ORIGINAL ARTICLE: GASTROENTEROLOGY: INFLAMMATORY BOWEL DISEASE
Corticosteroid Dosing in Pediatric Acute Severe
Ulcerative Colitis: A Propensity Score Analysis
y
Sapir Choshen, zHelen Finnamore, zMarcus K.H. Auth, yTali Bdolah-Abram, yEyal Shteyer,
§
David Mack, jjJeffrey Hyams, ôNeal Leleiko, #Anne Griffiths, and yDan Turner
See ‘‘Steroid Limbo in Acute Severe Ulcerative Colitis:
How Low Can You Go?’’ by Hansen and Russell on page 2.
ABSTRACT
Objectives: We aimed to explore the optimal dosing of intravenous-
corticosteroids (IVCS) using a robust statistical method on the largest
pediatric cohort of acute severe colitis to date.
Methods: Two hundred eighty-three children treated with IVCS for
ulcerative colitis were included and studied for 1 year (46% boys, age
12.1  3.9 years, disease duration 2 (interquartile range [IQR] 0–14)
months, baseline Pediatric Ulcerative Colitis Activity Index 69  13
points). Confounding by indication was addressed by matching high- and
low-IVCS dose patients according to the propensity score method, using 3
cutoffs (1 mg  kg1  methylprednisolone to 40 mg  day1, 1.25 mg  kg1 to
50 mg  day1 and 2 mg  kg1 to 80 mg  day1).
Results: The median IVCS dose in the entire cohort was 1.0
mg  kg1  day1 (IQR 0.8–1.4) and 44 mg  kg1  day1 (32–60).
Ninety-four of 283 children were matched in the low-dose cutoff
(1 mg  kg1  day1), 218 of 283 were matched in the middle cutoff
(1.25 mg  kg1  day1), and 86/283 in the high dose cutoff
(2 mg  kg1  day1). No differences were found in 25 pretreatment
baseline variables in the three cutoffs, implying successful matching.
There were no statistical differences in the outcomes of the two lower
cutoffs (including need for salvage therapy during admission and by 1 years,
Received September 26, 2015; accepted December 10, 2015.
From the The Juliet Keidan Institute of Pediatric Gastroenterology and
Nutrition, Shaare Zedek Medical Center, the yThe Hebrew University of
Jerusalem, Jerusalem, Israel, the zAlder Hey Children’s NHS Foundation
Trust, Liverpool, UK, the §Children’s Hospital of Eastern Ontario IBD
Centre and Department of Pediatrics, University of Ottawa, Ottawa,
Canada, the jjConnecticut Children’s Medical Center, Hartford, CT, the
ôHasbro Chidren’s Hospital/Rhode Island Hospital, Alpert School of
Medicine at Brown University, Providence, and the #SickKids Hospital,
University of Toronto, Toronto, Canada.
Address correspondence and reprint requests to Dan Turner, MD, PhD, the
Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, The
Hebrew University of Jerusalem, Shaare Zedek Medical Center, P.O.B
3235, Jerusalem 91031, Israel (e-mail: turnerd@szmc.org.il).
M.H.K.A. was supported by MSD and Dr Falk Pharma. J.H. by Janssen:
Advisory Board, speakers’s bureau; Abbvie-Advisory Board; UCB-
Advisory Board; Soligenix-consultant; TNI Biotech-consultant. D.T.
received consultation fee, research grant, royalties, or honorarium from
MSD, Janssen, Pfizer, Hospital for Sick Children, Ferring, Abbvie and
Abbott. A.G. was supported by Janssen, Abbvie; consultant for Abbvie,
Ferring, Janssen, Nestle, Nutricia, Receptos.
Copyright # 2016 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000001079
58
Copyright © ESPGHAL and NASPGHAN. All rights reserved.
What Is Known
 It is a common practice to use steroids in acute severe
colitis in a dose of 1 to 1.5 mg  kg1  day1 methyl-
prednisolone daily up to 40 to 60 mg daily in 1 to 2
divided doses.
 There are no clinical trials to support this recommen-
dation.
What Is New
 There does not seem to be a consistent superiority of
high dose (>2 mg  kg1  day1) versus standard
(1.25 mg  kg1  day1) or low-dose (1 mg  kg1 
day1) methylprednisolone in pediatric acute
severe colitis.
admission duration, and day-5 Pediatric Ulcerative Colitis Activity
Index<35 points; all P > 0.05). In the high cutoff, the higher doses were
somewhat better but this benefit reversed in a sensitivity analysis excluding
one center. High doses were not associated with better outcome also in a
propensity score-weighted regression model on the entire cohort.
Conclusions: Our data support present guidelines that doses of IVCS >1 to
