Transcript Induction of remission is usually a symptomatic endpoint although

Asia Pacific Consensus on Crohn’s
disease
Statements on Management
Aims in Mx of a patient with CD
Symptoms and
signs
Weight
Clinical
remission
DOES NOT DETERMINE CLINICAL
COURSE
INFLAMMATORY
PARAMETERS
CRP
IL-6
Faecal calprotectin
Faecal lactoferrin
Platelet
Inflammation
remissoin
STRUCTURAL
PARAMETERS
Endoscoy
MRI
CT
Intestinal
healing
INFLUENCE CLINICAL COURSE
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.
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- 17, 10 and 1
1993; 2003-2004 year for the
(three cohorts)
three cohort
respectively
237
January 1990 to
December 1993
124 mo (range,
108-144 mo)
Norway
(IBSEN)
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)
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 Denmark:1st yr after diagnosis,
– 55 % are in remission
– 15% have mild disease
– 35% have highly active disease.
• Similar data from Olmsted County, US
– > 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.
Natural History of CD
• Disease extent:
– Ileocolonic: 40–50%
– 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, (nonstricturing, non-penetrating disease
– With longer follow up: Development of either a stricture or a
fistula increases
Evolution of Disease Behavior in CD
Cumulative Probability (%)
100
90
80
70
Penetrating
60
50
40
Inflammatory
30
20
10
0
0
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240
Months
Patients at risk:
N=
2002
552
229
95
37
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.
Cumulative risk of hospitalization in Olmsted County, in
the pre-biological era: 211 diagnosed between Jan
1970 -June 1997 and followed until June 1997
Cumulative risk of intestinal resection 314 pts with CD
from Olmsted County, diagnosed between 1940-2001
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;
CD is a progressive disease
Predictors of natural history in adult
Crohn’s disease
Variable
Comment
Clinical Risk factors Age <40 years at diagnosis,
Need for systemic steroids for first flare,
Perianal disease
Terminal ileal disease
C-reactive protein
Endoscopic factors Mucosal healing
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.
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
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
<10%
>90%
Mucosal healing : less hospitalization/ surgical intervention
Rutgeert’s Gastroenterology 1990
• Mucosal healing appears to be an ideal
end point for assessment
Non invasive marker may be used to
determine activity in IBD
Acute
phase ESR, CRP, Orosomucoid, Platelet count
reactants
Serological tests
ASCA, pANCA, Lactoferrin, fibrinogen
Cytokines
Interleukins (IL-1,IL-2,IL-6,IL-8,IL-10,IL-15)TNF-α
Faecal
Indium labeled white cells, calprotectin, lactoferrin,
Nitric oxide, α-antitrypsin excretion, lysozyme excretion
Others
Indium labeled white cells scan, Intestinal permeability
test, whole gut lavage fluid for immunoglobulin and
albumin
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 α, and IL-1β, 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.
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 (>>than 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
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.
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.
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)
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
Phenotype of CD
Montreal classification
Age of onset
≤ 16 yrs (A1)
Location
lleal (L1)
Behavior
Non- stricturing, Nonpenetrating (B1)
Stricturing (B2)
17- 40 yrs (A2) Colonic (L2)
> 40 yrs (A3)
lleal-colonic (L4)
lsolated UGI (L4) Penetrating (B3)
+ ‘p’ if peri-anal disease
CD: Activity scoring system
Ulcerative colitis
Truelove and Witts (1955)
Crohn’s disease
Crohn’s Disease Activity Index
(Best WR, 1979)
Powell-Tuck (1978)
Harvey and Bradshaw(1980)
Complex clinical activity score, Oxford criteria (Myren J, 1984)
(Seo, 1995)
Simple clinical colitis index
(Walsemy, 1998)
Mayo index (Riley SA, 1991)
Crohn’s Disease Activity Index
Item(day)
No. liquid or very soft stools(each day for 7days)
Abdominal pain, sum of 7 d rating
(0=none,1=mild,2=moderate,3=severe)
General well being (1-4)
Exteraintestinal (1 per finding)
Arthritis/arthralgia
Mucocutaneous lesion
Iritis/uveitis
Anal disease (fissure, fistula,etc)
External fistula
Fever>36.8
Antidiarrheal use
Abdomial mass(none-0,equivocal-2,definite-5
Hematocrit (males-47) (Females-42)
Bodyweight (1-body weight/standard weight) ×100
Total CDAI Score
Weight
×2
×5
×7
×20
×30
×10
×6
×1
Harvey Bradshaw index
Variable
General well being
Abdominal pain
No. of liquid stools
Abdominal mass
Complications
Variable description
0= very well,
1=slightly poor,
2 =poor,
3= very poor,
4= terrible
0=none
1=mild
2=moderate
3=severe
Daily
0=none
1=dubious
2=definite
3=definite and tender)
Arthralgia, Uveitis, Erythema nodosum, aphthous
ulcer, pyoderma gangrenosum, Anal fissure, New fistula
Assessment of perianal CD activity index
Catogries affected by fistula
Discharge
Pain/restriction of activities
Restriction of sexual activity
Type of Perianal disease
Frequency
No discharge
Score
0
Minimal mucus discharge
Moderate mucous or purulent discharge
Substantial discharge
Gross fecal soiling
No activity restriction
Mild-discomfort, no restriction
Moderate discomfort, some limitation of activities
Marked discomfort, marked limitation
Severe pain, severe limitation
No restriction of sexual activity
Slight restriction of sexual activity
Moderate limitation of sexual activity
Marked limitation of sexual activity
Unable to engage in sexual activity
No perianal disease/skin tags
Anal fissure or mucosal tear
<3Perianal fistulae
>3 Perianal fistulae
1
2
3
4
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
Anal sphincter ulceration or fistulae with
significant undermining skin
Degree of indurations
No induration
Minimal induration
Moderate induration
Substantial induration
Gross fluctuance /abscess
0
1
2
3
4
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 >50%for 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.)
Crohn’s disease Endoscopic index for severity index
Number of recto-colonic segments, that deep ulceration are seen in divided by no. Sigmoid
of segment examined
Rectum
Transverse colon
Right colon
Ileum
Number of rectocolonic segments, that superficial ulceration are seen in divided by no. Sigmoid
of segment examined
Rectum
Transverse colon
Right colon
Ileum
Segmental surfaces involved by disease. The degree of disease involvement in each
segment is determined by examining each segment for the following 9 lesions,(Pseudopolyps, 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.
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.
Presence of non ulcerated stenosis in any of segments examined.
Presence of ulcerated stenosis in any of segments examined.
