Download CARE CONFERENCE REPORT ACG 2013 UEGW 2013

CARE GASTROENTEROLOGY FACULTY — CANADIAN PERSPECTIVES FROM ACG 2013 / UEGW 2013
CARE
ACG 2013 UEGW 2013
SAN DIEGO, CALIFORNIA
OCTOBER 11–16, 2013
Berlin, Germany
OCTOBER 12–16, 2013
CONFERENCE REPORT
CANADIAN PERSPECTIVES FROM ACG 2013
Augmented with Abstract and Presentation
Content from UEGW 2013
Supporting Commentary and Content Provided by the CARE Gastroenterology Faculty
INTRODUCTION
The CARE (Community, Academic & Resident Education) Gastroenterology Faculty is a national group
of specialists from across Canada who gather, discuss and address gaps in knowledge, with education
outputs framing news from a Canadian perspective. The mission of the CARE Gastroenterology Faculty is
to enhance medical education with the explicit goal of improving patient outcomes.
CARE Gastroenterology Faculty who have contributed to this report:
FACULTY CHAIR:
John Marshall
MD, FRCP(C), AGAF
Professor
Department of Medicine
McMaster University
David Armstrong
Brian Bressler
MD, FRCP(C), FACG, AGAF
MD, MS, FRCP(C)
Alain Bitton
Robert Myers
MD, FRCP(C)
MD, FRCP(C)
Professor
Department of Medicine
McMaster University
Associate Professor
Department of Medicine
McGill University Health Centre
Clinical Assistant Professor of Medicine,
Division of Gastroenterology
University of British Columbia
Assistant Professor, Liver Unit
Gastrointestinal Research Group
University of Calgary
CARE — CANADIAN PERSPECTIVES FROM ACG 2013 & UEGW 2013
The CARE Gastroenterology Faculty recently met at ACG 2013 (American College of Gastroenterology’s
annual conference in San Diego, California, October 11–16) to discuss news and developments in a range of
gastroenterological disorders.
Conference abstracts, plenary content and visuals that follow are drawn from ACG 2013 and are augmented
with abstract and session content from UEGW 2013 (United European Gastroenterology Week, Berlin,
Germany, October 12–16).
Commentary and perspectives have been provided by the CARE Gastroenterology Faculty. Information
and visuals are in the language in which they were presented.
TABLE OF CONTENTS
Functional Gastrointestinal Disorders ������������������������������������ 3
Ulcerative Colitis���������������������������������������������������������������� 14
Crohn’s Disease ��������������������������������������������������������������������8
Liver Disease ���������������������������������������������������������������������� 17
Upper GI Disorders ������������������������������������������������������������� 11
For additional information or to join CARE, please visit us at careeducation.ca or contact us at [email protected]
2 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
CARE Faculty — www.careeducation.ca
functional gastrointestinal disorders (FGID)
The abstract and presentation content/visuals that follow are drawn from Dr. Marshall’s presentation from the CARE at ACG 2013
meeting, and are augmented with additional content from UEGW 2013 and commentary from the CARE Gastroenterology Faculty.
Topics covered in this section include:
▶ IBS Inflammation
▶ Endoscopy in FGID
— Capsule Endoscopy for Pain
— Endoscopic Therapy for Achalasia
— Therapeutic endoscopy: A Paradigm Shift
in Managing Dysplasia and Early Cancer
▶ IBS Therapy
— CARE Update on Chronic Constipation
Treatment Algorithm
IBS Inflammation
Inflammation has, and continues to be a topic of interest
in IBD. Functional GI disorders have been associated with
an inflammatory or post-inflammatory state, potentially
triggered by allergies and infections.
Identification of inflammation is an
important area of research in functional
bowel disorders, as biomarkers related to
inflammation may identify patients who
are responsive to future anti-inflammatory
therapies.
Figure 1 below illustrates one potential mechanism
underlying symptoms in patients with IBS.
Figure 1: Potential Mechanism Underlying Symptoms in IBS
IBS
Non-IBS
Increased permeability
Inflammation
Cytokine release
Normal function
Phyla B
Phyla B
Phyla C
Phyla A
Phyla C
Phyla A
ACG and UEGW 2013 Abstracts of Interest:
ACG 2013 Abstract P498: Circulating Cytokines in IBS
Subgroups.
Orla Craig1, Paul Scully1, Eamonn M. Quigley1
Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
1
Purpose: IBS is a heterogeneous condition defined and
sub-grouped according to predominant symptoms. Subtle
irregularities in circulating cytokines have been observed
in IBS. However it is unclear whether the changes observed
are associated with gastrointestinal inflammation, reflect
associated co-morbidities or are a consequence of symptoms
or associated stress. Our aim was to determine whether
circulating cytokine levels are associated with distinct IBS
subgroups.
Results: Fifty-eight patients attended a baseline visit. Thirty
returned for a second visit after a mean interval of 69 days.
Twenty-two returned for a third visit after a mean interval
of 120 days (range 76–166 days) after the baseline visit.
Nineteen patients completed all three visits and met Rome
III criteria for IBS on at least one visit. Twenty-one healthy
controls completed a single visit. IFN-γ was significantly
lower [HC 3.04 (2.35–4.77) ρg/mL; IBS visit one: 1.76 (1.49–
2.45) ρg/mL; IBS visit two: 2.32 (1.78–2.93) ρg/mL; IBS visit
three: 1.92 (1.56–2.41); p < .05)] and IL-6 significantly higher
[HC 5.77 (4.39–7.68) ρg/mL; IBS visit one: 8.24 (6.07–11.19)
ρg/mL; IBS visit two: 7.72 (5.84–13.20) ρg/mL; IBS visit
three: 8.95 (5.49–14.55) ρg/mL; p < .05] in those with IBS
compared to healthy controls. IBS-D, IBS-M, acomorbid
depression, severe abdominal pain, and a comorbid
functional oesophageal disorder were all associated with
higher levels of IL-6. Multiple regression showed that both
depression and anxiety were independently associated
with higher levels of IL-6 in patients with IBS.
Conclusion: Higher levels of plasma IL-6 are associated
with the presence of psychological comorbidity in those
with IBS. This suggests that disturbances in circulating
cytokine levels in IBS may be centrally mediated rather
than reflecting inflammation at the mucosal level.
Talley NJ, Fodor AA. Gastroenterology 2011;141:1555-9
CARE Faculty — www.careeducation.ca
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 3
UEGW 2013 Abstract P1455: Chronic Treatment With
LPHA2DELTA Ligand Reduce Colonic Inflammation and
Inflammatory-Associated Hypersensitivity in Mice.
Speaker: ludivine Boudieu et al.
Introduction: Abdominal pain is a common feature of
patients suffering from inflammatory bowel disease
(IBD) or irritable bowel syndrome (IBS) for which current
analgesic therapies are still unsatisfactory. Recent studies
highlighted the antinociceptive effect of α2δ ligands,
initially commercialized as anticonvulsant, in patients
suffering from IBS. However, their impact on inflammationassociated visceral pain has been poorly investigated.
Results: Chronic pregabalin treatment alleviated the CHS
induced by DSS treatment, as revealed by a decreased
VMR to CRD test in pregabalin DSS-treated mice in
comparison to control DSS-treated mice. In addition to this
anti-nociceptive, pregabalin treatment reduced neutrophil
recruitment and pro-inflammatory cytokine production,
showing a new original anti-inflammatory effect of α2δ
ligands treatment
Conclusion: In summary, α2δ ligands showed beneficial
effects in the management of visceral hypersensitivity.
Moreover, our findings highlight their novel efficacy
in inflammatory CHS which could be, in part, due to an
anti-inflammatory effect. Finally, this work underlines the
interest in studying the clinical relevance of α2δ ligands in
IBD patients in remission to alleviate IBS-like symptoms,
particularly abdominal pain, but also to increase length of
remission periods by preventing initiation or triggering of
acute severe inflammation phases.
Endoscopy in FGID
Capsule Endoscopy for Pain
ACG 2013 Abstract P770: Diagnostic Yield of Small-Bowel
Capsule Endoscopy in Patients With Chronic Abdominal Pain:
A Single-Center Assessment.
Amir Zarrinpar1, Khushboo Kaushal2, Jeremy Egnatios3, Denise Kalmaz1
1
Univ. of California San Diego - Gastroenterology, La Jolla, CA, United States. 2Univ. of
California San Diego - Internal Medicine, La Jolla, CA, United States. 3Univ. of California
San Diego - School of Medicine, La Jolla, CA, United States.
Purpose: Chronic abdominal pain (CAP) is the second most
common indication for video capsule endoscopy (VCE).
Evidence of validity of VCE in patients with CAP is limited.
Our aim is to assess diagnostic yield of VCE in patients with
CAP. Patients with CAP will also be compared with those
who had VCE for all other indications.
Results: Of the 62 patients who had CAP, three also had
abnormal imaging (4.8%), ten complained of nausea/
vomiting, bloating and weight loss (16.1%), seven had
already been diagnosed with GI disease (i.e., Crohn’s
disease, collagenous colitis, Lynch syndrome, ulcerative
colitis, previous small bowel obstructions, 11.3%), ten also
complained of chronic diarrhea (16.1%), and eight also had
anemia (12.9%).
4 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
There were no significant differences between these
groups, hence they were compiled into one general
group. Compared to patients who had other indications
for VCE, those who had CAP were younger (55 vs. 43
years, p < .00001) and there was a trend toward being
female (51% vs. 63%, p = .10). There was no difference
between the general population and those with CAP in the
number of endoscopically placed capsules (22% vs. 25%,
p = n.s.), completed exams (i.e., capsule is seen entering
the cecum; 78% vs. 80%, p = n.s.), gastric transit time
(69 mins vs. 68 mins, p = n.s.), and small bowel transit time
(244 mins vs. 227 mins, p = n.s.). VCE was abnormal in only
14/62 CAP studies (23%, compared to 42%, p < .005). VCE
findings in the 14 abnormal CAP studies were 79% (11/14)
an inflammatory lesion (e.g., ulcers, erythema, jejunitis,
ileitis, stricture), 14% (2/14) a polypoid lesions, and 7% (1)
an angiectasia (7%). No patients had a mass or neoplasm.
Conclusion: Patients received VCE for CAP are younger and
tend to be more female when compared to those receiving
VCE for other indications. The yield of VCE in patients with
chronic abdominal pain is low (23%), consisting of mostly
inflammatory lesions.
Endoscopic Therapy for Achalasia
ACG 2013 Abstract #28: Randomized Study Comparing
Peroral Endoscopic Myotomy, Botulinum Toxin Injection and
Balloon Dilation for Achalasia: One-Year Follow-Up.
Enqiang Linghu1, Huikai Li1
The Chinese PLA General Hospital, Beijing, China.
1
Purpose: Endoscopic treatments for achalasia include
peroral endoscopic myotomy (POEM), botulinum toxin
injection (BTI) and balloon dilation (BD), yet no randomized
studies have compared POEM with the other two
treatments. This randomized study was aimed to compare
the efficacy and safety of the three treatments.
Results: Endoscopic treatments were successfully
performed in all of the 45 patients, and 93.3% of patients
were successfully followed up at one-year after treatment.