1.5 mg  kg1  day1 (maximum 40–60 mg  kg1  day1) are not justified in
acute severe colitis.
Key Words: corticosteroids, pediatric, propensity score, ulcerative colitis
(JPGN 2016;63: 58–64)
I n comparison with adult-onset disease, ulcerative colitis (UC)
occurring in childhood is much more often extensive (1,2) and,
as such, more likely to be associated with acute severe exacer-
bations treated with intravenous corticosteroids (IVCS) as first-line
therapy (3,4). Steroid-failure rate was 34% in a systematic review of
five pediatric studies including 291 children with acute severe
colitis (ASC) (5).
Based on common clinical practice, the recommended
steroid dosing in ASC is 1 to 1.5 mg  kg1  day1 methylpredni-
solone daily up to 40 to 60 mg daily in 1 to 2 divided doses (6–8).
No dose of IVCS, however, has been found to be superior to others
in ASC. Although some suggest that very high steroid doses may be
more effective than standard doses (9–11), this is not evidence
based.
It is important to optimize efficacy of steroids, if need for
second line salvage therapies is to be reduced. Because randomized
controlled dose-ranging trials of IVCS in ASC are not likely to be
conducted in children, we aimed to use a robust statistical method of
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JPGN  Volume 63, Number 1, July 2016
propensity score (PS), to compare high versus low dosing of IVCS
in pediatric ASC. The PS method is a powerful statistical tool
to control for confounding-by-indication bias in retrospective
longitudinal cohorts, but requires large datasets. We therefore
established the largest cohort to date of 283 children with ASC
treated with IVCS.
METHODS
This study used existing datasets of the prospective Outcome
of Steroid therapy in Colitis Individuals (OSCI) study (n ¼ 128 from
5 centers in North America) and the retrospective OSCI study
(n ¼ 99 from Toronto), both of which reported the 1-year outcome
of children admitted for ASC (2,12). In addition, 54 children were
added for the present study by chart review (from Jerusalem and
Liverpool) using the same design and dataset structure as the OSCI
studies. The Jerusalem cohort was added as a convenience sample,
and Liverpool was chosen because of the local general, but not
universal, tendency of prescribing higher IVCS doses.
Data acquisition was based on the same detailed protocol in
all cohorts. This includes similar eligibility criteria, case report
forms, timing of visits, and outcome. Explicit demographic,
clinical, and laboratory data were recorded at admission, at
3 and 5 days thereafter, at introduction of second line therapy, at
discharge and 1 year after admission. Disease activity was measured
using both subjective physician global assessment (PGA) using
100 mm visual analogue scale, and the Pediatric UC Activity Index
(PUCAI), a valid 6-item clinical measure of UC activity. The
responsiveness of the PUCAI to rapid change is high, allowing
capture of change in disease activity day by day (2,12–14).
Children were managed according to the discretion of the physician,
including corticosteroids dosing. Therefore, there was a significant
dosing variability in the cohorts, an essential asset to be used in the
PS matching to allow for dose-effect assessment.
Inclusion criteria were children with confirmed UC by
accepted criteria (15) at the age of 2 to 18 years, admitted for
IVCS treatment for ASC. In order to avoid repeated measures of the
same patients, only the first admission of each child was included.
Children with infectious gastroenteritis or other positive bacterial
cultures were excluded. Hydrocortisone and other types of corti-
costeroids were standardized as methylprednisolone-equivalent
using established conversion factors (16).
The cohort was divided 3 times into ‘‘high’’ and ‘‘low’’ dose
groups, based on 3 different cutoffs, justified from different prac-
tices (all of the doses are calculated based on the children weight on
admission):
1 1
1. 1 mg  kg  day methylprednisolone to 40 mg  day1,
referred herein as the ‘‘low cutoff’’;
1 1 1