12
6
1
1
3
3
Endoscopic scoring system for postop
recurrence (Rutgeerts score)
Grade
Endoscopic Findings
0
No lesions in distal ileum
1
<5 Aphthous lesion
2
>5 Aphthous lesion with normal mucosa between lesions or skip areas of larger
lesion lesions confined to ileocolonic anastomosis (i.e.<1cm in length)
3
Diffuse Aphthous ileitis with diffusely inflamed mucosa
4
Diffuse inflammation with already larger ulcers, nodules and/or narrowing
Histological Disease activity in CD
Histological finding
Score
Epithelial damage
0: Normal
1: Focal pathology
2: Extensive pathology
0: Normal
1: Moderately disturbed (<50%)
2: Severely disturbed (>50%)
0: Normal
1: Moderately increase
2: Severely increase
0: Normal
1: Moderately increase
2: Severely increase
1: In surface of epithelium
2: Cryptitis
3: Crypt abscess
0:No
1:Yes
0:No
1:Yes
0: None (0-6)
1: <33% (1 or 2-6)
2: 33%-66% (3 or 4-6)
3: >66% (5 or 6 of 6)
Architectural changes
Infiltration of mononuclear cells in the lamina propria
Polymorphonuclear cells in lamina propria
Polymorphonuclear cells in epithelium
Presence of erosions and ulcers
Presence of granuloma
No. of biopsy specimens affected
Treatment will depend on phenotype
of CD
Age of onset
≤ 16 yrs (A1)
Location
lleal (L1)
Behavior
Non- stricturing, Nonpenetrating (B1)
Stricturing (B2)
17- 40 yrs (A2) Colonic (L2)
> 40 yrs (A3)
lleal-colonic (L4)
lsolated UGI (L4) Penetrating (B3)
Rx will depend upon Phenotype of CD and
activity
Age of onset
≤ 16 yrs (A1)
Location
lleal (L1)
Behavior
Non- stricturing, Nonpenetrating (B1)
Stricturing (B2)
17- 40 yrs (A2) Colonic (L2)
> 40 yrs (A3)
lleal-colonic (L4)
lsolated UGI (L4) Penetrating (B3)
Activity of the disease
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 "
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
Drugs for CD
Induction of
remission
SSZ (site specific)
Mesalamines (site specific)
Conventional steroids
Budesonide (Site specific)
Immunosuppressants
Biologics
Maintenance
of remission
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 [IIIC].
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]
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]
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]
Rise of aminosalicytes in CD
• Prototypic 5-ASA: SSZ, used to treat CD for > 40 yrs.
• Late 1970s: 2 large multicenter RCTs showed SSZ
marginally superior to placebo for induction of
remission in active disease.
– National Cooperative Crohn’s Disease Study
– European Cooperative Crohn’s 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
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 1gm:23%
Controlled-release
mesalamine prep: safe and effective
– Pentase 2 gm:24%
at 4–g/day
in 4gm:
active
CD(Pof<ileum
colon. vs. 4 g/day).
Pentasa
43%
0.0017and
for placebo
• Pentasa 4 g/d:decrease of 72 points (placebo 21 )(P< 0.01).
• Pts with ileum-only disease: 93-point improvement (placebo 2
• Not associated with clinically significant toxicity.
Singleton et al Gastroenterology. 1993 May;104(5):1293-301.
Fall of SSZ
• On the basis of these data and an extensive
and satisfactory experience with the newer 5ASA formulations in UC,
• By the mid-1990s, Pentasa and other new 5ASA 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
2 more studies on Pentasa
Unpublished results of 2 additional large-scale
RCTs.
5-ASA formulations in induction of
remission of CD
Meta-analysis
Induction of remission in active CD
4 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
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
Induction of remission in CD:
Delayed-release mesalamine vs conventional CS
3 trials, (n=178)
No statistically significant
difference between mesalamine
and conventional CS
(RR 1.04; 95%CI 0.79 to 1.36)
Lim WC, Hanauer S, Cochrane review 2010
Induction of remission in CD
Controlled release mesalamine vs Budesonide
Budesonide >> Mesalamines for induction of remission
A single, (Pentasa with budesonide®), 182 pts (limited to distal ileum and AC)
Remission at 16 weeks
Pentasa:33.7% (30/89)
Budesonide: 60.2% (56/93) (RR 0.56; 95%CI 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 >
300) (11% Pentasa versus 41% budesonide, P = 0.01, RR 0.26 [95% CI 0.08)
Colonic involvement (23%versus 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
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 Crohn’s colitis.
Those with small bowel disease did not improve
Three trials,(n=289): 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 >> 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
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
Induction of remission in CD:
SSZ vs SSZ+Steroids
Sulfasalazine monotherapy: Less effective than
combination therapy with CS
Lim WC, Hanauer S, Cochrane review 2010
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 remission=0.83 95% CI=0.69-1.00),
• Mesalamine over placebo: 4 RCTs: No benefit
• RR=0.91; 95% CI=0.77-1.06)
• Neither SSZ nor mesalamine: Effective in preventing
quiescent CD relapse,
• Per protocol analysis of mesalamine: appeared to
reduce risk of relapse (RR=0.79; 95% CI=0.66-0.95,
NNT=13).
Ford AC, Am J Gastroenterol 2011 Apr
Efficacy: Location wise
Limitations in evidences for ASAs
• Inconsistent trial outcomes
heterogeneity in studies
– Enrollment of patients
– Inclusion and exlusion criteria,
– End-points,
– Duration,
– Dose,
– Delivery system
– Placebo responses
due
to
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
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
The
role of
5-ASAs in inducing remission of
in CDAI
scores,
active
preventing
relapse
of quiescent
– HaveCD
notand
been
consistently
effective
for induction of
mild to moderately
CDremission
remains in
uncertain,
and moreactive
RCTs CD
are
–
Are inferior to budesonide.
required.
• Mesalamine seems to be inferior to conventional
steroids.
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
Efficacy of Steroids in active CD
Population studies
Steroid Use
Steroid dose
Copenhagen study
109/196 (56%)
1 mg/kg
Olmsted County
74/173 (43%)
40-60mg/kg
Study period
1979-1987
1970-1993
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.
1-month
outcomes
12-month
outcomes
Remission
Improved
48%
32%
Remission
54%
Relapse
Improved
46%
57%
* Remission at 12 Months = 25%
No change
20%
Relapse
43%
Localisation of disease, age, sex or clinical symptoms did not significantly correlate
with outcome
Munkholm P, University of Coppenhagen, Denmark Gut. 1994
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
The natural history of corticosteroid therapy
for IBD: a population-based
Immediate
Outcome*
(n = 74)
1-Year Outcome
(n = 74)
Complete
Remission
58%
(n = 43)
Partial
Remission
26%
(n = 19)
No
Response
16%
(n = 12)
Prolonged
Response
32%
(n = 24)
Steroid
Dependent
28%
(n = 21)
Surgery
38%
(n = 28)
*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 2001;121:225
Summary of population studies
•
•
•
•
Only less than half require steroid
Prolonged steroid response in 44%,
Steroid dependency in 36%,
Steroid resistant in 20%
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 >> to placebo.
Azathioprine >> 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 Oct;77(4 Pt 2):847-69.
Corticosteroids in CD: Induction of Remission
92%†
p not calculated
100
82%*
% Patients
80
Corticosteroids
Placebo
60%*
60
38%
40
30%
20
0
NCCDS
17 weeks
ECCDS
GETAID
7 weeks
18 weeks
Clinical Remission
*Randomized controlled trial
†Multicenter prospective trial
Malchow H et al. Gastroenterology. 1984;86:249.