Symptom remission rate was 100% in POEM group, 5.4%
in BTI group and 64.3% in BD group, and the difference
was statistically significant between every two groups.
Complication rate was 20.0% in POEM group, 0% in BTI
group and 6.7% in BD group with no statistical difference
found between the three groups. LESP, maximum width of
esophagus were similar both before and three months after
treatment among the three groups.
Conclusion: Symptom remission of POEM was higher than
BTI and BD at one-year after treatment, and complications
were similar among the three groups.
CARE Faculty — www.careeducation.ca
Therapeutic Endoscopy: A Paradigm Shift in
Managing Dysplasia and Early Cancer
UEGW 2013 Abstract P004: Magnification Endoscopy in
Combination With Acetate Instillation and a Narrow-Band
Imaging System for Predicting Histologic Characteristics of
Gastric Mucosal Neoplasms.
Speaker: Kotaro Shibagaki et al.
Introduction: Magnification endoscopy with narrow-band
imaging (NBIME) that enables a detailed visualization of
the capillary patterns (CP) of superficial gastric neoplasms
is useful for predicting their histologic types, although CP is
often difficult to interpret. NBIME with acetate enhancement
(acetate-NBIME) is effective for the observation of mucosal
microstructure patterns (SP) of gastric mucosa.
Results: The kappa values of interobserver agreement
for CP and SP diagnosis were 0.61 (0.57–0.64) and 0.63
(0.55–0.71), showing good diagnostic concordances.
Adenomas, differentiated, and undifferentiated mucosal
adenocarcinomas were statistically related to type C1,
C2, and C3 (p < .01) in NBIME and to type S1, S2, and S3
(p < .01) in acetate-NBIME, respectively. Type C4 was
difficult to use as an indicator of specific histologic types.
The kappa values of diagnostic concordance between each
CP and SP and their related histologic types were 0.45 (0.30–
0.59) and 0.77 (0.68–0.87), showing a statistical difference.
Conclusion: Acetate-NBIME shows a good clinical
feasibility and the superiority to NBIME in predicting the
histologic types of gastric mucosal neoplasms.
efficacy of lubiprostone was observed in those patients
using diphenylheptane opioids; a third, similarly designed,
well-controlled study was also conducted in which patients
taking diphenylheptanes were excluded. In this analysis,
efficacy and safety data from the non-diphenylheptane
population from the three individual trials were pooled
and analyzed.
Results: Demographic characteristics were consistent
across the three trials. In the pooled analysis, mean CFB in
SBM frequency at week eight was significantly increased in
the lubiprostone group vs. the placebo group (CFB = 3.1 vs.
2.5 SBMs/week, respectively; p = .006). Mean CFBs in SBM
frequency were also significantly improved for lubiprostone
vs. placebo at week 12 (CFB = 3.2 vs. 2.7 SBMs/week,
respectively; p = .040) and overall (CFB = 3.0 vs. 2.3 SBMs/
week, respectively; p < .001). The median time-to-first SBM
was significantly shorter with lubiprostone vs. placebo
(28.5 h vs. 40.0 h, respectively; p < .001). Statistically
significant improvements in constipation severity, straining,
stool consistency, abdominal bloating, and abdominal
discomfort were also reported with lubiprostone vs.
placebo (p = .015). Overall, lubiprostone was well tolerated;
no clinically meaningful safety differences were observed.
Conclusion: Pooled analysis of phase 3 trials confirmed
the overall benefits of lubiprostone therapy in patients
with OIC resulting from chronic treatment with nondiphenylheptane opioids, as demonstrated by statistically
significant improvements in SBM frequency, time-to-first
SBM, and OIC-related symptoms.
Naloxegol
IBS Therapy
Lubiprostone
Lubiprostone was FDA approved in 2006 for CIC and
IBS-C in women. The bicyclic fatty acid is derived from
prostaglandin E1. It performs the following functions:
selectively activates apical CIC-2 channels, induces chloride
efflux and then sodium efflux, enhances fluid secretion and
may restore mucosal barrier function.
ACG 2013 Abstract of Interest:
ACG 2013 Abstract P1687: Lubiprostone Effectively
Relieves Opioid-Induced Constipation in Patients Using
Non-Diphenylheptane Opioids for Non-Cancer Pain: Pooled
Analysis of Three Randomized Controlled Trials.
Shadreck Mareya1, Douglas A. Drossman2, Taryn Joswick1, Gayle Dolecek1, Yijun Sun1,
Ryuji Ueno3
1
Sucampo Pharma Americas, LLC, Bethesda, MD, United States. 2University of North
Carolina at Chapel Hill, Chapel Hill, NC, United States. 3Sucampo AG, Zug, Switzerland.
Purpose: Oral lubiprostone (24 mcg twice daily [BID]) is
approved to treat opioid-induced constipation (OIC) in
adults with chronic non-cancer pain, but effectiveness has
not been established in OIC patients taking diphenylheptane
opioids (e.g., methadone). In two well-controlled studies
of lubiprostone in OIC, a dose-dependent decrease in the
CARE Faculty — www.careeducation.ca
Naloxegol is an oral peripherally-acting, mu-opioid receptor
antagonist. It is used for the treatment of opioid-induced
constipation (OIC), a common side effect of prescription
opioids.
ACG 2013 Abstract of Interest:
ACG 2013 Abstract #35: Naloxegol Symptom Responder Rates
in Patients With Opioid-Induced Constipation: Results From
Two Prospective, Randomized, Controlled Trials.
William D. Chey1, Jan Tack2, Lynn R. Webster3, Jaakko Lappalainen4, Peter Barker4, Mark
Sostek4
1
University of Michigan, Ann Arbor, MI, United States. 2University of Leuven, Leuven,
Belgium. 3CRI Lifetree Research, Salt Lake City, UT, United States. 4AstraZeneca,
Wilmington, DE, United States.
Purpose: Opioid-induced constipation (OIC), a side effect
associated with chronic use of opioid analgesics for pain
management, is characterized by symptom burden from
straining, hard stools, and incomplete evacuation of stool.
The objective of this analysis was to examine the efficacy
of the peripherally acting, μ-opioid receptor antagonist
naloxegol (NGL) in OIC patients using multiple OIC
response criteria.
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 5
Table 1: Results for Naloxegol 12.5 mg vs. 25 mg
Number (%) of Patients
Responding
K04
K05
Response:
SBMs
Response:
SBMs +
Symptoms
Response:
SBMs*
Response:
SBMs +
Symptoms
Placebo
63 (29.4)
54 (25.2)
68 (29.3)
53 (22.8)
Naloxegol 12.5 mg
87 (40.8)
71 (33.3)
81 (34.9)
65 (28.0)
Naloxegol 25 mg
95 (44.4)
83 (38.8)
92 (39.7)
80 (34.5)
Treatment Group
Results: The NGL 25-mg group showed an improvement
in the primary end point compared to placebo in both
studies (K04, p = .001; K05, p = .021) with improvements
maintained when symptoms were incorporated into
response (K04, p = .003; K05, p = .006, respectively). For
NGL 12.5 mg compared to placebo, significance for the
primary end point was seen in K04 (p = .015) but not K05
(p = .202), and response-incorporating symptoms was
p > .05 in both studies.
Conclusion: When using a stringent definition of treatment
response that incorporates both SBM frequency and
symptom improvement criteria, NGL 25 mg response rates
were higher versus placebo (p < .01) in both studies.
ACG 2013 Abstract of Interest:
ACG 2013 Abstract P1688: Follow-Up Study of Fecal
Microbiota Transplantation (FMT) for the Treatment of
Refractory Irritable Bowel Syndrome (IBS).
David Pinn , Olga Aroniadis , Lawrence J. Brandt
1
Conclusion: FMT resolved or improved symptoms in 70%
of our patients with refractory IBS, including abdominal
pain (72%), bowel habit (69%), dyspepsia (67%), bloating
(50%), and flatus (42%). FMT also resulted in improved
quality of life (46%).
Hypnosis
ACG 2013 Abstract of Interest:
Fecal Transplant
1
worsening of flatus was reported in one (8%), four (33%),
six (50%), and one (8%) patient, respectively (mean score:
1.75). Six patients (43%) had dyspepsia before FMT (mean
score: 1.83) and two patients (33.3%) reported resolution,
two (33.3%) noted improvement, and two (33.3%) had no
change after FMT (mean score: 1.17). In nine IBS-D patients,
pre-FMT score was 1.89 and post-FMT mean score was
0.78. Of the three patients with IBS-C, mean pre-FMT score
was 1.33 and post-FMT mean score was 0.33. One patient
had IBS-M and had improved diarrhea and constipation
after FMT. Three patients (23%) reported no improvement.
Before FMT, global well-being was reported as “good”
in zero patients, “acceptable” in four patients (30%), and
“poor” in nine patients (69%) (mean score: 2.69). After
FMT, global well-being was “good” in three patients (23%),
“acceptable” in six (46%) and “poor” in four (30%) (mean
score: 1.92).
1
Montefiore Medical Center, Bronx, NY, United States.
1
Purpose: The etiology of IBS is multifactorial, with
intestinal microbiota being increasingly implicated in its
pathogenesis. FMT restores fecal microbiome diversity
in patients with refractory C. difficile infection, and has
impressive cure rates. We postulated FMT treatment of
refractory IBS might result in similar benefit.
Results: Thirteen of 15 eligible patients (54% women)
completed the study. Average age was 45 years (range:
23–75 years). Patients had IBS for an average of 73 months
before FMT (range: 12–180 months). Average time from
FMT to data collection was 11 months (range: 6–18 months).
Nine patients (64%) had IBS-D, three (21%) had IBS-C and
one had IBS-M. Eleven patients (79%) had FMT once, one
patient twice, and one patient three times. Eleven patients
(79%) had abdominal pain before FMT (mean score: 2.55);
after FMT, resolution, improvement, or no change was
reported in three (27%), five (46%), and three (27%) patients,
respectively (mean score: 1.45). Twelve patients (80%)
complained of bloating before FMT (mean score: 2.25),
which resolved, improved, or did not change in two (17%),
four (33%), and six (50%) patients, respectively (mean score:
1.42). Before FMT, 12 patients (92%) had flatus (mean score:
2.4), and after FMT, resolution, improvement, no change, or
6 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
ACG 2013 Abstract P492: The Efficacy of Hypnotherapy in the
Treatment of Irritable Bowel Syndrome: Systematic Review
and Meta-Analysis.
Han Hee Lee1, Yoon Young Choi2, Myung-Gyu Choi1
1
Division of Gastroenterology, The Catholic University of Korea, College of Medicine, Seoul,
Korea, Republic of. 2Yonsei University College of Medicine, Seoul, Korea, Republic of.
Purpose: Hypnotherapy can be considered a promising
intervention for irritable bowel syndrome, but the evidence
is still too limited. We conducted a comprehensive review
of randomized controlled trials (RCTs) that estimated the
efficacy of hypnotherapy for the treatment of IBS.
