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1729
Rome III
1780
A classification is a way of seeing the
world at a point in time. There is no doubt
that scientific progress and experience
with the use of these guidelines
will ultimately require their
revision and update.
N Sartorius, WHO ICD-10, 1994
1743
Vision of Rome Foundation
 Promote clinical recognition and
legitimization of FGIDs
 Develop a scientific understanding of
the pathophysiological mechanisms
to achieve optimum treatment
1703
Medline Citations for Irritable Bowel Syndrome
700
600
500
400
#
citations
300
200
100
0
1963 1967 1971 1975 1979 1983 1987 1991 1995 1999 2003
1555b
Rome Publications
1st FGID
classification
1992-1995
5 Rome I
publications
2003
Rome
Foundation
2006
Gastroenterology
2000
Supplement
1999
+
1994
Rome II Book
Rome
II
1990
Rome III Book
Degnon Assoc.
1989
Gut
Rome I Book
Degnon Assoc.
Little Brown Supplement
Gastroenterology
International
Journal
1st IBS
criteria
1683
IBS
Rome Criteria Medline Citations
105
100
90
80
70
60
#
50
citations
40
30
20
10
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Year
1555a
Rome III
 Rationale for Diagnostic Criteria
1686
Rome III - Rationale for Symptom Criteria
 Symptoms not explained by abnormal motility
 Symptoms defined by multiple factors
Motility
Visceral hypersensitivity
Inflammation and mucosal immune dysfunction
Brain-gut dysfunction
 Epidemiological support
Factor analysis defines symptom-based subgroups
Frequencies similar across populations
 Treatment implications
 Provides diagnostic standards
For clinical trials and clinical care
Modeled after DSM system in psychiatry
1203
FGID - Conceptual Model
Early Life
• Genetics
• Environment
Psychosocial
Factors
• LIfe stress
• Psychologic state
• Coping
• Social support
Brain
CNS
Gut
ENS
Physiology
• Motility
• Sensation
• Inflammation
• Altered bacterial
flora
Outcome
FGID
• Symptoms
• Behavior
• Medications
• MD visits
• Daily function
• Quality of life
1035
Rome III
 Rationale for Diagnostic Criteria
 Administrative Structure
1687
Rome Foundation,
Inc. 1996
Board of Directors
D. Drossman (President)
E. Corazziari
M. Delvaux
R. Spiller
J. Kellow
Italy
France
UK
Australia
USA
N. Talley
W.G. Thompson
W. Whitehead
L. Chang
USA
Canada
USA
USA
Administration
George Degnon
Carlar Blackman
Kathy Haynes
Rome Committees
Working Teams
CD Committee
14 Committees
87 Members
18 Countries
2 Committees
16 Members
4 Countries
6 Committees
28 Members
7 Countries
Intnl. Resource
Committee
12 Pharmaceuticals
FDA, IFFGD, NIH
1682
Rome III
 Rationale for Diagnostic Criteria
 Administrative Structure
 Activities/Projects
1689
Rome III – Activities/Projects
 Rome III Book – August, 2006
 Gastroenterology 13th Issue – April, 2006
Reduced Versions of Chapters
 New Working Teams
 Severity,
 Brain Imaging,
 Role of Physiology in FGID’s
 Sponsored Research (Epidemiology, Validation,
Spanish Translation of Rome III)
 Validated Questionnaire with “Red Flags”
 Translations in numerous languages
 Web site: www.romecriteria.org
 CD Slide Set (6 Committees) - 2008
1690a
• UPDATE SLIDE
• Outcomes
• physiology
Rome III Working Teams
Guidelines for Brain Imaging in the FGIDs
Emeran Mayer, USA, Chair
Qasim Aziz, UK, Co-Chair
 Douglas Bremner, USA
 Mark Kern, USA
 Brad Kuo, USA
 Richard Lane, USA
 Bruce Naliboff, USA
 Irene Tracey, UK
Guidelines for Severity in the FGIDs
Douglas A. Drossman, USA, Chair
Lin Chang, USA, Co-Chair
 Nicholas Bellamy, Australia
 Hugo Gallo Torres, FDA, USA
 Tony Lembo, USA
 Fermin Mearin, Spain
 Nancy Norton, IFFGD, USA
 Peter Whorwell, UK
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Rome III CD Committees
Basic Science – Jack Wood, USA, Chair
Lionel Bueno, France
John Kellow, Australia
Epidemiology – Fermin Mearin, Spain, Chair
George Longstreth, USA
Paul Moayyedi, Canada
Nick Talley, USA
Diagnosis and Criteria – Arnold Wald, USA, Chair
Brooks Cash, USA
Enrico Corazziari, Italy
Tony Lembo, USA
Stu Spechler, USA
Jan Tack, Belgium
1797
Rome III CD Committees
Psychosocial, HRQOL, Brain Imaging – Ami Sperber, Israel, Chair
 Elspeth Guthrie, UK
 Rona Levy, USA
Bruce Naliboff, USA
 Kevin Olden, USA
Management, Treatment Trial Design - William Chey, USA, Chair