2. 1.25 mg  kg  day methylprednisolone to 50 mg  day ,
referred herein as the ‘‘standard cutoff’’;
1 1
3. 2 mg  kg  day methylprednisolone to 80 mg  day1,
referred herein as the ‘‘high cutoff’’.
The primary outcome was percentage of children failing
IVCS, based on the need for salvage therapy by hospital discharge
(colectomy or second-line medical therapy with infliximab or
calcineurin inhibitors). Secondary outcomes included percentage
of children who had at most mild disease at day 5 (defined by
PUCAI < 35 points), length of admission, and the need for salvage
therapy during the subsequent year.
Statistical Analysis
A simple comparison of the steroid dosing is not possible
because of confounding-by-indication bias. The latter is a term
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Corticosteroid Dosing in Pediatric Acute Severe Ulcerative Colitis
describing a bias in which the indication to allocate subjects to
either groups (ie, treating with high- or low-dose steroids) is related
to the outcome in ways other than the comparison of interest. In our
case, physicians may prefer higher steroids dose in the most severe
end of the spectrum, those who previously failed standard dosing, or
those with prolonged oral steroid course before admission. These
factors, among others, may affect outcome of treatment, indepen-
dently of the prescribed dose. This bias may be addressed by the PS
matching that allows controlling for many background covariates
simultaneously by matching on a single scalar variable. The PS in
our case is the probability that a child receives at admission either
high- or low-IVCS dose, given the observed covariates (17–28). By
matching pairs of children with similar probabilities of being treated
with high or low IVCS dose, and assuming no hidden bias, we
created a quasi-randomized experiment.
Another method for controlling for the confounding-by-
indication bias is the ‘‘doubly robust’’ weighted regression
(29,30). We used this model to validate our findings using the
entire cohort in regression models weighted by the inverse variance
of the PS and adjusted for the unbalanced baseline variables: age,
prior use of thiopurines, days of bloody stools before admission,
percent of weight loss during the month before admission, PUCAI,
albumin, C-reactive protein (CRP), platelets, and ESR. In addition,
we forced into the models 3 clinically important variables: number
of steroid courses in the year before admission, weight, and PGA
upon admission.
The explicit stages of matching and analysis with PS is
described elsewhere (19). Briefly, a logistic regression model
was constructed with high or low-dose IVCS as the dependent
variable (repeated using the 3 cutoff values defined above) and the
following 17 pretreatment variables as the explanatory variables:
sex, age, disease duration, prior 5-aminosalycilic acid treatment,
days of oral steroids before admission, days of bloody stools before
admission, number of steroid courses in the year before admission,
number of admissions in the year before the index admission,
disease activity at baseline (PUCAI score and PGA), temperature
at baseline, vomiting at baseline, and laboratory values at baseline
including CRP, ESR, albumin, platelets, and hemoglobin. Next,
according to the beta estimates of each variable, a PS was calculated
for each child according to his/her individual parameters. This
model is based only on baseline parameters and is simply a means
by which to assign a score for estimating the probability that a
subject receives either dose within our specific cohort. Overfitting is
thus of less concern because the model is not intended to predict
outcomes nor to be applied on unseen data.
Each child from the high-dose subgroup was individually
matched to a low-dose child according to the nearest value of the
logit of the PS, in a blinded fashion to all outcome variables (19),
within a caliper size of a quarter of a standard deviation, according
to Rosenbaum and Rubin (31). The goodness of the PS matching
was evaluated by the degree that these and other baseline covariates
were balanced between the groups.
