Arun's FULL THESIS 3.0

83 Pages·2014·1.02 MB·English

by  Arun Gupta

Understanding
 the
 role
 of
 infections

in
 the
 pathogenesis
 of
 inflammatory
 bowel
 disease,

and
 improving
 the
 quality
 and
 safety
 of
 treatment

By

DR
 ARUN
 GUPTA

MBBS
 (University
 of
 Melbourne,
 1998)

In
 July
 2014

SUBMITTED
 IN
 TOTAL
 FULFILMENT
 OF
 THE
 REQUIREMENTS

OF
 THE
 DEGREE
 OF
 DOCTOR
 OF
 MEDICINE
 (MD)

TO
 THE
 DEPARTMENT
 OF
 MEDICINE

AT
 THE
 UNIVERSITY
 OF
 MELBOURNE

SUPERVISOR

Professor
 Finlay
 Macrae

The
 Royal
 Melbourne
 Hospital

COSUPERVISOR

Associate
 Professor
 Carl
 Kirkwood

Murdoch
 Childrens
 Research
 Institute
page
 2
 of
 278

ABSTRACT

Inflammatory
 bowel
 disease
 (IBD),
 comprising
 Crohn’s
 disease
 and
 ulcerative

colitis
 are
 chronic
 inflammatory
 diseases
 of
 the
 gastrointestinal
 tract.

 These

conditions
 cause
 significant
 morbidity
 and
 reduced
 quality
 of
 life
 in
 patients
 who

are
 often
 young.

 The
 pathogenesis
 of
 IBD
 is
 uncertain,
 however
 the
 current

paradigm
 is
 mucosal
 inflammation
 caused
 by
 a
 dysfunctional
 interaction
 between

the
 innate
 immune
 system
 and
 the
 bacterial
 microbiota
 within
 the
 gastrointestinal

tract.

 Single
 nucleotide
 polymorphisms
 (SNPs)
 of
 genes
 related
 to
 innate

immunity
 such
 as
 pattern
 recognition
 receptors,
 mucosal
 barrier
 and
 autophagy

are
 likely
 to
 play
 an
 important
 role.

Despite
 the
 potential
 role
 of
 altered
 innate
 immunity,
 the
 mainstay
 of
 treatment
 of

inflammatory
 bowel
 disease
 is
 immunosuppressive
 medications.
 This
 includes

thiopurine
 drugs,
 which
 affect
 lymphocyte
 function,
 and
 monoclonal
 antibody

therapy
 based
 on
 inhibition
 of
 tumour
 necrosis
 factor
 α.

 Although
 often
 effective,

these
 medications
 have
 the
 potential
 to
 increase
 the
 risk
 of
 infections
 and

malignancy.

This
 thesis
 examines
 the
 role
 of
 infections
 in
 inflammatory
 bowel
 disease,
 initially

assessing
 the
 role
 of
 the
 bacterial
 microbiota
 through
 analysis
 for
 the
 putative

pathogen
 Mycobacterium
 avium
 subspp.
 paratuberculosis,
 and
 attempts
 to

correlate
 these
 findings
 with
 a
 multiplex
 analysis
 of
 SNPs
 previously
 associated

with
 IBD.

 The
 microbiota
 is
 then
 analysed
 more
 broadly
 using
 a
 metagenomic
 type

approach
 with
 a
 custom
 phylogenetic
 oligonucleotide
 microarray
 based
 on
 16s

ribosomal
 RNA
 probes.

Approaches
 to
 improving
 quality
 and
 safety
 in
 IBD
 are
 then
 examined.

 A
 survey
 of

Australian
 gastroenterologists
 in
 relation
 to
 screening
 for
 latent
 infections
 and

vaccination,
 with
 respect
 to
 immunomodulators
 and
 monoclonal
 antibody

therapies
 was
 carried
 out
 and
 discussed.
 A
 comprehensive
 audit
 of
 the
 use
 of

infliximab,
 an
 anti-­‐TNFα
 agent
 at
 a
 tertiary
 metropolitan
 hospital
 was
 undertaken.

