Asia Pacific Consensus on Crohn

1
Asia Pacific Consensus on Crohns
diseaseStatements on Management
2
Aims in Mx of a patient with CD
Symptoms and signs Weight
STRUCTURAL PARAMETERS Endoscoy MRI CT
INFLAMMATORY PARAMETERS CRP IL-6 Faecal
calprotectin Faecal lactoferrin Platelet
Clinical remission
Inflammation remissoin
Intestinal healing
INFLUENCE CLINICAL COURSE
DOES NOT DETERMINE CLINICAL COURSE
3
Management Statement 1

• Induction of remission is usually a symptomatic
  end point although increasingly, endoscopic
  mucosal healing is considered an important
  objective sign of therapeutic efficacy.
• Normalisation of inflammatory biomarkers
  including C-reactive protein and faecal
  calprotectin are other objective endpoints of
  therapeutic efficacy.
• Other goals of treatment include maintenance of
  the disease in the remission phase, and
  prevention of strictures and fistulae.

4
Population based studies Follow up data on
natural history of adult CD worldwide
Country Location No of incident CD Inclusion Median duration of FU
USA Olmsted County 314 1940-2004 14 years
Canada Manitoba 4,193 April 1984-March 2003 N/A
Denmark Copenhagen County 641 1962-1987 1991-1993 2003-2004 (three cohorts) 17, 10 and 1 year for the three cohort respectively
Norway (IBSEN) 237 January 1990 to December 1993 124 mo (range, 108-144 mo)
Sweden Stockholm County 20,120 1954-2000 N/A
7 European countries and Israel European collaborative Study Group on IBD 365 1991-2004 10.3 years (range, 9.4-11 years)
5
Natural History of CD

• Natural behaviour Remissions and relapses
• Most patients need to take medication for a large
  period of their life, mostly for maintenance of
  remission and intermittently additional induction
  therapy
• Population-based data from Denmark1st yr after
  diagnosis,
• 55 are in remission
• 15 have mild disease
• 35 have highly active disease.
• Similar data from Olmsted County, US
• gt Two-thirds (64.4) Medical or surgical
  remission
• One third active disease

Activity of disease in previous yr predicts the
course in subsequent yrs. A full year of
remission is followed by an 80 chance of
remission in following year, A recent flare only
has a 30 chance of remission in the following
year.
6
Natural History of CD

• Disease extent
• Ileocolonic 4050
• Isolated small intestine 30
• Pure colonic 30
• Changes in location of disease is minimal
• Only 10-15 show changes in localization 10 yrs
  after diagnosis.
• Change in Behaviour More frequent as disease
  becomes older
• At presentation Majority (90) have
  inflammatory, (non-stricturing, non-penetrating
  disease
• With longer follow up Development of either a
  stricture or a fistula increases

7
Evolution of Disease Behavior in CD
100
90
80
70
Penetrating
60
50
Cumulative Probability ()
40
Inflammatory
30
Stricturing
20
10
0
240
228
216
204
192
180
168
156
144
132
120
108
96
84
72
60
48
36
24
12
0
Months
Patients at risk
95
2002
552
229
37
N
Cosnes J et al. Inflamm Bowel Dis. 20028244.
8
Cumulative risk of hospitalization in Olmsted
County, in the pre-biological era 211 diagnosed
between Jan 1970 -June 1997 and followed until
June 1997
9
Cumulative risk of intestinal resection 314 pts
with CD from Olmsted County, diagnosed between
1940-2001
10
Natural history of a pt with CD Predicted
course based on Markov Model

• A representative patient spends
• Lifetime disease course
• 24 in medical remission
• 27 as mild disease
• 1 with severe drug-responsive disease,
• 4 with severe drug-dependent disease,
• 2 with severe drug-refractory disease,
• 1 in surgery,
• 41 in post surgical remission
• Over time,
• Decreasing in proportion of medical remission
  state
• Increase in proportion post-surgical remission
  state

11
CD is a progressive disease
12
Predictors of natural history in adult Crohns
disease
Variable Comment
Clinical Risk factors Age lt40 years at diagnosis, Need for systemic steroids for first flare, Perianal disease Terminal ileal disease
C-reactive protein
Endoscopic factors Mucosal healing
13
Mx Statement 1

• Induction of remission is usually a symptomatic
  end point although increasingly, endoscopic
  mucosal healing is considered an important
  objective sign of therapeutic efficacy.
• Normalisation of inflammatory biomarkers
  including C-reactive protein and faecal
  calprotectin are other objective endpoints of
  therapeutic efficacy.
• Other goals of treatment include maintenance of
  the disease in the remission phase, and
  prevention of strictures and fistulae.

14
Mucosal healing predicts better outcome
Population study

• Norwegian population-based study 141 CD Pts
• Endoscopic re-evaluation within 0.5 and 2 yrs
  after diagnosis,
• 50 evaluated 5 yrs after diagnosis
• Mucosal healing at base line was associated with
  less endoscopic disease activity at 5 years
• Decreased need for subsequent treatment with
  steroid
• In UC Mucosal healing after 1 yr of T/T strongly
  predictive of less surgery
• Discrepancies between UC and CD
• CD is a transmural disease,
• UC predominantly mucosal

15
Mucosa healing

• Complication of CD Deep ulcer, fistula,
  stricture
• If mucosa heal such complications decrease
• Recurrence in post op
• Endoscopy at 1 year
• Mild lesion Advanced lesion
• Recur over 5-10 yrs lt10 gt90

Mucosal healing less hospitalization/ surgical
intervention
Rutgeerts Gastroenterology 1990
16

• Mucosal healing appears to be an ideal end point
  for assessment

17
Non invasive marker may be used to determine
activity in IBD

Acute phase reactants ESR, CRP, Orosomucoid, Platelet count
Serological tests ASCA, pANCA, Lactoferrin, fibrinogen
Cytokines Interleukins (IL-1,IL-2,IL-6,IL-8,IL-10,IL-15)TNF-a
Faecal Indium labeled white cells, calprotectin, lactoferrin, Nitric oxide, a-antitrypsin excretion, lysozyme excretion
Others Indium labeled white cells scan, Intestinal permeability test, whole gut lavage fluid for immunoglobulin and albumin
18
C-reactive protein as a predictor for disease
activity and natural course

• CRP acute phase protein, synthesized in liver
  in response to stimulation by IL-6, TNF a, and
  IL-1ß, and is produced at site of inflammation.
• Functions as an opsonin for bacterial sequences
  and nuclear material expressed during apoptosis.
• Half life of CRP is small (19 Hrs),
• Concentration decreases once acute phase
  stimulus disappears.

19
C-reactive protein as a predictor for disease
activity and natural course

• CRP Only biological parameter, identified as
  predictor of a more severe clinical course of CD
• Norwegian population-based study 176 CD
• CRP levels measured at diagnosis, after 1 and 5
  yrs
• At diagnosis Mean CRP was 51 mg/L (gtgtthan in UC)
• At 1 yr Significant decrease from 51 to 16 mg/L
• Significant association between CRP levels at
  diagnosis and risk of surgery in next 5 yrs
• In those with L1 disease, the risk of surgery
  increased by a factor of six when CRP levels were
  above 53 mg/1

20
MANAGEMENT 1) Induction of remission is usually
a symptomatic endpoint although increasingly,
endoscopic mucosal healing is considered an
important objective sign of therapeutic efficacy.
Normalisation of inflammatory biomarkers
including C-reactive protein and faecal
calprotectin are other endpoints. Other goals of
treatment include keeping of the disease in
remission, and prevention of strictures and
fistulae.