Results: Seven RCTs (six papers) in 374 patients with IBS
were identified. Performance bias was high in all trials
because it was not possible to blind participants and
therapists in this type of intervention. The outcomes in this
study were evaluated at 3 months for short-term effects
and at 1 year for long-term effects. Abdominal pain change
score at 3 months showed a significant difference in favor
of the hypnotherapy group (SMD -0.83; 95% CI -1.65 to
-0.01). However, the same score at 1 year did not show a
significant difference. There was no significant difference
in constipation and diarrhea change score at both 3 months
and 1 year. In case of QOL, only one trial showed that
hypnotherapy is effective to improve QOL in refractory IBS
patients with statistical significance.
Conclusion: This study provided more determined
evidence that hypnotherapy has beneficial effects in
improving abdominal pain in patients with IBS at short
term.
CARE Faculty — www.careeducation.ca
CARE Update: Spotlight on Chronic Constipation
Chronic constipation management continues to be an area of consideration for the CARE Gastroenterology Faculty. The
treatment of chronic constipation has improved with new treatments, and available therapies that can effectively treat
patients when first-line therapies (fiber, diet and exercise, laxatives) have failed.
Resolving constipation with these therapies eliminates the need for further investigation, and
in turn, decreases the number of patients being referred to specialists unnecessarily.
Started in the fall of 2012, a needs assessment was conducted (led by Drs. David Armstrong, McMaster University, and
Steve Vanner, Queen’s University) that focused on the management of chronic constipation. Discussion of the results of
this needs assessment happened first at a working group meeting held at the DDW 2013 conference, and continued at a
working group meeting held at ACG 2013. It was decided that a standardized treatment algorithm, outlining an up to
date treatment strategy that involves both primary care, and GI specialists was needed. Drawing from this discussion,
as well as individual input from CARE Faculty members, a suggested “Chronic Constipation Management” algorithm
was created.
CARE Chronic Constipation Management Algorithm
History & Physical Including Careful Perineal/Rectal Examinationi
Secondary Causesiii
Rule out red flagsii
Specialist assessment
recommended (refer)
Red flag identified
Still constipated
No red flags
Type of Constipation?
Patient Education and Management of Expectationsxi
Assess for complex or complicating featuresxii
Lifestyle modifications (fibre, fluid, exercise)vii
IBS-Cvi
Pelvic Floor Dysfunctioniv
Slow Transitv
Specialist assessment
recommended (refer)
Initiate Osmotic
Laxativesiv
Constipation
Management
E.g., milk of magnesia,
lactulose or PEG titrate to
efficacy and tolerability
Attempt
improved
bowel regimen
Four-week trial at a reasonable
dose prior to reassessment
of maintenence or escalation
to prokinetic therapy
Rescue therapy for
occasional use:
1. Glycerine suppository
2. Stimulant laxatives
(e.g., bisacodyl)
3. Enema
Unsatisfactory response or
intolerant to side effects
Work on
bowel
routine
Osmotic
Laxatives
and
Prokinetic
Probiotics
Inadequate Intake
Management
of Functional
Symptoms
Pharmacological
E.g.,
tricyclic to
address the pain,
SSRI, SNRI
NonPharmacological
E.g.,
meditation,
relaxation,
hypnosis
Initiate Prokineticix
Four-week trial prior to
reassessment for maintenance
or consideration of referral for
specialist assessment
Unsatisfactory response or
intolerant to side effects
Specialist assessment
recommended (refer)
Contributing CARE Gastroenterology Faculty
members involved in the development of the
CARE Guidance on Chronic Constipation
Management:
John Marshall, MD, MSc, FRCP(C), AGAF
Professor of Medicine
McMaster University
Ted Xenodemetropoulos, MD, MSc, FRCP(C)
Assistant Professor, Department of Medicine,
Division of Gastroenterology
McMaster University
Brian Bressler, MD, MS, FRCP(C)
Clinical Assistant Professor of Medicine,
Division of Gastroenterology
University of British Columbia
Louis W. C. Liu, MEng, PhD, MD, FRCPC
Assistant Professor, University of Toronto
Division of Gastroenterology, Department of Medicine
University Health Network
Download a PDF of the Chronic Constipation Management algorithm at careeducation.ca/guidance.
The use of this algorithm at a primary care level in advance of referral may in many cases eliminate the need
for further investigation, and in turn, decrease the number of patients being referred to specialists.
The CARE Gastroenterology Faculty encourages you to share this algorithm with your collegues.
Interested in joining or learning more about CARE?
Please visit us at careeducation.ca and contact us at [email protected]
CARE Faculty — www.careeducation.ca
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 7
Crohn’s Disease
The abstract and presentation content/visuals that follow are drawn from Dr. Brian Bressler’s presentation at the CARE at ACG 2013
meeting, and are augmented with additional content from UEGW 2013 and commentary from the CARE Gastroenterology Faculty.
Topics covered in this section include:
▶ Treatment Strategy ▶ Medical Therapy▶ Safety
­— Anti-TNF Agents
— Other Agents
Treatment Strategy
Medical Therapy
UEGW 2013 Abstract of Interest:
Anti-TNF Agents
UEGW 2013 Abstract P057: Optimising Post-Operative
Crohn’s Disease Management: Best Drug Therapy Alone
Versus Endoscopic Monitoring With Treatment Step-Up: The
POCER Study.
ACG and UEGW 2013 Abstracts of Interest:
Peter De Cruz, Michael Kamm, Amy Hamilton, Kathryn Ritchie, Soula Krejany, Alexandra
Gorelik, Danny Liew, Lani Prideaux, Ian Lawrance, Jane Andrews, Peter Bampton, Miles
Sparrow, Timothy Florin, Peter Gibson, Henry Debinski, Richard Gearry, Finlay Macrae,
Rupert Leong, Ian Kronborg, Graham Radford-Smith, Warwick Selby, Michael Johnston,
Rodney Woods, Ross Elliott, Sally Bell, Steven Brown, William Connell, Paul Desmond.
Introduction: Disease recurs in the majority of patients with
Crohn’s disease requiring intestinal resection. Given the
absence of strategy to prevent recurrence we investigated
whether endoscopic monitoring and treatment step-up
for early recurrence is superior to optimal drug therapy
alone commenced immediately after surgery. Endoscopic
mucosal healing has been shown previously to be predictive
of subsequent clinical remission, and was therefore the goal
in this “treat to target” study.
Results: 174 patients (83% high risk) were enrolled. Of
the 122 active care patients 45 (37%) underwent treatment
step-up. At 18 months endoscopic recurrence was observed
in 60 / 122 (49%) active care patients versus 35 / 52 (67%)
standard care (p = .028). Complete mucosal normality (i0)
was observed in 22% vs. 8% (p = .029); severe disease (i3
and i4) occurred in 12% vs. 15% (p = .466) respectively.
Conclusions: Treating according to risk of recurrence, with
6 month colonoscopy and treatment step-up for recurrence,
is significantly superior to optimal drug therapy alone, in
preventing post-operative recurrence of Crohn’s disease.
Selective potent immune suppression, adjusted if needed
based on colonoscopy, rather than its use in all high risk
patients, leads to effective disease control in a majority of
patients.
CARE Faculty Perspective:
Routine colonoscopy should be considered by
practitioners at six to eight months following surgery to
adjust treatment planning based on endoscopic status.
8 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
ACG 2013 Abstract #64: Correlation of Intestinal Tissue AntiTNF Drug Levels With Endoscopic Disease Activity in Patients
With Inflammatory Bowel Disease: The ATLAS Study.
Andres J. Yarur1, Scott Hauenstein2, Daniel A. Sussman1, Jamie S. Barkin1, Amar R.
Deshpande1, Maria A. Quintero1, Steven Lockton2, Sharat Singh2, Maria T. Abreu1
1
Division of Gastroenterology - University of Miami, Miami, FL, United States.
2
Prometheus Labs., San Diego, CA, United States.
Purpose: Studies have found a higher concentration of
tumor necrosis factor (TNF) in serum and gastrointestinal
tissue of patients with Crohn’s disease and ulcerative colitis
when compared to healthy controls. Serum anti-TNF levels
correlate with efficacy of the drug and mucosal healing,
but there are no studies looking at the importance and
applicability of tissue anti-TNF levels. The aim of this study
was to assess whether tissue anti-TNF levels correlated with
endoscopic mucosal inflammation, and whether the levels
varied in inflamed, versus normal, tissue. We also sought to
study the pharmacokinetics of the drug by comparing drug
level between inflamed vs. normal tissue and the correlation
between body weight, serum anti-TNF concentration, and
anti-TNF tissue level for each drug.
Results: Seventy-five samples were analyzed from 25
patients (25 serum, 22 colonic, 28 ileal). Patients with active
mucosal inflammation had a significantly lower level of
anti-TNF in both tissue and serum (p < .04 for all). Higher
numeric value of TNF was found in tissue and serum of
patients with endoscopic mucosal inflammation, but
did not reach statistical significance. Anti-TNF levels in
tissue and serum correlated (R-square = .13; p = .01). In
patients on ADA, body weight was inversely correlated
with tissue, but not serum drug levels (R-square = 0.4;
p = .01 and R-square = .01; p = 0.6), but this was not found
in patients on IFX (R-square = < .01; p = 0.9 for tissue, and
R-square = 0.1, p = 0.2 for serum drug level).
Conclusion: A lower anti-TNF level in the gastrointestinal
tissue is associated with intestinal mucosal inflammation in
CD and UC. Lower levels in the tissue also correlate with
lower serum levels. In patients on ADA, tissue, but not
serum levels, were inversely correlated with the patient’s
body mass. This finding was not seen on those receiving
IFX, which may suggest that tissue drug monitoring may
play a role in a selected group of patients.
CARE Faculty — www.careeducation.ca
UEGW 2013 Abstract P293: Restoration of Health Related
Quality of Life in Crohn’s Disease Patients With Adalimumab
Maintenance Therapy.
LB arm (RR 3.3; 95% CI 1.4–7.7; p < .01). At the end of MP,
three patients were ATI positive in the CB vs. none in the
LB arm (p = 0.1). All three patients were ATI negative at
screening and developed ATI during MP.
Introduction: In Crohn’s disease, adalimumab maintenance
therapy provides sustained clinical remission and
improvement of health related quality of life (HRQOL).
However, there is scarce information about its long-term
effect on HRQOL and whether it is able to induce a sustained
restoration of normal patient’s perception of health.
Conclusions: Dose-to-target optimisation of IFX allowed to
achieve TLI within the interval of 3–7 µg/ml which resulted
in a more efficient use of drug. The maintenance phase
did not show superiority for continued level based drug
adjustment over clinically based adjustment. Treatment
guided by levels resulted in less ATI formation but the
proportion of patients in clinical and biological remission
was similar for both groups.
Francesc Casellas, Virginia Robles, Antonio Torrejón, Ester Navarro, Esther Ruiz, Natalia Borruel.
Results: From 63 eligible patients, 43 patients with CD in
stable clinical remission sustained over 1 year were included.
During the follow-up, at 12 months 43 patients remained in
remission, at 24 months 30 patients, at 36 months 15 and in
the last visit at 48 months remained nine patients in clinical
remission. Overall score of IBDQ-36 remained unchanged in
patients with stable inactive CD, even with a tendency to score
better with time (median global score of 226 at 12 months
and 241 at 4 years). Restoration of health increased with time
(72% to 100% at 1 and 4 years follow-up respectively).