Modigliani R et al. Gastroenterology. 1990;98:811.
Summers RW et al. Gastroenterology. 1979;77:847.
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; P< 0.00001).
Absolute risk reduction: 30% (95% CI 20% to 41%)
NNT 3.33(95%CI 2.4 to 5.0).
Although raw data were not available for meta-analysis, it was clear from lifetable 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
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 ( I2=88 % ,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
Induction of remission: CS vs 5-ASA compounds
3 studies (164/158pts) compared efficacy of CS & 5ASA for induction of late remission (>15 wks).
Pooled analysis;
CS >> 5-ASA in inducing late remission
RR 1.65; 95% CI 1.33 to 2.03; P < 0.00001
Abs risk reduction: 27% (95% CI 17% to 37%)
NNT: 3.7 (95% CI 2.7 to 5.9).
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).
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 > 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
Tapering of steroid
• Current evidence suggests that the algorithm used for CS tapering
after achieving an initial response is unlikely to influence the longterm outcome in patients with CD or UC.
• In the NCCDS, the dosage of prednisone was adjusted during the 17wk 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 <150: 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.
Tapering of steroids
• Dose of steroid
– Oral: 40–60 mg/d or 1 mg/kg/d of prednisone or equivalent
– Parenteral CS:
• Hydrocortisone 200–300 mg/d
• Methylprednisolone: 40–60 mg/day
• Induction of response: Averages 7–14 d
• Tapering:
– 5 mg/wk of prednisone (or equivalent) to a dose of 20 mg
– Then, 2.5–5 mg/wk below 20 mg
• For patients failing to respond to 7–14 d of high-dose
oral prednisone or equivalent CS, use parenteral CS
• Budesonide: Gradually taper from 9 mg to 6mg and
subsequently 3 mg.
Budesonide
• Limited systemic bioavailability due to extensive (90%) first
pass hepatic metabolism by cyt p-450 enzymes,
• First described in pilot studies in early 1990’s (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
Induction of remission in active CD
Budesonide 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 (n=67), 9 mg (n=61) &15 mg (n=64) 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(n=79)
– 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
Induction of remission in active CD
Budesonide Vs Placebo
At all three time points, budesonide>> 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 (95%CI, 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 <
0.05).
Budesonide effective for IR
Medium time for response 27 d
EL: 1
RG 1
Seow CH, Cochrane review, 2009
Induction of remission in active CD
Budesonide vs Conventional CS
9 RCTs compared budesonide to CS.
At 8 wks, a total of 750 pts in 8
trials.
Budesonide << conventional CS
(RR 0.85 (95% CI 0.75 to 0.97).
Seow CH, Cochrane review, 2009
Induction of remission:
Conventional CS > Budesonide
Six RCTs, 669 pts with distal ileal, IC, rt-sided colonic CD
Failure to achieve remission:
Conventional CS: 116/304 (38.2 % )
Budesonide:173/365 (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 (RR=1.64; 95 % CI 1.34–2)
Ford AC, Am J Gastroenterol 2011
Induction of remission in active CD
Budesonide 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) (P< 0.05)
Seow CH, Cochrane review, 2009
Induction of remission in SEVERELY active CD
Budesonide Vs Conventional CS
2 studies examined proportion of pts
with severe disease (CDAI > 300)
who achieved remission.
Pooled RR for remission
0.52 (95% CI, 0.28 to 0.95),
in favour of CS steroids.
Seow CH, Cochrane review, 2009
IR in active CD: Effect on CDAI
Budesonide 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
IR in Ileal or right sided ileo-colonic disease
Budesonide Vs Conventional CS
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
Induction of remission: Steroid side effects
Budesonide vs 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 < Conv steroids (RR 0.64, 95%CI 0.54 to 0.76).
None of the studies reported mortality outcomes.
Seow CH, Cochrane review, 2009
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
Induction of remission in active CD (CDAI>300)
Budesonide 9 mg Vs Mesalamine
Seow CH, Cochrane review, 2009
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
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).
AJG: IR in CD
Conv 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= 0.82;95% CI 0.68 – 0.98
NNT: 11 (95 % CI 6 – 50) (To achieve remission in 1 pt)
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.
Azathioprine
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.
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
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.
Induction of remission: Effect of duration
of AZA/6-MP on remission rate
Present 1980: Mean time to response with 6MP in active CD : 3.1 mo
19% of pts who responded took > 16 wks to
respond.
Time for response with AZA mono: Long
As monotherapy, not a suitable
inducing
Durremission
of T/T Response
rate drug
NNT
(2-12mo)
<17 wks
1.55 (95%CI 0.52-4.59
18
>17 wks
2.61 (95%CI 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
Induction of remission: Steroids sparing effect of
AZA/6-MP
Ability to reduce prednisolone dose is an
important outcome measure
It can be assessed
1) the ability to follow a pre-defined
steroid tapering regimen,
2) Ability to reduce steroid dose to < 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)
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)
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)
Induction of remission: Immunosuppressive
therapy
Overall data for IS vs. placebo
Combining the studies
IS therapy >> placebo: statistically significant
(RR = 0.84;95 % 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
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)
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
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)
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.
•
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.
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
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.
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.
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)
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.
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.
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.
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]
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.
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? "
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
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.
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 Arch
1998;Oberhuber, Gastroenterology 1997
Quality of literature on Gastroduod CD
• No high-quality-level evidence-based data,
– Small uncontrolled retrospective case series
– Anecdotal reports,
– Clinical experience,
– Pathophysiological theories
– Result extrapolation from studies performed on
more distal disease.
Activity of concomitant distal CD usually
determines the indication for T/T
Proton-Pump Inhibitors
• No data are available on this topic
• As gastric acid may also perpetuate
gastrduodenal ulcers due to CD, there acid
supppression is important
• Acid suppression alone probably does not
control the idiopathic mucosal infl ammatory
process.
• Both acid suppresion and antiinflammatory/immunosuppressive seems
appropriate.
Mesalamines and SSZ in GD CD
• Sulfasalazine: no place in Mx of proximal
CD
• Mesalamine: No place
• Pentasa: may be
– No data
Steroids in GD CD
• A small retrospective study in 10 pts with
symptomatic CD showed, in every patient, a good
clinical response with oral corticosteroids
• Similar results in a retrospective case series.
– Of 46 patients treated with steroids for nonobstructingdisease, 42 had good to excellent results,
concomitant medication with sulfasalazine, anH 2 RA
or intermittently with azathioprine or metronidazole.