• Comments
• What are we trying to say?
• Statement is too complex
• Too many substatements here will make the voting
  difficult
• Should we add a word or two about "quality of
  life"?
• Too many parameters in this statement.

21
Revised Mx Statement 1

• The goals of treatment include induction and
  maintenance of remission, prevention of
  strictures, fistulae and other complications and
  improving quality of life.

22
Revised Mx Statement 1

• Induction of remission is usually a symptomatic
  endpoint though increasingly endoscopic mucosal
  healing is considered an important objective sign
  of therapeutic efficacy.( goes to text)
• Normalisation of inflammatory biomarkers
  including C-reactive protein and faecal
  calprotectin are other objective endpoints of
  therapeutic efficacy.
• (EL 3, RG C)

23
Mx Statement 2

• All patients with CD should be assessed for the
  extent of the disease, activity of the disease
  and their behaviour should also be assessed.
  Treatment of CD depends upon extent of the
  disease, behaviour of the disease and activity of
  the disease

24
Phenotype of CD Montreal classification
Age of onset Location Behavior
16 yrs (A1) lleal (L1) Non- stricturing, Non-penetrating (B1)
17- 40 yrs (A2) Colonic (L2) Stricturing (B2)
gt 40 yrs (A3) lleal-colonic (L4)
lsolated UGI (L4) Penetrating (B3)
p if peri-anal disease
25
CD Activity scoring system
Ulcerative colitis Crohns disease
Truelove and Witts (1955) Crohns Disease Activity Index (Best WR, 1979)
Powell-Tuck (1978) Harvey and Bradshaw(1980)
Complex clinical activity score, (Seo, 1995) Oxford criteria (Myren J, 1984)
Simple clinical colitis index (Walsemy, 1998)
Mayo index (Riley SA, 1991)
26
Crohns Disease Activity Index
Item(day) Weight
No. liquid or very soft stools(each day for 7days) 2
Abdominal pain, sum of 7 d rating (0none,1mild,2moderate,3severe) 5
General well being (1-4) 7
Exteraintestinal (1 per finding) Arthritis/arthralgia Mucocutaneous lesion Iritis/uveitis Anal disease (fissure, fistula,etc) External fistula 20
Fevergt36.8
Antidiarrheal use 30
Abdomial mass(none-0,equivocal-2,definite-5 10
Hematocrit (males-47) (Females-42) 6
Bodyweight (1-body weight/standard weight) 100 1
Total CDAI Score
27
Harvey Bradshaw index
Variable Variable description
General well being 0 very well, 1slightly poor, 2 poor, 3 very poor, 4 terrible
Abdominal pain 0none 1mild 2moderate 3severe
No. of liquid stools Daily
Abdominal mass 0none 1dubious 2definite 3definite and tender)
Complications Arthralgia, Uveitis, Erythema nodosum, aphthous ulcer, pyoderma gangrenosum, Anal fissure, New fistula
28
Assessment of perianal CD activity index
Catogries affected by fistula Frequency Score
Discharge No discharge 0
Discharge Minimal mucus discharge 1
Discharge Moderate mucous or purulent discharge 2
Discharge Substantial discharge 3
Discharge Gross fecal soiling 4
Pain/restriction of activities No activity restriction 0
Pain/restriction of activities Mild-discomfort, no restriction 1
Pain/restriction of activities Moderate discomfort, some limitation of activities 2
Pain/restriction of activities Marked discomfort, marked limitation 3
Pain/restriction of activities Severe pain, severe limitation 4
Restriction of sexual activity No restriction of sexual activity 0
Restriction of sexual activity Slight restriction of sexual activity 1
Restriction of sexual activity Moderate limitation of sexual activity 2
Restriction of sexual activity Marked limitation of sexual activity 3
Restriction of sexual activity Unable to engage in sexual activity 4
Type of Perianal disease No perianal disease/skin tags 0
Type of Perianal disease Anal fissure or mucosal tear 1
Type of Perianal disease lt3Perianal fistulae 2
Type of Perianal disease gt3 Perianal fistulae 3
Anal sphincter ulceration or fistulae with significant undermining skin 4
Degree of indurations No induration 0
Degree of indurations Minimal induration 1
Degree of indurations Moderate induration 2
Degree of indurations Substantial induration 3
Degree of indurations Gross fluctuance /abscess 4
29
Fistula activity score
Endpoint Definition
Improvement Closure of individual fistulas defined as no fistula drainage despite gentle finger compression. Improvement defined as a decrease from baseline in the number of opening draining fistulas of gt50for at least consecutive visits (i.e., at least 4 weeks.)
Remission Remission defined as closure of all fistulas that were draining at baseline for at least 2 consecutive visits (i.e., at least 4 weeks.)
30
Crohns disease Endoscopic index for severity
index
Number of recto-colonic segments, that deep ulceration are seen in divided by no. of segment examined Sigmoid 12
Number of recto-colonic segments, that deep ulceration are seen in divided by no. of segment examined Rectum 12
Number of recto-colonic segments, that deep ulceration are seen in divided by no. of segment examined Transverse colon 12
Number of recto-colonic segments, that deep ulceration are seen in divided by no. of segment examined Right colon 12
Number of recto-colonic segments, that deep ulceration are seen in divided by no. of segment examined Ileum 12
Number of rectocolonic segments, that superficial ulceration are seen in divided by no. of segment examined Sigmoid 6
Number of rectocolonic segments, that superficial ulceration are seen in divided by no. of segment examined Rectum 6
Number of rectocolonic segments, that superficial ulceration are seen in divided by no. of segment examined Transverse colon 6
Number of rectocolonic segments, that superficial ulceration are seen in divided by no. of segment examined Right colon 6
Number of rectocolonic segments, that superficial ulceration are seen in divided by no. of segment examined Ileum 6
Segmental surfaces involved by disease. The degree of disease involvement in each segment is determined by examining each segment for the following 9 lesions,(Pseudo-polyps, healed ulcers, frank-erythema, frank-mucosal-swelling, aphthoid ulcers, superficial ulcer, deep ulcer, non nucleated stenosis, ulcerated stenosis) and estimating the no. of cm of involvement (1 or more lesion present) in a representative 10 cm portion from each segment. The average segmental surface involved by disease is calculated by dividing the sum of each of individual segmental surfaces involved by disease by the no. of segments examined. 1
Segmental surfaces involved by ulcerations. The degree of ulceration in each segment is determined by examine each segment for ulceration (aphthoid ulcers, superficial ulcers, deep ulcers, ulcerated stenosis) and estimating the number of cm of intestine involved by ulceration in a representative 10 cm portion from each segment. The average segmental surface involved by ulceration is calculated by dividing the sum of each of individual segmental surfaces involved by ulceration by the no. of segments examined. 1
Presence of non ulcerated stenosis in any of segments examined. 3
Presence of ulcerated stenosis in any of segments examined. 3
31
Endoscopic scoring system for postop recurrence
(Rutgeerts score)
Grade Endoscopic Findings
0 No lesions in distal ileum
1 lt5 Aphthous lesion
2 gt5 Aphthous lesion with normal mucosa between lesions or skip areas of larger lesion lesions confined to ileocolonic anastomosis (i.e.lt1cm in length)
3 Diffuse Aphthous ileitis with diffusely inflamed mucosa
4 Diffuse inflammation with already larger ulcers, nodules and/or narrowing
32
Histological Disease activity in CD
Histological finding Score
Epithelial damage 0 Normal
Epithelial damage 1 Focal pathology
Epithelial damage 2 Extensive pathology
Architectural changes 0 Normal
Architectural changes 1 Moderately disturbed (lt50)
Architectural changes 2 Severely disturbed (gt50)
Infiltration of mononuclear cells in the lamina propria 0 Normal
Infiltration of mononuclear cells in the lamina propria 1 Moderately increase
Infiltration of mononuclear cells in the lamina propria 2 Severely increase
Polymorphonuclear cells in lamina propria 0 Normal
Polymorphonuclear cells in lamina propria 1 Moderately increase
Polymorphonuclear cells in lamina propria 2 Severely increase
Polymorphonuclear cells in epithelium 1 In surface of epithelium
Polymorphonuclear cells in epithelium 2 Cryptitis
Polymorphonuclear cells in epithelium 3 Crypt abscess
Presence of erosions and ulcers 0No
Presence of erosions and ulcers 1Yes
Presence of granuloma 0No
Presence of granuloma 1Yes
No. of biopsy specimens affected 0 None (0-6)
No. of biopsy specimens affected 1 lt33 (1 or 2-6)
No. of biopsy specimens affected 2 33-66 (3 or 4-6)
No. of biopsy specimens affected 3 gt66 (5 or 6 of 6)
33
Treatment will depend on phenotype of CD
Age of onset Location Behavior
16 yrs (A1) lleal (L1) Non- stricturing, Non-penetrating (B1)
17- 40 yrs (A2) Colonic (L2) Stricturing (B2)
gt 40 yrs (A3) lleal-colonic (L4)
lsolated UGI (L4) Penetrating (B3)
34
Rx will depend upon Phenotype of CD and activity
Age of onset Location Behavior
16 yrs (A1) lleal (L1) Non- stricturing, Non-penetrating (B1)
17- 40 yrs (A2) Colonic (L2) Stricturing (B2)
gt 40 yrs (A3) lleal-colonic (L4)
lsolated UGI (L4) Penetrating (B3)
Activity of the disease
35
2) All patients with CD should be assessed for
the extent of the disease, activity of the
disease and their behaviour should also be
assessed. Treatment of CD depends upon extent of
the disease, behaviour of the disease and
activity of the disease.