In order to test the hypothesis that children treated with oral
prednisone before the admission may require higher steroid doses
because of downregulation of receptors, we performed a sensitivity
analysis in which only children that were treated with prednisone
upon admission were included in the PS-matched analysis.
Data are presented as means  standard deviation or medians
(interquartile range (IQR)), as appropriate. Paired data of matched
children were compared using McNemar test (categorical) and
paired Student t test (continuous) and the signed-rank test as
appropriate for the distribution normality. Unpaired data were
compared using x2 test, student t test, or Wilcoxon rank sum test,
as appropriate. Imputation was performed using the hot deck
method for parameters with <10% missing data occurring at
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Choshen et al
random (32). No outcome measures were missing. All of the
comparisons were made using 2-sided significance levels of
P < 0.05. Statistical analyses were performed using SPSS version
22.0 (IBM SPSS Statistics, Armonk, NY). The study was approved
by the institutional review board of each participating center.
RESULTS
A total of 283 children were eligible and included in the study
(Table 1), of whom 127 (45%) had at most mild disease by day 5 of
admission (ie, PUCAI < 35); 89 (31%) had failed IVCS and
required salvage therapy during the admission after a median
of 12 (8–16) days. The overall colectomy rate by discharge was
20% (n ¼ 57), and the median admission duration was 9 days (IQR
6–19). By 1 year after discharge, 122 children (43%) required
salvage medical therapy, of whom 89 (31% of the entire cohort)
required colectomy.
The median IVCS dose in the entire cohort was 1.0
mg  kg1  day1 (IQR 0.8–1.4) and 44 mg  kg1  day1 (32–
60). We split our cohort as per present guidelines that dictate dose
limit of 40 to 60 mg per day for children >40 kg, rather than dosing
per kilogram (33). The median IVCS dose for children weighing
<40 kg was 1.2 mg  kg1  day1 (IQR 1–1.8) and 32 mg  day1
(24–50) (Fig. 1a). For children weighing >40 kg, the median IVCS
dose was 0.95 mg  kg1  day1 (0.77–1.19) and 58.5 mg  day1
(40–60) (Fig. 1b).
Unadjusted, there was a poor but significant correlation
between the dose used and total PUCAI score at day 5 when using
mg  kg1  day1 in those <40 kg (Spearman rho ¼ 0.19,
P ¼ 0.03) (Fig. 2a) but not with mg  kg1  day1 in those weighing
>40 kg (Spearman rho ¼ 0.15, P ¼ 0.06) (Fig. 2b). When compar-
ing the baseline disease severity in the high- and low-dose groups
(standard cutoff), the low-dose group, however, had significantly
lower CRP (1.3 mg/dL (IQR 0.6–2.5) vs 1.8 mg/dL (0.9–3.3);
P ¼ 0.047) but similar PUCAI scores (75 points (IQR 65–80) vs 70
points (60–80); P ¼ 0.2). Moreover, 1 center using a local protocol
with 2 to 20 mg  kg1  day1 steroids and intravenous antibiotics
obtained a lower colectomy rate of 12%. These findings support the
following use of PS-based matching for elucidating conclusions.
Standard Cutoff (Below or Above a Dose of
1.25 mg  kgS1 or 50 mg  dayS1)
A total of 136 (48%) children were treated with doses
<1.25 mg  kg1 50 mg  day1 (standard dosing), and the other
147 (52%) children above either value. Matching the 2 groups
according to the PS yielded 109 matched pairs (Fig. 3). Fifty-two
percent of the children in the prospective OSCI cohort, 60% of the
retrospective OSCI cohort, 20% of the children in Jerusalem, and
15% of the children in Liverpool were treated with low-dose IVCS.
In the lower dose group, the median dose was 0.8 mg  kg1  day1
(0.7–1.0) or 34 mg  day1 (25–40), and in the higher dose group
1.5 mg  kg1  day1 (1.0–2.0) or 60 mg  day1 (52–80). No
significant differences were found in all of the 25 pretreatment
baseline parameters included in the PS calculation (Table 1 and
other variables not presented), implying successful matching.
None of the following outcomes were significantly different
between the low- and high-dose groups: the need for salvage
therapy during admission (30% vs 31%; P ¼ 0.88), rates of
