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REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY
AND HEPATOLOGY
Robert F. Schwabe and John W. Wiley, Section Editors
Converging Goals of Treatment of Inflammatory Bowel Disease
From Clinical Trials and Practice
Barrett G. Levesque,1 William J. Sandborn,1 Joannie Ruel,2 Brian G. Feagan,3 Bruce E. Sands,2
and Jean-Frederic Colombel2
1
Division of Gastroenterology, University of California San Diego, La Jolla, California; 2Dr Henry D. Janowitz Division of
Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; and 3Robarts Clinical Trials, Robarts
Research Institute, Department of Medicine, Western University, London, Ontario, Canada
It is important to have clear goals for treating inflammatory
bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn’s
disease have been based on composite indices, such as the
Mayo Clinic Score and the Crohn’s Disease Activity Index;
these indices incorporate symptoms, signs, and findings from
laboratory tests and sometimes endoscopic assessments.
Although definitions of clinical response and remission have
been based on these indices for regulatory purposes, they are
difficult to apply to practice because they are complex and not
intuitive to clinicians. This has caused a disconnect between
clinical trials and practice. Recently, the use of composite
indices in trials has been reevaluated in Food and Drug
Administration–sponsored Gastroenterology Regulatory
Endpoints and the Advancement of Therapeutics workshops
due to concerns about the validity of the indices. Alternative
measures of outcome and definitions of response are being
developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify
symptoms. A combination of end points, comprising patientreported outcomes and objective evaluation of inflammation
by endoscopy, offers a clinically meaningful and scientifically
valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and
patient-reported outcomes can be readily applied in practice.
This convergence of outcome assessment in clinical trials and
practice could expedite implementation of “treat-to-target”
algorithms, in which therapy is progressively intensified until
a specific treatment goal is reached. This approach could
improve patient care by reducing rates of disease-related
complications, surgery, and hospitalization.
treatment focuses more on the consequences of inflammation rather than the inflammatory process itself. This situation is not ideal, because there is a substantial overlap
between the symptoms of IBD and other conditions, such as
irritable bowel syndrome, bile salt diarrhea, steatorrhea,
bacterial overgrowth, and scarring, that are unlikely to
respond to anti-inflammatory therapy.3 Furthermore, it is
well established that the Crohn’s Disease Activity Index
(CDAI), which is heavily weighted toward symptoms, correlates poorly with endoscopy.4 Although there is a better
correlation between symptoms and endoscopy in ulcerative
colitis (UC), in many circumstances assessment of symptoms
alone lacks sufficient precision for decision making. Based on
these observations, we contend that an evolution in the
measurement of IBD disease activity is needed that emphasizes development and use of disease activity indices that
incorporate validated independent measures of both symptoms and inflammation into a coprimary end point.5
Previous reviews6,7 have characterized the clinical,
endoscopic, and composite indexes historically used in IBD
clinical trials. Existing instruments are predominantly
symptom based, are in most instances empirically derived,
and do not adequately assess either symptoms from the
patient’s perspective or the underlying inflammatory process. At present, there are no patient-reported outcome
(PRO) or clinician-reported outcome (ClinRO) instruments
that have been created according to the guidance of the US
Food and Drug Administration (FDA).8 Valid PROs, based on
items generated from qualitative patient interviews, must
be both reliable and responsive to clinically meaningful
changes in health status. Clinically useful PROs should be
Keywords: GREAT; CDAI; Outcome Measure; IBD Therapy.
I
nflammatory bowel disease (IBD) is caused by
immune dysregulation of the digestive tract1,2 that results in chronic inflammation. Consequently, symptoms of
abdominal pain, diarrhea, and bleeding occur that result in
impaired quality of life. Although medical therapy is focused
on controlling inflammation, disease activity is assessed in
clinical trials by composite indices that predominantly measure signs and symptoms. In clinical practice, assessment of
symptoms predominates. Thus, our traditional approach to
Abbreviations used in this paper: CD, Crohn’s disease; CDAI, Crohn’s
Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index of
Severity; CI, confidence interval; ClinRO, clinician-reported outcome; FDA,
Food and Drug Administration; GETAID, Groupe D’Etudes Therapeutiques
Des Affections Inflammatoires due Tube Digestif; HBI, Harvey–Bradshaw
Index; IBD, inflammatory bowel disease; ICC, intraclass correlation coefficient; MBS, modified Baron score; MCS, Mayo Clinic Score; MRE,
magnetic resonance enterography; PRO, patient-reported outcome; SESCD, Simple Endoscopic Score in Crohn’s Disease; UC, ulcerative colitis;
UCEIS, Ulcerative Colitis Endoscopic Index of Severity.
© 2015 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2014.08.003
REVIEWS AND
PERSPECTIVES
Gastroenterology 2015;148:37–51
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both easily administered and readily interpretable by patients and clinicians.9 Similarly, a ClinRO for IBD trials must
be a reliable measure of mucosal inflammation with welldefined operating properties.9 Examples of PROs that meet
FDA standards for other conditions include the VVSymQ
score (BTG International Ltd, London, England, UK), which
was the primary end point in trials that led to the approval
of Varithena (polidocanol injectable foam; Provensis Ltd) for
treatment of varicose veins.10 VVSymQ is a PRO based on
daily patient assessment of the symptoms of varicose veins
determined to be most important to patients: heaviness,
achiness, swelling, throbbing, and itching. Similarly, the
modified Myelofibrosis Symptom Assessment Form PRO, in
addition to spleen volume, led to the approval of Jakafi
(Incyte Corporation, Wilmington, DE) (ruxolitinib) for
myelofibrosis.11 The modified Myelofibrosis Symptom
Assessment Form is a cumulative daily diary that scores the
core symptoms of myelofibrosis (abdominal discomfort,
pain under the left ribs, night sweats, itching, bone/muscle
pain, and early satiety). Clinical trials in rheumatoid arthritis
offer an example of coprimary end points in trials for
regulatory approval. Cimzia (UCB, Inc, Brussels, Belgium)
(certolizumab pegol) was approved in 2009 for trials in
rheumatoid arthritis that included the coprimary end point
of ACR20 (a composite index of swollen joint count, tender
joint count, physician’s assessment of disease activity, and
patient’s assessment of physical function and levels of acute
phase reactant) and the mean change from baseline in the
modified total Sharp score of joint radiographs at week
54.12 The major secondary end point was a PRO: the
Disability Index of the Health Assessment Questionnaire. It
is important to recognize that simple composite measures
that assess both PRO and ClinRO elements, such as a physician’s global assessment,13 are problematic because the
concepts being evaluated are highly heterogeneous, making
it difficult to assign a single measure of disease activity.9
As a response to this situation, an evolution in thinking
has emerged contending that the degree of inflammation
should be measured by clinicians using objective instruments
such as endoscopy (and potentially in the future histology
and cross-sectional imaging) and that the patients’ experience should be assessed by a validated PRO. Definitions of
response and remission used for study end points should
require improvement in both of these domains as a coprimary
end point. This concept is attractive because it reflects clinical
practice, in which in a typical patient encounter, physicians
ask patients such questions as “How many stools are you
having?”, “How frequently do you experience abdominal
pain?”, and “Are you seeing blood in your bowel movements?”. Subsequently, clinicians objectively assess disease
activity with endoscopy or potentially other measures of
inflammation. In essence, this construct specifies that clinicians integrate both the patient experience and objectively
measured disease activity before formulating a treatment
plan or determining whether treatment goals have been met.