A
 novel
 electronic
 clinical
 decision
 support
 system
 was
 designed
 with
 the
 aim
 of

improving
 the
 clinical
 governance
 related
 to
 these
 agents,
 and
 the
 impact
 of
 this

system
 was
 examined.
 A
 study
 to
 assess
 the
 use
 of
 pharmacogenetics
 and

measurement
 of
 thiopurine
 metabolites
 to
 improve
 the
 safety
 of
 thiopurine
 use

was
 conducted
 in
 addition.
page
 3
 of
 278

DECLARATION

In
 presenting
 this
 thesis
 in
 full
 fulfillment
 of
 the
 requirements
 of
 a
 higher
 degree
 at

the
 University
 of
 Melbourne,
 I
 declare
 that
 this
 thesis
 comprises
 only
 my
 original

work
 except
 where
 indicated
 in
 the
 Preface.

Due
 acknowledgement
 has
 been
 made
 in
 the
 text
 to
 all
 other
 material
 used,
 and

the
 thesis
 is
 fewer
 than
 100
 000
 words
 in
 length,
 exclusive
 of
 tables,
 maps,

bibliographies
 and
 appendices.

 (Signature)

 ___________________
page
 4
 of
 278

PREFACE

The
 work
 submitted
 in
 this
 submitted
 in
 this
 thesis
 is
 the
 original
 work
 of
 the

candidate
 apart
 from
 the
 following
 declarations.

In
 chapter
 one
 (analysis
 of
 inflammatory
 bowel
 disease
 mucosal
 microbiota
 and

correlation
 with
 patient
 genotype),
 microbial
 analysis
 of
 specimens
 for

Mycobacterium
 avium
 subspp.
 paratuberculosis
 was
 performed
 in
 collaboration

with
 Dr.
 Josef
 Wagner
 and
 Associate
 Professor
 Carl
 Kirkwood
 (cosupervisor)
 at
 the

Murdoch
 Childrens
 Research
 Institute.

 In
 chapter
 two,
 design
 of
 the

oligonucleotide
 microarray
 and
 specimen
 analysis
 was
 performed
 in
 collaboration

with
 Dr.
 Seungha
 Kang
 and
 Dr.
 Chris
 McSweeney
 of
 the
 Commonwealth
 Scientific

and
 Industrial
 Research
 Organisation,
 Department
 of
 Livestock
 Industries
 in
 St

Lucia,
 Queensland,
 Australia.

In
 chapter
 three
 (vaccination
 and
 screening
 for
 infections
 in
 patients
 with

inflammatory
 bowel
 disease:
 a
 survey
 of
 Australian
 gastroenterologists),
 Professor

Peter
 Gibson
 of
 Box
 Hill
 Hospital
 (at
 the
 time)
 assisted
 with
 study
 design
 and

analysis
 for
 the
 journal
 article
 published
 in
 Internal
 Medicine
 Journal.

In
 chapter
 five
 (a
 qualitative
 study
 of
 the
 use
 of
 a
 clinical
 decision
 support
 system

to
 improve
 quality
 and
 safety
 in
 inflammatory
 bowel
 disease),
 this
 was

collaboration
 with
 Dr.
 Kirsty
 Buising
 of
 the
 Victorian
 Infectious
 Diseases
 Services

at
 The
 Royal
 Melbourne
 Hospital.

 Dr.
 Buising
 helped
 design
 the
 online
 modules
 in

the
 Guidance
 system.

In
 chapter
 six
 (Thiopurine
 methyltransferase
 and
 thiopurine
 metabolite
 testing
 in

patients
 with
 inflammatory
 bowel
 disease
 on
 a
 stable
 dose
 of
 thiopurine

medications),
 this
 study
 was
 performed
 in
 collaboration
 with
 Professor
 Leslie

Sheffield
 of
 Genetic
 Health
 Services
 Victoria
 at
 the
 Murdoch
 Childrens
 Research

Institute,
 and
 Dr.
 Peter
 Irving
 and
 Dr.
 Miles
 Sparrow
 at
 Box
 Hill
 Hospital.

 Only
 the

data
 acquired
 by
 the
 author
 at
 The
 Royal
 Melbourne
 Hospital
 is
 presented
 and

analysed
 in
 this
 thesis,
 separate
 to
 the
 grouped
 analysis
 published
 in
 the
 journal

Pharmacogenomics.