• Comments
• Yes exept assessing the upper GI tract and small
  bowel is not indicated in all patients
• We should evaluate "high risk patients". (i.e,
  young age onset, anal lesion, etc)
• "When should there be assessed?
• Double-barrelled statement "

36
Conventional Mx Statement 2

• All patients with CD should be assessed for the
  extent of the disease, activity of the disease
  and their behaviour should also be assessed. (
  bury in subtext)
• Treatment of CD depends upon extent of the
  disease, behaviour of the disease and activity of
  the disease

EL 3, RG C
37
Drugs for CD
Induction of remission Maintenance of remission
SSZ (site specific)
Mesalamines (site specific)
Conventional steroids
Budesonide (Site specific)
Immunosuppressants
Biologics
38
Induction Mx Statement 3

• Mild to moderately active CD involving terminal
  ileum (L1) or localised ileocaecal disease should
  be treated with budesonide. Conventional steroids
  should be used if budesonide is unavailable or
  failure of response. IA
• For severe disease conventional corticosteroids
  is the initial treatment of choice. IA Surgical
  resection III-C and anti-TNF are alternatives
  III-C.

39
Induction Mx Statement 4

• Sulphasalazine can be used for mild CD limited
  to the colon. IA
• There is no evidence of efficacy of mesalazine.
  IA
• Moderately severe or severe colonic disease
  should be treated with conventional
  corticosteroids. IA

40
Induction Mx Statement 5

• For extensive small intestinal disease, patients
  should be treated with conventional
  corticosteroids. III-C
• Alternative include anti-TNF agent and surgery.
  III-C

41
Induction Mx Statement 6

• For ileocolonic disease (L3), patients should be
  treated with conventional corticosteroids. I-A
• Alternative include anti-TNF agent and surgery.
  III-C

42
Rise of aminosalicytes in CD

• Prototypic 5-ASA SSZ, used to treat CD for gt 40
  yrs.
• Late 1970s 2 large multicenter RCTs showed SSZ
  marginally superior to placebo for induction of
  remission in active disease.
• National Cooperative Crohns Disease Study
• European Cooperative Crohns Disease Study
• Remission rates 40 in SSZ vs (30 in placebo)
• Problem Side-effects
• Azad Kahn 5-ASA is active component of SPS.
• Newer formulations of 5-ASA were developed
  without sulfa
• This innovation facilitated adm of higher doses
  of 5-ASA with better tolerability and less side
  effects

43
Rise of aminosalicytes in IBD

• Initial studies of various 5-ASA formulations
  equivocal results
• Singleton et al, 1993 16-week trial Pentasa CD
  Study Group had a profound effect on clinical
  practice.
• In this dose-finding trial evaluated 310 patients
  for 16 wks,
• Primary outcome Change in CDAI from baseline to
  final visit.
• Remission rates
• Placebo 18
• Pentasa 1gm23
• Pentase 2 gm24
• Pentasa 4gm 43 (P lt 0.0017 for placebo vs. 4
  g/day).
• Pentasa 4 g/ddecrease of 72 points (placebo 21
  )(Plt 0.01).
• Pts with ileum-only disease 93-point improvement
  (placebo 2
• Not associated with clinically significant
  toxicity.

Controlled-release mesalamine prep safe and
effective at 4 g/day in active CD of ileum and
colon.
Singleton et al Gastroenterology. 1993
May104(5)1293-301.
44
Fall of SSZ

• On the basis of these data and an extensive and
  satisfactory experience with the newer 5-ASA
  formulations in UC,
• By the mid-1990s, Pentasa and other new 5-ASA
  formulations became treatments of choice for mild
  to moderately active CD,
• None of the new agents was ever approved for this
  indication by the U.S. FDA)
• Gastroenterologists abandoned SSZ

45
2 more studies on Pentasa

• Unpublished results of 2 additional large-scale
  RCTs.