 Lin Chang, USA
Michel Delvaux, France
 E. Jan Irvine, Canada
 W. Grant Thompson, Canada
Pediatric – Carlo Di Lorenzo, USA, Chair
Marc Benninga, Netherlands
 Ernesto Guiraldes, Chile
 Jeffrey Hyams, USA
 Paul Hyman, USA
1798
Rome III
 Rationale for Diagnostic Criteria
 Administrative Structure
 Activities/Projects
 Timeline for Slide Set Committees
1691
Rome III – Timeline for CD Committees
 Board selects Chair/Co-Chairs* – October 2005
 Chairs/Co-Chairs select committees* – December 2005
 Chairs/Co-Chairs conference call – December 2005
 Content Development – February–May 2006
 Orientation/Process Learning at DDW – May 2006
 Graphic Development I – May–December 2006
 CD Committee Meeting I – January 2007
 Graphic Development II – January-April 2007
 CD Committee Meeting II – May 2007
 Graphic Development III – May-October 2007
 Submission to Board and Release – January 2008
* Criteria: 1) Research record, 2) Intl. recognition, 3) Ability to work in group
4) Geographical diversity
1781
Rome III Committees
 Rationale for Diagnostic Criteria
 Administrative Structure
 Activities/Projects
 Timeline for Slide Set Committees
 Chapter Structure
1693
Rome III Committees – Chapter Structure
Criteria Related Chapters
Introduction
Diagnostic Entities
Definition
Epidemiology
Diagnostic Criteria
Justification for Change in Criteria
Clinical Evaluation
Physiological Features
Psychological Features
Treatment
Recommendations for Future Research
 Content Area Chapters
Revised chapters maintain same structure
New chapter formats created by chair/co-chair
1694
Rome III Committees
 Rationale for Diagnostic Criteria
 Administrative Structure
 Activities/Projects
 Timeline for Slide Set Committees
 Chapter Structure
 Changes for Rome III
1695
Changes for Rome III – Classification and Criteria
 Time Frame: “Criteria fulfilled in last 3 months with symptom
onset at least 6 months prior to diagnosis”
 Classification Changes:
 Rumination now a Functional Gastroduodenal Disorder
 FAPS is a separate Category (not Functional Bowel)
 Two Pediatric Categories:
 Neonate/Toddler
 Child/Adolescent
 Functional Dyspepsia De-emphasized for Research
 Postprandial Distress Syndrome
 Epigastric Pain Syndrome
 More Restrictive Criteria for GB and SO Dysfunction
 Stool Consistency to Identify IBS Subtypes
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Rome III Criteria* –
Irritable Bowel Syndrome
Recurrent abdominal pain or discomfort at least 3 days/month
In the last 3 months associated with 2 or more :
Improvement
with
defecation
and
Onset
associated with
a change in
frequency of
stool
and
Onset
associated with
a change in
form
(appearance) of
stool
* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.
Longstreth GF, Gastroenterology 2006
1782
Rome III – Subtypes of IBS
100
75
%
Hard or lumpy 50
stools
IBS-C
IBS-M
IBS-U
IBS-D
25
0
0
25
50
75
100
% Loose or watery stools
1709
Rome III
Functional Dyspepsia (B1a)
FD
Postprandial
Distress
Syndrome
(B1a)
PDS
EPS
Epigastric
Pain
Syndrome
(B1b)
1792
Rome III
Diagnostic Criteria* for Functional Dyspepsia
Must include one or more of the following:
Bothersome
postprandial
fullness
or
Early
satiation
or
Epigastric
pain
or
Epigastric
burning
And
 No evidence of structural disease (including
at upper endoscopy) that is likely to explain
the symptoms
* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.
1793
Rome III
Diagnostic Criteria* for
Postprandial Distress Syndrome
Must include one or both of the following:
Bothersome
postprandial fullness
 occurring after
ordinary-sized meals
 at least several times
a week
or
Early satiation
 that prevents finishing
a regular meal
 and occurs at least
several times a week
* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.
1794
Rome III
Diagnostic Criteria* for
Epigastric Pain Syndrome
Must include all of the following:
Pain or burning which is:
 intermittent,
 localized to the epigastrium of at least moderate severity,
at least once per week,
 and NOT: generalized or
relieved by
fulfilling
localized to
other
abdominal or
chest regions
defecation or
flatulence
criteria for
gallbladder or
sphincter of
Oddi disorders
* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.