Given these considerations, it is notable that most
existing practice guidelines are exclusively symptom based.
For example, the 2009 American College of Gastroenterology guidelines for management of Crohn’s disease (CD)
Gastroenterology Vol. 148, No. 1
defined remission as patients with an absence of symptoms;
mild to moderate disease as ambulatory patients without
systemic toxicity, dehydration, tenderness, <10% weight
loss, obstruction, or abdominal mass; and fulminant disease
as patients with severe symptoms including fever, those
with complications such as bowel obstruction, and those
failing to respond to therapy.14 Ultimately, such definitions
have limited value in clinical practice because they are
imprecise and not based on objective and practicable
criteria. Alternatively, definitions of response and remission
based on the composite disease activity indices that up until
now have been routinely used for regulatory approval have
not become accepted for use in patient care due to their
complexity and apparent lack of face validity.
Commensurate with our understanding of the limitations
of our traditional outcome measures and disease definitions
has been the developing concept that therapy in IBD should
be based on specific, well-defined treatment targets that
include both resolution of inflammation and symptoms.
Treatment strategy trials in which the efficacy and safety of
multilevel therapeutic algorithms are evaluated for their
ability to achieve specific goals of therapy (“treat to target”)
have recently been initiated in IBD. The intent of these studies
is to identify therapeutic strategies that will reduce the longterm burden of IBD. This review outlines the literature that
describes the evolution currently taking place in assessment
of treatment goals in clinical trials and clinical practice.
What Has Treating to Clinical Response
and Remission Accomplished?
In patients with UC, important reductions in rates of
colorectal cancer and colectomy have been observed over the
past several decades.15 However, much of this improvement
appears to come from the widespread use of mesalamine for
induction and maintenance therapy in patients with mild to
moderate UC and/or the widespread practice of surveillance
colonoscopy, with little evidence that the prognosis for patients with moderate to severe UC who require corticosteroid
therapy has improved.16–22 In CD, approximately 50% of
patients develop disease-related complications such as a
stricture, fistula, or abscess that frequently require surgery
within 10 years of diagnosis.23,24 For example, the cumulative
probability of surgery was not different between 2 Spanish
cohorts of patients with newly diagnosed CD that were
accrued from 1994 to 1997 and from 2000 to 2003.25 Similarly, 2 nationwide inpatient cohorts of patients with CD in
the United Sates from 1993 to 2004 and from 1998 to 2005
did not show a decrease in the overall rate of surgery.25–27
One potential explanation for these observations is that the
use of clinical symptoms as a treatment target fails to ensure
that the underlying inflammation is adequately controlled,
without which complications ensue.
Where Have We Been? Prior End Points
in Clinical Trials in IBD
As noted previously, the traditional outcome measures
in UC trials consist of composite instruments that
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Indices
UC
Baron score (endoscopic items)
MBS (endoscopic items)
MCS (endoscopic and clinical items)
Partial MCS
UCEIS
CD
CDAI
HBI
CDEIS
SES-CD
a
Descriptors
Spontaneous bleeding, friability, moisture, distensibility, valves, vascular patterna
Normal mucosa (0), granular with an abnormal vascular pattern (1), friable (2),
microulcerations with spontaneous bleeding (3), gross ulceration (4)
Endoscopic response: improvement by 2 grades in the MBS
Endoscopic remission: MBS score of 0
Stool frequency, rectal bleeding, physician’s global assessment, endoscopic severity
Range: 0–12
Complete response: MCS score of 0 in all subscores
Partial response: substantial but incomplete improvement in the subscores
Stool frequency and rectal bleeding
Vascular pattern (1–3), bleeding (1–4), erosions and ulcers (1–4)
Severity of abdominal pain, general well-being, frequency of liquid stool, extraintestinal
manifestations, need for antidiarrheal drugs, presence of an abdominal mass, body
weight, hematocrit
Range: 0–600
Clinical response: reduction from baseline of 70 to 100 points
Clinical remission: <150
Abdominal pain, abdominal mass, general well-being, extraintestinal manifestations,
number of liquid stools for the previous day
Remission score: <5, correlates with CDAI score <150
Deep ulcerations, superficial ulcerations, percentage of involved mucosa, percentage of
ulcerated mucosa in 5 segments, and global evaluation of lesion severity
Complete remission: score 3
Remission: <6
Response: decrease of >5 points
Presence and size of ulcer, extent of ulcerated surface, extent of affected surface,
presence and type of narrowings
3 levels for each descriptor in 5 segments
Remission: 0–2
With >60% interobserver agreement.
incorporate symptoms, laboratory criteria, and sigmoidoscopic findings. The end points in the trial by Truelove and
Witts of cortisone in patients with UC was based on symptoms, laboratory results, and a 3-point endoscopy scale that
were required to be met independently.28 These scores
were not validated. Subsequently, multiple UC and CD
composite clinical indices were used from 1960 to
1990.6,7,29 None of these scores were completely validated.