46
5-ASA formulations in induction of remission of
CDMeta-analysis
47
Induction of remission in active CD4 gm Pentasa
vs. placebo
There is no significant decrease in CDAI with
pentasa
3 studies ,(n 615). (Pentasa placebo) A
non-significant decrease in CDAI -19.8 (95 CI
-46.2 to 6.7, P 0.14) Clinically significant
decrease in CDAI is 50
Lim WC, Hanauer S, Cochrane review 2010
48
Induction of remission in active CD Contr-release
Mesalamine 1-2 g/d Vs placebo
8 trials, in treatment of mildly-moderately
active CD Controlled-release mesalamine
(Pentasa), Delayed-release mesalamine (Asacol)
Olsalazine (Dipentum)
8 trials, (n 342). Induction of remission 1
to 2 g/day was not superior to placebo RR 1.46
95 CI 0.89 to 2.40 P 0.14.
Lim WC, Hanauer S, Cochrane review 2010
49
Induction of remission in CD Delayed-release
mesalamine vs conventional CS
3 trials, (n178) No statistically significant
difference between mesalamine and conventional
CS (RR 1.04 95CI 0.79 to 1.36)
Lim WC, Hanauer S, Cochrane review 2010
50
Induction of remission in CD Controlled release
mesalamine vs Budesonide
Budesonide gtgt Mesalamines for induction of
remission
A single, (Pentasa with budesonide), 182 pts
(limited to distal ileum and AC) Remission at 16
weeks Pentasa33.7 (30/89) Budesonide 60.2
(56/93) (RR 0.56 95CI 0.40 to 0.78 P
0.0007), ABI 26.5, NNT 4. Lower remission
with pentasa for pts with more severe disease at
entry (CDAI gt 300) (11 Pentasa versus 41
budesonide, P 0.01, RR 0.26 95 CI
0.08) Colonic involvement (23versus 56
respectively, P 0.03, RR 0.41) Median time to
remission Longer for mesalamine (28 vs 58 d, P
0.12)
Lim WC, Hanauer S, Cochrane review 2010
51
Induction of remission in CD SSZ with placebo
SSZ at 3 to 6 g/d only modest efficacy over
placebo. A pooled RR of 1.38 (38 higher chance
of achieving rem) Limited to pts with Crohns
colitis. Those with small bowel disease did not
improve
Three trials,(n289) SSZ Placebo (a trend
towards stat sig) RR 1.51 95 CI 0.97 to 2.35 P
0.07, Combining data from only NCCDS and ECCDS
(similar efficacy measures, therapeutic endpoints
and duration of therapy) SSZ gtgt placebo in
inducing remission RR 1.38 95 CI 1.02 to
1.87, P 0.04 ABI 13, NNT 8.
Lim WC, Hanauer S, Cochrane review 2010
52
Induction of remission in CD SSZ Vs steroids
Two trials (n 260), SSZ clearly inferior to
CS RR 0.66 95 CI 0.53 to 0.81, P 0.0001.
SSZ-treated pts had 34 less chance of achieving
remission than those treated with CS
Lim WC, Hanauer S, Cochrane review 2010
53
Induction of remission in CD SSZ vs SSZSteroids
Sulfasalazine monotherapy Less effective than
combination therapy with CS
Lim WC, Hanauer S, Cochrane review 2010
54
Induction of remission Efficacy of 5-ASA in CD
Another Meta-analysis

• 3,061 citations 22 RCT eligible
• 6 RCTs 5-ASA with placebo in active CD for IR
• SSZ over placebo 2 RCT
• RR of failure to achieve remission0.83 95
  CI0.69-1.00),
• Mesalamine over placebo 4 RCTs No benefit
• RR0.91 95 CI0.77-1.06)
• Neither SSZ nor mesalamine Effective in
  preventing quiescent CD relapse,
• Per protocol analysis of mesalamine appeared to
  reduce risk of relapse (RR0.79 95
  CI0.66-0.95, NNT13).
• Ford AC, Am J Gastroenterol 2011 Apr

55
Efficacy Location wise
56
Limitations in evidences for ASAs

• Inconsistent trial outcomes due to heterogeneity
  in studies
• Enrollment of patients
• Inclusion and exlusion criteria,
• End-points,
• Duration,
• Dose,
• Delivery system
• Placebo responses

57
SSZ for induction of remission in CD Summary

• Sulfasalazine at 3 to 6 g/day Only modestly
  superior to placebo,
• Benefit confined to those with colitis.
• Sulfasalazine Inferior to corticosteroid
• Sulfasalazine not an useful adjunct to
  corticosteroid

Lim WC, Hanauer S, Cochrane review 2010
58
5-ASA for induction of remission in CD Summary

• Low dose (1 to 2 g/d) of olsalazine and
  mesalamine Ineffective and not superior to
  placebo.
• Higher doses of mesalamine at 3 to 4.5 g/day
• Statistically significant but clinically
  insignificant changes in CDAI scores,
• Have not been consistently effective for
  induction of remission in mild to moderately
  active CD
• Are inferior to budesonide.
• Mesalamine seems to be inferior to conventional
  steroids.

The role of 5-ASAs in inducing remission of
active CD and preventing relapse of quiescent CD
remains uncertain, and more RCTs are required.
59
Steroids for active CD

• Conventional CS
• Population studies
• 2 RCTs
• Meta-analysis (Cochrane review ACG Task Force)
• Budesonide
• Compared with placebo
• Compared with 5-ASA prep
• Coventional CS vs Budesonide

60
Efficacy of Steroids in active CD Population
studies
Copenhagen study Olmsted County
Steroid Use 109/196 (56) 74/173 (43)
Steroid dose 1 mg/kg 40-60mg/kg
Study period 1979-1987 1970-1993
61
Outcome of Corticosteroid in CD
Outcome of the first steroid course evaluated
prospectively regional cohort of 196 patients
with CD diagnosed 1979-1987. Immediate outcome
at day 30 Prolonged outcome 30 days after
treatment had stopped In all 109 patients
treatment was analysed.
Remission at 12 Months 25
Localisation of disease, age, sex or clinical
symptoms did not significantly correlate with
outcome
Munkholm P, University of Coppenhagen, Denmark
Gut. 1994
62
The natural history of corticosteroid therapy for
IBD a population-based

• Patients All pts with IBD in Olmsted County,
  Minnesota,
• CD (n 173) or UC (n 185)
• Intervention Systemic corticosteroids during
  1970-93
• Outcome
• Immediate outcome (30 days)
• 1-year outcome after the first course of
  corticosteroids
• Use of corticosteroids
• CD 74/173 (43)
• UC 63/185 (34)
• Faubion WA Jr, Gastroenterology. 2001

63
The natural history of corticosteroid therapy for
IBD a population-based
Partial Remission 26 (n 19)
No Response 16 (n 12)
Complete Remission 58 (n 43)
Immediate Outcome (n 74)
Surgery 38 (n 28)
Steroid Dependent 28 (n 21)
Prolonged Response 32 (n 24)
1-Year Outcome (n 74)
30 days after initiating corticosteroid therapy
Most patients with CD and UC initially respond
to corticosteroids. At 1 year, 32 of patients
with Crohn's disease and 48 with ulcerative
colitis are corticosteroid free without operation.
Faubion W et al. Gastroenterology 2001121225
64
Summary of population studies