1795
Rome III
Functional Gall Bladder and Sphincter of Oddi Disorders
Diagnostic Criteria: Must include episodes of pain located in the
epigastrium and/or right upper quadrant and ALL of the following:
 Episodes lasting 30 minutes or longer
 Recurrent symptoms occurring at different intervals (not daily)
 Pain:
 Builds up to a steady level
 Is moderate to severe enough to interrupt daily activities
 Is not relieved by:
 Bowel movements
 Postural change
 Antacids
 Other structural symptoms that could explain symptoms are
excluded
Supportive Criteria: The pain may present with one or more of:
 Association with nausea or vomiting
 Radiates to the back and/or right infra subscapular region
 Awakens from sleep in the middle of the night
1800
Rome III
Functional Gall Bladder Disorder
Diagnostic Criteria: Must include ALL of the following:
Criteria for
functional
gallbladder and
sphincter of
Oddi disorder
Gallbladder
is present
Normal liver
enzymes,
conjugated
bilirubin, and
amylase/lipase
1801
Rome III
Functional Biliary Sphincter of Oddi Disorder
Diagnostic Criteria: Must include BOTH of the following:
Criteria for
functional
gallbladder and
sphincter of Oddi
disorder
Normal
amylase/lipase
Supportive Criterion:
Elevated serum transaminases, alkaline phosphatase, or conjugated
bilirubin temporarily related to at least two pain episodes
Functional Pancreatic Sphincter of Oddi Disorder
Diagnostic Criteria: Must include BOTH of the following:
Criteria for
functional
gallbladder and
sphincter of Oddi
disorder
Abnormal
amylase/lipase
1802
Rome III Committees
 Rationale for Diagnostic Criteria
 Administrative Structure
 Activities/Projects
 Timeline for Committees
 Chapter Structure
 Changes for Rome III
 Issues and Limitations
1698
Rome III Committees – Issues and Limitations
 Criteria Not Fully Evidence Based
Limited data for most functional GI disorders
Original criteria by consensus
Changes based on new evidence
New changes need validation
 The Field is Expanding and Growing
Information not “set in stone”
Knowledge can quickly become outdated
Classifications will change – e.g., “Organification”
 Need for Quality Control
Disclosure of relationships with Pharmaceuticals
Confidentiality statements
International Resource Committee
Embargo on information until final editing stages
1778
Future Issues for Rome Foundation
 Global educational programs
 Support for validation studies
 Partner with regulatory agencies
 Working team initiatives
 Mechanism for research support
 Diversification in structure
1703
What’s new?
Functional dyspepsia
• Dyspepsia as previously defined unhelpful
• De-emphasize functional dyspepsia
• New syndromes suggested for research: PDS and EPS
Nausea and vomiting
• Two new syndromes (CIN and CVS)
Definition of Dyspepsia
“Pain or discomfort centered in the
upper abdomen”
Rome Working Teams I and II
Rome III discards this definition
Talley et al. Gut 1999;45:II37-42
Functional Dyspepsia: Rationale for
Changes from Rome II
 No single symptom present in all patients with functional
dyspepsia
 Considerable variation in symptom pattern between patients
 Despite Rome II recommendations, studies still include heartburn
and acid regurgitation as
“dyspepsia”1
1Armstrong
et al. Can J Gastroenterol 2002; 16; 439-50
Peura et al. Am J Med 2004; 116: 740-8
Moayyedi et al. Gastroenterology 2004; 127: 1329-37
Dyspepsia Usually Polysymptomatic
Aliment Pharmacol Ther. 2003;17:1481-91
99% >2; > 80% >5; < 0.1% 1 symptom
Functional Dyspepsia (FD): Rome II
 12 weeks (within 12 months) of persistent or recurrent dyspepsia
(pain or discomfort centered in upper abdomen)
 No evidence of organic disease likely
to explain symptoms (including EGD)
 Not irritable bowel syndrome (IBS)
 Subgroups (ulcer-like, dysmotility-like) based on predominant
symptom
Talley et al. Gut 1999;45(Suppl. 1):I28–31
Subdividing FD by Predominant Symptom
50
GE Delay Hypersens
n = 720; 489 women; mean age, 41
*
45
40
Prevalence (% of
patients)
35
30
25
Sens
85%
33%
Spec
25%
44%
*
20
15
10
5
Predominant discomfort (n=562)
0
Predominant pain (n=158)
Delayed solid
Delayed liquid
Hypersensitivity
Impaired
H. pylori
emptying
emptying
to gastric
accommodation
infection
distention
Karamanolis et al. Gastroenterology 2006; 130:296-303
Unexplained pain or discomfort centered in upper
abdomen (Rome II FD)
 Not one disorder
 Lack of evidence for the
predominant symptom as
criterion
 Support from factor analysis in
tertiary care and in general
population
 Expert opinion
De-emphasize FD
Functional Dyspepsia
FD
PDS
EPS
Rome III functional dyspepsia
Bothersome
postprandial
fullness
or
Early
satiation
or
Epigastric
pain
or
Epigastric
burning
Functional Dyspepsia
FD
Postprandial
Distress
Syndrome
PDS
EPS
Epigastric
Pain
Syndrome
Rome III
 FD retained for clinical practice
 PDS and EPS proposed for research based on
factor analysis and expert opinion
Rome III
Diagnostic Criteria* for
Postprandial Distress Syndrome (PDS)
Must include one or both of the following:
or
Bothersome
postprandial fullness
 that prevents finishing a
 occurring after
ordinary-sized meals
 at least several times
week
Early satiation
regular meal
a
 and occurs at least
several times a week
* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.