 The
 analysis
 of
 this
 data
 and
 formulation
 of
 results
 and

discussion
 were
 performed
 by
 the
 author
 independently.
page
 5
 of
 278

TABLE
 OF
 CONTENTS

ABSTRACT
 .................................................................................................................
 2

DECLARATION
 ...........................................................................................................
 3

PREFACE
 ....................................................................................................................
 4

TABLE
 OF
 CONTENTS
 .................................................................................................
 5

LIST
 OF
 FIGURES
 ........................................................................................................
 7

LIST
 OF
 TABLES
 ..........................................................................................................
 9

GLOSSARY
 ...............................................................................................................
 11

SECTION
 ONE:

 ANALYSIS
 OF
 THE
 MICROBIOTA
 AND
 GENETIC
 FACTORS
 IN

INFLAMMATORY
 BOWEL
 DISEASE
 ...........................................................................
 12

HYPOTHESIS
 ....................................................................................................................
 13

AIMS
 ...............................................................................................................................
 13

LITERATURE
 SEARCH
 ................................................................................................
 15

INTRODUCTION
 ...............................................................................................................
 15

GENETICS
 .........................................................................................................................
 19

MICROBIOLOGY
 OF
 IBD
 ...................................................................................................
 33

CHAPTER
 1:
 ANALYSIS
 FOR
 MYCOBACTERIUM
 AVIUM
 SUBSPP
 PARATUBERCULOSIS

AND
 COMPARISON
 WITH
 GENOTYPE
 .......................................................................
 65

ABSTRACT
 .......................................................................................................................
 65

HYPOTHESIS
 ....................................................................................................................
 66

AIMS
 ...............................................................................................................................
 67

GENOTYPING
 FOR
 SINGLE
 NUCLEOTIDE
 POLYMORPHISMS
 ..............................................
 70

RESULTS
 ..........................................................................................................................
 73

DISCUSSION
 .....................................................................................................................
 87

CHAPTER
 2:
 MICROBIOTA
 ANALYSIS
 USING
 OLIGONUCLEOTIDE
 MICROARRAY
 ........
 91

ABSTRACT
 .......................................................................................................................
 91

HYPOTHESIS
 ....................................................................................................................
 92

AIMS
 ...............................................................................................................................
 92

METHODS
 ........................................................................................................................
 93

RESULTS
 ..........................................................................................................................
 95

DISCUSSION
 ...................................................................................................................
 105

SECTION
 TWO:

 QUALITY
 AND
 SAFETY
 IN
 INFLAMMATORY
 BOWEL
 DISEASE
 ..........
 109

HYPOTHESIS
 ..................................................................................................................
 110

LITERATURE
 SEARCH
 ..............................................................................................
 112

INTRODUCTION
 .............................................................................................................
 112

TREATMENT
 OF
 IBD
 .......................................................................................................
 114

ADVERSE
 EVENTS
 DUE
 TO
 MEDICATIONS
 USED
 TO
 TREAT
 IBD
 .......................................
 118

VACCINATION
 IN
 IBD
 .....................................................................................................
 129

CLINICAL
 DECISION
 SUPPORT
 SYSTEMS
 (CDSS)
 ..............................................................
 147

CHAPTER
 3:
 VACCINATION
 AND
 SCREENING
 FOR
 INFECTIONS
 IN
 PATIENTS
 WITH

INFLAMMATORY
 BOWEL
 DISEASE:
 A
 SURVEY
 OF
 AUSTRALIAN

GASTROENTEROLOGISTS
 .......................................................................................
 150

ABSTRACT
 .....................................................................................................................
 150
page
 6
 of
 278

HYPOTHESIS
 ..................................................................................................................
 151

METHODS
 ......................................................................................................................
 152

RESULTS
 ........................................................................................................................
 152

DISCUSSION
 ...................................................................................................................
 158

CHAPTER
 4:
 AN
 AUDIT
 OF
 TUMOUR
 NECROSIS
 FACTOR
 ALPHA
 INHIBITORS
 USED
 FOR

INFLAMMATORY
 BOWEL
 DISEASE
 IN
 A
 TERTIARY
 HOSPITAL
 ..................................
 166

ABSTRACT
 .....................................................................................................................
 166

HYPOTHESIS
 ..................................................................................................................
 167

METHODS
 ......................................................................................................................
 168