• Budesonide: No data
Azathioprine, 6-Mercaptopurine
• Only anecdotal clinical experience has been published
• Indications:
– Those who remain symptomatic on steroids,
– Steroid-dependent
– Maintenance therapy
• Korelitz et al. Am J Gastroenterol 1993
– 20 years of clinical experience with 6-MP
– All achieved in healing or marked improvement in
gastroduodenal lesion
• Miehsler W, Inflam Bowel Dis 2001
– 12 pts with UGI CD treated with AZA
– Prednisone could be discontinued in 7 after 4–6 mo
– A significant decrease in CDAI score
Infliximab
• Resolution of severe esophagogastric and
esophago-bronchial fistula with Infliximab
Heller, IBD 1999; Ho JCG 2002
• 4 cases of severe isolated gastroduodenal CD
– 2 were treated with infliximab, 1 healed, other did not
Grubel, Dig Dis Sci 2003
• Severe gastric and duodenal CD with diffuse
thickening and ulceration throughout the antrum
and duodenum: Responded to Infliximab
Firth JJ, Am J Gastroenterol 2002
Gastroduodenal CD
Balloon Dilation
• Presence of a stenosis with obstruction
indicates a severe disease
• If medical therapy with steroid and
immunosppr drugs does not alleviate
symptoms, balloon dilation or surgery
• Successful dilatation for obstructive
gastroduodenal CD
Matsui et al, Murthy; Kelly and Hunter
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.
Comments:
•the evidence of the efficacy of PPI in upper GI CD is insufficient. Biologics should be considered in
severe upper GI lesions.
Revised Mx: Statement 8
• Esophageal or gastro-duodenal Crohn's
disease (L4) is treated with conventional
corticosteroids and thiopurines or
methotrexate. Short term use of a proton
pump inhibitor should be considered for
upper GI symptoms. [III-C]
Maintenance Mx: Statement 9
• Treatment for the maintenance of remission should
be recommended in almost all CD patients. [II-2-B]
• Conventional steroid and budesonide are not
recommended in the maintenance of remission. [IA]
• The first line of treatment for maintenance of
remission is thiopurines. Methotrexate can also be
used. [I-A]
• Alternative to immunomodulators is anti-TNF
therapy.
Mention in text some patients do not require treatment.
Maintenance of remission
5-ASA Vs Placebo
16 RCT, 2,496 pts, Rate of relpase
5-ASA vs control: 55.8 % vs 57.0 %
RR of relapse with 5-ASA
0.97 (95 %CI = 0.90 – 1.05),
5-ASA no more effective than control in maintaining remission
Ford AC, Am J Gastroenterol 2011 Apr
Steroid for Maintenance
Maintenance of remission: Budesonide
• 11 studies included
– 8 studies: Budesonide Vs placebo,
– I study: Budesonide Vs 5-ASA
– I study: Budesonide Vs conventional CS
– 1 study: Budesonide two doses
• 8 studies used a controlled ileal release
budesonide, while one used a pH-modified
release formulation.
Benchimol EI, Cochrane review, 2010
•
•
•
•
•
•
•
•
6 mg daily was no more effective than placebo for maintenance of remission at 3 months (RR 1.25;
95% CI 1.00 to 1.58; P = 0.05), 6 months (RR 1.15; 95% CI 0.95 to 1.39; P = 0.14), or 12 months (RR
1.13; 95% CI 0.94 to 1.35; P = 0.19).
Budesonide was not more effective than weaning doses of prednisolone for maintenance of
remission at 12 months (RR 0.79; 95% CI 0.55 to 1.13; P =0.20), but was better than mesalamine 3
grams per day (RR of remission 2.51; 95% CI 1.03 to 6.12; P = 0.04).
Budesonide 3 mg daily was more effective than placebo at 3 months (RR 1.31; 95% CI 1.03 to 1.67;
P = 0.03). This benefit was not sustained at 6 months (RR 1.10; 95% CI 0.81 to 1.50; P = 0.53), or 12
months (RR 1.04; 95% CI 0.84 to 1.30; P = 0.70).
No differences in efficacy were detected based on the different formulations of budesonide,
methods used to induce remission, or budesonide dose.
The use of budesonide 6 mg resulted in slight improvements in CDAI scores when assessed at 6
months (WMD -24.3; 95% CI -46.31 to -2.29; P = 0.03) and 12 months (WMD -23.49; 95% CI -46.65
to -0.32; P = 0.05) and mean time to relapse of disease (WMD 59.93 days; 95% CI 19.02 to 100.84; P
= 0.004).
Adverse events were more frequent in patients treated with 6 mg of budesonide compared with
placebo (RR 1.49; 95% CI 1.01 to 2.19; P = 0.05), but not in patients using lower doses of
budesonide.
These events were relatively minor and did not result in increased rates of study withdrawal.
Abnormal adrenocorticoid stimulation tests were seen more frequently
in patients receiving both 6 mg daily (RR 2.88; 95% CI 1.72 to 4.82; P < 0.0001) and 3 mg daily (RR
2.73; 95% CI 1.34 to 5.57; P = 0.006) compared with placebo.
Benchimol EI, Cochrane review, 2010
Placebo-controlled trials of budesonide for maintenance of
medically induced remission in Crohn’s disease
Author
Löfberg
(1996)
No. of Dosage
(mg/day)
patients
96a
6
Duration
(Months)
12
3
Greenberg
(1996)
105a
6
75a
6
12
179
3
74
63
P
NS
61
12
46
67
NS
67
Controlled
Controlled
Ileal release
60
NS
Controlled
Ileal release
48
12
formulation
Ileal release
70
3
Gross
(1998)
Budesonide Placebo
59
3
Ferguson
(1998)
Relapse
65
NS
pH-modified
release
Continued:
Author
Cortol
(2001)
Hanauer
(2005)
Duration
Relapse
No. of Dosage
(mg/day) (Months)
patients
Budesonide Placebo
120
6
4-5
33
65
110
6
12
40
47
formulatio
n
P
0.05 at Controlled
3 months ileal release
NS
Controlled
ileal release
Maintenance of remission in CD
6mg Budesonide = Placebo
Only 1 study: stat sifgnificant benefit at 3
mo (RR 1.90; 95%CI 1.29 to 2.81).
Pooled RR of continued rem with budesonide
At 3 mo: 1.25 (95% CI 1.00 to 1.58; P= 0.05)
At 6 mo: 1.15 (95% CI 0.95 to 1.39; P= 0.14)
At 12 mo: 1.13 (95% CI 0.94 to 1.3; P= 0.19),
Budesonide 6 mg/d is not effective
for maintenance of clinical remission in CD
Benchimol EI, Cochrane review, 2010
Maintenance of remission in CD
3mg Budesonide = Placebo
Maintenance of remission:
At 3 mo: Budesonide>> placebo
(RR1.3; 95%CI 1.03 to 1.6; P= .03),
NNT: 8.
At 6mo (RR1.10; 95% CI 0.8 to 1.5;P =0.5)
At 12mo:(RR 1.04;95%CI 0.8 to 1.3; P 0.7
Not effective at 6 mo and 12 mo
Benchimol EI, Cochrane review, 2010
Maintenance of remission in CD
3mg Budesonide = 6 mg budesonide
Benchimol EI, Cochrane review, 2010
Maintenance of remission in CD
9mg Budesonide = 6mg in
Benchimol EI, Cochrane review, 2010
Maintenance of remission
Budesonide 9 mg = Conventional CS
One study compared CIR budesonide 9 mg to prednisolone 40 mg/d with a
weaning schedule (Schoon 2005).