Factor Analysis Supports EPS and PDS
45% of the U.S. population report upper
GI symptoms
Telephone survey of 21,128 adults
Camilleri et al. Clin Gastroenterol Hepatol. 2005;3:543-52
Factor analyses in populations and referral
practice
All found a meal related factor
Study
Westbrook 2002
Population
Population sample
n
2300
Result
3 dyspeptic symptom factors
Tertiary care
438
4 dyspeptic symptom factors
Jones 2003
Population sample
888
3 dyspeptic symptom factors
Kwan 2003
Tertiary care
1012
3 dyspeptic symptom factors
Whitehead 2003
Tertiary care
1041
4 dyspeptic symptom factors
Population sample 21128
3 dyspeptic symptom factors
Fischler 2003
Camilleri 2005
Piessevaux submitted Population sample
2025
3 or 4 dyspeptic symptom factors
Tack in preparation
638
3 dyspeptic symptom factors
Tertiary care
Rome III
Diagnostic Criteria* for
Epigastric Pain Syndrome (EPS)
Must include all of the following:
Pain or burning which is:
 Intermittent,
 Localized to the epigastrium of at least moderate
severity, at least once per week,
 and NOT:
generalized or
localized to other
abdominal or
chest regions
relieved by
defecation or
flatulence
fulfilling criteria
for gallbladder
or sphincter of
Oddi disorders
* Criteria fulfilled for the last 3 months with symptom onset at least
6 months prior to diagnosis.
Distinct Dyspepsia Subgroups:
New Data
Olmsted County population data
EPS
135
(39%)
9 (3%)
Comparison of overlap of subgroups
between observed and expected
CIN
n=37
(11%)
Observed (n)
Expected
(n)
p-value
EPS
vs. CIN
16
35
0.006
EPS
vs. PDS
32
83
<0.001
PDS
vs. CIN
23
33
0.078
7 (2%)
25
(7%)
16
(5%)
PDS (early
satiety)
114 (32%)
Choung et al. DDW 2006
* Assuming the subgroups were independent
Rome III
Overlap with GERD
Heartburn does not exclude a
diagnosis of FD (PDS or EPS)
if dyspepsia persists despite a trial of
adequate acid suppression
Evidence: expert opinion
Rome III
50
45
Coexisting IBS no
major impact on
symptom pattern
or putative
pathophysiologica
l mechanisms
Prevalence (% of patients)
Overlap with IBS
Dyspepsia
Dyspepsia + IBS
*
40
35
30
* P<0.05
25
20
15
10
5
0
Delayed emptying H. pylori positive Hypersensitivity
Impaired
accommodation
Corsetti et al. Am J Gastroenterol. 2004;99:1152-9
Nausea and Vomiting
 Cyclic vomiting syndrome (CVS) now a recognized
syndrome in adults
AJG 2001; 96: 684-8
Rome III
Cyclic vomiting syndrome (CVS)
At least 3 months, with onset at least 6 month previously, of:
 Stereotypical episodes of vomiting regarding onset (acute) and
duration (less than one week)
 3 or more discrete episodes in the prior year
 Absence of nausea and vomiting between episodes
Supportive criteria: History of migraine headaches or a family history
of migraine headaches
Rome III
Chronic idiopathic nausea (CIN)

Separate from FD (factor analyses)

Bothersome nausea, occurring at least several times per
week in the last 3 months

Not usually associated with vomiting

Absence of abnormalities at upper endoscopy or metabolic
disease that explains the nausea
Rome III: What’s new?
Functional dyspepsia
• Dyspepsia as previously defined unhelpful: focus on early
satiation and/or postprandial fullness and/or epigastric pain
• De-emphasize functional dyspepsia
• New syndromes suggested for research: PDS and EPS
Nausea and vomiting
• Two new syndromes (CIN and CVS)
Functional Bowel Disorders
 Irritable Bowel Syndrome
 Functional Bloating
 Functional Constipation
 Functional Diarrhea
 Unspecified Functional Bowel Disease
Main Changes in IBS Criteria
• Introduction of a frequency threshold of 3 days/ month over 3
months for symptoms
• Reduction of the duration of symptoms before one can make
firm diagnosis from 12 to 6 months
• Refining of subtypes
Rome II
Diagnostic criteria for IBS
At least 12 weeks, which need not be consecutive, in the
preceding 12 months of abdominal discomfort or pain that
has two of three features:
 Relieved with defecation; and/or
 Onset associated with a change in
and/or
frequency of stool;
 Onset associated with a change in form (appearance) of stool.
Thompson et al Gut 1999;45 Suppl 2:II43-II47
Rome III
Diagnostic Criteria for IBS*
 Recurrent abdominal pain or discomfort
 3 days per month in the last three months
associated with two or more of the following
 Improvement with defecation; and/or
 Onset associated with a change in frequency of stool; and/or
 Onset associated with a change in form (appearance) of stool
* Criteria fulfilled for the last 3 months with symptom onset  6 months
prior to diagnosis
Subclassifying IBS
Why bother?
 Important for choosing therapies which alter bowel habit
 Subtypes likely to have different pathophysiology
 Transit
 Stool consistency
 Rectal sensitivity?