RESULTS
 ........................................................................................................................
 168

DISCUSSION
 /
 ANALYSIS
 ................................................................................................
 179

CHAPTER
 5:
 A
 QUALITATIVE
 STUDY
 OF
 THE
 USE
 OF
 A
 CLINICAL
 DECISION
 SUPPORT

SYSTEM
 TO
 IMPROVE
 QUALITY
 AND
 SAFETY
 IN
 INFLAMMATORY
 BOWEL
 DISEASE
 185

ABSTRACT
 .....................................................................................................................
 185

HYPOTHESIS
 ..................................................................................................................
 186

METHODS
 ......................................................................................................................
 187

RESULTS
 ........................................................................................................................
 189

DISCUSSION
 ...................................................................................................................
 200

CHAPTER
 6:
 THIOPURINE
 METHYLTRANSFERASE
 AND
 THIOPURINE
 METABOLITE

TESTING
 IN
 PATIENTS
 WITH
 INFLAMMATORY
 BOWEL
 DISEASE
 ON
 A
 STABLE
 DOSE
 OF

THIOPURINE
 MEDICATIONS
 ...................................................................................
 210

ABSTRACT
 .....................................................................................................................
 210

HYPOTHESIS
 ..................................................................................................................
 211

METHODS
 ......................................................................................................................
 212

RESULTS
 ........................................................................................................................
 213

DISCUSSION
 ...................................................................................................................
 223

CHAPTER
 7:
 CONCLUDING
 CHAPTER
 ......................................................................
 228

INTRODUCTION
 .............................................................................................................
 228

MICROBIOTA
 STUDIES
 ...................................................................................................
 229

QUALITY
 AND
 SAFETY
 IN
 IBD
 .........................................................................................
 232

CONCLUSION
 .................................................................................................................
 238

REFERENCES
 ..........................................................................................................
 241

APPENDIX
 ..............................................................................................................
 278
page
 7
 of
 278

LIST
 OF
 FIGURES

FIGURE
 1
 STRUCTURE
 OF
 NOD2
 PROTEIN
 AND
 LOCATION
 OF
 ASSOCIATED
 SNPS.
 ADAPTED
 FROM

VERMEIRE
 AND
 RUTGEERTS
 (2005)
  21

FIGURE
 2
 CONTINGENCY
 TABLE
 WITH
 CORRELATION
 OF
 PRESENCE
 OF
 MYCOBACTERIUM
 AVIUM

PARATUBERCULOSIS
 (MAP)
 AND
 NOD2
 GENOTYPE
  71

FIGURE
 3
 POWER
 CALCULATIONS
 FOR
 NOD2
 /
 MAP
 CONTINGENCY
 TABLE
  72

FIGURE
 4
 CONCURRENT
 MEDICATION
 USE
 AMONGST
 PATIENTS
 WITH
 CROHN'S
 DISEASE
  76

FIGURE
 5
 BETWEEN
 GROUP
 ANALYSIS
 BETWEEN
 CROHN’S
 DISEASE
 INFLAMED
 (CDI),
 CROHN’S
 DISEASE

NON-­‐INFLAMED
 (CDNI),
 ULCERATIVE
 COLITIS
 (UC),
 AND
 THE
 CONTROL
 GROUP
 (‘NOR’)
  95

FIGURE
 6
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 FAECALIBACTERIUM
 PRAUSNITZII
 IN

DIFFERENT
 GROUPS
 (P=0.04)
  97

FIGURE
 7
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 ENTEROCOCCUS
 AVIUM
 IN
 DIFFERENT

GROUPS
 (P=0.162)
  98

FIGURE
 8
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 CLOSTRIDIUM
 PROTEOLYTICUM
 IN

DIFFERENT
 GROUPS
 (P=
 0.002)
  98

FIGURE
 9
 HEAT
 MAP
 ANALYSIS
 COMPARING
 CROHN’S
 DISEASE
 (INFLAMED)
 AND
 CONTROL
 GROUPS
  99

FIGURE
 10
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 F.
 PRAUSNITZII
 BETWEEN
 CDI
 AND

CONTROL
 GROUPS
 (P
 VALUE
 =
 0.02)
  100

FIGURE
 11
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 XENORHABDUS
 BOVIENII
 BETWEEN