PUCAI < 35 points at day 5 (44% vs 40%; P ¼ 0.68), median
admission days (9 [IQR 15–18] vs 10 [6–21]; P ¼ 0.27), and the
need for salvage therapy during the year after admission (47% vs
38%; P ¼ 0.22) (Fig. 4).
Similarly, the day-5 median laboratory tests values were not
different between the low- versus high-dose groups: CRP (0.62 mg/
60
Copyright © ESPGHAL and NASPGHAN. All rights reserved.
JPGN  Volume 63, Number 1, July 2016
dL (IQR 0.12–1.62) vs 0.82 (0.24–2.42); P ¼ 0.62), ESR (32 mm/
hour (12–45) vs 31(15–50); P ¼ 0.92), hemoglobin (10.25 g/dL
(8.5–11.3) vs 10.1 (8.7–11.4); P ¼ 0.42), albumin (31 g/L (28–36)
vs 31(28–35); P ¼ 0.58), and platelets (450  103/mL (383–576) vs
449 (393–575); P ¼ 0.57, respectively.
Low Cutoff (Below or Above a Dose of
1 mg  kg  dayS1 or 40 mg  dayS1)
A total of 51 (18%) children were treated with IVCS doses
lower than the low cutoff, and the other 232 children were treated
with higher doses. Matching of the 2 subgroups according to the PS
was successful to yield 47 matched pairs. In the low-dose subgroup,
the median dose was 0.8 mg  kg1  day1 (IQR 0.6–0.9) or
25 mg  day1 (20–32), and in the high-dose subgroup it was
1.2 mg  kg1  day1 (0.9–1.9) or 48 mg  day1 (40–60). No
significant differences were found in all 25 baseline parameters
(Table 1) nor in the tested outcomes, including the need for salvage
therapy during admission (28% in the low-dose subgroup vs 30%
in the high-dose; P ¼ 1.0), rates of PUCAI < 35 points at day 5
(46% vs 46%; P ¼ 1.0), median admission days (11 (IQR 5–22) vs
11 (6–21); P ¼ 0.4), and the need for salvage therapy during the
year after admission (38% vs 38%; P ¼ 1.0).
High Cutoff (Below or Above a Dose of
2 mg  kg  dayS1 or 80 mg  dayS1)
A total of 44 (16%) children were treated with IVCS doses
higher than the high cutoff. Matching the low and high subgroups
according to the PS yielded 43 matched pairs (median dose
1.1 mg  kg1  day1 (IQR 1.0–1.6) or 56 mg  day1 (30–60)
and 4.3 mg  kg1  day1 (2.0–22.4) or 200 mg  day1 (80–
730), respectively). No significant differences were found in all
of the 25 baseline parameters (data not shown), implying successful
matching. It is, however, noteworthy that 19 children (44%) of the
high-dose group were treated in 1 center as part of local practice of
commencing high doses, as opposed to only 2 (5%) in the low-dose
subgroup. The only significant outcome between the 2 matched
groups was the rates of PUCAI < 35 points at day 5 (60% vs 35%
favoring the high-dose group; P ¼ 0.03). The other outcomes were
numerically better in the high-dose group but did not reach stat-
istical significance: need for salvage therapy during admission
(46% vs 26%; P ¼ 0.09), median admission days (12 (IQR 7–
24) vs 11 (6–23); P ¼ 0.38), and need for salvage therapy during the
year after admission (56% vs 35%; P ¼ 0.11). Given the consider-
ation that the outcomes may have been influenced by local practice,
the 19 patients with high-dose steroids from 1 center were
excluded in a sensitivity analysis, yielding 21 matched pairs.
The median IVCS dose was 1.1 mg  kg1  day1 (IQR 0.9–1.4)
or 60 mg  day1 (IQR 50–60) in the low-dose group and
2.7 mg  kg1  day1 (1.6–3.8) or 100 mg  day1 (80–190) in
the high dose. Of the 25 baseline variables, platelet count
(433  172 in the low dose vs 515  111 in the high dose;
P ¼ 0.03) and prior 5-aminosalycilic acid treatment (71% in the
low dose vs 29% in the high dose; P ¼ 0.02) were significantly
different between the matched groups. In this sensitivity analysis,
all of the outcomes were numerically better in the ‘‘low’’ dose
groups except PUCAI at day 5, but none reached statistical sig-
nificance—need for salvage therapy during admission (29% in the
low dose vs 48% in the high group; P ¼ 0.39), PUCAI < 35 points at
day 5 (29% vs 33%; P ¼ 1.0), median admission duration (11 days
(IQR 5–29) vs 21 (10–29.5); P ¼ 0.38) and need for salvage
therapy during the year after admission (38% vs 62%; P ¼ 0.27).
The 34 children from the center excluded for the sensitivity analysis
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TABLE 1. Baseline characteristics of the included cohort