Previous Features Used to Subclassify
IBS Patients
1. Fewer than three bowel movements a week
2. More than three bowel movements a day
3. Hard or lumpy stools
4. Loose (mushy) or watery stools
5. Straining during a bowel movement
6. Urgency (having to rush to have a bowel movement)
 Constipation-predominant 1 or more of 1, 3, or 5 and none of 2, 4, or 6
(or 2 of 1, 3 or 5 and 1 of 2, 4 or 6)
 Diarrhea-predominant 1 or more of 2, 4, or 6 and none of 1, 3, or 5 (or
2 of 2, 4 or 6 and 1 of 1 or 5 but not 3)
Problems With Old System
 Complex to apply and caused confusion in both patients and
clinicians!
 Multidimensional but different dimensions don’t correlate
well
 Failed to deal adequately with patients with both hard and
loose stools
IBS Patients with Features of Both
Constipation and Diarrhea are Common
Reference
N
IBS-D
IBS-C
IBS-M
Mearin 2003
209
10
24
37
Tillisch 2005
1102
32
17
32
Drossman
2005
317
36
34
31
Rome III subtyping is based on
Stool Consistency alone
• Assessed from stool form
Defining Stool Consistency
Bristol Stool Form Scale
Hard
Normal
Loose
Why Stool Consistency as Main
Determinant of Subtype?
 Correlates best with colonic transit
Colonic Transit & Stool Form
80
Colonic transit
time (hours)
40
0
1
2
3
4
5
Bristol stool form score
O'Donnell et al Br Med J 1990;300:439-40
6
7
Why Stool Consistency as Main
Determinant of Subtype?
 Correlates best with colonic transit
 Correlates best with what patients and community
samples think of as “diarrhoea”
 Principle determinant of incontinence
 Other features occur in IBS with both loose & hard stools
 Stool frequency <3/weeks or >3/day
 Urgency, Sense of incomplete evacuation
Association of bowel symptoms with
stool consistency
Tillisch et al Am J Gastroenterol. 2005; 100:896-904
Proposed New Subtyping Based on Stool
Consistency Alone
 IBS with constipation
 IBS with diarrhoea
 IBS mixed type
 (IBS unsubtyped
- IBS-C
- IBS-D
- IBS-M
- IBS-U)
 IBS-mixed : patients with both hard & loose stools over
periods of hours or days
Alternating IBS
 Patients who change subtype over periods
of weeks and months
Rome III Subtypes of IBS
100
75
% Hard or
Lumpy Stools
50
IBS-C
17%
IBS-M
46%
IBS-U
3.9%
IBS-D
32%
25
0
0
25
50
75
%Loose or Watery Stools
Tillisch et al Am J Gastroenterol. 2005;100:896-904
100
Quantifying Stool Form
Date
Pain
Pain
Severity
Urgency
Y/N
Bloating
Y/N
1
2 3
4
5
Pain: grade 0-10
0= absent
5=moderate
10 very severe
Stool form
1= separate hard lumps, like nuts
6 = fluffy pieces with ragged edges
2= sausage shaped but lumpy
7 = watery, no solid pieces
3= like a sausage or snake, but with cracks
on its surface
4= like a sausage or snake, smooth and soft
5= soft blobs with clear cut edges
6
7
8
Changes to IBS classification
Rome III Summary
 No change to basic criteria
 Length of time needed to define chronicity reduced to 6
months
 Threshold 3 days / month introduced for frequency of
pain / discomfort
 Subtyping simplified (stool consistency)
 Stability of subtypes and link to other features like
visceral sensitivity and response to treatment remain to
be determined
FUNCTIONAL GALLBLADDER
AND
SPHINCTER OF ODDI DISORDERS
Motility abnormalities of the Gallbladder, the
Biliary, and Pancreatic Sphincter of Oddi
Epigastric or right
upper quadrant pain
NOT EXPLAINED BY STRUCTURAL ABNORMALITIES
DIAGNOSTIC CRITERIA FOR FUNCTIONAL GALLBLADDER AND
SPHINCTER OF ODDI DISORDERS
Epigastric or right upper
quadtrant pain
severe
Pain located in the
epigastrium and/or
right upper quadrant
PAIN
Steady
moderate
mild
30 min
Relieved by
Bowel Movements
Postural Change
Antacids
The pain is moderate to
severe enough to
interrupt the patient’s
daily activities or lead to
an emergency department
visit
time
Episodes lasting 30 minutes or longer The
pain builds up to a steady level
Not
1.
2.
3.