• Only less than half require steroid
• Prolonged steroid response in 44,
• Steroid dependency in 36,
• Steroid resistant in 20

65
National Cooperative Crohn's Disease Study NCCS
study

• 569 pts in a placebo-controlled, randomized,
  multicenter cooperative trial
• Active and quiescent CD Prednisone,
  sulfasalazine, or azathioprine
• In active disease Prednisone and sulfasalazine
  significantly gtgt to placebo.
• Azathioprine gtgt placebo, but the difference did
  not reach conventional levels of statistical
  significance.
• Pts with colonic involvement were especially
  responsive to sulfasalazine,
• Pts with small bowel involvement were especially
  responsive to prednisone.
• Patients' drug therapy immediately before entry
  to the study significantly affected subsequent
  response.
• For patients with quiescent disease None of
  drugs was superior to placebo in prophylaxis
  against flare-up or recurrence.
• There is less than a 5 risk that a clinically
  significant prophylactic effect of any of the
  drug regimens was missed.
• Summers RW, Gastroenterology. 1979 Oct77(4 Pt
  2)847-69.

66
Corticosteroids in CD Induction of Remission
92
p not calculated
Corticosteroids
100
82
Placebo
80
60
60
38
Patients
40
30
20
0
17 weeks
18 weeks
7 weeks
Clinical Remission
Randomized controlled trial Multicenter
prospective trial
Malchow H et al. Gastroenterology.
198486249. Modigliani R et al.
Gastroenterology. 199098811. Summers RW et al.
Gastroenterology. 197977847.
67
Steroids for induction of remission in CD
Cochrane review
Two studies Diff doses in both study Same
remission rate. Remission with steroids Pooled
RR 1.99 95 CI 1.51 to 2.64 Plt 0.00001).
Absolute risk reduction 30 (95 CI 20 to 41)
NNT 3.33(95CI 2.4 to 5.0).
Although raw data were not available for
meta-analysis, it was clear from life-table data
(Summers 1979) Corticosteroids showed benefit
over placebo within 1 wk of initiation Benefit
plateau at wks 8-10 when approx 70-80 of at risk
pts enter remission.
A strong placebo effect (Summers 1979), After wk
10, approx 40 of at-risk pts continued to enter
remission while on placebo.
Benchimol EI, Cochrane review 2010
68
Efficacy safety of Conventional CS vs. placebo
Induction of remission in active luminal CD

• 2 trials 267 patients
• Failure to achieve remission
• Conventional CS 53/132 (40.2 )
• Placebo 93/135 (68.9)
• Statistically sig rate of remission in both
  studies individually
• No significant difference in remission in active
  CD
• (RR of failure to achieve remission 0.46 95
  CI 0.17 1.28)
• Because of the heterogeneity between studies (
  I288 ,P 0.004)
• Small number of trials.
• Indeed, if risk difference was used as summary
  statistic, then the treatment effect was
  significant (NNT 3 95 CI 2 11).

Ford AC, Am J Gastroenterol 2011
69
Induction of remission CS vs 5-ASA compounds
3 studies (164/158pts) compared efficacy of CS
5-ASA for induction of late remission (gt15 wks).
Pooled analysis CS gtgt 5-ASA in inducing late
remission RR 1.65 95 CI 1.33 to 2.03 P lt
0.00001 Abs risk reduction 27 (95 CI 17 to
37) NNT 3.7 (95 CI 2.7 to 5.9).
70
Conventional steroids in induction of remission
in CD Summary
Analyses conducted in the reviews are limited by
the design quality of the included studies and
the unavailability of raw data

• CS effective for induction of remission in CD
• Better than 5-ASA for late remission
• Whether steroids are more effective than 5-ASA in
  short-term therapy more studies required (Highly
  unlikely such trials will be performed).

71
Steroid dosing for induction of remission in CD

• No CS dose-ranging study in pts with CD,
• Population based studies Prednisone 1mg/kg/d
  achieves high rate of remission
• In pts with UC 3 doses of prednisone (20,40, 60
  mg/d)
• 40 and 60 mg gt 20 mg
• 60 mg/d associated with a higher toxicity
• But not more effacious than 40 mg/d dose
• A small study in pts with UC Splitting of
  dosing 6 h, no better than OD dosing
• Continuous infusion no better than bolus dosing

72
Tapering of steroid

• Current evidence suggests that the algorithm used
  for CS tapering after achieving an initial
  response is unlikely to influence the long-term
  outcome in patients with CD or UC.
• In the NCCDS, the dosage of prednisone was
  adjusted during the 17-wk induction period based
  on the severity of disease activity as measured
  by
• CDAI 300 0.75mg/kg/d for a
• CDAI 150 and 300 0.5 mg/kg/d
• CDAI lt150 0.25 mg/kg/d
• In the ECCDS, 6-methylpred was given initially
  and tapered over 6 wks
• Induction 48 mg/d in wk 1
• tapered to 32 mg/d in wk 2,
• 24 mg/day in wk 3,
• 20 mg/day in wk 4,
• 16 mg/day in wk 5,
• 12 mg/day in wk 6.
• In patients who received placebo after induction
  of remission, about 35 remained in remission at
  2 years.

73
Tapering of steroids

• Dose of steroid
• Oral 4060 mg/d or 1 mg/kg/d of prednisone or
  equivalent
• Parenteral CS
• Hydrocortisone 200300 mg/d
• Methylprednisolone 4060 mg/day
• Induction of response Averages 714 d
• Tapering
• 5 mg/wk of prednisone (or equivalent) to a dose
  of 20 mg
• Then, 2.55 mg/wk below 20 mg
• For patients failing to respond to 714 d of
  high-dose oral prednisone or equivalent CS, use
  parenteral CS
• Budesonide Gradually taper from 9 mg to 6mg and
  subsequently 3 mg.

74
Budesonide

• Limited systemic bioavailability due to extensive
  (90) first pass hepatic metabolism by cyt p-450
  enzymes,
• First described in pilot studies in early 1990s
  (Lofberg 1993).
• Contr release prep designed to deliver in distal
  small intestine
• Two formulations
• Controlled-ileal release
• uses a gelatin capsule containing acid-stable
  microgranules composed of an inner sugar core
  surrounded by a layer of budesonide in
  ethylcellulose and an outer acrylic-based resin
  coating (Eudragit) that dissolves at a pH of 5.5
  or higher.
• Absorption of this formulation in ileocecal
  region is approx 69
• pH-dependent release budesonide
• pH-dependent release formulations are available
  as capsules which contain 400 pellets with a
  diameter of 1 mm, coated with Eudragit

75
Induction of remission in active CDBudesonide Vs
Placebo

• 2 large multicentre, DBRCT Greenberg 1994
  Tremaine 2002).
• Greenberg 1994 Conducted over 27Canadian centres
• Tremaine 2002 study recruited across 24 American
  centres.
• Greenberg 1994 258 participants were randomized
  into 4 gp
• 3 groups assigned budesonide,3mg (n67), 9 mg
  (n61) 15 mg (n64) in 2 dd,
• Fourth group received placebo (n 66).
• In the Tremaine study, 200 randomized into three
  groups
• 2 budesonide groups received 9 mg as either 9 mg
  OD (n 80) or 4.5 mg BD(n79)
• Third group received placebo (n 41).
• Primary outcome measure was assessed at 8 wks, at
  which point medications were tapered.
• Total treatment duration 10 wks.