CROHN’S
 DISEASE
 (INFLAMED)
 AND
 NORMAL
 GROUPS
  100

FIGURE
 12
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 SHIGELLA
 FLEXNERI
 BETWEEN
 CDI
 AND

CONTROL
 GROUPS
 (P
 VALUE
 =
 0.04)
  101

FIGURE
 13
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 DOREA
 LONGICATENA
 BETWEEN

CROHN’S
 DISEASE
 (INFLAMED)
 AND
 NORMAL
 GROUPS
  101

FIGURE
 14
 HEAT
 MAP
 ANALYSIS
 COMPARING
 NORMAL
 AND
 ULCERATIVE
 COLITIS
 (UC)
 SAMPLES
  102

FIGURE
 15
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 YERSINIA
 PESTIS
 BETWEEN
 UC
 AND

CONTROL
 GROUPS
 (P
 VALUE
 =
 0.02)
  103

FIGURE
 16
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 EUBACTERIUM
 RECTALE
 BETWEEN
 UC

AND
 CONTROL
 GROUPS
 (P
 VALUE
 =
 0.04)
  103

FIGURE
 17
 BOX
 CHART
 ANALYSIS
 COMPARING
 ABUNDANCE
 OF
 FAECALIBACTERIUM
 PRAUSNITZII

BETWEEN
 NORMAL
 AND
 ULCERATIVE
 COLITIS
 GROUPS
  103

FIGURE
 18
 CLUSTER
 ANALYSIS
 COMPARING
 OF
 CROHN’S-­‐DISEASE
 INFLAMED
 VS.
 NON-­‐INFLAMED
  104

FIGURE
 19
 THE
 ELEMENTS
 OF
 CLINICAL
 GOVERNANCE
 (FROM
 STAREY,
 2001)
  114

FIGURE
 20
 BRITISH
 THORACIC
 SOCIETY
 ALGORITHM
 FOR
 SCREENING
 FOR
 LTBI
 FOR
 PATIENTS
 ON

IMMUNOMODULATORS
 PRIOR
 TO
 THE
 USE
 OF
 ANTI-­‐TNFα
 THERAPY
 (RAMPTON
 ET
 AL,
 2005)
  126

FIGURE
 21
 GUIDELINES
 FROM
 THE
 CENTERS
 FOR
 DISEASE
 CONTROL
 FOR
 SCREENING
 FOR
 LATENT

TUBERCULOSIS
 INFECTION
 PRIOR
 TO
 THE
 USE
 OF
 ANTI-­‐TNFα
 AGENTS
  126

FIGURE
 22
 RECOMMENDATIONS
 REGARDING
 IMMUNISATION
 IN
 PATIENTS
 WITH
 INFLAMMATORY

BOWEL
 DISEASE
 (SANDS
 ET
 AL,
 2004)
  132

FIGURE
 23
 EUROPEAN
 CROHN’S
 AND
 COLITIS
 ORGANISATION
 RECOMMENDATIONS
 REGARDING

SCREENING
 AND
 VACCINATION
 (VIGET
 ET
 AL,
 2008)
  134

FIGURE
 24
 GUIDELINES
 FOR
 MANAGING
 INFUSION
 REACTIONS
 AT
 THE
 INFUSION
 (CHEIFETZ
 ET
 AL,
 2003)

