohn’s disease. Inflamm Bowel Dis . 2007;13:424–430.3116 Dig Dis Sci (2017) 62:3110–3116
123