Seow CH, Cochrane review, 2009
76
Induction of remission in active CDBudesonide Vs
Placebo
At all three time points, budesonidegtgt placebo
Week 2 RR 2.97 (95 CI, 1.67 to 5.29) Week 4
RR 1.67 (95 CI, 1.12 to 2.47) Week 8 RR 1.96
(95CI, 1.19 to 3.23).
Time to remission Greenberg 1994 No diff (9 mg
and 15 mg) Time to remission in bud vs plac not
provided. Tremaine 2002 On post hoc analysis
Med time to remission shorter for budesonide (27
days vs 66 days P lt 0.05).
EL 1 RG 1
Budesonide effective for IR Medium time for
response 27 d
Seow CH, Cochrane review, 2009
77
Induction of remission in active CDBudesonide vs
Conventional CS
9 RCTs compared budesonide to CS. At 8 wks, a
total of 750 pts in 8 trials. Budesonide ltlt
conventional CS (RR 0.85 (95 CI 0.75 to 0.97).
Budesonide less effective than Conv CS
Seow CH, Cochrane review, 2009
78
Induction of remission Conventional CS gt
Budesonide
Six RCTs, 669 pts with distal ileal, IC, rt-sided
colonic CD Failure to achieve remission
Conventional CS 116/304 (38.2
) Budesonide173/365 (47.4 ) RR of failure to
achieve remission (stat significant) 0.82 95
CI 0.68 0.98 in favour of CS
CS related adverse events commoner (RR1.64 95
CI 1.342)
Ford AC, Am J Gastroenterol 2011
79
Induction of remission in active CDBudesonide vs
Conventional CS
Gross 1996 Mean time for remission Budesonide
22.3 12.1 d Prednisolone 20.0 17.7 days.
Tursi 2006 Mean time to remission (budesonide
faster) Budesonide 27 d (range 23 to 31
d) Beclomethasone 41 d (36 to 46 d) (Plt 0.05)
Seow CH, Cochrane review, 2009
80
Induction of remission in SEVERELY active
CDBudesonide Vs Conventional CS
2 studies examined proportion of pts with severe
disease (CDAI gt 300) who achieved remission.
Pooled RR for remission 0.52 (95 CI, 0.28 to
0.95), in favour of CS steroids.
Budesonide is inferior to conventional steroids
for treatment of severe CD
Seow CH, Cochrane review, 2009
81
IR in active CD Effect on CDAIBudesonide Vs
Conventional CS
Reduction in CDAI more with Conventional CS
Limited information available on the change in
CDAI. Statistically larger change in CDAI in
conventional CS Weighted mean diff in CDAI of
42.27 points (95 CI 14.86 to 69.67)
Seow CH, Cochrane review, 2009
82
IR in Ileal or right sided ileo-colonic
diseaseBudesonide Vs Conventional CS
Conventional steroid Budesonide
A pooled analysis of six studies of pts with
terminal ileal, or ileo-colonic disease, A
non-significant trend in favour of Conv CS RR for
remission 0.86 (95 CI, 0.75 to 1.00 P 0.05).
Seow CH, Cochrane review, 2009
83
Induction of remission Steroid side
effectsBudesonide vs Conventional CS
Budesonide safer than conventional CS
Budesonide is approx 13 less effective than
conventional CS for ind of rem in CD Kane
2002 Present study 15 less
Six RCT (703 pts) Frequency of CS-related
adverse events Budesonide lt Conv steroids (RR
0.64, 95CI 0.54 to 0.76). None of the studies
reported mortality outcomes.
Seow CH, Cochrane review, 2009
84
Induction of remission in active CD Budesonide 9
mg vs Mesalamine
A single trial of 182 pts compared budesonide
with mesalamine More favorable response with a
longer duration of t/t with budesonide Relative
risk At 2 weeks 1.23 (95 CI, 0.85 to 1.78), P
NS At 4 weeks, 1.26 (95 CI, 0.88 to 1.79), P
NS At 8 weeks, 1.63 (95 CI, 1.23 to 2.16 P
0.0007) At 12 weeks, 1.59 (95 CI, 1.17 to
2.15 P 0.003), At 16 weeks, the relative risk
was 1.79 (95 CI, 1.28 to 2.50 P 0.0007).
Seow CH, Cochrane review, 2009
85
Induction of remission in active CD (CDAIgt300)
Budesonide 9 mg Vs Mesalamine
Budesonide gtgt mesalamine in severe disease
Seow CH, Cochrane review, 2009
86
Budesonide in induction of remission Confidence
and Caveat

• These results are similar to those found in
  previous 3 meta-analyses (Papi 2000 Kane 2002
  Otley 2005).

Caveat Budesonide was given at full dose (9
mg) for first 8 wks of study and then tapered,
but not discontinued at the final study
evaluation, whereas conventional CS were given at
full dose for two wks, and then tapered
87
Efficacy and safety of budesonide vs. placebo in
inducing remission in active luminal CD

• 2 eligible RCTs involving 458 pts
• Included patients with terminal ileal,
  ileocolonic, or right-sided colonic CD.
• Failure to achieve remission
• Budesonide 192 (54.7 ) of 351
• Placebo 81 (75.7 ) of 107
• With a statistically significant effect in favor
  of budesonide (RR of failure to achieve remission
  0.73 95 CI 0.63 0.84.
• NNT with budesonide to achieve remission in one
  patient was 5 (95 CI 3 9).
• Side effects
• Budesonide 312 (88.9 ) of 351 budesonide
  patients and
• Placebo 88 (82.2 ) of 107 placebo patients (RR
  1.05 95 CI 0.91 1.22).

88
AJG IR in CDConv steroid vs Budesonide
Six RCTs ,669 pts with distal ileal ileocecal, or
right-sided colonic CD, Failure to achieve
remission Conv steroid 116 (38.2 ) of
304 Budesonide 173 (47.4 ) of 365 RR of
failure to achieve remission 0.8295 CI 0.68
0.98 NNT 11 (95 CI 6 50) (To achieve
remission in 1 pt)
89
Steroids for induction of remission Summary

• Benefit of corticosteroids over 5-ASA at inducing
  remission with short-term therapy is unclear,
• Unavailability of raw data,
• poor study design and
• poor study enrollment.
• Most clinicians treat active CD with full-dose
  steroids for 3 to 6 weeks followed by a gradual
  wean. The total course of therapy is often 3 to 4
  mo in duration and the benefits to patients
  receiving corticosteroids shown by this review at
  longer follow-up periods are clinically
  applicable.
• Future studies
• Comparison of short term outcome between steroids
  and 5-ASA Non-inferiority trial design.
• Additional studies
• corticosteroid delivery,
• phenotype and disease location in predicting the
  likelihood of inducing remission with
  corticosteroids,
• with particular attention to comparing steroids
  to 5-ASA therapy in patients with colonic disease.