Remission rates (defined by CDAI 200) were not significantly different
3 months (RR 0.81; 95 CI 0.60 to 1.09),
6 months (RR 0.79; 95% CI 0.56 to 1.12),
12 months (RR 0.79; 95% CI 0.55 to 1.13).
Benchimol EI, Cochrane review, 2010
Maintenance of remission in CD
Budesonide 6mg >> Mesalamine 3 g
One study compared
Budesonide Vs pH-dep mesalamine in steroid-dept CD
Remission rates after 1 yr of Rx
Budesonide >> mesalamine (RR2.51;95% CI 1.03 to 6.12; P=0.04).
Benchimol EI, Cochrane review, 2010
Mean time to relapse of disease with budesonide used
for maintenance
• Budesonide 6 mg versus placebo
– Budesonide 6 mg significantly increased mean time to relapse (59.9d; 95%C 19
to 100.8; P=0.004).
• Budesonide 3 mg versus placebo
– Significant benefit for mean time to relapse for budesonide(30.5d; 95%CI 9.1
to 52.09; P=0.005),
• Budesonide 6 mg versus budesonide 3mg :
Amongst
dowas
relapse,
– Meanpts
timewho
to relapse
not significantly different in patients
Budesonide
timebudesonide
to relapse6 by
• Budesonideprolong
9 mg versus
mg:approx 60 d with
– Median
to relapse
in 6daily
mg group was 809 days (95% CI 360 to
6mg/d
or 30time
d with
3 mg
1259 days)
– Median time to relapse in 9 mg group was 1049 days (95% CI 384 to
1713 days).
– there was no significant difference between groups.
• Budesonide 9 mg versus traditional corticosteroids: Study did
not report
• Budesonide 6 mg versus mesalamine 3 g: Study did not report
Benchimol EI, Cochrane review, 2010
Why budesonide or steroid are not effective for
maintenance?
• Not entirely clear
– Use of systemic corticosteroids may contribute to reduced
immune cell apoptosis (Towers 2005).
– Early use of steroids may propagate abnormal immune response
in pts with CD resulting in repeated episodes of inflammation
and tissue damage
– Decreased efficacy of corticosteroids with repeated or long-term
use (Van Den Brande 2002).
• It is also possible that the location of disease in pts
receiving budesonide who relapse: Is outside of location
of budesonide greatest effect (ileo-cecal region).
Benchimol EI, Cochrane review, 2010
Azathioprine for maintenance of remission in CD
• 1118 references reviewed,
• 21 potentially eligible studies were identified.
– Thirteen of these studies were excluded for various reasons.
– 8 trials were identified that satisfied the inclusion criteria as placebo
controlled RCT,
• Maintenance Rx with AZA was compared to no Rx
• 1 trial (Hanauer 2004) used 6-MP for maintenance of remission.
AZA for maintenance of remission
• 5 studies dealt exclusively with quiescent disease
• In total 550 pts included,
– 208 received azathioprine,
– 47 received 6-MP
– 295 received placebo
• 2 studies included steroid dep pts & attempted to
withdraw steroids after adding AZA or placebo
• 2 other studies (O’Donaghue 1978, Lemann 2005)
identified pts who were in remission on AZA and
randomized them to receive a 12mo or 18 month of
either AZA or placebo.
AZA/6-MP: Maintenance of Remission in CD
Overall remission rate
AZA: 147/208 (71%; 95% CI 64% to 77%)
6-MP: 24/47 (51%; 95% CI 36% to 66%)
Placebo: 141/255 (55%; 95% CI 49% - 61%)
Peto OR for response
AZA: 2.32 (95% CI 1.55 to 3.49)
6-MP: 3.32 (95%CI 1.40 to 7.87).
NNT:
AZA: 6 for prevention of 1 recurrence
6-MP: 4 for prevention of 1 recurrence
Increase in dose of AZA increases
response rate
• When the maintenance therapy data were
analysed for the effect of azathioprine dose
range 1.0 to 2.5 mg/kg/day),
Adequate
dosing of AZA is important
Peto
OR for response
Do we really use 2-2.5mg dose in Asia
– At 1 mg/kg/d: 1.20 (95% CI 0.60 to 2.41)
– At 2 mg/kg/d: 3.01 (95% CI 1.66 to 5.45)
– At 2.5 mg/kg/d: 4.13 (95% CI 1.59 to 10.71)
During maintenance t/t: AZA withdrawal due to drug
side effects
Drug withdrawal due to adverse event:
AZA: 6%
6-MP: 19%
Placebo: 3%
AZA/6-MP>Placebo
AZA: Peto OR 3.74; 95% CI 1.48 to 9.45).
Number needed to harm (NNH) was 20.
6-MP: similar results
(Peto OR 2.04; 95%CI 0.63 to 6.60).
Common events for withdrawal
Pancreatitis,
Leukopenia,
Nausea,
Allergic reaction
Infection.
During maintenance T/T: Steroid withdrawal on
AZA
Although desired
Data very small and non-convincing
Two very small studies reporting steroid withdrawal data:
Ability to reduce or discontinue steroid on maintenance:
AZA: 13/15 (87%; 95% CI 60% to 98%) compared to
Placebo: 8/15 (53%; 95% CI 27% to 79%)
Peto OR 5.22; 95% CI 1.06 to 25.68)
NNT for reduction in steroid =3
Summary: AZA for maintenance
At this time AZA appears to be an effective agent for
maintenance of remission and may be effective as a
steroid sparing agent.
Strength of evidence: Weak
Available studies and eligible patients: Relatively small
(208 AZA; 47 6-MP; 295 placebo)
How long to use AZA for maintenance?
• The current literature does not provide a great
deal of guidance on this point.
• Bouhnik 1996:Patients might be maintained
on AZA for 42 mo before stopping
How long to use AZA: Long-term efficacy of AZA does not wane
after four years of continuous treatment
• Pts with steroid-dep CD in remission on AZA (2-2.5 mg/kg) for
between 2-8 yrs were assigned into two groups.
– Group A (n=58) : Treated continuously for 2 to 4 yrs
– Group B (n=42): Treated continuously for 4 to 8 yrs.
• Assessment:
– FU every mo for 1 yr with physicals, compliance
– CDAI, IBD QOL: 3 monthly ; Colonoscopy with CDEIS at baseline and at end
• Endpoints:
– primary end point: was relapse after 1 year.
– Secondary end points: safety of treatment, QOL, and endoscopic healing.
• Relapse rates per protocol: 19.6% and 11.9%, respectively (p: NS).
• No sig differences in overall and at each time point between two
t/t groups regarding compliance, safety, CDAI, IBDQ, and CDEIS
• Multivariate analysis: No identifiable factor influencing remission
• Long-term Rx with AZA for steroid-dep CD is efficacious and safe.
Mantzaris GJ, J Crohns Colitis 2007 Sep;1(1):28-34 Athens, Greece
How long to use AZA?
• Further research is required to determine if patients
can stop taking AZA after long-term use without
risking relapse.