Matched <1.25 mg  kg1  day1 Matched 1.25 mg  kg1  day1 Matched <2 mg  kg1  day1 Matched 2 mg  kg1  day1
Entire cohort and <50 mg  day1 or 50 mg  day1 and <80 mg  day1 or 80 mg  day1
(n ¼ 283) (n ¼ 109) (n ¼ 109) P (n ¼ 43) (n ¼ 43) P

Males 130 (46%) 43 (39%) 50 (46%) 0.39 29 (67%) 23 (53%) 0.29

Age, y 12.1  3.9 11.9  3.6 12  4.4 0.76 11.7  4.8 11.3  4.4 0.71
Range, y 2–18 3–18 2–18 1.7–17.6 1.9–17.4
Disease extent 0.56 0.77
Extensive 241 (85%) 95 (87%) 91 (84%) 35 (81%) 37 (86%)
Left-sided 42 (15%) 14 (13%) 18 (17%) 8 (19%) 6 (14%)
Volume 63, Number 1, July 2016

Disease duration, mo 2 (0–14) 2.1 (0–14) 1 (0–12) 0.94 0.1 (0–3.5) 0.7 (0–10.5) 0.07
Steroid courses in 0 (0–1) 0 (0–1) 0 (0–1) 0.85 0 (0–1) 0 (0–1) 0.59

previous year
Aminosalicylates use 76 (27%) 29 (27%) 27 (25%) 0.87 3 (7%) 9 (21%) 0.11
at admission
Prednisone before 0 (0–14) 0 (0–15) 0 (0–12.5) 0.7 0 (0–13) 0 (0–13) 0.82
admission, days
Bloody stools before 21 (10–56) 21 (9–39) 21 (13–56) 0.11 20 (10–56) 30 (15–75) 0.15
admission, days
Height, cm 148  25 147  23 148  27 0.77 146  28 144  26 0.87
Weight, kg 42.8  17.5 40.6  14.5 43.0  18.7 0.28 43.2  22.1 38.9  17.8 0.33
Weight loss in the 5.9 (1.9–8.6) 6.2 (3.0–8.8) 6.4 (3.1–9.1) 0.68 6.4 (0.9–8.3) 7.5 (3.4–9.7) 0.9
month before
admission, %
Disease activity— 74  12 74  13 74  13 0.8 72  16 74  11 0.34
PGA (0–100 mm)
PUCAI 69  13 70  11 70.4  14 0.98 65  13 66  16 0.66
Moderate ( 60) 73 (26%) 22 (20%) 27 (25%) 16 (37%) 14 (32%)
Severe (65) 210 (74%) 87 (80%) 82 (75%) 27 (63%) 29 (67%)
Temperature, oC 37.3  0.8 37.3  0.6 37.3  0.9 0.84 37.3  1.2 37.2  0.8 0.47
Albumin, g/L 32.9  6.5 32.8  5.8 33.1  6.7 0.72 32.0  6.8 33.0  7.5 0.51
C-reactive protein, 1.6 (0.9–2.5) 1.25 (0.6–2.5) 1.9 (1.0–2.5) 0.28 1.75 (1–3.35) 1.28 (0.8–2.5) 0.2
mg/dL
ESR, mm/h 40 (26–56) 40 (28–60) 41 (24–59) 0.73 41 (30–56) 45 (21–58) 0.67
Hemoglobin, g/dL 10.3  2.2 10.2  2.1 10.3  2.3 0.69 10.0  2.2 10.2  2.3 0.71

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PGA ¼ physician global assessment; PUCAI ¼ Pediatric Ulcerative Colitis Activity Index.