Conclusion: Sustained clinical remission of CD achieved
with maintenance adalimumab treatment restores HRQOL,
which remains stable at long-term follow-up.
CARE Faculty Perspective:
This drug’s ability to sustain clinical remission
of CD is appealing, as there are currently limited
options for this group of patients.
UEGW 2013 Abstract OP001: Randomized Controlled Trial
of Drug Level Versus Clinically Based Dosing of Infliximab
Maintenance in IBD: Final Results of the TAXIT Study.
Niels van de Casteele, Ann Gils, Vera Ballet, Griet Compernolle, Miet Peeters, Kristel van
Steen, Steven Simoens, Marc Ferrante, Gert van Assche, Séverine Vermeire, Paul Rutgeerts.
Background: Treat-to-target dosing based on infliximab
(IFX) trough levels (TLI) has been suggested to increase
efficacy, safety and cost-effectiveness of IFX treatment,
although prospective data are lacking. In the optimisation
phase of the TAXIT study we showed that dose
intensification of IFX in CD patients with TLI < 3 µg/ml
resulted in a better disease control, whereas dose reduction
in CD and UC patients with TLI > 7 µg/ml resulted in
lower drug exposure and lower IFX cost whilst maintaining
disease control.
Results: After optimisation, median TLI and CRP were equal
in the CB and LB arm (respectively 4.9 µg/ml [3.8–5.9] vs.
5.0 µg/ml [4.0–5.7] and 1.3 mg/l [0.6–4.5] vs. 1.5 mg/l [0.7–
4.1]). 226/251 patients (90%) completed the MP of whom
69% of the CB vs. 72% of the LB arm achieved the primary
end point (p = 0.7). During MP, 11 patients (4.4%) (5 CB vs.
6 LB) were failures and 14 patients (5.6%) (7 CB vs. 7 LB)
were excluded (e.g., due to pregnancy or lost to follow-up).
After one year, 56% in the CB vs. 78% in the LB arm had TLI
between 3–7 µg/ml (p < .001). During MP, undetectable TLI
were more frequently observed in the CB than in the LB arm
(RR 3.7; 95% CI 1.7–8.0; p < .001) which may have influenced
the higher frequency rate of ATI observed in the CB vs. the
CARE Faculty — www.careeducation.ca
Other Agents
ACG 2013 Abstract of Interest:
ACG 2013 Abstract #26: Role of Non-Steroidal AntiInflammatory Drugs in Exacerbations of Inflammatory Bowel
Disease.
Millie D. Long1, Michael D. Kappelman1, Christopher F. Martin1, Wenli Chen1, Kristen
Anton1, Robert S. Sandler1
1
UNC, Chapel Hill , NC, United States.
Purpose: Inflammatory bowel diseases are chronic
immunologic diseases of the gastrointestinal tract
characterized by periods of exacerbation and remission.
Data are limited as to causative factors of exacerbations.
Non-steroidal anti-inflammatory drugs (NSAIDs) are
commonly used for pain, and have been reported to lead
to exacerbations of IBD. We aimed to determine rates of
NSAID use in the IBD population, and whether NSAID use
increases the risk of exacerbation of IBD.
Results: A total of 711 individuals with IBD (519 with CD and
192 with UC) in remission, based on short Crohn’s disease
activity index (sCDAI < 150) or simple clinical colitis activity
index (SCCAI = 2) reported NSAID use patterns. Disease
activity was assessed 6 months later. A total of 308 (43.3%)
reported any NSAID use, 146 (20.5%) reported = 5 uses/
month, and 125 (17.6%) met criteria for a flare at 6-month
follow up. Those on any NSAIDs flared at similar rates to
those not on any NSAIDS (19.5% vs. 16.1%, p = .25). Results
were similar when stratified by CD or UC. Those with = 5
uses/month were more likely to flare when compared to
those with < 5 uses/month (24.0% vs. 15.9%, p = .02), risk
ratio (RR) 1.50 (95% CI 1.07–2.13) overall IBD, RR 1.22 (95%
CI 0.64–2.33) for UC, and RR 1.66 (95% CI 1.10–2.50) for
CD. After controlling for smoking, IBD medication use, and
acetaminophen use, the results for overall IBD remained
similar (adjusted RR 1.46; 95% CI 1.03–2.08). Acetaminophen
use was also independently associated with flare of disease
(adjusted RR 1.57, 95% CI 1.08–2.27).
Conclusion: NSAID use is common amongst individuals
with IBD in remission. Those reporting = 5 uses/month
of NSAIDs had a significantly higher risk of flare when
compared to those with < 5 uses/month. However, those
using acetaminophen also had an increased risk of flare,
demonstrating that the requirement for any pain medication
while in remission may be a marker of occult disease, or that
a mechanism common to both drugs (cyclooxygenase-2 or 3
inhibition) may be associated with flare.
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 9
Safety
ACG 2013 Abstract P573: Long Term Safety of Adalimumab in
Pediatric Patients with Crohn’s Disease.
ACG and UEGW 2013 Abstracts of Interest:
ACG 2013 Abstract P1658: Reductions in Corticosteroid Use
in Patients With Ulcerative Colitis or Crohn’s Disease Treated
With Vedolizumab.
Bruce Sands1, Stephen Hanauer2, Jean-Frédéric Colombel1, Silvio Danese3, Maria T.
Abreu4, Vineet Ahuja5, Terry Ponich6, Ida Hilmi7, Serap Sankoh8, Michael Smyth9, Brihad
Abhyankar9, Irving Fox8, Brian G. Feagan10
1
Icahn School of Medicine at Mount Sinai, New York, NY, United States. 2University of
Chicago, Chicago, IL, United States. 3Istituto Clinico Humanitas, Milan, Italy. 4University
of Miami Miller School of Medicine, Miami, FL, United States. 5All India Institute of
Medical Sciences, New Delhi, India. 6University of Western Ontario, London, ON, Canada.
7
University of Malaya, Kuala Lumpur, Malaysia. 8Millennium Pharmaceuticals, Inc.,
Cambridge, MA, United States. 9Takeda Global Research & Development Centre (Europe)
Ltd., London, United Kingdom. 10Robarts Research Institute, University of Western
Ontario, London, ON, Canada.
Purpose: Long-term corticosteroid use in ulcerative colitis
and Crohn’s disease leads to adverse effects/dependence.
The effect of vedolizumab (VDZ), an anti–α4β7 integrin
antibody, on corticosteroid reduction has been studied in
UC and CD patients.
Results: See Table 2.
Conclusion: VDZ treatment led to corticosteroid-free
remission in UC and CD patients. Future studies are
needed to confirm whether 6-week clinical remissions and/
or mucosal healing are predictive of 52-week steroid-free
remissions.
CARE Faculty Perspective:
Vedolizumab is effective in induction and maintenance
of clinical remission in Crohn’s disease.
Robert N. Baldassano1, Frank Ruemmele2, Joel Rosh3, William Faubion4, Jaroslaw Kierkus5,
Jeffrey Hyams6, Andreas Lazar7, Yaqin Wang8, Samantha Eichner8, Roopal B. Thakkar8
1
Children’s Hospital of Philadelphia, Philadelphia, PA, United States. 2Universite Sorbonne
Paris-Cite, Hospital Necker-Enfants Malades, Paris, France. 3Goryeb Children’s Hospital/
Atlantic Health, Morristown, NJ, United States. 4Mayo Clinic, Rochester, MN, United
States. 5Children’s Memorial Health Institute, Warsaw, Poland. 6Connecticut Children’s
Medical Center, Hartford, CT, United States. 7AbbVie Deutschland, Ludwigshafen,
Germany. 8AbbVie Inc., North Chicago, IL, United States.
Purpose: The safety profile of adalimumab (ADA) in
children with moderately to severely active Crohn’s
disease enrolled in the clinical trial IMAgINE 1 up to
week 52 has been reported previously.1 Cumulative safety
data including the ongoing open-label extension (OLE) is
presented in this report.
Results: 192 pediatric pts had received ADA for CD,
totaling 304.1 PY of exposure. As of 31 Jul 2011, 29/192
(15%) pts had up to 3 years of exposure. The most common
AE for all pts was injection site reaction; all were nonserious. The most common serious AE (SAE) was flare
or worsening of CD. Rates of SAEs, infections and AEs
leading to discontinuation were consistent with IMAGINE
1.1 Serious AEs were experienced by significantly more pts
exposed to prior IFX than IFX-naïve pts. No malignancies,
TB, demyelinating disease, or deaths were reported.
Conclusion: Prolonged ADA treatment, up to 3 years, in
children with moderately to severely active CD has a safety
profile that is consistent with known ADA data1 and no
new safety signals have been identified.
Reference:
1. Hyams JS, Griffiths A, Markowitz J, et al. safety and efficacy of adalimumab for moderate
to severe Crohn’s disease in children. Gastroenterology 2012;143:365-374
Table 2: Corticosteroid Use in Patients With UC or CD
UC (GEMINI I)
VDZ
Q8W
Q4W
CD (GEMINI II)
PB
VDZ
Q8W
Q4W
PB
n = 70
n = 73
n = 72
n = 82
n = 80
n = 82
Wk 52 CS-free remission, %
p value
31.4
0.0120
45.2
< 0.0001
13.9
—
31.7
0.0154
28.8
0.0450
15.9
­—
Wk 52 remission and CS free for 90 d, %
p value
30.0
0.0192
45.2
< 0.0001
13.9
—
30.5
0.0240
25.0
0.1433
15.9
—
Wk 52 remission and CS free for 180 d, %
p value
28.6
0.0082
42.5
< 0.0001
11.1
—
30.5
0.0139
23.8
0.1353
14.6
—
Wk 6 mucosal healing and wk 52 CS-free remission, %
p value
n = 48
41.7
0.0043
n = 56
50.0
0.0002
n = 51
15.7
—
—
—
—
Wk 6 remission and wk 52 CS-free remission, %
p value
n = 23
39.1
0.1230
n = 29
58.6
0.0030
n = 23
17.4
—
n = 29
48.3
0.1449
n = 29
37.9
0.3418
n = 35
28.6
—
10 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
CARE Faculty — www.careeducation.ca
UPPER GI
The abstract and presentation content/visuals that follow are drawn from Dr. David Armstrong’s presentation at the CARE at ACG 2013
meeting and are augmented with additional commentary from the CARE Gastroenterology Faculty.
Topics covered in this section include:
▶ Gastro-Esophageal Reflux Disease
▶ Eosinophilic Esophagitis
Gastro-Esophageal Reflux Disease (GERD)
ACG 2013 Abstracts of Interest:
ACG 2013 Abstract #2: Electrical Stimulation Therapy (EST)
of the Lower Esophageal Sphincter (LES) — An Effective
Therapy for Refractory GERD — Interim Results of an
International Multicenter Trial.
Peter Siersema1, Arjan J. Bredenoord2, Alex Escalona3, Jose Conchillo4, Michael Booth5, Jelle
P. Ruurda1, Justin Wu6, D. N. Reddy7, Edy Soffer8
1
University Medical Center, Utrecht, Netherlands. 2Academic Medical Center, Amsterdam,
Netherlands. 3Pontificia Universidad Catolica de Chile, Santiago, Chile. 4Maastricht
University Medical Center, Maastricht, Netherlands. 5Waitemata Specialist Centre,
Auckland, New Zealand. 6Chinese University of Hong Kong, Hong Kong, Hong Kong.