Recurrent symptoms
occurring at different
intervals (not daily)
Supportive Criteria
The pain may present with one or more of
the following:
a. Associated with nausea and vomiting
b. Radiates to the back and/or right
infra subscapular region
c. Awakens from sleep in the middle of
the night
ROME III ALGORITHM FOR FUNCTIONAL GB DISORDERS
Diagnostic criteria for functional GB and SO disorders
LFTs/pancreatic, enzyme, US
Esophagogastroduodenoscopy
Structural
alterations
Normal findings
Appropriate
investigation and
treatment
GB CCK cholescintigraphy
GBEF < 40%
GBEF > 40%
Cholecystectomy
Reassess
ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO
DISORDERS
Structural
alterations explaining
the symptoms
Cholecystectomized
Diagnostic criteria for functional GB and SO disorders
LFTs/pancreatic enzymes, US
Esophagogastroduodenoscopy
EUS, MRCP
Appropriate
Investigation
and treatment
Milwaukee
Classification
 Pain and
Milwaukee
Classification
 LFTs in Revised
2
 Pain
and
occasions
and
 At
LFTs
ERCPin 2 occasions
and

Dilated CBD >12mm
ATand
US

Dilated
CBD
>8mm
Delayed
contrast
drainage
Biliary
Type I
Biliary
Type II
Pain and
One or two of type
I criteria
Biliary
Type III
Pain and
None of the type
I criteria
ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO
DISORDERS
Cholecystectomized
Diagnostic criteria for functional GB and SO disorders
LFTs/pancreatic enzymes, US
Esophagogastroduodenoscopy
EUS, MRCP
Structural
alterations explaining
the symptoms
Appropriate
Investigation
and treatment
Biliary
Type I
Biliary
Type II
Biliary
Type III
ES
Abnormal
SOM
ES
ERCP
with SOM
Normal
SOM
Reassesses
ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO
DISORDERS
Cholecystectomized
Diagnostic criteria for functional GB and SO disorders
LFTs/pancreatic enzymes, US
Esophagogastroduodenoscopy
EUS, MRCP
Structural
alterations explaining
the symptoms
Biliary
Type I
Biliary
Type II
Biliary
Type III
Pharmacological
trials
Appropriate
Investigation
and treatment
No
response
Abnormal
SOM
ES
ERCP
with SOM
Normal
SOM
Reassesses
Response
ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO
DISORDERS
Cholecystectomized ,
Criteria for functional GB and SO Disorders
Clinical history, LFTs/pancreatic enzymes, US
Esophagogastroduodenoscopy
EUS, MRCP
Structural
alterations
explaining
the
symptoms
Biliary
Type I
Biliary
Type III
Biliary
Type II
BILI[CHOLEDOCHO]SCINTIGRAPHY
Appropriate
Investigation
and
treatment
ES
Pharmacological
trials
No
response
Abnormal
SOM
ES
ERCP
with SOM
Normal
SOM
Reassesses
Response
ROME III ALGORITHM FOR FUNCTIONAL PANCREATIC
SO DISORDERS
Criteria for functional GB and SO disorders,
Elevated amylase and lipase
No obvious association with alchool, gallstones, drugs, Ca2+
US, Esophagogastroduodenoscopy, CT, EUS,MRCP
Diagnostic ERCP
Structural
abnormalities
No Structural
abnormalities
SO manometry
Sphincterotomy
Abnormal
Normal
Reassess
Functional
Esophageal
Functional
Abdominal Pain
Functional
Billiary
Functional
Gastroduodenal
Rome III
Diagnostic
Questionnaire
IBS &
Functional Bowel
Functional
Anorectal
Rationale for Changing to Ordinal Scales to
Measure Symptom Frequency
• Rome II questionnaire applied the same frequency threshold to
all symptoms
• Some symptoms are not clinically meaningful unless they occur
daily while others are significant if they occur at all
• Rome II questions were difficult to understand because they
incorporated multiple frequency thresholds
• Scales for judging relative severity would be useful
Goals of the Questionnaire Development
and Validation Process
• Develop a questionnaire that incorporates the Rome III
criteria as an aid to diagnosis
• Insure that questions are understandable
• Validate the questionnaire & the criteria by comparing
to diagnoses made by clinicians
Study I
Compare 4 Alternative Response Scales
• Subjects 120 healthy controls & 84 FGID
• Design: 4 versions of the questionnaire were completed
in counterbalanced order
– Binary: No or rarely vs. often
– Specific Frequency: Monthly, weekly, daily
– Relative Frequency: Occasionally, often, always
– Bothersome: A little bit, moderately, quite a bit
Subjects are Inconsistent in How They Use the
Binary Response Scale
Frequency of Abdominal Pain or Discomfort
100%
"never or rarely"
"often"
80%
60%
40%
20%
0%
never
monthly
>weekly
Principal Findings of Study I
• For intermediate symptom frequencies, ordinal scales
are more reliable
• Specific Frequency Scales give the best balance
between sensitivity & specificity but Relative
Frequency Scales perform almost as well
• Bothersome Scale performs similar to Relative
Frequency Scale but is not appropriate to some
symptoms
Two Scales Selected for Rome III
Specific Frequency Scale
Relative Frequency Scale
Never
Never or rarely
Less than 1 day a month
Sometimes
One day a month
Often
One day a week
Most of the time
More than 1 day a week
Always
Every day
Questionnaire Development
• Rome board suggested initial questions
• Working teams provided additional items
• Questionnaire Committee met for 2 days to insure
that the questions matched the diagnostic criteria
• Data from the validation study were referred back to
the Rome board & working teams for revisions to
criteria & thresholds
Sample Question
In the last 3 months, how
often did you have discomfort
or pain anywhere in your
abdomen?