None received anti-TNF before admission.
Corticosteroid Dosing in Pediatric Acute Severe Ulcerative Colitis

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Choshen et al JPGN  Volume 63, Number 1, July 2016

A Children ≤40kg (n = 131) B Children >40kg (n = 152)

35 50

30
40
25

30
N

20

N
15 20

10
10
5

0 0
0 0.5 1 1.5 2 >2.5 0 10 20 30 40 50 60 70 80 90 >100
Methylprednisone (mg/kg) Methylprednisone (mg/day)
FIGURE 1. Steroid dosing of 283 children admitted for acute colitis. A, IVCS dose for children weighing 40 kg or less (18 children were treated with
doses >2.5 mg  kg1  day1 [2.7–31 mg  kg1  day1]). B, IVCS dose for children >40 kg (14 with doses 100 mg  day1 [100–1000
mg  day1]). IVCS ¼ intravenous corticosteroids.

demonstrated the need for salvage therapy by 1 year of 11%
(reported in a seperate manuscript in this issue).
Entire Cohort
We used the ‘‘doubly robust’’ PS-weighting technique on the
entire cohort, using the standard cutoff, the unbalanced baseline
variables, and the 3 clinically important variables. The only sig-
nificantly different outcome was the length of admission with a
clinically irrelevant effect size (median of 9 days (IQR 5–16) in the
low-dose group vs 10 days (6–21) in the high-dose group,
P ¼ 0.005). The need for salvage therapy during admission
(OR ¼ 1.0 (95% CI ¼ 0.6–1.5); P ¼ 0.92), rates of PUCAI < 35
points at day 5 (OR ¼ 1.2 (0.8–1.8); P ¼ 0.42), and the need for
salvage therapy during the year after admission (OR ¼ 1.3 (0.9–
2.0); P ¼ 0.18) were similar.
In the PS-matched sensitivity analysis, performed on the
children that were treated with prednisone upon admission, no
significant difference was found in the outcomes of the high- versus
low-dose subgroups in all of the 3 aforementioned cutoffs (data not
presented), supporting the notion that high dose is not required also
in those who failed oral steroids.
DISCUSSION
We assembled the largest cohort to date of children with ASC
to compare the effectiveness of different IVCS doses using a robust
statistical method across several outcomes and subgroups. We were
successful in balancing 25 possible confounders, approximating
random allocation. For most outcomes and analyses, we could not
find superiority of the high doses, including the need for salvage
therapy during admission, mean admission duration, and the need

Children ≤40 kg (n = 131) Children >40 kg (n = 152)

100 r = −0.19; P = 0.03 100 r = −0.15; P = 0.06

80 80
Day 5 PUCAI

60 60

40 40

20 20

0 0

0.5 1.0 1.5 2.0 >2.5 20 40 60 80 ≥100

Methylprednisone (mg/kg) Methylprednisone (mg/day)
FIGURE 2. Scatter plot of IVCS dose versus PUCAI at day 5. A, Children weighing 40 kg (18 children were treated with doses
>2.5 mg  kg1  day1 [2.7–31 mg  kg1  day1]). B, Children weighing >40 kg (14 with doses 100 mg  day1 [100–1000 mg  day1]).
IVCS ¼ intravenous corticosteroids; PUCAI ¼ Pediatric Ulcerative Colitis Activity Index.

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JPGN  Volume 63, Number 1, July 2016 Corticosteroid Dosing in Pediatric Acute Severe Ulcerative Colitis

30 use of antibiotics in that center that provided a large portion of the

very high dose to patients. When patients from that center were
High dose excluded in a sensitivity analysis, the superiority of the high dose
25 Low dose was eliminated, consistent with the other comparisons. Moreover,
except for this cutoff, no dose-effect association was noted in the
other cutoffs which included the very same patients but with a
20 different seperation.
Unfortunately, there is a surprising paucity of literature
regarding the minimal effective dosing of IVCS in ASC. A
Frequency