7
Asian Institute of Gastroenterology, Hyderabad, India. 8University of Southern California,
Los Angeles, CA, United States.
Purpose: Previous single-center trial showed that LES-EST
significantly improved long-term outcomes in GERD. The
aim of this ongoing international multicenter trial is to
evaluate the safety and efficacy of LES-EST in refractory
GERD patients treated by multiple operators.
Results: Twenty-five patients (median age 52.5; men = 14)
have been enrolled and implanted to-date. One patient had
small-bowel trocar perforation during the implant procedure
that was successfully repaired and device prophylactically
removed. The remaining 24 patients are continuing with the
LES-EST; 20 patients have completed their 3-month and 17
their 6-month evaluation. The median (IQR) off-PPI GERDHRQL scores at baseline were 32 (26.5–37.0), which improved
to 4.0 (3.5–10.3; p < .001) on EST at months 3, and 5.0 (3.0–9.0;
p < .001) at month 6. There was significant improvement
in GERD-HRQL at both month 3 and 6 compared to their
baseline on-PPI GERD-HRQL scores of 16.5 (8.8–22.0;
p < .01). Patients’ median esophageal pH at baseline was
11.8% (8.9–15.1) which improved to 3.6% (2.7–12.0; p < .001)
at 3 and 3.5% (2.4–6.8; p < .001) at 6 months; 88% (15/17) of
patients at 6 months reported being able to discontinue ALL
PPI medication with one patient using PPI < 50% of diarydays. Fifty AEs in 17 patients were reported. Two SAE (trocar
perforation and AV nodal reentrant tachycardia — not device
or procedure related-successfully ablated) were reported;
48 non-serious events include 26 possible/probable device
or procedure, and one definite procedure related. There were
two instances of mild, transient dysphagia in 9/24 patients
undergoing hiatus closure at the time of device implant, both
resolved within 4 weeks without intervention. There were
no stimulation-related GI side effects or sensations reported.
▶ Drug Safety
ACG 2013 Abstract P398: Healthcare Resource Utilization and
Costs of Newly Treated GERD Patients Initiating Therapy With
Dexlansoprazole and Esomeprazole in the United States.
Emily Durden1, Reema Mody2, Lorena Lopez-Gonzalez1, David Smith1
1
Truven Health Analytics, Austin, TX, United States. 2Takeda Pharmaceuticals
International, Deerfield, IL, United States.
Purpose: To describe the healthcare resource utilization and
costs of newly treated patients with gastroesophageal reflux
disease who are initiating treatment with dexlansoprazole
(DEX) or esomeprazole (ESO).
Results: 965 and 4,749 newly treated patients initiating
therapy with DEX (age = 49.0 ± 13.0; 67.2% female) and
ESO (age = 50.7 ± 13.4; 64.1% female), respectively, were
identified. Patients treated with DEX had a lower mean
Charlson Comorbidity Index score than patients treated
with ESO (0.5 ± 1.0 vs. 0.6 ± 1.2; p < .0129). Total unadjusted
all-cause costs during the post-index period of patients
treated with DEX ($14,501 ± $24,884) were significantly
lower (p < .0002) than those of patients treated with ESO
($16,931 ± $34,295). The adjusted total annual mean cost
in the DEX group was $7,710 compared to $8,094 for the
ESO group. Total GERD-attributable costs in the post-index
period were also lower for patients treated with DEX ($1,086
± $1,808) (p < .0001) than for those treated with ESO ($1,225 ±
$1,763). Adjusted GERD-attributable annual mean cost was
$380 for patients treated with DEX vs. $441 for those treated
with ESO. Differences in total all-cause costs between DEX
and ESO groups can be attributed to differences in the costs
of outpatient services ($8,876 ± $13,956 vs. $9,509 ± $17,564;
p < .0001) and outpatient pharmacy claims ($2,886 ± $3,990
vs. $3,370 ± 6,732; p < .0001), whereas the differences in
GERD-related costs are largely attributable to differences
in the costs of outpatient pharmacy claims ($613 ± $622 vs.
$832 ± $847; p < .0001).
Conclusion: The one-year post-index healthcare costs of
newly treated GERD patients initiating therapy with DEX
were lower than those of patients initiating treatment with
ESO
CARE Faculty Perspective:
Proton-pump inhibitors (PPIs) continue to be the
standard of care for GERD treatment. However,
there is a subset of GERD patients that do not respond
well to PPI therapy that remain a particular treatment
challenge.
Conclusion: Interim results show that LES-EST is effective
in treating refractory GERD. There was a significant
improvement in patients’ esophageal pH, GERD symptoms,
and elimination of PPI usage. LES-EST was safe with no GI
side-effects. Long-term results in a larger group of patients
are being collected.
CARE Faculty — www.careeducation.ca
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 11
Eosinophilic Esophagitis (EoE)
ACG recently updated and published (April 2013) clinical
guidelines on the diagnosis and management of EoE. These
guidelines included many important and applicable points
to practice. Notable highlights from the review include the
following:
Diagnostic challenges: PPI-responsive esophageal
eosinophilia and GERD
▶ Proton-pump inhibitor esophageal eosinophilia
(PPI-REE) should be diagnosed when patients have
esophageal symptoms and have histologic findings of
esophageal eosinophilia, but demonstrate symptomatic
and histologic response to proton-pump inhibition.
At this time, the entity is considered distinct from
EoE, but not necessarily a manifestation of GERD.
(Recommendation conditional, evidence low.)
▶ To exclude PPI-REE, patients with suspected EoE
should be given a two-month course of PPIs followed
by endoscopy with biopsies. (Recommendation strong,
evidence low.)
Dietary treatments
▶ Dietary elimination can be considered as an initial
therapy in the treatment of pediatric and adult EoE.
(Strong recommendation, evidence moderate.)
▶ The decision to use a specific dietary approach
(elemental, empiric or targeted elimination diet)
should be tailored to individual patient needs and
available resources. (Recommendation conditional,
evidence moderate.)
Pharmacologic treatments
▶ Topical steroids (i.e., fluticasone or budesonide,
swallowed rather than inhaled, for an initial duration
of 8 weeks) are a first-line pharmacologic therapy for
treatment of EoE. (Recommendation strong, evidence
high.)
Reference: Dellon et al. Am J Gastroenterol 2013; 108:679–692; doi: 10.1038/ajg.2013.71
ACG 2013 Abstract of Interest:
ACG 2013 Abstract P618: Medical Intervention for Eosinophilic
Esophagitis: A Systemic Review and Meta-Analysis.
Tarek Sawas1, Mubarak Sayyar1, Ruben Hernaez2
1
Georgetown University Washington Hospital Center, Washington, DC, United States.
2
The Johns Hopkins School of Medicine, Baltimore, MD, United States
Purpose: Eosinophilic esophagitis is an uprising diagnosis
of dysphagia. The underlying pathophysiology is not well
understood, but allergic and immune mediated mechanisms
are suggested. Current medical therapies include steroids,
leukotriene receptor antagonists and immune modulators.
Whereas some patients has a histological response to topical
glucocorticoids as demonstrated by a decrease in eosinophil
counts, symptom improvement is not consistent. Given that
the condition is rare, we aimed to improve the power to
detect clinically significant effects by conducting a systematic
review and meta-analyses on medical therapies for EE.
12 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
Results: Out of 288 studies, twelve RCTs were selected
involving 787 patients. Symptomatic improvement (n = 7
studies, 303 participants) was noted in 56% of all treatment
groups comparing to 44% in the control group, Risk
difference RD: 0.11 (95% CI: -0.01, 0.24, p = .18), a RR of 1.18
(I-squared 32.8%). Treatment subgroup analysis showed
topical steroid treatment (n = 5 studies, 145 participants)
induced symptomatic improvement in 54.5 % compared to
45.6% in the placebo group, RD: 0.18 (95% CI: 0.01, 0.24,
p = .39). No meta-analysis was done on PPI and biologic
drugs since only one study in each group was included
in symptomatic improvement. Histologic Improvement
(n = 9 studies, 291 participants) was 37.6 % and 31.7% in
all treatment groups comparing to placebo respectively
RD: 0.07 (95% CI: -0.15, 0.29, p < .001). Subgroup analysis
for the histologic improvement showed that topical steroid
(n = 7 studies, 219 participants) induced complete response
in 36,8% compared to 22.8 in the placebo group RD: 0.13
(95% CI: -0.12, 0.37, p < .001).
Conclusion: Our finding shows that topical steroid induced
statistically significant histologic improvement. There was
a trend toward symptomatic improvement with topical
steroids but it was not statistically significant. There was
not enough data about PPI and biologic drugs to reach a
definite conclusion.
Drug Safety
Domperidone
ACG 2013 Abstract of Interest:
ACG 2013 Abstract P402: Changes in Domperidone
Prescribing Practices After a “Black Box” Warning: Are We
Exposing Inpatients to Unnecessary Cardiac Risk?
Nauzer Forbes1, Mohan Cooray1, Raed Al-Dabbagh1, Yuhong Yuan1, Frances Tse1, Louis
Liu2, Ted Xenodemetropoulos1
1
McMaster University, Hamilton, ON, Canada. 2University of Toronto, Toronto, ON,
Canada.
Purpose: Domperidone is used in Canada as a motility and
antiemetic agent. Inappropriate use is of particular concern
because of its associated risks of life-threatening ventricular
arrhythmias and sudden cardiac death. This study aimed
to assess the impact of a Health Canada advisory in 2012 on
domperidone prescription patterns.
Results: A total of 577 patients were included: 290 in 2005
(mean age 62.4) and 287 in 2012 (mean age 67.9). Compared
to 2005 (prior to the Health Canada advisory), significantly
less domperidone was initiated in hospital (71.4% vs.
39.4%, p < .0001), or was prescribed for non-approved
indications (84.8% vs. 58.2%, p < .0001) or at inappropriate
doses > 30 mg/day (65.5% vs. 47.4%, p < .0001) in 2012
(after the Health Canada advisory). In a multivariable
model, in-hospital initiation (OR = 7.01, 95% CI 4.52–
10.87, p < .0001) and domperidone use as a sole GI drug
(OR = 2.51, 95% CI 1.38–4.55, p = .002) predicted prescription
with non-approved indications. Basic cardiac risk
assessment and the performance of baseline laboratory tests
were not routinely done prior to initiation of domperidone,
although there was improvement in 2012 compared to 2005.
CARE Faculty — www.careeducation.ca
Conclusion: There has been more appropriate use of
domperidone following the Health Canada warning. Yet,
inappropriate utilization and inadequate pre-treatment
assessment remain common. Increased awareness of
domperidone’s indications and adverse effects could serve
to reduce inappropriate prescription and thereby improve
patient safety and reduce cost.
Proton Pump Inhibitors
ACG 2013 Abstract of Interest:
ACG 2013 Abstract P72: Impact of the FDA Safety
Communication on Prescription Trends of Clopidogrel in
Combination With Proton Pump Inhibitors.
Annie Guerin1, Reema Mody2, Valerie Carter1, Eric Wu1
1. Analysis Group, Inc., Boston, MA, United States. 2. Takeda Pharmaceuticals
International, Inc. , Deerfield, IL, United States.