Our review will focus on indices that have been used for
regulatory approval between 2005 and 2014 (Table 1).
Recent Developments in Trial End
Points in UC
Modification of the Baron Score
Baron et al explored the interrater agreement of 8
endoscopic scoring descriptors in the first endoscopic
index validation study30 (Table 1). Categorical score items
(friability, bleeding) had higher agreement (90% and 87%,
respectively) than continuous score items (erythema,
granularity) (30% and 47%, respectively). Agreement was
not adjusted for chance, the score was not validated against
clinical symptoms, and no definition of endoscopic remission was given. The Baron score was developed using rigid
sigmoidoscopy, and friability was determined by touching
the mucosa with a cotton swab inserted through the rigid
instrument. Subsequently, the Baron score was used with
fiber-optic scopes and then video endoscopes. In 2005, the
Baron score was empirically modified by Feagan et al; the
modified Baron score (MBS) has 5 grades (0–4).31 The
modification removed qualitative assessment of different
levels of bleeding (moderately, severely) and defined the 4
levels by categorical items (normal, granular, friable,
bleeding, ulcerated). Endoscopic response is defined as an
improvement of 2 grades in the MBS, and endoscopic
remission is defined as an MBS score of 0.
The Mayo Clinic Score
The Mayo Clinic Score (MCS) is a composite instrument
that includes both endoscopic and clinical items.13 The MCS
(range, 0–12 points) was created empirically for a clinical
trial in patients with mild to moderate UC. The items and
severity levels were based on the investigators’ clinical
experience. The MCS consists of 4 descriptors: stool frequency, rectal bleeding, physician’s global assessment, and
assessment of endoscopic severity based on fiber-optic
flexible sigmoidoscopy (Table 1). Complete response is
defined as an MCS score of 0 in all subscores. Partial
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Table 1.Indices Used for Regulatory Approval From 2005 to 2014
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response is defined as “substantial but incomplete improvement in the subscores.” The index has been used in
multiple clinical trials of mesalamine, budesonide MMX,
infliximab, adalimumab, and golimumab.13,32–35 Some trials
have modified the instrument such that mild friability is
scored as a 2 rather than a 1 on the Mayo endoscopic
subscore36 (Figure 1).
The MCS has important limitations; it is a composite
score that assimilates items (symptoms and endoscopy) that
are not logically combinable and are not easy to appropriately weight. These properties increase measurement variability and decrease statistical efficiency.9
As a response to these limitations, the MCS has been
adapted to functionally create coprimary end points for
trials by separating its subcomponents into symptom-based
and endoscopic criteria of response and remission. In 2
clinical trials that compared infliximab with placebo in patients with moderate to severe UC, clinical response was
defined as a reduction in the MCS of at least 3 points and a
decrease of 30% from the baseline score, with a decrease of
at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1.32 Clinical remission was
defined as a MCS of 2 and no subscore >1. Mucosal
healing was defined as an endoscopic subscore of 0 or 1.
Partial MCSs have been defined as 3-item (stool frequency,
rectal bleeding, and physician’s global assessment) and
2-item (stool frequency and rectal bleeding) instruments.37
These instruments, which do not include endoscopy, have
good correlation with the full MCS. The 2-item MCS only
includes items that are reported by patients and from a
practical perspective comprises a PRO. This evolution in
using the MCS illustrates the desire to independently assess
symptoms and inflammation defined by endoscopy. The
score has not been completely validated.
CDAI
The CDAI has been the primary outcome measure for
clinical trials since publication of the National Cooperative
Crohn’s Disease Study trial in 1979.38,39 The CDAI was
created by regressing 18 clinical items identified by physicians (ie, abdominal pain, pain awakening patient from
sleep, appetite), physical signs (ie, average daily temperature, abdominal mass), use of medication (ie, loperamide or
opiate use for diarrhea), and laboratory tests (ie, hematocrit) against the dependent variable of a 4-point global
rating of disease activity generated by physicians. Eight independent predictors were identified: severity of abdominal
pain, general well-being, liquid stool frequency, extraintestinal symptoms, need for antidiarrheal drugs, presence
of an abdominal mass, body weight, and hematocrit.
Regression coefficients (weights) for the 8 predictors were
then standardized to create an overall CDAI score that
ranged from 0 to 600. Benchmarks for disease activity were
then as follows: CDAI <150, clinical remission; 150 to 219,
mild actively disease; 220 to 450, moderately active disease;
and >450, very severe disease. Clinical response was subsequently defined as a reduction from the baseline score of
70 or 100 points.
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Figure 1. UC with friability. Complete loss of vascular pattern.
The CDAI has served as the basis for acceptance into
clinical practice and in many instances regulatory approval of
multiple drugs, including prednisone, azathioprine, methotrexate, controlled ileal release budesonide, infliximab,
adalimumab, certolizumab pegol, and natalizumab.40–46
The majority of the CDAI score comes from the symptombased diary card items (pain, stool frequency, well-being).
Studies have shown that the CDAI can be simplified to
these patient-reported items without a large loss of instrument responsiveness.47,48
The Harvey–Bradshaw Index (HBI) was derived to
simplify calculation of the CDAI. The HBI consists of 5
descriptors: general well-being, complications, abdominal
mass, and abdominal pain and number of liquid stools for
the previous day. Remission is defined as a score of <5.49
Recently, Vermiere et al correlated HBI and CDAI scores.50
A 3-point change in the HBI correlated with a 100-point
change in the CDAI. An HBI 4 corresponded with a CDAI
score 150.