  139
page
 8
 of
 278

FIGURE
 25
 METABOLISM
 OF
 THIOPURINE
 DRUGS
 (ADAPTED
 FROM
 VAN
 ASSELDONK
 ET
 AL,
 2010
 AND

GEARRY
 ET
 AL,
 2010)
  143

FIGURE
 26
 PROVISIONAL
 GUIDELINES
 FOR
 SCREENING
 FOR
 LATENT
 TUBERCULOSIS
 INFECTION
 IN
 AN

AUSTRALIAN
 POPULATION
 BASED
 ON
 INTERFERON
 GAMMA
 RELEASE
 ASSAY
 TESTING
  159

FIGURE
 27
 HISTOGRAM
 OF
 AGES
 OF
 PATIENTS
 TREATED
 WITH
 ANTI-­‐TNFα
 AGENTS
  169

FIGURE
 28
 DISEASE
 LOCATION
 (MONTREAL
 CLASSIFICATION)
  169

FIGURE
 29
 DISEASE
 BEHAVIOUR
 (MONTREAL
 CLASSIFICATION)
  170

FIGURE
 30
 TOTAL
 NUMBER
 OF
 INFLIXIMAB
 INFUSIONS
 PER
 PATIENT
  171

FIGURE
 31
 INFLIXIMAB
 DOSES
 (IN
 MILLIGRAMS)
  172

FIGURE
 32
 QUANTIFERON-­‐TB
 GOLD
 RESULTS
 (TOTAL
 NUMBER
 OF
 RESULTS
 =
 29)
  173

FIGURE
 33
 USE
 OF
 PREMEDICATION
 BEFORE
 INFLIXIMAB
 INFUSIONS
  177

FIGURE
 34
 GUIDANCE
 DS
 MAIN
 SCREEN
  188

FIGURE
 35
 SCREENING
 MODULE
 -­‐
 INTRODUCTION
 SCREEN
  190

FIGURE
 36
 SCREENING
 MODULE
 -­‐
 TUBERCULOSIS
 SCREEN
  191

FIGURE
 37
 SCREENING
 MODULE
 -­‐
 TUBERCULOSIS
 OUTCOME
 SCREEN
  191

FIGURE
 38
 SCREENING
 MODULE
 -­‐
 HEPATITIS
 B
  192

FIGURE
 39
 SCREENING
 MODULE
 -­‐
 PHENOTYPE
 INFORMATION
  193

FIGURE
 40
 PAST
 MEDICATION
 HISTORY
  193

FIGURE
 41
 SECTION
 100
 MODULE
 FOR
 INFLIXIMAB
  195

FIGURE
 42
 CROHN'S
 DISEASE
 ACTIVITY
 INDEX
 CALCULATOR
  195

FIGURE
 43
 AN
 EXAMPLE
 OF
 RESULTS
 FROM
 THE
 SCREENING
 FOR
 LTBI
 MODULE
  196

FIGURE
 44
 BARRIERS
 TO
 PHYSICIAN
 ADHERENCE
 TO
 PRACTICE
 GUIDELINES
 IN
 RELATION
 TO
 BEHAVIOUR

CHANGE
 (CABANA
 ET
 AL,
 1999)
  203

FIGURE
 45
 PROCESS
 MAPPING
 FOR
 APPLICATION
 FOR
 INFLIXIMAB
 UNDER
 MEDICARE
 100
 SCHEME

(SIMPLIFICATION)
  209

FIGURE
 46
 HISTOGRAM
 OF
 AGE
 DISTRIBUTION
 OF
 PATIENTS
 (TOTAL
 NUMBER
 39)
  214

FIGURE
 47
 HISTOGRAM
 OF
 DOSING
 OF
 THIOPURINE
 PER
 BODY
 WEIGHT
 FOR
 ALL
 PATIENTS
 IN
 MG/KG

(TOTAL
 NUMBER
 39)
  215

FIGURE
 48
 HISTOGRAM
 OF
 6-­‐TGN
 LEVELS
 IN
 ALL
 PATIENTS
  216

FIGURE
 49
 HISTOGRAM
 OF
 6-­‐METHYLMERCAPTOPURINE
 (6-­‐MMP)
 LEVELS
 IN
 ALL
 PATIENTS
  216

FIGURE
 50
 SCATTER
 PLOT
 COMPARING
 PAIRED
 6-­‐TGN
 AND
 6-­‐MMP
 VALUES
  217

FIGURE
 51
 6TGN
 LEVELS
 IN
 PATIENTS
 WITH