• Most clinicians, however use for a longer duration
Relapse while on AZA
• ECCO Statement 6E:
• Patients receiving azathioprine or mercaptopurine who relapse
should be evaluated for adherence to therapy and have their
dose optimised. Change of their maintenance therapy to
methotrexate [EL1b RG B] or anti-TNF therapy [EL1a RGB] should
be considered.
• Surgery should always be considered as an option in localised
disease [EL4, RG D].
• Patients receiving azathioprine or mercaptopurine who relapse
whilst on standard maintenance doses can have their dose
escalated (N2.5 mg/kg/day or N1.5 mg/kg respectively) until
leucopenia occurs [EL3, RG D], or according to 6-TGN
concentrations [EL2a, RG B] (see Section 5.4.6).
• Methotrexate is another option [EL1b, RG B] (see Section 6.2.5).
Anti-TNF therapy has also proven to be
Methotrexate for remission
The probability for maintaining clinical remission as a function of time in the 50
patients who achieved this therapeutic goal after 3 months and were maintained on
MTX are presented in Figure 2. The cumulative probability not to relapse was 95.3%
(95% CI: 75.9–100%), 89.5% (95% CI: 69.6–100%), 70.6% (95% CI: 47.1–94.1%)
and 62.8% (95% CI: 33.5–92.0%) at 6 months, 1, 2, and 3 years after starting MTX
treatment, respectively. There was a significant decrease in the mean HBI from 4.5
points at the beginning of MTX therapy to 2.1 points after 3 months of treatment (P
< 0.001). Subsequently, the mean HBI remained unchanged for up to 3 years.
Guidelines
9) Maintenance of remission: Most patients with CD will require treatment for maintenance of remission.
Systemic steroids including bedesonide are ineffective in maintenance of remission. The first line of
treatment for maintenance of remission in patients with terminal ileal disease, colonic (L2), ileocolonic
disease, extensive small intestinal disease, or localised ileocaecal disease is thiopurines. Methotrexate can
also be used. Alternative to thiopurines can be anti-TNF therapy.
Comments:
•Spelling mistakes- Budesonide
•Combined therapy with thiopurines and anti-TNF agents can also be used.
•Too many ideas in the statements
•The wording needs tweaking. The problem with longterm steroids is adverse-effects rather than
efficacy in maintenance. This should be highlighted.
Revised Mx: Statement 9
• Maintenance of remission: Most patients with CD
will require treatment for maintenance of remission.
• Systemic steroids including budesonide are
ineffective in maintenance of remission. (EL 1, RG A)
• The first line of treatment for maintenance of
remission in patients with terminal ileal disease,
colonic, ileocolonic disease, extensive small
intestinal disease, or localised ileocaecal disease is
thiopurines. (EL 1, RG 1)
• Methotrexate can also be used.
• Alternative to thiopurines can be anti-TNF therapy.
(EL 3, RG C)
Mx: Statement 10
• Patients on azathioprine need close
monitoring. Some patients may be unduly
sensitive and develop pancytopenia even with
smaller doses. The dose should therefore be
tailored to the individual.
• Where ever available TMPT testing should be
done prior to starting of azathioprine.
AZATHIOPRINE
84%
6-THIOURIC ACID
XO
TPMT
6-MERCAPTOPURINE
6-METHYL
MERCAPTOPURINE
HGPRT
IMPDH
6-THIOXANTHOSINE
5’- MP
6-THIOISONINE
5’- MP
HGPRT
TPMT
GMPS
6-THIOGUANOSINE
5’- MP
6-METHYLTHIOINOSINE
5’-MONOPHOSPHATE
MPK
6-THIOGUANOSINE
5’-DIPHOSPHATE
DPK
6-THIOGUANOSINE
5’-TRIPHOSPHATE
6-THIOGUANOSINE
NUCLEOTIDES
Three enzymes: Competitive state
TPMT
• TPMT enzyme activity in general population:
– Low or absent level (Homozygous): Approx 0.3%
– Intermediate level: 11%
– High level: 89%
• only 25% of leukopenia: associated with the presence of one
of genetic polymorphisms
• Prospective studies evaluating dose optimization based on
measurements of TPMT, 6-TGN, or 6-MP: Lacking
• Despite the lack of such data, routine use of TPMT genotype
or enzyme activity is currently recommended by the FDA
before initiation of therapy with either AZA or 6-MP
Monitoring
• At initiation:
– Complete blood count with differential every
other week till dose is stablized.
• Thereafter: At least once every 3 months.
• Periodic LFT
• FDA:
– individuals should have TPMT genotype or
phenotype assessed before initiation of therapy
with AZA or 6-MP in an effort to detect individuals
who have low enzyme activity (or who are
homozygous defi- cient in TPMT) in an effort to
avoid AZA or 6-MP therapy in these patients and
thus avoid potential adverse events
10) Patients on azathioprine need close monitoring. Some patients may be unduly sensitive and
develop pancytopenia even with smaller doses. The dose should therefore be tailored to the
individual. Where ever available TMPT testing should be done prior to starting of azathioprine.
Comments:
•Should give guidance as to how we suggest the dose is tailored - lymphocyte count, MCV, thiopurine
metabolites ...
•Whether it is cost effective to test EVERYONE for TPMT is debatable. Agreed close monitoring is essential
•TMPT may not be sensitive enough in some
•"""...close monitoring of FBC and LFT, at least 1-2 weekly initially.""
•""Educate patients to cease thiopurines in the event of allergic reactions."""
•TPMT test results do not have a defintie association with azathioprine adverse events
•In addition, MRP4 testing and ITPase testing may be helpful for tailored medicine.
•Reduceda
•"Many substatements...not clear what we are voting for.
•""Patients on azathioprine need close monitoring particularly to test for TPMT deficiency""....sounds more
like what we are looking for"
Revised Mx Statement 10
• Patients on thiopurines need close monitoring
for myelotoxicity and hepatotoxicity.
• More evidence of the benefit of TPMT testing
in Asia is required. [III-C]
Dose
Mx: Statement 11
• Patients receiving systemic steroids for more
than three weeks should receive calcium
supplementation.
Steroids and Bone
• Effect of CS on bone modelling
–
–
–
–
Impair osteoblast function,
induce osteoblast apoptosis,
reduce intestinal calcium absorption,
increase renal excretion of calcium.