 Never
 Less than 1 day a month
 One day a month
 Two to three days a month
 One day a week
 More than one day a week
 Every day
Study II: Validation Study
• Subjects
– 554 healthy controls (75% participation)
– 399 FGIDs (66% participation)
• 328 IBS, 27 constipation, 10 FD, 32 miscellaneous
• There were 4 study sites: UNC, Mayo Clinic, University of
Michigan, & University of Toronto
• Test – retest agreement on diagnosis assessed in 53 controls &
51 patients over 2 weeks
Understandability
• 18 of 77 questions were rated difficult to understand by
1% or more of subjects
• 4 questions were rated difficult by 2%
• All but one of these 18 questions were revised
• No revision for, “In the last 3 months, how often did you
feel uncomfortably full after a regular sized meal.”
(Rated difficult by 1.2%)
Selecting Frequency Thresholds so That
Less Than 10% of Controls are “Abnormal”
Frequency of Abdominal Pain or Discomfort
40%
35%
30%
25%
20%
15%
10%
Healthy
y/
m
1
da o
y/
2m
3
o
da
y/
m
1
da o
y/
w
>1
k
da
y/
w
Ev
k
er
yd
ay
<1
da
N
ev
er
5%
0%
Selecting Frequency Thresholds so That
Less Than 10% of Controls are “Abnormal”
Frequency of Abdominal Pain or Discomfort
40%
35%
30%
25%
20%
15%
10%
Healthy
IBS
y/
m
1
da o
y/
2m
3
da o
y/
m
1
da o
y/
w
>1
k
da
y/
w
Ev
k
er
yd
ay
<1
da
N
ev
er
5%
0%
Effects of Different Thresholds
on Sensitivity & Specificity
539 healthy controls & 326 IBS patients
Abdominal pain
Frequency threshold
Sensitivity Specificity
of IBS Dx of IBS Dx
>1 day a week
48.5%
98.2%
1 day a week
55.5%
94.3%
2-3 days per month
70.7%
87.8%
Specificity: Percent of Healthy
Controls Who Would be
Misclassified
Misdiagnosed
Estimated
Controls
Specificity
IBS
Constipation
12.2%
3.5%
87.8%
96.5%
Diarrhea
Functional dyspepsia
Postprandial distress
Epigastric pain
0.1%
5.9%
0.7%
0
99.1%
94.1%
99.3%
100%
0.9%
99.1%
Chronic idiopathic nausea
Reliability: Test-Retest Agreement
Over a 2-Week Interval
Specificity
Test-Retest
Agreement
IBS
Constipation
Diarrhea
87.8%
96.5%
99.1%
81.7%
93.3%
96.2%
Functional dyspepsia
Postprandial distress
Epigastric pain
94.1%
99.3%
100%
84.6%
85.6%
98.1%
99.1%
96.2%
Chronic idiopathic nausea
Conclusions
• A major innovation of Rome III is ordinal scale with
individual frequency thresholds
• Rome III diagnostic questionnaire is reliable:
– Questions reflect the criteria & are understandable
– Test-retest reliability is excellent
– Specificity of diagnostic criteria is excellent
Application of Diagnostic Criteria
Consensus derived criteria
Questionnaire
Validation
Published trial and survey data
Can it be applied to my patient?
To Interpret Data Obtained Using
Rome III Questionnaire, I Must Consider:
1. Was the questionnaire altered?
2. What was the purpose of the study?
3. How was the study population selected?
4. Can the data (evidence) from that trial or
be applied to my patient?
survey
1. Was the Questionnaire Altered?
Questions – how were they asked?
Also, algorithms, inclusions and exclusions
 Determined by consensus, existing data
 To suit their study, investigators may adjust:
 Time requisite (acute vs. chronic)
 Cut-off levels for inclusion
 Exclusions
1. (cont) Was the questionnaire altered?
Frequency Scale “Cut-offs”
How often in last 3 months did you have pain?
a. Never
b. Once a month or less
c. Two to three times/month
d. Once a week
e. Several times a week
f. Every day
Rome III
Cut-offs determine who is included!
1. (cont) Was the questionnaire altered?
Frequency Scale “Cut-offs”
How often in last 3 months did you have pain?
a. Never
b. Once a month or less
Survey
c. Two to three times/month
d. Once a week
e. Several times a week
f. Every day
Cut-offs determine who is included!
1. (cont) Was the questionnaire altered?
Frequency Scale “Cut-offs”
How often in last 3 months did you have pain?
a. Never
b. Once a month or less
c. Two to three times/month
d. Once a week
e. Several times a week
f. Every day
Clinical trial
Cut-offs determine who is included!
1. (cont) Was the questionnaire altered?
Exclusions
Q8. ..did you often have heartburn..?
Q9. ..did you .. have difficulty swallowing..?
Rome II coding:
Functional heartburn; Q8=yes, and no to dysphagia
Functional dysphagia; Q9=yes, and no to heartburn
1. If “yes” to both, neither disorder exists because,
according to the coding, one excludes the other.