Purpose: In 2009, FDA’s safety communication warned that
omeprazole reduced the antithrombotic effect of clopidogrel
by almost half. The aim of this study was to assess the
impact of the FDA safety communication on prescription
trends of clopidogrel in combination with PPIs.
Results:
Figure 2: Among Clopidogrel Users, Proportion of Patients Using a PPI-Clopidogrel
Combination
FDA Safety Communication
11/17/2009
Pre-Safety Communication Period
2006S01 - 2009S01
Pre-Safety Communication Period
2009S02 - 2011S02
Conclusion: The FDA safety communication resulted in an
overall decrease of PPI use by patients using clopidogrel.
However, among patients receiving combination therapy,
about one third still used omeprazole and a similar
proportion still used esomeprazole after the FDA safety
communication.
CARE Faculty — www.careeducation.ca
ACG 2013 Abstract P1271: The Role of Physician Knowledge
and the Inappropriate Initiation of PPI Therapy for Stress Ulcer
Prophylaxis in the ICU.
Sonaly Patel1, Eric Pauley1, Bhavik Bhandari1
Drexel University College of Medicine, Philadelphia, PA, United States.
1
Purpose: Our objective was to calculate the rate of
inappropriate PPI initiation in an academic ICU and the
contributing role of the prescribing physicians’ knowledge
of stress ulcer prophylaxis (SUP), as established by the
American Society of Health-System Pharmacists (ASHP).
Secondary aims were to determine the subsequent rate
of continuation of a PPI on hospital discharge, the rate
of missed indications for starting SUP and the rate of
gastrointestinal bleeding in patients not started on a PPI.
Results: Of 477 total patients, 212 patients were excluded
due to concurrent acid suppression therapy. One hundred
seventy seven patients were started on a PPI for SUP and
88 patients were not. The average age was 54 years, 56%
of the patients were male, 54% were Caucasian, 39% were
African-American, with an average ICU length of stay
of 6.7 days. Of the 177 patients, 101 patients (57%) were
inappropriately started on a PPI for SUP. However, only
three of these patients were subsequently discharged from
the hospital on a PPI. Of the 88 patients not begun on a
PPI, no indications for SUP were missed and no incidents
of gastrointestinal bleeding were reported. Fifty residents
who staff the ICU responded correctly to only 42% of the
questions for a knowledge deficit of 58% for SUP.
Conclusion: Our study demonstrates that 57% of
patients started on SUP were done so inappropriately.
The questionnaire suggested that the major determinant
was a lack of knowledge of ASHP guidelines. We believe
that the inclusion of a PPI in the ICU admission order set
leads to reflexive ordering. The rate of patient discharge
on inappropriate PPI prescription was very low, likely
due to a medication reconciliation program that requires
documentation of an appropriate indication. Given the
implications of PPI use on Clostridium difficile infection,
pneumonia, and the associated incremental costs, we have
proposed targeting this knowledge gap with each resident
receiving laminated cards with ASHP guidelines, posting
these on all ICU computers, and removing PPIs from
the admission order set. Based on the outcomes of our
intervention we hope to implement such targeted measures
in other areas.
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 13
Ulcerative Colitis
The abstract and presentation content/visuals that follow are drawn from Dr. Alain Bitton’s presentation at the CARE at ACG 2013
meeting, and are augmented with additional content from UEGW 2013 and commentary from the CARE Gastroenterology Faculty.
Topics covered in this section include:
▶ Medical Therapy▶ Disease Activity▶ Safety
­— 5-ASA Therapy
— Anti-TNF Therapy
­— Novel Therapy
Medical Therapy
5-ASA Therapy
ACG 2013 Abstracts of Interest:
ACG 2013 Abstract P439: Comparison of Long-Term
Outcomes of MMX Mesalamine Maintenance Treatment for
Ulcerative Colitis (UC) Between Patients (Pts) in Complete
Remission (CR) and Partial Remission (PR) Following
Induction.
David Rubin1, Susi Inglis2, Elizabeth Magee3, Paul Streck3, Dory Solomon3, Geert D’Haens4
University of Chicago Medicine, Chicago, IL, United States. 2Shire Pharmaceutical
Development Ltd, Basingstoke, United Kingdom. 3Shire Development LLC, Wayne, PA,
United States. 4Academic Medical Centre, Amsterdam, Netherlands.
1
Purpose: To determine whether pts with UC who achieved
CR (clinical and endoscopic remission) after induction
therapy with MMX mesalamine had better long-term
outcomes than those who demonstrated only PR after
induction therapy with MMX mesalamine.
Results: A total of 722 pts enrolled in the induction
phase; 717 were treated and 472 achieved either CR or
PR. Subsequently, 469 pts enrolled in the maintenance
phase, 461 were treated, and 459 had = 1 post-dose efficacy
assessment. Common reasons for early withdrawal from
maintenance (total n = 96) were lack of efficacy (n = 40)
and adverse events (AEs; n = 24). At mo 12 of maintenance:
47.8% (87/182) of pts in CR at mo, 0 remained in CR and
26.0% (72/277) of pts in PR at mo 0 achieved CR. At mo 12,
76.4% of pts in CR at mo, 0, and 63.5% in PR at mo 0 had
endoscopy scores of = 1; 65.4% and 57.0% had rectal bleeding
scores of 0, and 62.6% and 42.6% had stool frequency scores
of 0. A total of 37.2% (68/183) and 50.0% (139/278) of pts in
CR and PR at mo 0 experienced = 1 treatment-emergent AE
(TEAE). The most frequent TEAEs were (pts in CR at mo 0;
pts in PR at mo 0): UC (7.7%, 10.4%), headache (3.3%, 3.6%),
influenza (1.6%, 2.9%), and nasopharyngitis (2.7%, 2.2%).
Conclusion: This is the first study to explore scheduled
dose reduction from induction phase to maintenance phase
in pts with UC treated with MMX mesalamine. In this
analysis of the final dataset, the study’s primary endpoint
was met: after completion of maintenance treatment,
significantly more pts were in CR who began maintenance
in CR compared with those who began maintenance in PR.
The safety profile observed was consistent with previous
MMX mesalamine clinical studies.
14 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
ACG 2013 Abstract #1056: Impact of Non-Adherence to
Mesalamine on Relapse Rates and Healthcare Costs in Patients
With Ulcerative Colitis in Clinical Practice.
Kristin Burke1, Anne Gifford1, Adam Cheifetz1, Alan C. Moss1
1
Beth Israel Deaconess Medical Center, Boston, MA, United States.
Purpose: Non-adherence to maintenance mesalamine
has been associated with higher costs and relapse rates in
patients with ulcerative colitis. Little is known regarding
its impact in the clinical practice setting. We sought to
measure long-term relapse rates and healthcare costs in
a prospectively enrolled observational cohort of patients
with ulcerative colitis in clinical practice.
Results: We enrolled 107 patients and followed them for a
mean of 21 months. Low-adherent patients had a significantly
increased relapse rate as compared to high-adherent patients
(0.95 vs. 0.27 relapses/patient-year, p = .03). Time to relapse
was significantly shorter in low-adherent patients when
compared to high-adherent patients (mean 5 months vs.
7 months; p = .04). Low-adherent patients also had higher
healthcare utilization costs as compared to high-adherent
patients ($10,705.29 vs. $8,175.02, p = .10).
Conclusion: Low adherence to mesalamine is associated
with higher relapse rates, shorter time to relapse, and higher
associated healthcare costs in patients with ulcerative colitis
in clinical practice. This data should inform the benefits of
mesalamine adherence in the clinical setting.
CARE Faculty Perspective:
This study reinforced that adherence to therapy is
very important in terms of clinical outcomes. Patient
adherence should be taken into consideration when
making treatment decisions, with many products
available in this category.
Many patients do not adhere to conventional multi-dose
treatment regimens (2–3 times daily), which can result in
reduced efficacy, poor long-term prognosis, and increased
cost of care. Poor adherence can be especially challenging
when the disease appears dormant, because patients
who are not experiencing symptoms have no incentive to
take their medication. Although there are many factors
influencing medication adherence in patients with UC, it
is commonly believed that high pill burden and multidose regimens are major determinants.
CARE Faculty — www.careeducation.ca
There are once-daily dosing treatment regimens available
that reduce pill burden and can improve adherence and
outcomes. The PODIUM study presented at UEGW 2012
showed that once-daily, slow-release mesalazine dosing
was similarly effective to a twice-daily regimen. It was also
found to have higher patient compliance in terms of the
percentage of sachets used and higher compliance scores.
> 99%; 10 mg OR = 2.12, 95% CI 1.26, 3.57, p (better) > 99%).
This remained the case for sustained mucosal healing at week
52 (5 mg OR = 1.51, 95% CI 0.69, 3.31, pn (better) = 85%; 10 mg
OR = 1.54, 95% CI 0.70, 3.35, p (better) = 86%).
Conclusion: Based on indirect comparison of RCT evidence,
IFX seems more efficacious to induce and maintain long term
response than ADA among moderate to severe UC patients.
CARE Faculty Perspective:
Cost-effectiveness studies comparing the various antiTNF therapies currently available may influence the
selection of these therapies by healthcare payers.
Anti-TNF Therapy
ACG and UEGW 2013 Abstracts of Interest:
ACG 2013 Abstract P444: Time to Remission and Response
in Adalimumab-Treated Patients With Moderately to Severely
Active Ulcerative Colitis From ULTRA 2.
Jean-Frédéric Colombel , Scott Plevy , William Sandborn , Geert D’Haens
Icahn School of Medicine at Mt Sinai, New York, NY, United States. 2UNC School of
Medicine, Chapel Hill, NC, United States. 3UCSD, La Jolla, CA, United States. 4Academic
Medical Center, Amsterdam, Netherlands.
1
2
3
4
1
Purpose: To determine the time to achieve remission and
response per partial Mayo score (PMS) in patients with
moderately to severely active ulcerative colitis treated with
adalimumab (ADA) enrolled in ULTRA 2.
Results: The median time to remission was significantly
shorter for ADA-treated than PBO-treated pts (20 wks vs. 29
wks, respectively, p = .015). Similar results were observed for
median time to response (4 wks ADA-treated vs. 10 wks PBOtreated, p < .001). In subgroup analyses, ADA-treated pts, naïve
to prior anti-TNF therapy, achieved remission and response
significantly faster than PBO pts. In anti-TNF-experienced
pts, median time to response was similar for both treatment
groups (8 wks ADA-treated vs. 12 wks PBO-treated).
Conclusion: In ULTRA 2, pts with moderately to severely
active UC randomized to ADA had shorter times to
remission and response than pts randomized to PBO, even
though the latter included pts who moved from PBO to OL
ADA. Pts naïve to anti-TNF therapy derived the greatest
treatment benefit.
UEGW 2013 Abstract P340: Efficacy of Infliximab and
Adalimumab for the Treatment of Ulcerative Colitis ­— An
Indirect Comparison of RCT Evidence.
Megan Chen, Sruti Gurunath, Christopher Matthew Black, Tao Fan, Mohammad Ashraf
Chaudhary, Jeroen P. Jansen.