• Increases risk of fracture
• Greatest bone loss occurring in the initial months of
treatment
• Decrease in fracture risk back toward baseline after
stopping glucocorticoid
• Prednisone, prednisolone, and methylprednisolone: major
• Budesonide, a locally acting corticosteroid, better
Risk Factors for Glucocorticoid-Induced Osteoporosis
Advanced age
Low body-mass index (<24)
Underlying disease: IBD, RA, SLE
Prevalent fractures, smoking, excessive alcohol consumption,
frequent falls, family history of hip fracture
Glucocorticoid receptor genotype
Increased 11β-HSD1 expression
High glucocorticoid dose (high current or cumulative dose; long
duration of therapy)
Low bone mineral density
Guidelines for management of glucocorticoidinduced osteoporosis
Variable
ACR
NDF
RCP(L)
Dose & durn of ≥ 7.5mg/d for
glucocorticoids atleast 3 mo
≥ 5 mg/d for
atleast 3 mo
Any dose for 9.3mg/day for
atleast 3 mo atleast 3 mo
Yearly BMD
Yes
Yes
Yes
Calcium suppl
1200-1500
mg/d
1200mg /d
Only for pts For all
with low Ca patients
intake(<1g/d
Vit D suppl
800-1000 IU
vit D/d
2000 units of
vit D/d
vit D
deficiency
•ACR- American college of Rheumatology
•NDF- National Osteoporosis Foundation
•RCP(L)- Royal collage of Physicians of London
•BBC- Belgian Bone club
BBC
Yes
Survey of gastroenterologists' awareness and
implementation of AGA guidelines on osteoporosis in
IBD patients
• 1000 physicians: Surveyed about awareness about implementation of
guidelines on osteoporosis
• Of 304 responders, 258 respondents were analysed.
• 49% used guidelines in decision-making or in Mx
• Physician
saw more
IBD pts more
likely to do
assess
osteoporosis
Mostwho
of the
responding
physicians
notforutilize
compared
to those
who sawon
lessmetabolic
(P < 0.0001).bone disease in
the AGA
Guidelines
• Only 16% who saw <25% IBD pts, treated osteoporosis (P < 0.0001).
IBD patients.
• Barriers:
– IBD should be the focus of the visit (48, 42%);
– osteoporosis should be managed by another physician: 30%
– Lack of time: 11%)
– Cost: 10. 9%
– Lack of knowledge: 10, 9%
Wagnon JH, Inflamm Bowel Dis. 2009
Do guidelines matter: Implementation of the ACG and AGA
osteoporosis screening guidelines
• ACG and AGA have both recently issued guidelines
• 100 IBD patients underwent DEXA
• Indications for screening
– Prolonged past or concurrent steroid use (92%),
– Postmenopausal status (7%),
– History of low trauma fracture (7%).
•
•
•
•
42% had osteopenia
12% had osteoporosis
44% had normal BMD
Factors predicting a greater likelihood of osteoporosis
– Diagnosis of Crohn's disease
– Low body mass index in women, and postmenopausal status.
• Implementation of the Guidelines led to the detection of
osteopenia or osteoporosis and initiation of specific therapies
in a majority of patients
Kornbluth A, Am J Gastroenterol. 2006
11) Patients receiving systemic steroids for more than three weeks should receive calcium
supplementation.
Comments:
•And vitamin D status should be measured and replaced if deficient. Perhaps referring the
reader to local osteoporosis guidelines would be best as well. There may be times where
bisphosphanates are commened early.
•?and vitamin D or variable within the region.
•"Now, Ca and Vit D supplementation to avoid osteoporosis are not 1st choice in general
population.
•Bisphosphonate or Vit K are recommended.
•So, even in IBD, we do not have enough evidence that Ca supplementation is effective. "
•Calcium supplements should be given even if steroids are given for less than 3 weeks
•=+Vit D + shot with steroids
Revised Mx: Statement 11
• Patients receiving systemic steroids should
also be prescribed calcium supplementation
and vitamin D. III-C
• ** Check level of evidence
Mx: Statement 24
• At present, there is no definite role of antimycobacterial avium para-tuberculosis
therapy in patients with CD.
Isolation of MAP in pts with CD
Country
Method
CD
UC
Healthy
control control
2010
Mendoza
Spain
Blood Culture
(MGIT) 18-m0
0/30
0/29
0/10
2009
Kirkwood
Australia
BACTEC 12B
4/10 (40%)
0/2
0/4
2009
Reddy DN
India
PCR-IS900
0/81
0
0/85
Maryland
USA
BACTEC 460
0/130
0
0/130
4/5 (80%)
0
0/130
19/30
(63.3%)
0/2
10.3%
Year, Author
2009
Parrish
NM
2008
Singh AV
2005,
Sechi21
PCR-IS900
India
Italy
MGIT Tissue culture
Isolation of MAP in pts with CD
Year,
Author
Country
Method
Pts with CD
2004,
Naser20
USA
Lancet
Blood culture 14/28 (50%)
(MGIT)
2/9 (22%)
2003, Bull
TJ19
UK, JCM
Tissue
culture
(MGIT)
14/33(42%)
(after 14-88
wks)
3/33(9%)
2000,
Schwartz
Clin Micro
Infect
Culture
MGIT
Surgical sp
6/7 (86%)
4/20 (20%)
2/36
(5.6%)
2000
Collins48
USA
(JCM)
BACTEC 12B
0
0
1993
Wall S49
UK (JCM)
6/30
UC control Healthy
control
Comments
0/15
MAP lies in
submucosa
0
None
positve
Identified
by DNA
MAP (As detected by PCR)
Meta-analysis
Anti-MAP therapy in patients with CD
Author (year)
Pts
Trial
Antibiotic
combination
Concom
steroid
TT (mos)
Primary endpoints
Efficacy (main result):
Treatment/placebo (%)
Elliott (1982)
51
RCT
Sulfadoxine,
No
pyrimethamine
12
Changes in CDAI scores
Clinical remission: 38/50
Schaffer (1984)
27
RCT
Ethambutol,
rifampin
No
12
Changes in CDAI scores (or
any clinical indicator of
disease activity)
Clinical remission: 36/64
Basilisco (1989)
24
RCT
Rifabutin
No
6
Changes in the HarveyBradshaw index
Clinical remission: 29/38
Hampson (1989) 20
Open
label
Ethambutol,
rifampin,
isoniazid,
Yes
clofazimine (or
pyrazinamide)
9
Clinical remission defined
as CDAI < 150
Clinical remission: 50
Prantera (1989)
5
Open
label
Dapsone
No
1
Changes in CDAI scores and
Clinical remission: 40
mucosal healing
Afdhal (1991)
49
RCT
Clofazimine
Yes
12
Clinical remission (use of
modified CDAI scores)
Clinical remission: 64/50
Anti-MAP therapy in patients with CD
Author (year)
Rutgeerts
(1992)
Pts
16
Prantera (1994) 40
Swift (1994)
Thomas (1998)
Trial
Antibiotic
combination
Efficacy (main
result):
Treatment/placebo
(%)
Concom
steroid
TT
(mos)
No
6–12
Endoscopic healing in the
neoterminal ileum
Mucosal healing: 0
9
Clinical remission and mucosal
healing
Clinical remission:
84/35
24
Changes in the Harvey-Bradshaw
index and CDAI scores, steroid
sparing, need for surgery,
radiological change
Clinical remission:
35/38
Induction of clinical
remission: 93.5
Clinical remission:
32/48
Open label
Rifabutin,
ethambutol
RCT
Clofazimine, rifampin Yes
Primary endpoints
126 RCT
Ethambutol,
rifampin, isoniazid
Gui (1997)
46
Open label
Rifabutin,
clarithromycin (or
azithromycin)
Yes
19
Changes in the Harvey-Bradshaw
index and serum CRP, steroid
sparing, need for surgery
Leiper (2000)
25
Open label
Clarithromycin
Yes
1–15
Changes in the Harvey-Bradshaw
index and serum CRP
No
Goodgame
(2001)
31
RCT
Clarithromycin,
ethambutol
Yes
3
Changes in the
Changes in the lactulose-mannitol Harvey-Bradshaw
test and the Harvey-Bradshaw
index in the active
index
arm: P = .08 vs
placebo
Shafran (2002)
36
Open label
Clarithromycin,
rifabutin
Noa
4–17
Response defined as marked
improvement in CDAI scores
Clinical response:
58.3
Borody (2002)
12
Open label
Clarithromycin,
Yes
rifabutin, clofazimine
24
Changes in the Harvey-Bradshaw
index
Clinical remission: 25
Anti-MAP therapy in CD
• Induction phase
– Oral prednisolone 40 mg/day, taper to 0 over 16 weeks,
• Randomization: Either antibiotic combo or placebos from wk 1
– Clarithromycin 250 mg/d for wk 1, 250 mgx2 for wks 2 &3then 750 mg/d from wk
4.