90
Azathioprine
91
Induction of remission in CD Combining steroids
and AZA

• Role of combined antimetabolite and steroid in
  active disease has been controversial.
• NCCD Study failed to show a statistically
  significant benefit for aza monotherapy and has
  been criticized for not allowing concurrent
  steroid therapy during the lag period before
  azathioprine could act
• Combination of azathioprine steroids may lead
  to a higher response rate with less steroid use.

92
Induction of remission in CD Immunosuppressive
drugs Cochrane Review 2010

• 8 Plcebo controlled RCT using aza and 6-MP in
  adult pts with CD
• 5 dealt with active disease
• 3 had multiple therapeutic arms

93
Induction of remission AZA/6-MP vs Placebo
8 studies (6 AZA, 2 6MP) Overall response rate
Drugs 113/209 (54 95 CI 47 to 61)
Placebo 72/216 (33 95 CI 27 to 40) Pooled
odds ratio for response AZA or 6-MP 2.43 (95
CI 1.62 to 3.64). NNT one patient to respond was
5
AZA Vs Placebo Pooled OR 2.06 (95 CI 1.25 to
3.39). 6-MP Vs placebo Pooled OR 3.34 (95 CI
1.67 to 6.66). NNT for one pt to respond was
about 3.
94
Induction of remission Effect of duration of
AZA/6-MP on remission rate
Present 1980 Mean time to response with 6-MP in
active CD 3.1 mo 19 of pts who responded took
gt 16 wks to respond.
Time for response with AZA mono Long As
monotherapy, not a suitable remission inducing
drug
Dur of T/T (2-12mo) Response rate NNT
lt17 wks 1.55 (95CI 0.52-4.59 18
gt17 wks 2.61 (95CI 1.69-4.03) 4

In an attempt to accelerate the onset of action,
a trial evaluating the efficacy of a high-dose
36h infusion was no more effective than
conventional oral dosing
95
Induction of remission Steroids sparing effect
of AZA/6-MP

• Ability to reduce prednisolone dose is an
  important outcome measure
• It can be assessed
• the ability to follow a pre-defined steroid
  tapering regimen,
• Ability to reduce steroid dose to lt 10 mg/d while
  maintaining remission.

In 5 studies reporting data on reduction of
steroid consumption Reduction in steroids in
Pts receiving anti-metabolites 76/117 (65 95
CI 56 to 74) Pts receiving placebo 39/109
(36 95 CI 27 to 45) Pooled OR in favour of
anti-metab 3.69 (95 CI 2.12 to 6.42)
Indicating a significant steroid sparing effect.
NNT 3 (to obtain a steroid sparing effect in 1
pt)
96
Induction of remission Fistula healing with AZA
AZA heals fistula no definite evidence
Response of fistulae to AZA or 6-MP reported by
four studies Two trials reported no difference
between AZA and placebo One trial (Present 1980)
reported the no of fistulae that responded rather
than the no. pts with fistulae that responded,
Overall response rate Therapy 6/11
(55) Placebo 2/7 (29) Pooled OR of 4.68
(95 CI 0.60 to 36.69) favouring fistula healing.
(NS)
97
AZA/6-MP Adverse event during IR
Most common adverse effects Allergic reactions
(2.3) Leucopenia (1.4) Pancreatitis
(1.4) Nausea (1.4) No malignancies or deaths
Adverse events severe enough to cause withdrawal
AZA/6-MP 20/214 (9.3 95 CI 5.8 to 14.1)
Placebo 5/215 (2.3 95 CI 0.1 to 5.3)
Pooled OR 3.44 (95 CI 1.52 to 7.77) in favour
of AZA. NNT 14 (to observe an adverse event in
1 pt)
98
Induction of remission Immunosuppressive therapy
Overall data for IS vs. placebo Combining the
studies IS therapy gtgt placebo statistically
significant (RR 0.8495 CI 0.76 0.94)
NNT 8 (95 CI 5 20).
Suppressing immune system Have some impact on
inducing remission in CD Differing M/A of each
class of IS drugs Not appropriate to pool data.
No significant difference between each of three
classes of drugs and for each individual class
there was no statistically significant effect in
favour of Rx
Khan KJ, AJG, 2011
99
Mx Statement 3

• III A Terminal ileal or localised ileocaecal
  disease Mild to moderately active CD involving
  terminal ileum (L1) or localised ileocaecal
  disease should be treated with budesonide 9 mg
  daily.
• IIIB If there is no response systemic
  corticosteroids should be used.
• IIIC Steroids should be tapered over 3 months.
  (EL
• IIID Severely active CD involving terminal ileum
  (L1) or localised ileocaecal disease should be
  treated using systemic corticosteroids. (EL 1, RG
  1)

100
3) Terminal ileal or localised ileocaecal
disease Mild to moderately active CD involving
terminal ileum (L1) or localised ileocaecal
disease should be treated with budesonide 9 mg
daily. If there is no response systemic
corticosteroids should be used. Steroids should
be tapered over 3 months. Severely active CD
involving terminal ileum (L1) or localised
ileocaecal disease should be treated using
systemic corticosteroids.

• Comments
• You could also argue that those with severe ileal
  disease with strictures or fistulae should
  undergo surgery with resection as a primary
  therapy
• The use of budesonide depends on availability and
  cost.
• Need to give some alternatives
• ASA may be useful in mild disease.
• It would be better to use the conventional
  instead of systematic
• Budesonide 9mg (Availability?)
• Depend on the situation in countries. Budesonide
  is not available in some countries including
  Japan.Statement should consider the difference of
  medical situation in Asian countries.
• Steroid should be used at initial stage, but AZA
  or infliximab can be considered for maintenance.
• there is good evidence either for budesonide or
  CS to induce remission
• Reduced too lengthy.
• Not all need steroids.
• Too many substatements here will make the voting
  difficult

101
Revised Mx Statement 3

• III A Terminal ileal or localised ileocaecal
  disease Mild to moderately active CD involving
  terminal ileum (L1) or localised ileocaecal
  disease should be treated with budesonide 9 mg
  daily. (EL 1, RG 1)
• IIIB If there is no response conventional
  corticosteroids should be used. (EL 1, RG 1)
• IIIC Steroids should be tapered over 3 months.
  (EL
• IIID Severely active CD involving terminal ileum
  (L1) or localised ileocaecal disease should be
  treated using sys(Conventional) corticosteroids.
  (EL 1, RG 1)

102
Mx Statement 4

• Colonic disease (L2) Sulphalazine can be used
  for mild CD limited to the colon.
• Mesalamines are not effective.
• Moderately severe or severe colonic disease
  should be treated with systemic corticosteroids.

103
4) Colonic disease (L2) Sulphalazine can be used
for mild CD limited to the colon. Mesalamines are
not effective. Moderately severe or severe
colonic disease should be treated with systemic
corticosteroids.