 WILD
 TYPE
 VS.
 HETEROZYGOUS
 TPMT
 GENOTYPE
  218

FIGURE
 52
 6MMP
 LEVELS
 IN
 PATIENTS
 WITH
 ‘WILD
 TYPE’
 VS
 HETEROZYGOUS
 MUTATIONS
 OF
 TPMT
 219

FIGURE
 53
 SCATTERPLOT
 OF
 HARVEY-­‐BRADSHAW
 INDEX
 AND
 6-­‐TGN
 LEVELS
 IN
 PATIENTS
 WITH
 CROHN'S

DISEASE
  221

FIGURE
 54
 SCATTERPLOT
 OF
 SCCAI
 COMPARED
 TO
 6-­‐TGN
 LEVELS
 IN
 PATIENTS
 WITH
 ULCERATIVE

COLITIS
  221

FIGURE
 55
 SCATTER
 PLOT
 OF
 MEAN
 CELL
 VOLUME
 (MCV,
 Y
 AXIS)
 VS.
 6-­‐THIOGUANINE
 LEVELS
 (6TGN,
 X

AXIS).
  222

FIGURE
 56
 SCATTER
 PLOT
 OF
 ALANINE
 TRANSAMINASE
 (ALT)
 VS.
 6-­‐METHYLMERCAPTOPURINE
 LEVELS

(CORRELATION
 COEFFICIENT
 0.36)
  223
page
 9
 of
 278

LIST
 OF
 TABLES

TABLE
 1
 SINGLE
 NUCLEOTIDE
 POLYMORPHISMS
 ASSOCIATED
 WITH
 ULCERATIVE
 COLITIS
  32

TABLE
 2
 METABOLIC
 SUBSTRATES
 IN
 THE
 GASTROINTESTINAL
 TRACT
 (ADAPTED
 FROM
 BLAUT
 ET
 AL,

2007)134
  45

TABLE
 3
 MOUSE
 MODELS
 OF
 INFLAMMATORY
 BOWEL
 DISEASE
 (ADAPTED
 FROM
 NELL
 ET
 AL
 2010)
  46

TABLE
 4
 MONTREAL
 CLASSIFICATION
 OF
 CROHN’S
 DISEASE
  68

TABLE
 5
 LIST
 OF
 SINGLE
 NUCLEOTIDE
 POLYMORPHISMS
 TESTED
  70

TABLE
 6
 OVERVIEW:
 ALL
 PATIENTS
 RECRUITED
 &
 NUMBER
 OF
 BIOPSY
 LOCATIONS
  73

TABLE
 7
 CHARACTERISTICS
 OF
 PATIENTS
 WITH
 CROHN’S
 DISEASE
  74

TABLE
 8
 PHENOTYPE
 OF
 CROHN'S
 DISEASE
 PATIENTS
 USING
 MONTREAL
 CLASSIFICATION
  75

TABLE
 9
 CHARACTERISTICS
 OF
 PATIENTS
 WITH
 ULCERATIVE
 COLITIS
  75

TABLE
 10
 MAP
 STATUS
 OF
 PATIENTS
 WITH
 CROHN’S
 DISEASE
  78

TABLE
 11

 CROHN’S
 DISEASE
 –
 MAP
 STATUS
 COMPARED
 TO
 PRESENCE
 OF
 INFLAMMATION
  78

TABLE
 12
 MAP
 STATUS
 OF
 PATIENTS
 WITH
 ULCERATIVE
 COLITIS
 (NOTE:
 0.5
 REPRESENTS
 AN

INTERMEDIATE
 PCR
 RESULT)
  79

TABLE
 13
 MAP
 STATUS
 COMPARED
 TO
 PRESENCE
 OF
 INFLAMMATION
 IN
 PATIENTS
 WITH
 ULCERATIVE

COLITIS
  79

TABLE
 14

 INCIDENCE
 OF
 MAP
 IN
 BIOPSIES
 FROM
 INFLAMED
 VS
 NON-­‐INFLAMED
 TISSUE
  80

TABLE
 15
 IBD
 -­‐
 MAP
 STATUS
 IN
 PATIENTS
 WITH
 INFLAMMATORY
 BOWEL
 DISEASE
 COMPARED
 TO

CONTROLS
  80

TABLE
 16
 PATIENTS
 WITH
 CROHN’S
 DISEASE
 –
 IMMUNOMODULATOR
 USE
 VS.
 MAP
 STATUS
  83

TABLE
 17
 GENOTYPING
 RESULTS
 FOR
 ALL
 PATIENTS
 TESTED,
 COMPARED
 TO
 PHENOTYPE
 AND
 MAP