Introduction: Biologics have been demonstrated to be
effective in the treatment of patients with moderate to
severe ulcerative colitis.
Results: As induction treatment, IFX 5 mg showed greater
response (odds ratio = 2.13; 95% CI, 1.26, 3.61) and remission
(OR = 2.28; 95% CI, 1.12, 4.67) than ADA 160/80/40 mg. This
also holds for IFX 10 mg (response: OR, 1.98; 95% CI, 1.17, 3.34;
remission: OR = 1.76; 95% CI, 0.85, 3.64). Sustained response
(OR = 1.75; 95% CI 0.80, 3.93; p (better) = 92%) and remission
(OR =1.68; 95% CI 0.53, 5.49, p (better) = 81%) at 52 weeks
follow-up was more likely with IFX 5 mg than with ADA. IFX
10 mg showed similar results. IFX 5 mg and 10 mg showed
greater improvement in mucosal healing after induction than
adalimumab. (5 mg OR = 2.20, 95% CI 1.30, 3.71, p (better)
CARE Faculty — www.careeducation.ca
Novel Therapy
ACG 2013 Abstracts of Interest:
ACG 2013 Abstract #443: Early and Sustained Remission After
Treatment With Subcutaneously Administered Golimumab Is
Associated With Normalized Health-Related Quality of Life in
Patients With Moderate to Severe Ulcerative Colitis: PosthocAnalysis From PURSUIT Induction and Maintenance Trials.
William Sandborn1, Jean-Frederic Colombel2, Brian G. Feagan3
University of California San Diego, La Jolla, CA, United States. 2CHU, Lille, France.
3
Robarts Research Institute, London, ON, Canada.
1
Purpose: The PURSUIT studies were randomized, doubleblind, placebo-controlled studies to evaluate the safety and
efficacy of subcutaneous (SC) golimumab (GLM) in adults
with moderate to severe ulcerative colitis. Our purpose is to
assess the impact of early and sustained clinical remission
on heath-related quality of life (HRQOL) of patients with
active UC after SC administered GLM therapy.
Results: Compared to PBO, a significantly greater
proportion of GLM-treated patients achieved remission
at week 6. GLM-treated patients who achieved clinical
remission at week 6 had greater mean improvement in PCS,
MCS, EQ-5D, and IBDQ than those who did not achieve
remission (PCS: 8.0 vs. 2.9, p < .001; MCS: 10.7 vs. 2.6,
p < .001; EQ-5D: 21.4 vs. 7.2, p < .001; and IBDQ: 54.7 vs.
17.7, p < .001). Patients in clinical remission were more likely
to achieve normalized PCS, normalized MCS, and IBDQ
remission than those who did not achieve clinical remission
(PCS: 53.6% vs. 25.3%, p < .001; MCS: 63.6% vs. 31.6%,
p < .001; IBDQ: 85.5% vs. 32.2%, p < .001). Additionally,
GLM-treated patients who achieved clinical remission
during induction AND maintained clinical remission
at week 54 in maintenance were more likely to achieve
normalized PCS, MCS, and IBDQ remission than those
who did not (PCS: 73.5% vs. 22.7%, p < .001; MCS: 63.3%
vs. 28.4%, p < .001; IBDQ remission: 89.8% vs. 22.7%,
p < .001). Similarly, those who achieved clinical response or
mucosal healing also demonstrated better improvement in
HRQOL than those who did not achieved these outcomes,
but improvements in HRQOL were numerically lower than
in patients in clinical remission.
Conclusion: Early and sustained clinical remission was
associated with normalized HRQOL outcomes, and should
be considered as a treatment goal for patients with moderate
to severe UC.
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 15
CARE Faculty Perspective:
Study results on golimumab were first presented at
DDW 2011 as a late breaking abstract, then again with
induction and maintenance data from both ACG and
UEGW 2012. It is anticipated that golimumab will
be on the market within the next year or two. It was
positive to see that some patients achieved a response
within 2 weeks.
ACG 2013 Abstract P1636: Response Rates in the Control
Arms of Randomized Controlled Trials: A Systematic Review
and Meta-Analysis of Trials on Monoclonal Antibodies in
Ulcerative Colitis.
Michelle Buresi1, Gilaad G. Kaplan1, Guanmin Chen1, Subrata Ghosh1, Remo Panaccione1,
Ali Rezaie1
1
University of Calgary, Calgary, AB, Canada.
Purpose: Monoclonal antibodies (mAbs), which target
specific inflammatory molecules and/or pathways have
revolutionized the management of inflammatory bowel
diseases, including ulcerative colitis and Crohn’s disease.
Several randomized controlled trials (RCTs) assessing the
efficacy of mAbs have observed considerable response
rates in the control (i.e., placebo) arms. We performed a
systematic review and meta-analysis of RCTs on mAbs in
patients with UC to assess the magnitude and determinants
of clinical remission, clinical response, and mucosal healing
rates in the placebo arms.
Results: Of 1,077 potentially relevant studies, 15 RCTs
assessing anti-tumor necrosis factor, anti CD-20, anti CD-3,
anti-interlukin-2, and anti α4β7 Abs were included in the
analysis. One study assessed the “maintenance of remission,”
ten studies assessed the “induction of remission” and four
studies assessed both. For induction studies, the pooled
estimates of remission, response, and mucosal healing were
11% (95% CI 8–13), 37% (95% CI 32–43), and 29% (95% CI
22–36), respectively. For maintenance studies, the pooled
remission, response, and mucosal healing rates were 13%
(95% CI 9–16), 23% (95% CI 19–28), and 21% (95% CI 16–27),
respectively. Intravenous drugs were more likely to induce
remission than subcutaneous route (13% vs. 8%, p 0.03), but
clinical response and rate of mucosal healing were similar.
Studies which included < 40% females had higher clinical
response rates than studies with > 40% females (47% vs. 35%,
p 0.04), but clinical remission and rate of mucosal healing
were similar. We found no other trial/patient-related
characteristics to explain the heterogeneity of the data.
Conclusion: Significant clinical remission and response
rates are observed in the control arms of the RCTs on mAbs
in UC. Approximately one-third of the patients in the
placebo arms had objective mucosal healing. This may be
due to the relapsing and remitting clinical course of UC,
rather than any specific trial/patient-related characteristics.
Remission rates in the control arms are significantly lower
than mucosal healing rates. This may be due to overlapping
irritable bowel syndrome-like symptoms leading to
overestimation of activity indices. These results should
be considered in the design and sample size calculation of
future trials in UC.
16 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
Disease Activity
ACG 2013 Abstracts of Interest:
ACG 2013 Abstract P1647: Monocytosis and a Low
Lymphocyte to Monocyte Ratio Are Effective Biomarkers of
Ulcerative Colitis Activity Comparable to ESR and CRP.
Cynthia Cherfane1, Luke Gessel1, Dominic Cirillo2, Polyak Steven1
Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College
of Medicine, Iowa City, IA, United States. 2Department of Biostatistics and College of
Public Health, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa
City, IA, United States.
1
Purpose: ESR and CRP are routinely used as biomarkers
of ulcerative colitis disease activity, but are limited by their
sensitivity of 50–60%. Alterations in leukocyte subtypes have
been studied as biomarkers in inflammatory diseases, and
are routinely checked in patients with UC. The neutrophil
to lymphocyte ratio (NLR) was recently found to correlate
with UC disease activity. However, effects of medications
and infections on these parameters are unknown. The aim
of this study was to examine alterations in the leukocyte
profiles as markers of UC activity, including the effects of
medications and their potential to differentiate UC from
infectious colitis and subjects without inflammatory bowel
disease.
Table 3: Results
UC
active
UC
remission
p
value*
C. diff
p
value*
NonIBD
p
value*
Monocyte
count
594
[515–
684]
446
[397–
502]
< 0.001
754
[619–
919]
0.02
463
[397–
540]
0.002
Neutrophil
count
4472
[3892–
5137]
3807
[3398–
4266]
0.01
7298
[5928–
8987]
3735
< 0.001 [3205–
4352]
0.02
Lymphocyte
count
1462
[1268–
1685]
1514
[1371–
1671]
0.49
1339
[1095–
1638]
0.39
1867
[1609–
2166]
0.001
Lymphocyte
to monocyte
ratio
2.42
[2.03–
2.87]
3.36
[2.97–
3.80]
< 0.001
1.75
[1.362.25]
0.01
4
[3.32–
4.82]
< 0.001
Neutrophil to
lymphocyte
ratio
3.09
[2.57–
3.72]
2.59
[2.19–
3.06]
0.04
5.53
[4.25–
7.19]
< 0.001
2.01
[1.65–
2.44]
< 0.001
Conclusion: Monocytosis can distinguish active UC
from UC in remission, despite concurrent use of immune
mediating medications. A low LMR is also associated with
active UC, and, along with NLR, can differentiate from C. diff
colitis. These inexpensive and readily available laboratory
values can serve as inflammatory markers, comparable to
ESR and CRP, that will help alert clinicians to increased
disease activity in UC.
CARE Faculty — www.careeducation.ca
Safety
ACG 2013 Abstracts of Interest:
ACG Abstract P466: Long-Term Safety of Vedolizumab for the
Treatment of Ulcerative Colitis or Crohn’s Disease.
Jean-Frédéric Colombel1, Bruce Sands1, Stephen Hanauer2, Paul Rutgeerts3, William Sandborn4
1
Icahn School of Medicine at Mount Sinai, New York, NY, United States. 2University
of Chicago Medical Center, Chicago, IL, United States. 3Katholieke Universiteit and
University Hospital Gasthuisberg, Leuven, Belgium. 4University of California San Diego,
La Jolla, CA, United States.
Purpose: Vedolizumab (VDZ) is an investigational,
humanized monoclonal antibody targeting a4β7 integrin
for treating ulcerative colitis or Crohn’s disease.
Table 4: Results
UC (n = 704) %
CD (n = 1118) %
Drug related AE
37%
40%
AE leading to D/C
9%
10%
Serious AE
Serious infection
Drug related
18%
4%
2%
25%
7%
5%
< 1% (n = 3)
< 1% (n = 3)
Death
Conclusion: Results support the long-term safety of VDZ
treatment in UC and CD. The safety profile was consistent
with that observed in previous 1-year, phase 3 randomized,
placebo-controlled trials.
CARE Faculty Perspective:
The long-term safety data of vedolizumab use for UC
patients is positive, especially considering there have
been no recorded cases of progressive multifocal
leukoencephalopathy (PML). Vedolizumab, similar
to golimumab, will soon be on the market with
approval anticipated within a year.
LIVER DISEASE
The abstract and presentation content/visuals that follow are drawn from Dr. Rob Myers’ presentation at the CARE at ACG 2013 meeting
and are augmented with commentary from the CARE Gastroenterology Faculty.
Topics covered in this section include:
▶ HCV Screening
▶ Novel Therapies in HCV
HCV Screening
HCV-related morbidity/mortality is increasing in North
America due to aging of the affected population. Since
many patients are unaware of their infection (> 60% in U.S.),
the CDC has recommended HCV screening among Baby
Boomers (born 1945–1965) in addition to risk factor-based
screening. There is a high prevalence of HCV infection in
this population (3.6% in the U.S.), and these patients have
the highest admission rates.