2. Data not applicable to excluded patients.
2. What was the Purpose of the Study?
1. To aid diagnosis
2. To select subjects for clinical research
3. To survey populations
2. What was the Purpose of the Study?
1. To aid diagnosis
 Severity/frequency relevant
 Inclusive
 Symptoms now
2. To select subjects for clinical research
 Severity/frequency more relevant
 Exclusive
 Symptoms now
3. To survey populations
 Severity/frequency less important
 Inclusive
 Symptoms ever, or during defined period
3. How was the Study Population Selected?
 Were Rome III criteria used?
 How were subjects recruited (adverts,
tertiary care, CROs)?
 Were there investigator adjustments (e.g.
time requirement, cut-offs, exclusions)?
4. Can Data from a Trial or Survey be Applied to
my Patient?
 Does my patient fulfill the same criteria?
 Is he or she similar to the study population?
 Do the time requisites, scales, and exclusions used in
the study exclude my patient?
 In a trial where placebo effect>therapeutic gain, will my
patient realize a similar placebo effect?
Summary: When Applying Results of a Study where
the Rome Criteria were Used, Ask:
1. How were criteria translated into questions:
– Time requirement, cut-offs, and exclusions?
2. Were there unique adjustments for:
– Clinical Trial?
– Epidemiological survey?
– Clinical Practice?
- severe cases now
- include all cases
- precision
3. Does my local population or my patient resemble the
study’s population?
4. Will my management help my patient achieve as great a
placebo effect as those in the study?
Use of the Rome Criteria
Clinical
Trials
Clinical
Research
Clinical
Practice
Existing Trials
Improved methodology
Existing Trials
Meta-analyses
Negative trials?
Regulatory Authorities
Regulatory
Authorities
EMEA PTC
2003
FDA Advices
Expert Panels
Definition of a Responder, Vienna 1998
Expert Panels
European Panel, APT 2003
Rome I, Rome II
Challenges for FGIDs clinical trials
 Natural course of the condition
–Unstable symptom pattern
–Fluctuating intensity
 Multicomponent pathophysiology
–Multiple therapeutic targets
–Multiple endpoints
 Bias of outcome measures
–High placebo response
–Difficulty to maintain double masking
–Contamination by parallel interventions
–Lack of placebo control for some interventions
• Psychotherapy, hypnotherapy, sphincterotomy
 Avoiding harm
–FGID non-life-threatening
Definition of the Studied Population



Clearly define the FGID to be treated
Define subgroups
 Transit abnormalities
Explicit inclusion/exclusion criteria
 Gender
 Symptoms intensity
 Comorbidities
 Treatment exclusions
Compromise between the largest target in the
population and a strictly homogenous group
The Standard Trial Design
• Superiority trial
– The most robust design:
• parallel groups, randomized allocation, double
blind
– Single intervention
– Placebo-controlled
Placebo
Run-in
Treatment Phase
Intervention
Run-out
70
Percentage of responders
80
*p < 0.05
**p < 0.001
70
60
50
*
* * * * * *
* * *
60
*
50
* * *
40
*
40
30
30
20
10
20
Alosetron (n = 237)
Placebo (n = 221)
Treatment
Follow-up
0
0
0
2
4
6
8
Weeks
Tegaserod
Placebo
10
10
12
Camilleri et al.
Lancet 2000; 355: 1035-1040.
14
16
-2
1
3
Run-in
5
7
9
11 13 15
Follow-up
Novick et al.
APT 2002; 16:1877-1888.
From Rome II to Rome III
• Unsolved issues with standard design
 Duration of the treatment intervention
 4 weeks versus 12 weeks
 Longer treatments: 6 months
 Outcome measures
 Alternative trial designs
 On-demand or « Pro Re Nata (PRN) » treatments
 Treatment – Re-treatment design
Treatment – Re-treatment
EMEA PTC 2003
NR
Carry-over
Active Drug
Unblinding
Active Drug
R
of the intervention
Enrichment in
responders
Placebo
Natural cycle of symptoms
NR
Ethical considerations
No symptom
Active Drug
Active Drug
R
Placebo
NR
Symptoms +
Placebo
1
RT
NR
50
Responders (%)
Active drugst
40
1 T
R
4 weeks
RT
Active drug
1stT
symp(37%
R)
4 weeks
No symp
Placebo
Tegaserod
 Placebo
R
30
Placebo
NR
20
=9.3%
=16.6%
=9.1%
=15.91%
10
0
IBS-C
symptoms
Tack et al. Gut 2005; 54: 1707-1713
Abdominal
discomfort/pain
Definition of Outcome Measures
 Primary outcome
 Global assessment
 Adequate relief
 Definition of a responder
 Symptom questionnaire
 Pain assessment
 Secondary outcomes
 Mechanism of intervention
 Symptoms influenced by a
specific pharmacodynamic
effect
 Quality of life
 Health economics
 Tolerance and safety
Definition of a Responder
Symptom Relief
Completely
Markedly
Somewhat
25 %
50 %
75 %
100 %
Time
Conclusion
 Rome criteria have driven significant methodological
advances over the last two decades for the design of
FGIDs clinical trials.
 Alternative designs need to be further explored but
should not replace standard comparative trials.
 Outcome measures and definition of a responder are
critical issues influencing the clinical relevance of the
results.