15
10
0 pediatric ASC (35). A randomized controlled trial of 66 adults
0 ing outcomes of 35 adult patients treated with either adrenocorti-
0.2 0.4 0.6 0.8
Propensity score
FIGURE 3. Distribution of the PSs of the low- and high-dose groups in
the standard cutoff (ie, 1.25 mg  kg  day1 to 50 mg  day1), show-
ing the matching zone. Children with similar PS were treated with
different doses and were therefore good candidates for matching.
for salvage therapy during the year following admission. This was
evident for matched children treated with doses lower or higher than
1 mg  kg1  day1 and 1.25 mg  kg1  day1. Similarly, in a
controlled analysis of the entire cohort, high-dose steroids were
not associated with any of the 5 outcomes explored.
Although some outcomes were better in the higher doses
when considering a cutoff of 2 mg  kg1  day1 (or 80 mg  day1),
it is likely this was influenced by further differences in local
practice protocols in one center. For instance, the more frequent
meta-regression of cohort studies that encompassed 1991 patients
did not demonstrate a dose-colectomy association or advantage of
doses of methylprednisolone-equivalent >60 mg  day1 (34). A
prospective trial assessed 128 children (included also in this report)
and found that the severity of disease on admission predicted IVCS
responsiveness rather than the administered dose (2,12). Glucocor-
ticoid bioassay did not predict response to corticosteroids in
admitted for ASC showed equivalency between continuous and
bolus IVCS dosing (36). A double-blind randomized trial compar-
1 cotropic hormone or hydrocortisone failed to identify significant
differences in response (37). Finally, an outpatient randomized trial
compared 3 doses of oral prednisolone and found that 40 and
60 mg  day1 were as effective, and superior to 20 mg  day1 (38).
The anecdotal evidence for the effectiveness of very high-
dose pulse steroids of up to 1000 mg  day1 is limited to case
reports and is inconsistent (9–11) (39). A prospective study of 20
patients treated with pulse steroids showed remission rates of only
60%, similar to the rates found in local historical controls (10). A
retrospective Japanese report found that pulse dosing in 20 children
achieved remission faster than in 17 children treated with standard
dosing; however, treatment was successful in all 37 children and
none required salvage therapy (9–11). A national survey from
Japan showed 55% short-term remission among 21 children treated
with pulse steroid therapy; the comparative results of the other 41
children treated with the traditional dosing are not reported (11).

60
P = 0.68 Matched-lower than
60
1.25 mg/kg/day
50 mg/day (n = 109)

50 Matched-higher than
P = 0.22 1.25 mg/kg/day 50
50 mg/day (n = 109)

40
40
Number of days

P = 0.88
%

30 30

20 20

P = 0.39
10 10

0
0
Salvage therapy Moderate-severe Salvage therapy on the Admission days
during admission disease at day 5 year following admission

FIGURE 4. Outcomes of the low- and high-dose matched groups according to the standard cutoff (1.25 mg  kg  day1 to 50 mg  day1
methylprednisolone).

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Choshen et al
Taken together, the present anecdotal evidence does not support
superiority of pulse steroids over the known
70% response to major corticosteroids: pharmacokinetics and cell trafficking and cortisol
standard dosing [11].
The nonsignificant differences in the outcomes of predni-
sone-treated children that received high- or low-dose IVCS may
indicate that also these children do not require higher IVCS doses.
Data for this large cohort were collected in a variety of
hospitals in North America, Europe, and Israel, including a wide
spectrum of patients and health systems. The variety is an essential
asset when using PS. This is, however, still a post hoc analysis
study, and we cannot exclude the possibility that unknown con-
founding variables were missed. Given the paucity of children
treated with doses <1 mg  kg1  day1, we could not subdivide
this group. Common wisdom, however, supports a minimal dose of
1 mg  kg1  day1 up to 40 mg daily. Finally, we did not collect
data on adverse events as dictated by the original OSCI datasets.
Nonetheless, higher steroid doses are associated with more adverse
events (40), although these depend on the duration of treatment, and
are mostly reversible. Despite the inherent limitations, this study
provides for the first time a comprehensive approach on a large
cohort of children to explore the dose-effect relation of IVCS in
pediatric ASC. The consistent results across several analyses sup-
port the use of lower IVCS doses, as dictated by the present
guidelines (1–1.5 mg  kg1  day1 up to 40–60 mg  day1)
(33). Additional studies are, however, needed to determine the best
dose with more certainty.
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