Relationships between the CDAI and endoscopic
disease. The CDAI has several limitations as a valid index
for clinical trials of CD. First, the CDAI correlates poorly with
endoscopic inflammation (Spearman rank correlation coefficient, 0.15), serum biomarkers of inflammation (C-reactive
protein and interleukin-6), and fecal biomarkers of inflammation (calprotectin and lactoferrin).4,51 Second, a prospective cross-sectional cohort study of patients with either
CD or irritable bowel syndrome found a CDAI score >150 in
the majority of patients with irritable bowel syndrome.52
Third, the CDAI is an inefficient primary outcome measure
that has been associated with high placebo rates in clinical
trials (natalizumab, 48.6%46; certolizumab, 27%45; and
sargramostim, 51%53). An analysis of SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease) revealed that 18% of patients who met the trial
inclusion criteria of a CDAI score >220 lacked objective
evidence of endoscopic disease, implying that their symptoms arose from noninflammatory sources.54 In these patients, no treatment effect of combination therapy with
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infliximab and azathioprine was observed. Finally, the CDAI
was not created according to FDA guidance for PRO development, which specifies that index items must be generated
by patients. Based on these deficiencies, the FDA recently
indicated that the CDAI will no longer be acceptable as a
measure of disease activity in clinical trials of CD.9
Crohn’s Disease Endoscopic Index of Severity
In 1989, the Groupe D’Etudes Therapeutiques Des Affections Inflammatoires due Tube Digestif (GETAID) presented their multiphase study of the development of the
first validated endoscopic index for CD.55 In the development phase, 2 endoscopists simultaneously assessed colonoscopies from 75 patients and scored 9 items, the
percentage of mucosa involved by disease, the percentage of
ulcerated mucosa in 5 segments (ileum, right colon, transverse colon, sigmoid and left colon, and rectum), and a
global evaluation of lesion severity (Supplementary
Figure 1). The interobserver agreement was high. Intraclass correlation coefficients (ICCs) for the Crohn’s Disease
Endoscopic Index of Severity (CDEIS) and global evaluation
of lesion severity were 0.96 and 0.86, respectively
(P < .001). The 2 endoscopists were in the same room while
scoring took place, thus potentially compromising independence. Regression modeling and weighting of independent
items that correlated with the global evaluation of lesion
severity were used to create the CDEIS. Four descriptors
(superficial and deep ulcerations and both ulcerated and
nonulcerated stenosis) are summed with the average extents
of ulcerated and affected mucosa disease in the explored
segments (Figure 2). The total CDEIS score ranges from 0 to
44. Subsequently, the GETAID investigators empirically
defined complete endoscopic remission as a score of <3,
endoscopic remission as a score of <6, and endoscopic
response as a decrease of >5 points.56 Other studies defined
a CDEIS response as a decrease from baseline of 3 points,57
5 points,58 or 75%.59 Levels of disease severity (mild,
moderate, severe) have been described as CDEIS scores <5,
5 to 15, and >15, respectively.60 The CDEIS has been used as
an inclusion criterion58,61 and end point58,62–89 in clinical
trials but has not been completely validated.
Figure 2. Ulcerated surface in CD.
as 0.985 (95% confidence interval [CI], 0.939–1.000) and
0.994 (95% CI, 0.976–1.000) for CDEIS and SES-CD,
respectively90; however, the independence of SES-CD
scoring during the trial was limited because the endoscopists were in the same endoscopy suite and were not
blinded to clinical disease activity. Similar to the CDEIS, the
SES-CD showed a weak correlation with the CDAI
(Spearman rank correlation coefficient, 0.206). The investigators recommended the SES-CD as a simple to use and
reliable endoscopic scoring instrument for CD. A separate
study of repeat procedures performed in patients with
active disease showed that changes in the CDEIS and SES-CD
were highly correlated (r ¼ 0.828 between DCDEIS and
DSES-CD; P < .001). The investigators91,92 have empirically
created the following grades of disease activity: remission,
0–2; mild inflammation, 3–6; moderate inflammation, 7–16;
and severe inflammation, >16. The SES-CD has recently
been used for assessment of assessment of eligibility93 and
outcome94–103 in clinical trials. Although it has been
partially validated, its responsiveness to change remains to
be defined.
Simple Endoscopic Score in Crohn’s Disease
Presence or Absence of Ulceration as an
Endoscopic Outcome
In 2004, Daperno et al developed the Simple Endoscopic
Score in Crohn’s Disease (SES-CD) to improve the CDEIS,
which they found to be cumbersome for use in both clinical
trials and practice.90 The 4 descriptors selected from the
CDEIS for use in the SES-CD were ulcer size, proportion of
surface covered by ulcer, proportion of surface covered by
other lesions, and stenosis. Each descriptor is graded based
on 3 levels and is scored in 5 segments (ileum, right colon,
transverse colon, left colon, and rectum). The total score is
calculated as the sum of all the items in each segment and
can range from 0 to 60 (Supplementary Figure 2). Interobserver ICCs for the SES-CD and CDEIS were 0.9815 and
0.9090, respectively. The CDEIS item “superficial ulcers” had
the lowest level of agreement (0.628–0.767). In the SES-CD
validation phase, the interobserver agreement was reported
Although the SES-CD is easier to calculate than the
CDEIS, the presence or absence of ulcerations is an even
simpler measure of endoscopic disease activity. In the
endoscopic substudy of ACCENT I (A Randomized, Doubleblind, Placebo-Controlled Trial of Anti-TNFa Chimeric
Monoclonal Antibody [Infliximab, Remicade] in the Longterm Treatment of Patients With Moderately to Severely
Active Crohn’s Disease) and SONIC with infliximab, endoscopic mucosal healing was defined as the absence of ulceration among patients with ulcerations at baseline.43,54
The EXTEND (Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing) trial with adalimumab
was the first controlled trial in CD in which endoscopic
mucosal healing, defined as the absence of ulceration at
week 12, was the primary end point.59 Twenty-seven
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percent of patients in the adalimumab group had this
outcome compared with 12% in the placebo group
(P ¼ .056). The major limitation of using the presence/
absence of endoscopic ulcers as an outcome measure is that
it is cannot measure changes from baseline that fall short of
complete ulcer healing, which may define a meaningful
treatment effect. Ferrante et al recently examined the
change from baseline in the CDEIS and SES-CD that predicted subsequent sustained clinical benefit.104 Using
receiver operating characteristic curves, endoscopic
response (defined by the cutoff of a decrease from baseline
in the CDEIS and SES-CD of 50%) and endoscopic mucosal
healing (defined as the absence of ulceration 26 weeks after
initiation of treatment) were the most robust predictors of
corticosteroid-free clinical remission at week 50. Endoscopic response at week 26 predicted corticosteroid-free
remission at week 50 with an area under the curve of
0.611 (95% CI, 0.538–0.683). The minimally important
difference and responsiveness to change of all endoscopic
scoring indices require further definition.