ACG 2013 Abstracts of Interest:
ACG 2013 Abstract P228: Effectiveness of Birth Cohort
Screening for Hepatitis C: An Inner-City Experience.
Ayotokunbo Olosunde1, Prashant Sharma1, Gopal Kaza1, Ayyappa Mysore Rangaraju1
Interfaith Medical Center, Brooklyn, NY, United States.
1
Background: Persons born during 1945–1965 account for
approximately three-quarters of all chronic HCV infections
among adults in the United States. The CDC recommends
one-time testing for hepatitis C infection for this age group.
The objective of the study was to determine the effectiveness
of this birth cohort screening.
Results: A total of 396 patients were enrolled; 45 persons
who desired to be screened did not get the blood tests
done, 34 patients refused to have initial screening done,
CARE Faculty — www.careeducation.ca
157 persons had a known hepatitis C antibody status prior
to our encounter with them, and 85 persons were positive.
We screened 160 patients. 64.9% were African Americans,
and about 23.7% were Hispanics. 76% had a high school
level of education or less. Only one patient was found to
be positive out of 160 patients screened during the study
period, but this patient had a risk factor. About 87.2% of the
patients who were hepatitis C-positive were between the
ages of 48–68 years, but all had at least one risk factor. Age
based screening alone, however, did not show significant
correlation. 50.9% of the patients we screened had no
known risk factors, and were negative. 1.1 % of the hepatitis
C-positive patients did not have a risk factor documented.
Conclusions: In our patient population, a detailed history of
known risk factors for hepatitis C will detect the vast majority
of patients with the disease. Age only was insufficient as the
only criteria for screening. There was no patient within the
age cohort 1945 –1965 who was hepatitis C-positive, who
did not have at least one risk factor. In order to increase
detection rate of hepatitis C, educating the community on
the risk factors, and thereby increasing the awareness in
the community would lead to more patients presenting for
testing. In conclusion, birth cohort screening for hepatitis
C infection alone may not be cost-effective, given the large
number of negative results. Targeted screening based on at
least one known risk factor may detect a higher percentage
of undiagnosed new cases. Large community-based studies
are needed before cost-effective guidelines are adopted.
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 17
CARE Faculty Perspective:
In this study from inner city NY, a detailed history of
HCV risk factors detected the vast majority of infected
patients. There was no baby boomer who was HCVpositive that did not describe at least one HCV risk factor,
suggesting that age alone is an insufficient criterion for
screening. In order to increase the diagnosis of HCV,
educating the community on risk factors would lead
to more patients presenting for testing. Although risk
factor-based testing has proven somewhat inadequate
in Canada (i.e., an estimated ~30% of patients remain
undiagnosed), the applicability and cost-effectiveness
of birth cohort screening to our country is unclear
since the prevalence of HCV in baby boomers is likely
lower than in the U.S. Additional studies are needed to
address this issue in Canada.
ACG 2013 Abstract P852: HCV Screening: Are Primary Care
Physicians Following the New CDC Guidelines?
CARE Faculty Perspective:
If we adopt birth-cohort HCV screening in Canada,
uptake will be slow and education will be necessary for
both patients and physicians.
Novel Therapies in HCV
Currently available antiviral regimens for HCV (PEG-IFN/
RBV ± telaprevir or boceprevir) are limited due to suboptimal response rates in difficult-to-cure subgroups (e.g.,
patients with cirrhosis or prior non-response) and toxicity.
Particularly troubling adverse effects include anemia
(~40%), and rash (~40% with telaprevir), as well as a 5% risk
of decompensation and 2% risk of death among cirrhotic
patients (shown in the CUPIC study). The first-generation
protease inhibitors (boceprevir and telaprevir) also have
potential drug-drug interactions, a high pill burden, and
the need for prolonged therapy in many cases.
A new era of HCV treatment is coming with
cure rates > 90%, minimal toxicity, and few
pills/simple regimens.
Ritu Gupta1, Nizar Talaat1
1
Oakwood Hospital and Medical Center, Dearborn , MI, United States.
Background: To establish the current hepatitis C virus
screening rate for patients born between 1945–1965 in the
outpatient primary care clinics according to the new Center
for Disease Control (CDC) guidelines released in 2012.
Results: The total number of charts reviewed is 1,578. Males
represented 36% (569) of the total population and females
represented 64% (1,009) of the total population. The mean
age for all eligible patients was 56 years, with a standard
deviation of 6 years. Two percent (31) of patients from our
total enrolled patients were screened for HCV. A higher
number of patients (1,547) did not receive HCV screening,
representing 98% of the total eligible patients. The mean
age for the screened group was 57 years, compared to 56
years in the non-screened (p = .535). Among those who got
screened, 68% (21) were males, and 32% (10) were females,
compared to 35% (548) males and 65% (999) females in the
non-screened group (p < .001). Ninety-seven percent of the
screened patients had anti-HCV antibody testing, and 3%
had HCV RNA testing. Out of the 31 screened patients,
four patients (13%) tested positive for HCV; these patients
were referred to HCV specialists for further evaluation and
treatment.
Conclusions: Hepatitis C virus infection is the most
common indication for liver transplantation in the United
States and is a leading cause of hepatocellular carcinoma.
More than three-quarters of the newly diagnosed cases have
been identified as baby boomers, verified by studies done
by the CDC. The CDC has recently updated HCV screening
guidelines to include patients who were born between
1945–1965, regardless of their risk factors. Our study shows
the extremely low rates of HCV screening in the primary
care setting. These findings support the need to increase
awareness about hepatitis C screening. Adhering to these
guidelines would result in early detection and referral of
HCV positive patients for appropriate management. Future
educational interventions should target both patients and
primary care physicians, with frequent assessment and
re-evaluation of these interventions.
18 — ­­­­CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013
With a higher cure rate and the future availability of
interferon-free regimens, we can anticipate more patients
being treated. Having gastroenterologists in community
practice and primary care physicians treat will be necessary
to manage increased patient numbers if the goal is to reduce
the burden of HCV in our country.
Although many novel therapies are appear promising,
there are still questions that remain unanswered.
▶ What will be the optimal regimens in different
patient subgroups? There are many drugs coming,
so this will be a very competitive market.
▶ How will we choose what therapies to use with
which patients?
▶ How much will these therapies cost and who will
pay for them?
▶ When will they be available for public
reimbursement?
ACG 2013 Abstracts of Interest:
ACG 2013 Abstract #39: Safety and Efficacy of IFN-Free
Regimens of ABT-450/r, ABT-267, ABT-333 ± RBV in Patients
With Chronic HCV GT1 Infection: AVIATOR.
Kris Kowdley1, Eric Lawitz2, Fred Poordad2, Daniel E. Cohen3
Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States.
2
University of Texas Health Science Center, San Antonio, TX, United States. 3AbbVie, N
Chicago, IL, United States.
1
Background: To assess safety and efficacy of regimens of
ABT-450/r (HCV protease inhibitor dosed with ritonavir
100 mg, identified as a lead compound by AbbVie and
Enanta) with ABT-267 (NS5A inhibitor) and/or ABT-333
(non-nucleoside NS5B inhibitor) +/- ribavirin (RBV).
Overall ITT SVR12 rate for 12-week treatment with three
DAAs + RBV was 98.7% (78/79) in treatment-naïve patients,
and 93.3% (42/45) in null responders.
CARE Faculty — www.careeducation.ca
Results: There is no difference seen between 12 and 24
weeks therapy.
Figure 3: Results of SVR24 Rates
Conclusions: Comparable responses were seen with 12 and
24 weeks of treatment, supporting selection of a 12-week
duration of therapy in these populations. Consistently high
SVR rates were achieved in naïve and prior null responder
patients with a 3-DAA + RBV regimen, across HCV subtype,
IL28B genotype, baseline HCV-RNA, or severity of fibrosis.
CARE Faculty Perspective:
The objective of this study was to evaluate the safety and
efficacy of this interferon-free regimen that includes a
protease inhibitor, polymerase inhibitor, and NS5A
inhibitor (with ribavirin). The study demonstrated very
high cure rates (> 90% in naïve and null responders
with HCV genotype 1) with no difference between 12
and 24 weeks therapy. Toxicity was minimal. Phase 3
data is eagerly anticipated.
ACG 2013 Abstract #38: Sofosbuvir + RBV ± PEG-IFN is WellTolerated & Associated With High SVR Rates: Integrated Results
From 4 Phase 3 Trials in HCV Genotype 1-6.
Kris Kowdley1, Mitchell Shiffman2, Aasim M. Sheikh3, Alessandra Mangia4
1
Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States.
2
Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News,
VA, United States. 3GI Specialists of Georgia, Marietta, GA, United States. 4Casa Sollievo
della Sofferenza Hospital, San Giovanni Rotondo, Italy.
Background: To evaluate the efficacy and safety of
sofosbuvir (SOF) combination treatment in patients
chronically infected with hepatitis C virus.
Results: See Table 5.
Conclusions: Twelve weeks of SOF combination therapy
was well-tolerated and effective in the treatment of HCV
GT 1–6. Previously treated patients with GT 3 infection may
benefit from extending treatment to 16 weeks.
CARE Faculty Perspective:
The objective of this study was to evaluate the safety
and efficacy of sofosbuvir. The results showed excellent
cure rates (e.g., ~90% in patients with genotype 1), no
resistance in treatment failures, and minimal toxicity
(treatment D/C only 0–2% in all SOF arms). Patients
with cirrhosis were included in these studies, with very
good response rates (80% in patients with genotype 1 with
sofosbuvir/peginterferon, and ribavirin). Sofosbuvir
has been submitted for Health Canada approval, and
will hopefully be approved shortly.
Table 5: Results for Treatment in HCV GT 1–6
GT 1, 4, 5, 6
G2/3
NEUTRINO
FISSION
POSITRON
FUSION
SOF/PEG/RBV
(n = 327)
SOF/RBV
(n = 253)
PEG/RBV
(n = 243)
SOF/RBV
(n = 207)
PBO
(n = 71)
SOF/RBV 12W
(n = 100)
SOF/RBV 16W
(n = 95)
Overall
91%
67%
67%
78%
0%
50%
73%
G2
N/A
97%
78%
93%
0%
86%
94%
G3
N/A
56%
63%
61%
0%
30%
62%
Non-Cirrhotic
93%
72%
74%
81%
0%
61%
76%
Cirrhotic
80%
47%
38%
61%
0%
31%
66%
CARE Faculty — www.careeducation.ca
CARE Gastroenterology Faculty Conference Report ACG 2013 / UEGW 2013 — 19
UPCOMING CARE EVENT
CARE
@ DDW 2014
CHICAGO, ILLINOIS
MAY 2014
CAREEDUCATION.CA
COMMUNITY, ACADEMIC & RESIDENT EDUCATION
This CONFERENCE REPORT provides educational updates on current trends in medicine. Views expressed in this report are those of the faculty. All information
is provided for general informational purposes only, on an “as is” basis, without any representations, warranties or conditions, whether express or implied,
statutory or otherwise, including, without limitation, any representations, warranties or conditions as to quality, accuracy, completeness, currency, reliability,
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report was provided by Abbvie, Boehringer Ingelheim, Ferring, Janssen, Shire, Takeda and Warner Chilcott.