– Rifabutin dose increased at the same time points 150 mg, 300 mg, and 450 mg.
– Clofazimine 50 mg daily.
• Subjects were stratified for use of thiopurine therapy.
• Subjects not achieving remission at wk 16 and those unable to
tolerate full doses of were considered Rx failures, withdrawn.
• Maintenance phase
– Subjects in remission at week 16 continued trial medications.
– If a subject had a subsequent relapse (CDAI >150 with an increase ≥60), retreated
with “rescue” prednisolone.
– Failure to respond to this retreatment was an indication for withdrawal.
• Follow-up phase
– At 104 wks, the trial medications were ceased.
– Selby W, Gastroenterology 2007 (Sydney Au)
Result: Primary outcome measure
Relapse
Antibiotic
Placebo
1 relapse, 16-52 wk
39% (26/67)
56% (31/55)
(P = .054; OR, 2.04 [95%CI: 0.84–4.93]
Wk 104
26% (11/42)
43% (12/28
(P =0 .14; OR, 2.22 [95%CI: 0.62–7.96]
Wk 156
59% (20/34)
50% (10/2
(P = .54; OR, 0.70 [95%CI: 0.18–2.74].
Remission at 3 yrs
14 (13.7%
10 (9.0%
Summary: Anti-MAP therapy in CD
• Insufficient evidence
• Many limitations
• Anti-MAP therapy: Not known
– The drugs, How many
– How long
– What doses
• In-sufficient evidence to recommend ati-MAP therapy
in CD
24) At present, there is no definite role of anti-mycobacterial avium para-tuberculosis therapy in
patients with CD.
Comments:
NIL
Revised Mx: Statement 24
• At present, there is no definite role of antimycobacterial avium para-tuberculosis
therapy in patients with CD. [I-A]
Text: drug dose efficacy duration.
Mx: Statement 25
• Medication use Fertility, pregnancy,
breast feeding, nutrition and
osteoporosis are important
considerations in the management of CD.
Pregnancy outcome in CD
13 studies comparing the pregnancy outcomes in IBD.
12 included (1986 and 2005)
3907 patients with IBD and 320531 controls.
63% CD and 36% UC
Outcome of interest studies Pts
Control OR (95% CI)
LBW
2
597
3357 2.82 (1.42 to 5.60)
Premature birth
7
1005 61565 1.97 (1.36 to 2.87)
Still births
3
589
3558 1.91 (0.69 to 5.31)
SGA
2
220
1373 5.72 (0.62 to 52.81)
Caesarean section
4
321 57935 1.65 (1.19 to 2.29)
Cong abnormalities
3
307
1712 2.14 (0.97 to 4.74)
p Value
0.003
<0.001
0.22
0.12
0.003
0.06
Cornis J, Gut 2007
Effect of drugs for IBD in pregnancy
Outcomes
5‐ASA
AZA
CS
Anti‐TNFα pop incidence
(%)
Studies
Women
Pregnancies
Successful pregnancies
Spontaneous abortion
Elective termination
Still births
LBW
Premature birth
Ectopic pregnancy
Major congenital defect
14
3
4
2
.
1026
37
883
106
.
648
39
581
92
.
612 (94) 33 (84) 124 (94) 65 (70)
.
16 (2.4) 1 (2)
2 (<1)
11 (12)
20
7 (1)
2 (5)
0
16 (17)
0.02
4 (<1)
0
1 (<1)
0
<1
4 (<1)
1 (3)
4 (3)
1 (1)
7.6
7 (1)
5 (15) 3 (2)
3 (5)
6
1 (<1)
0
0
0
1
14 (2.4)
2 (3)
<1
10 (1.5) 2 (6)
Food and drug administration categories
Class
Risk
A
B
C
Controlled studies show no risk
No evidence of risk in human
Risk cannot be ruled out, animal studies showed
adverse effects on fetus
Positive evidence of risk in humans, risk/ benefit
ratio should be considered
contraindicated
D
X
Nursing and disease activity
• Detriment to maternal health secondary to nursing
after delivery is controversial.
• A few reports: associations between nursing and
increased disease activity, (whether related to
disease course or cessation of medication)
• Population based study:
– No increased risk of flare during breastfeeding (Moffatt
[39]
• OR 2.2 (95% CI: 1.2-2.7) of disease flare for women
who breastfeed compared to those who did not (
Kane et al[31])
Breast feeding in CD
Few data and advice is based on anecdotes
Drug
Safety
Sulfasalazine
sulfapyridine moiety is absorbed in
minimal amounts and is excreted in
milk, but the milk: serum ratio is low
Safe
Mesalamines
Confirmed in many prospective trials
Safe
Prednisone
Detected in breast milk
To minimise exposure, a 4-hour delay
after oral dosing
AZA/6-MP
Undetectable or in nanomolar conc
Acceptable
IFX
Not detected in breast milk
Acceptable
Metro/Cipro
Excreted in milk
Unsafe
As with all drugs, discuss carefully and individually
Osteoporosis and osteopenia in IBD
• Prevalence of osteopenia: 22-77%
• Prevalence of osteoporosis: 17%-41%,.
Osteopenia and osteoporosis common in IBD
 Mean calcium intake was <200 mg/day in almost 90%
 Significantly lower values of BMD at the spine and hip in
both UC and CD as compared with Indian healthy
controls.
 29 (63%) and 21 (45.6%) patients had either osteopenia
or osteoporosis at the spine and hip region, respectively.
AIIMS, Ind J Gastroenterol, 2008
Avoidance of milk and milk products is a
Myth
Calcium supplementation
• Must whenever steroids are used for more
than 2 weeks
 Nutrition and osteoporosis are important
considerations in the management of UC.
[III,B]
25) Fertility, pregnancy, breast feeding, nutrition and osteoporosis are important considerations in
the management of CD.
Comments:
•what is the focus here?
Revised Mx: Statement 25
• Nutrition and osteoporosis are important
considerations in the long term management of CD.
• Medication use and surgical options should take into
consideration fertility, pregnancy and breastfeeding.
• [III-C]