The Future of Outcome Assessments in
IBD: New PROs and ClinROs
The MCS, CDAI, and other composite clinical outcome
measures were not created according to FDA guidance for
development of a PRO. The development of a valid PRO
includes patient concept elicitation interviews, expert interviews, item generation, content validity, patient cognitive
interviews, and a quantitative validation study.8 The
patients themselves need to generate the items, and the
process can take years to complete. Efforts are under way to
develop PROs for both UC and CD. While these new PROs
are under development, there is a need for interim PRO-like
measures that can be used for drug development over the
next few years. Fortunately, 2 interim PRO measures have
evolved. For UC, a 2-item PRO developed from the rectal
bleeding and stool frequency components of the MCS has
been described (partial MCS). Lewis et al analyzed patientlevel data in a randomized controlled trial of rosiglitazone
for UC. Cutoffs for detecting remission, defined by a patient
rating of disease activity as “perfect or very good,” were 4.5
for the full MCS (sensitivity of 88% and specificity of 78%),
2.5 for the partial MCS (sensitivity of 71% and specificity of
84%), and 1.5 on a 6-point MCS (sensitivity of 65% and
specificity of 81%). Using the outcomes of clinical remission
and clinical response, the effect size of the partial MCS was
similar to that estimated by the full MCS.37 For CD, a 2-item
PRO composed of the abdominal pain and stool frequency
items from the CDAI has been developed (PRO-2). Khanna
et al analyzed patient-level data in randomized controlled
trials of rifaximin and methotrexate.105 Cutoffs were an
average daily stool frequency 1.5 points and abdominal
pain score 1 point. The total PRO-2 score is calculated like
the CDAI, that is, the daily scores for abdominal pain and
stool frequency, averaged over 7 days, are weighted with
the original CDAI multiplication factors; then, the weighted
average scores for both items are summed. Using the
outcomes of clinical remission and corticosteroid-free
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remission, the effect size for a treatment of known
efficacy of the PRO-2 was similar to CDAI-defined remission
(13%–20%). Values corresponding to CDAI scores of 150,
220, and 450 points were 8, 14, and 34 points, respectively,
and the corresponding values for change from baseline in
CDAI scores of 50, 70, and 100 points were 2, 5, and 8
points, respectively, for the PRO-2.
Ulcerative Colitis Endoscopic Index of Severity
In contrast to the previous empiric efforts to develop
endoscopic scoring systems for UC, Travis et al recently
developed the Ulcerative Colitis Endoscopic Index of
Severity (UCEIS) based on a formal quantitative validation
process.106 The score was derived by the analysis of 630
assessments of 60 videos by 10 IBD specialists. Weighted
k scores were modest and ranged from 0.34 (contract friability) to 0.65 (erosions and ulcers). Regression modeling
against an overall assessment of disease severity created the
UCEIS, which accounted for 90% of the variation in the
overall evaluation of disease severity. The UCEIS was
initially an 11-point score composed of erosions/ulcers
(score 1–4), vascular pattern (score 1–3), and bleeding
(score 1–4). Weighted k scores for interobserver variation of
the grades were 0.45, 0.42, and 0.37, respectively. The 48
combinations of items (4 4 3) were each correlated
with an assessment of severity. The UCEIS was subsequently
simplified to an 8-point instrument with the items of erosions and ulcers (score 0–3), vascular pattern (score 0–2),
and bleeding (score 0–3). In a reliability study, interobserver agreement was moderate (k of 0.5).107 A high
correlation was shown overall between a global assessment
of endoscopic disease activity and UCEIS scores (correlation
coefficient, 0.93).107 The cutoffs for remission and severe
disease have not yet been defined, and this instrument has
not yet been used in a clinical trial. For the future, the UCEIS
has the potential to measure changes from baseline that fall
short of complete endoscopic mucosal healing yet represent
a potentially meaningful treatment effect. This increased
sensitivity in comparison to existing instruments may be
advantageous for dose finding in early drug development
programs.
Toward Central Reading of Endoscopic Indices in
UC and CD
ClinRO-reported outcome measures need clear definitions of index items to ensure reproducibility. Reproducibility is a fundamental property of a valid index for clinical
trials.5 Observer variation in endoscopic assessments can
lead to differences in the rates of response to treatment with
placebo. In UC, central reading of endoscopic videos has
recently been shown to be highly reliable and to reduce the
rate of placebo response.108 A recent trial of mesalamine for
mild to moderate UC measured intraobserver and interobserver agreement among scoring of 7 expert central readers
of videos of flexible sigmoidoscopy for multiple endoscopic
scores: the MBS, MCS, and UCEIS. ICCs were used to quantify
agreement. The strength of agreement was evaluated according to the criteria of Landis and Koch, whereby ICCs of
Emerging Treatment Goals in IBD Trials and Practice
<0.00, 0.00 to 0.20, 0.21 to 0.40, 0.41 to 0.60, 0.61 to 0.80,
and 0.81 to 1.00 indicated poor, slight, fair, moderate, substantial, and almost perfect agreement, respectively.109 The
intrarater agreement for the MBS, modified MCS, and UCEIS
was 0.88 (95% CI, 0.84–0.92), 0.89 (95% CI, 0.85–0.92), and
0.89 (95% CI, 0.85–0.93), respectively, and the interrater
agreement was 0.78 (95% CI, 0.71–0.85), 0.79 (95% CI,
0.72–0.85), and 0.83 (95% CI, 0.77–0.88), respectively.5 In
the clinical trial, where the modified Ulcerative Colitis Disease Activity Index (analogous to the modified MCS for
endoscopy scores) was interpreted by the site investigator
in real time and after the fact by a blinded central reader,
31% of patients with modified MCS endoscopic scores 2
points by the site endoscopists had their scores downgraded
to a score <2 points by central reading and would have
been ineligible for the trial. Exclusion of the ineligible patients reduced placebo response rates at weeks 6 or 10 from
20% and 21%, respectively, to 13% and 16%, respectively.