STATUS
 (SORTED
 BY
 PHENOTYPE)
  84

TABLE
 18
 INCIDENCE
 OF
 HETEROZYGOUS
 AND
 HOMOZYGOUS
 MUTATIONS
 FOR
 ALL
 POOLED
 SAMPLES

  85

TABLE
 19
 OBSERVED
 AND
 EXPECTED
 INCIDENCE
 OF
 SINGLE
 NUCLEOTIDE
 POLYMORPHISMS
 (CONTINUED

IN
 TABLE
 20)
  85

TABLE
 20
 OBSERVED
 AND
 EXPECTED
 INCIDENCE
 OF
 SINGLE
 NUCLEOTIDE
 POLYMORPHISMS
 (PART
 II)
  86

TABLE
 21
 INCIDENCES
 OF
 GENETIC
 MUTATIONS
 IN
 MAP
 POSITIVE
 SAMPLES
  86

TABLE
 22
 BETWEEN
 CLASS
 COMPARISONS
 BETWEEN
 THE
 FOUR
 GROUPS
 FOR
 DIFFERENT
 ORGANISMS
 97

TABLE
 23
 IMMUNISATION
 PROGRAM
 SCHEDULE
 FOR
 AUSTRALIA
 (C/O
 AUSTRALIAN
 GOVERNMENT

DEPT.
 OF
 HEALTH
 &
 AGING)
  135

TABLE
 24
 CLASSIFICATION
 OF
 INFUSION
 REACTIONS
 (COURTESY
 OF
 MAYER
 ET
 AL)
  138

TABLE
 25
 CLINICAL
 CRITERIA
 FOR
 DIAGNOSING
 ANAPHYLAXIS
 (SAMPSON
 ET
 AL,
 2006)465
  140

TABLE
 26
 INTERPRETATION
 OF
 THIOPURINE
 METABOLITE
 RESULTS
 IN
 PATIENTS
 WITH
 ONGOING

DISEASE
 ACTIVITY
 (ADAPTED
 FROM
 DASSOPOULOS
 ET
 AL,
 2012)
  146

TABLE
 27
 SUMMARY
 OF
 SCREENING
 RECOMMENDATIONS
 FOR
 PATIENTS
 WITH
 IBD
  163

TABLE
 28
 SUMMARY
 OF
 VACCINATION
 RECOMMENDATIONS
 FOR
 PATIENTS
 WITH
 IBD
  165

TABLE
 29
 MONTREAL
 CLASSIFICATION
 OF
 CROHN’S
 DISEASE
  170

TABLE
 30
 CLASSIFICATION
 OF
 INFUSION
 REACTIONS
 (COURTESY
 OF
 MAYER
 ET
 AL)456
  175

TABLE
 31
 INFUSION
 REACTIONS
 IN
 EPISODIC
 VS.
 MAINTENANCE
 THERAPY
  175
page
 10
 of
 278

TABLE
 32
 INFUSION
 REACTIONS
 TO
 INFLIXIMAB
  176

TABLE
 33
 PREMEDICATION
 USE
 DEPENDING
 UPON
 PRESENCE
 OF
 INFUSION
 REACTIONS
  177

TABLE
 34
 PROPOSED
 NEW
 GUIDELINES
 FOR
 MANAGEMENT
 OF
 INFUSION
 REACTIONS
  184

TABLE
 35
 'TEN
 COMMANDMENTS'
 FOR
 EFFECTIVE
 CDSS
 (BATES
 ET
 AL
 2003)
  206

TABLE
 36
 EXAMPLE
 OF
 GENOTYPING
 RESULT
 AND
 ANALYSIS
 FOR
 A
 SINGLE
 PATIENT
  213

TABLE
 37
 THIOPURINE
 DRUG
 DOSAGE
 EQUIVALENTS
 IN
 HETEROZYGOTES
 COMPARED
 TO
 WILD
 TYPES

  219

TABLE
 38
 THIOPURINE
 DOSAGE
 STRATIFIED
 BY
 6-­‐TGN
 LEVELS
  220

TABLE
 39
 INTERPRETATION
 OF
 THIOPURINE
 METABOLITE
 RESULTS
 IN
 PATIENTS
 WITH
 ONGOING

DISEASE
 ACTIVITY
 (ADAPTED
 FROM
 DASSOPOULOS
 ET
 AL,
 2012)
  226

TABLE
 40:
 APPROACHES
 TO
 STARTING
 A
 THIOPURINE
 DRUG
  227