• Comments
• "Need to amend statement.
• (i) Sulphalazine can be used for mild CD limited
  to the colon, (ii)Mesalamines are not effective
  are contradicting as Sulphalazine also contra
  Mesalamines(5-ASA)"
• Balsalazide and meszavant are options. Also,
  5-ASAs work as well and given in higher doses can
  target the colon. Sulpha intolerance and allergy
  are common.
• 5ASA/S2P are both acceptable therapies for
  mild-mod CD
• Biologics are also indication for moderately
  severe or severe colonic disease.
• Mesalamines can be used in colon type CD.
• Topical 5-ASA can be useful for distal colonic CD
  and may be useful as an adjunct therapy for Lt
  sided colonic CD.

104
Revised Mx Statement 4

• IVa. Colonic disease (L2) Sulphalazine can be
  used for mild CD limited to the colon. (EL 1, RG
  1)
• IVb. Mesalamines are not effective. (EL 1, RG 1)
• IVc. Moderately severe or severe colonic disease
  should be treated with systemic corticosteroids.
• EL 1, RG 1

105
Mx Statement 5

• Extensive small intestinal disease (L1, L4) For
  extensive small intestinal disease, mesalamines
  or sulphasalazine are ineffective both for the
  induction of remission or maintenance of
  remission.
• Patients with mild to moderate or severely active
  disease should be treated with systemic
  corticosteroids.
• Immunosuppressive drugs (azathioprine, 6-MP or
  methotrexate) should be started simultaneously.
  Those who are sick may be treated with
  intravenous steroid. Alternatives to
  corticosteroid is anti-TNF agent.

106
5) Extensive small intestinal disease (L1, L4)
Mesalamines or sulphasalazine are ineffective
both for the induction of remission or
maintenance of remission. Patients with active
disease should be treated with systemic
corticosteroids. Severe disease may require
intravenous steroids. Alternative to
corticosteroid is anti-TNF agent.
Immunosuppressive drugs (azathioprine, 6-MP or
methotrexate) should be started simultaneously.

• Comments
• This is unclear. do you mean that IS drugs should
  be started simultaneously with steroids or
  biologis or both.
• Avoid "ineffective". "Consider starting
  immunosuppressive early, especially with
  recurrent or severe disease" may be better.
• "If patients' adherence is good, enteral
  nutrition therapy is also indication for small
  intestinal Crohn's disease.
• Especially, it should be considered in pediatric
  CD."
• Intravenous steroid should not be used in CD
  patients, and anti-TNF is recommended.
• Reduced
• Too many substatements here will make the voting
  difficult
• The statement should be clear that we are talking
  about anti-TNF being the alternative for severe
  extensive small bowel disease not responding to
  IV steroids.

107
Revised Mx Statement 5

• Va. Extensive small intestinal disease (L1, L4)
  For extensive small intestinal disease,
  mesalamines or sulphasalazine are ineffective
  both for the induction of remission or
  maintenance of remission. (EL 3, RG C)
• Vb. Patients with mild to moderate or severely
  active disease should be treated with
  Conventional corticosteroids.
• (EL 3, RG 3)
• Vc. Immunosuppressive drugs (azathioprine, 6-MP
  or methotrexate) should be started
  simultaneously. Those who are sick may be treated
  with intravenous steroid. (EL 3, RG C)
• Vd. Alternatives to corticosteroid is anti-TNF
  agent. (EL 3, RG C)

108
Mx Statement 6

• Ileo-colonic disease (L3) Mesalamines or
  sulphasalazine alone are ineffective both for the
  induction of remission or maintenance of
  remission.
• Mild to moderate disease and severe disease
  should be controlled using systemic
  corticosteroids.
• Immunosuppressive drugs (azathioprine, 6-MP or
  methotrexate) should be started simultaneously.
• Those who are sick may be treated with
  intravenous corticosteroid.
• Alternative to corticosteroid is anti-TNF agent.

109
6) Ileo-colonic disease (L3) Mesalamines or
sulphasalazine alone are ineffective both for the
induction of remission or maintenance of
remission. Moderate and severe disease should be
controlled using systemic corticosteroids.
Immunosuppressive drugs (azathioprine,
mercaptopurine or methotrexate) may be started
simultaneously or commenced for relapse or
failure of corticosteroids. Severe disease may
require intravenous corticosteroid. Alternative
to corticosteroid is anti-TNF agent.

• Comments
• What about using antibiotics?
• Severity of disease should be defraud
• Sulfasalzine may be effective in inducing
  remission in mild cases
• Intravenous steroid should be avoided.
• Too many substatements here will make the voting
  difficult
• Again, stament should be clear that anti-TNF is
  the alternative for severe disease not responding
  to IV steroids.

110
Mx Statement 6

• Ileo-colonic disease (L3) Mesalamines or
  sulphasalazine alone are ineffective both for the
  induction of remission or maintenance of
  remission.
• Mild to moderate disease and severe disease
  should be controlled using systemic
  corticosteroids.
• Immunosuppressive drugs (azathioprine, 6-MP or
  methotrexate) should be started simultaneously.
• Those who are sick may be treated with
  intravenous corticosteroid.
• Alternative to corticosteroid is anti-TNF agent.

111
Conventional Mx Statement 7

• Active Crohn's disease with a concomitant
  abdominal abscess should be treated with
  antibiotics, percutaneous or surgical drainage
  followed by delayed resection if necessary, in
  addition to specific medical management of CD.
  III-C

112
Evidences

• There are no RCTs
• When active small bowel CD is associated with a
  concomitant abdominal abscess,
• Drainage followed by medical treatment if there
  are no obstructive symptoms
• Percutaneous drainage and delayed resection if
  there are obstructive symptoms.
• Some abscesses do not lend themselves to
  percutaneous drainage.
• There are no randomized studies in the literature
  Although most case series favour a delayed
  elective resection
• Opinions vary.

113
7) Active small bowel Crohn's disease with a
concomitant abdominal abscess should preferably
be managed with antibiotics, percutaneous or
surgical drainage followed by delayed resection
if necessary.

• Comments
• Surgery may be the first line in some cases
• Primary surgery can often manage perforating
  disease unless there is severe soiling or very
  immunosuppressed patients with risk of
  anastomotic breakdown.
• What about the role of biologicts/immunomodulation
  when others has been controlled
• Reduced
• "Anti inflammatory?
• Surgery as first line? "

114
Revised Mx Statement 7

• Active small bowel Crohn's disease with a
  concomitant abdominal abscess should preferably
  be managed with antibiotics, percutaneous or
  surgical drainage followed by delayed resection
  if necessary.
• EL 3, RG C

115
Induction Mx Statement 8

• Esophageal or gastro-duodenal Crohn's disease
  (L4) may best be treated with a proton pump
  inhibitor, if necessary together with systemic
  corticosteroids and thiopurines or methotrexate.

116
Gastroduodenal CD

• GD involvement in CD mostly as a Hp-negative
  focal gastritis,
• Endoscopically in 20
• Histological 40
• Mostly in pts with concomitant distal disease
  usually ileal.
• Mostly asymptomatic, only 4 symptomatic
• Dysphagia, odynophagia, pyrosis for esophageal
• Nausea, anorexia, epigastric pain, dyspepsia for
  GD CD
• Alcanta, Endoscopy 193 Oberhuber G Virchows