Subsequent studies have defined the responsiveness to
change of these endoscopic scores in a trial of mesalamine
therapy.108,110 In these studies, the UCEIS had the greatest
numerical responsiveness as well as the greatest reproducibility. However, the MCS functioned well and was not
substantially inferior to the UCEIS. Now that the favorable
operating characteristics of these instruments in a central
reading environment are clear, it may be feasible to conduct
relatively small proof-of-concept and dose-finding trials in
which centrally read endoscopy is the primary outcome
measure and statistically efficient techniques such as
measuring shifts from baseline in distributions of index
scores are used for data analysis.
In CD, Khanna et al recently examined the reproducibility of evaluation of independent central readers of the
CDEIS and SES-CD. Four independent central readers scored
50 representative videos 3 separate times. The readers had
“almost perfect” intrarater agreement (intraobserver ICC,
0.89; 95% CI, 0.86–0.93). However, interrater agreement
was lower (ICC, 0.71; 95% CI, 0.61–0.79).111 A key area of
disagreement between the readers was the definition of
superficial versus deep ulceration, which is used as
an item in the CDEIS (similar to the original GETAID
development study). In comparison, central reading of the
SES-CD had “substantial” to “almost perfect” intraobserver
43
and interobserver reliability (intraobserver ICC, 0.91
[95% CI, 0.87–0.94]; interobserver ICC, 0.83 [95% CI,
0.75–0.89]).112
Assessment of Histological Inflammation
An important question for both clinical trials and clinical
practice is whether or not to treat beyond endoscopic
remission to histological remission. Truelove and Richards
first reported that active histological inflammation was
commonly present in patients with UC who had normalappearing mucosa at endoscopy and that such patients
were at an increased risk for relapse.113 This finding has
been replicated by other investigators who showed that
plasmacytosis on biopsy increases the chance of relapse.114
A retrospective cohort study in patients with UC found that
21% of 385 patients with mucosal healing had persistent
histological activity.115 Conversely, the decrease in plasmacytosis on biopsy after therapy has been reported.116,117
These relationships support the possibility that a future
definition of complete mucosal healing could include both
endoscopic and histological healing.
There is a need for a valid histological index if a definition of complete mucosal healing that includes histological
healing will one day be included in clinical trials. A recent
systematic review identified multiple indexes that have
been used to measure histological disease activity in UC.118
Commonly included index items assessed the degree of
acute and chronic inflammation, the presence or absence
of architectural distortion of colonic crypts, and the integrity
of the colonic epithelium (Table 2 and Figure 3). Mosli et al
recently evaluated the intrarater and interrater agreement
of expert pathologist central reader scoring in several
commonly used UC histological indices.119 The Geboes
score and modified Riley score intrarater agreement was
“substantial” to “almost perfect,” respectively, whereas the
interrater agreement was “moderate” to “substantial,”
respectively. Items that require additional definition were
identified, including crypt distortion and basal plasmacytosis. In CD, potential histological indices include the global
histological activity score and the Naini Cortina score.120-121
Items included in these indices evaluate architectural damage, epithelial damage, neutrophilic infiltrate,
Table 2.Potential ClinROs: Histological Indices
Histological indices
UC
Geboes score
Modified Riley score
CD
Global histological activity score
Naini Cortina score
Descriptors
Architectural changes, chronic inflammation infiltrate, lamina propria neutrophils and
eosinophils, neutrophils in epithelium, crypt destruction, erosion or ulceration
Neutrophils in epithelium, lamina propria neutrophils, erosion or ulceration
Epithelium damage, architectural changes, infiltration of mononuclear cells in the
lamina propria, infiltration of polymorphonuclear cells in the lamina propria,
polymorphonuclear cells in the epithelium, presence of erosions and/or ulcers,
presence of granulomas, number of biopsies affected
Architectural distortion, increased lymphocytes and plasma cells in lamina propria,
neutrophilic inflammation including erosions/ulcers, granulomas
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REVIEWS AND
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been correlated with histopathologic inflammation in the
terminal ileum (Kendall s, 0.40; 95% CI, 0.11–0.64; P ¼ .02).
Future trials are needed to determine the predictive value of
bowel healing as measured by MRE, low-dose radiation,
computed tomographic enterography, or ultrasonography
for clinically relevant outcomes such as disease progression,
hospitalization, and surgery.
Treat-to-Target, Therapeutic Drug Monitoring,
and Treatment Strategy Trials
Figure 3. Histopathology showing severe acute inflammatory
infiltrate and marked neutrophils in the lamina propria.
erosions/ulcers, granulomas, and the number of biopsy
specimens affected. Additional studies are needed to
determine the predictive value of histological healing on
long-term outcomes such as disease progression, hospitalization, and surgery.
Radiographic Assessment of Inflammation
Another potential ClinRO to assess inflammatory disease
activity in CD is magnetic resonance enterography (MRE).
MRE can identify the presence of important disease complications before initiation of therapy and can measure the
progression of bowel damage over time (Lemann score).122
MRE has high diagnostic accuracy for both the detection
of CD-related complications (ie, stenosis, fistula, and
abscesses), which are key sequelae to inflammatory disease,
and for assessment of luminal disease activity and extent.
Two MRE indices have been formally derived to quantitate
inflammatory activity in CD: the Magnetic Resonance Index
of Activity123 and the London Index.124 The Magnetic
Resonance Index of Activity, which is scored in both the
terminal ileum and the colon, is highly correlated (r > 0.80;
P < .001) with the CDEIS.83 Similarly, the London Index has
The treat-to-target strategy is based on the hypothesis
that treating endoscopic mucosal inflammation not only
improves symptoms but also decreases the long-term
burden of disease125 (Figure 4). There is emerging evidence that treating to endoscopic healing as a target meets
this standard. In a 5-year, 157-patient cohort study, patients
with UC without complete mucosal healing had greater rates
of hospitalization (hazard ratio, 3.6; 95% CI, 1.6–8.5) and
were more likely to undergo colectomy (hazard ratio, 8.4;
95% CI, 1.3–55.2) than those with complete mucosal healing.126 In trials of infliximab for moderate to severe UC,
patients with Mayo Clinic endoscopic scores of 0 or 1 had
less risk of hospitalization or surgery at 1 year compared
with those with higher scores. In addition, patients with an
endoscopic score of 0 had less need for future treatment
with corticosteroids than those with a score of 1.127 In the
ACCENT I trial of infliximab for moderate to severe CD,
mucosal healing at week 10 and week 54 was associated
with a trend toward fewer hospitalizations and surgeries.
Similarly, the absence of mucosal ulceration in CD within 1
year of diagnosis or initiating therapy has been associated
with reduced corticosteroid use and decreased clinical disease activity,128 fewer major abdominal surgeries,129 and
sustained corticosteroid-free remission.130 Conversely, deep
colonic ulcerations in CD are associated with an increased
risk of colectomy.131 Treating to target can also be described
as treat-to-target anti–tumor necrosis factor trough concentrations (ie, therapeutic drug monitoring). In the optimization phase of the TAXIT (Trough Level Adapted
Infliximab Treatment) trial, adjusting infliximab dosing to
Figure 4. Treat-to-target
strategy.
goal trough concentrations between 3 and 7 mg/mL led to
improved outcomes and costs.132 Utilization of a target drug
concentration is possible once a robust relationship has
been established between drug pharmacokinetics and the
desired pharmacodynamics effect. The cost-effectiveness of
treat-to-target strategies and therapeutic drug monitoring
remains to be shown. A recent decision analytic model
showed cost savings by testing for inflammation, trough
concentration, and antibodies to infliximab in patients who
lose responsiveness to infliximab.133 These savings remain
to be validated in larger clinical trials134 in CD and UC of
testing strategies, assessments of antibodies, trough concentrations, and response to therapy with colonoscopy or
MRE. Although biomarkers such as fecal calprotectin or
C-reactive protein levels may have a future role in these
strategies, their lack of sensitivity and specificity135 for
inflammation and responsiveness to therapy precludes a
recommendation to use them as a target for clinical practice
or clinical trials at the present time.
Treating to target has been shown to be a feasible
strategy in clinical practice. A pilot study of 60 patients with
UC who underwent 2 to 5 endoscopies over a median
follow-up of 76 weeks showed cumulative mucosal healing
rates of 60% and cumulative histological healing rates of
50%. Any adjustment in medical therapy for persistent
endoscopic activity was associated with mucosal healing
(hazard ratio, 9.8; 95% CI, 3.6–34.5; P < .0001).136 Similarly, in a pilot study of 67 patients with CD who underwent
2 to 4 endoscopies over a median follow-up of 62 weeks,
cumulative mucosal rates of 51%, and cumulative endoscopic improvement rates of 61% were observed. Factors
associated with mucosal healing were less than 26 weeks
between endoscopic procedures (hazard ratio, 2.35; 95% CI,
1.15–4.97; P ¼ .035) and adjustment of medical therapy for
persistent mucosal inflammation (hazard ratio, 4.28; 95%
CI, 1.9–11.5; P ¼ .0003).137
In clinical practice, disease activity is often assessed
through evaluation of symptoms and severity of intestinal
inflammation by endoscopy. Given the evolution of clinical
trial end points for UC toward a 2-item partial MCS PRO
(rectal bleeding and stool frequency) and endoscopy (MCS
endoscopy score 0 or 1), it is now possible to directly apply
these clinical trial end points to clinical practice, treating to
a target of symptom resolution and endoscopic mucosal
healing. Given the evolution of clinical trial end points for
CD toward a PRO-2 (abdominal pain and stool frequency)
and endoscopy, it should be possible to directly apply these
clinical trial end points to clinical practice, with the intent of
treating to the targets of symptom resolution and endoscopic mucosal healing.
Testing treatment strategies in the future may take the
shape of either traditional patient-level trials in which
patients are randomized to one strategy or another or novel
cluster randomization trial designs in which centers are
randomized to different strategies. These trials will go
beyond testing the efficacy of individual drugs to testing
treatment algorithms and strategies that aim to change the
natural history of CD and UC, seeking to prevent bowel
damage, surgical resection, and disability. In 2000, D’Haens
Emerging Treatment Goals in IBD Trials and Practice
45
et al conducted the first trial of alternative treatment algorithms in CD, which showed that the early combination of
azathioprine and infliximab led to significantly more
mucosal healing than a traditional “step-up” approach.132
Recently, REACT-1 (A Cluster Randomized Controlled Trial
of a Treatment Algorithm for the Management of Crohn’s
Disease) showed that clinical practice outcome goals can be
tested for real-world effectiveness and their impact on
hospitalization and surgery.138 In a cluster randomization
trial, 21 centers (1084 patients) were assigned to early
combination therapy and 18 centers (898 patients) to conventional management. The proportion of patients in
symptomatic remission (as measured by the HBI) at 12 and
24 months did not differ statistically between the 2
approaches (3.7%; 95% CI, 4.1% to 11.5%; P ¼ .354; at 24
months). However, significant and clinically important differences in the rates of complications, surgeries, and the
combined outcome of hospitalizations, complications, and
surgeries were observed in favor of early combination
therapy over 24 months (27.7% and 35.1% in the early
combination and conventional groups, respectively) (difference, 7.4%; hazard ratio adjusted for CD caseload and
country, 0.74; 95% CI, 0.62–0.87; P < .001). In summary,
the effectiveness of a treat-to-target strategy could be due to
a patient’s disease (location, duration, patient genetics), the
drug (pharmacokinetics), and/or the treatment strategy.139
Conclusions
Clinical trials in IBD need to include patients with both
symptoms as defined by PROs and documented inflammation as defined by ClinROs. Currently, symptomatic remission and endoscopic improvement are appropriate
coprimary end points for clinical trials. The individual end
points are meaningful to patients (PRO remission) and show
that the therapy is affecting the underlying inflammatory
process (endoscopic improvement). The combination of
symptomatic remission and endoscopic improvement may
also be useful in clinical practice as the target in treat-totarget disease management strategies. Additional studies
are needed to show that treat-to-target strategies will
change the natural history of IBD by preventing bowel
damage and disability.
Supplementary Material
Note: To access the supplementary material accompanying
this article, visit the online version of Gastroenterology at
www.gastrojournal.org, and at http://dx.doi.org/10.1053/
j.gastro.2014.08.003.
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Received May 17, 2014. Accepted August 5, 2014.
Reprint requests
Address requests for reprints to: William J. Sandborn, MD, University of
California San Diego, 9500 Gilman Drive, MC 9056, La Jolla, California
92093-9056. e-mail: [email protected]; fax: (858) 657-5022; or JeanFrédéric Colombel, MD, Icahn School of Medicine at Mount Sinai, One
Gustave L. Levy Place, Box 1069, New York, New York 10029. e-mail: [email protected]; fax: (646) 537-8647.
Conflicts of interest
The authors disclose the following: B.G.L. has received consulting fees from
AbbVie, Takeda, Nestle Health Sciences, Santarus, and Prometheus
Laboratories and has served on a speakers bureau for Warner Chilcott and
UCB Pharma. W.J.S. has received consulting fees from Abbott Laboratories,
ActoGeniX, AGI Therapeutics Inc, Alba Therapeutics Corp, Albireo, Alfa
Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys Inc,
Atlantic Healthcare Ltd, Aptalis, BioBalance Corp, Boehringer Ingelheim,
Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon
Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado
Biosciences, Cytokine PharmaSciences, Eagle Pharmaceuticals, EnGene Inc,
Eli Lilly, EnteroMedics, Exagen Diagnostics Inc, Ferring Pharmaceuticals,
Flexion Therapeutics Inc, Funxional Therapeutics Ltd, Genzyme Corp, Gilead
Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences,
Ironwood
Pharmaceuticals,
KaloBios
Pharmaceuticals,
Lexicon
Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck Research
Laboratories, Merck Serono, Millennium Pharmaceuticals, Nisshin Kyorin
Pharmaceuticals,
Novo
Nordisk,
NPS
Pharmaceuticals,
Optimer
Pharmaceuticals, Orexigen Therapeutics Inc, PDL BioPharma, Pfizer Inc,
Procter & Gamble, Prometheus Laboratories, ProtAb Ltd, PurGenesis
Technologies Inc, Relypsa Inc, Roche, Salient Pharmaceuticals, Salix
Pharmaceuticals, Santarus, Schering-Plough Corp, Shire Pharmaceuticals,
Sigmoid Pharma Ltd, Sirtris Pharmaceuticals, SLA Pharma UK Ltd,
Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA,
UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Ltd, Warner
Chilcott UK Ltd, and Wyeth; has received research grants from Abbott
Laboratories, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen,
Millennium Pharmaceuticals, Novartis, Pfizer Inc, Procter & Gamble, Shire
Pharmaceuticals, and UCB Pharma; has received payments for lectures/
speakers bureau from Abbott Laboratories, Bristol-Myers Squibb, and
Janssen; and holds stock/stock options in EnteroMedics. J.R. has received
consulting fees from AbbVie, Janssen, and Takeda. B.G.F. has received
grant/research support from Millennium Pharmaceuticals, Merck, Tillotts
Pharma AG, Abbott Laboratories, Novartis Pharmaceuticals, Centocor Inc,
Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGeniX,
and Wyeth Pharmaceuticals; has received consulting fees from Millennium
Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva
Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, Abbott
Laboratories, AstraZeneca, Serono, Genentech, Tillotts Pharma AG, Unity
Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals,
Novo Nordisk, GlaxoSmithKline, ActoGeniX, Prometheus Therapeutics and
Diagnostics, Athersys, Axcan, Gilead Sciences, Pfizer Inc, Shire, Wyeth,
Zealand Pharma, Zyngenia, gIcare Pharma, and Sigmoid Pharma; and has
served on a speakers bureau for UCB, Abbott Laboratories, and Johnson &
Johnson/Janssen. B.E.S. has received consulting fees from AbbVie, Amgen,
AstraZeneca, Avaxia Biologics, Bristol-Myers Squibb, Janssen Biotech,
Luitpold Pharmaceuticals, MedImmune, Pfizer Inc, PureTech Ventures, Salix,
Shire, Takeda, TopiVert Pharma Ltd, and Vedanta Biosciences; has received
research grants for his institution from AbbVie, Amgen, Celgene, Janssen
R&D, Millennium Pharmaceuticals, Pfizer Inc, and Prometheus Laboratories;
has received honoraria for lecturing in a CME program from Imedex,
Strategic Consultants International, Focus Medical Communications, Curatio
CME Medical Institute/Huntsworth Health NA, Creative Educational Concepts,
and Scripps; has received honoraria for work as an associate editor from the
American Gastroenterological Association Institute; and holds stock in
Avaxia Biologics, a nonpublicly traded company. J.-F.C. has served as
consultant, advisory board member, or speaker for AbbVie, AB Science,
Amgen, Bristol-Myers Squibb, Celltrion, Danone, Ferring Pharmaceuticals,
Emerging Treatment Goals in IBD Trials and Practice
51
Genentech, Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals,
Merck & Co, Millennium Pharmaceuticals, Nutrition Science Partners Ltd,
Pfizer Inc, Prometheus Laboratories, Protagonist, Receptos Inc, Sanofi,
Schering-Plough, Second Genome, Takeda, Teva Pharmaceuticals, UCB
Pharma, Vertex, and Dr August Wolff GmbH & Co and holds stock options in
Intestinal Biotech Development.
REVIEWS AND
PERSPECTIVES
January 2015
51.e1
Levesque et al
Gastroenterology Vol. 148, No. 1
Supplementary
Figure 1. Calculation
CDEIS.
Supplementary
Figure 2. Calculation
SES-CD.
of
of