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The Patient With Small Bowel Crohn’s Disease. David T. Rubin, MD Associate Professor of Medicine Program Director, The Fellowship in Gastroenterology, Hepatology, and Nutrition Co-Director, The Inflammatory Bowel Disease Center University of Chicago Medical Center Chicago, Illinois. :00. - PowerPoint PPT Presentation
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The Patient With Small Bowel Crohn’s Disease
The Patient With Small Bowel Crohn’s Disease
David T. Rubin, MDAssociate Professor of Medicine
Program Director, The Fellowship in Gastroenterology, Hepatology, and Nutrition
Co-Director, The Inflammatory Bowel Disease CenterUniversity of Chicago Medical Center
Chicago, Illinois
David T. Rubin, MDAssociate Professor of Medicine
Program Director, The Fellowship in Gastroenterology, Hepatology, and Nutrition
Co-Director, The Inflammatory Bowel Disease CenterUniversity of Chicago Medical Center
Chicago, Illinois
2
Audience Question 1
What is your first-line approach to treating moderately-to-severely active CD of the ileum?
A. Mesalamine
B. Budesonide
C. Prednisone
D. AZA/6-MP
E. Anti-TNF therapy
F. AZA/6-MP + anti-TNF combination therapy
G. MTX + anti-TNF combination therapy
3
Audience Question 1
What is your first-line approach to treating moderately-to-severely active CD of the ileum?
14%18%14%10%17%11%15% A. Mesalamine
B. Budesonide
C. Prednisone
D. AZA/6-MP
E. Anti-TNF therapy
F. AZA/6-MP + anti-TNF combination therapy
G. MTX + anti-TNF combination therapy
4
Audience Question 2
For a CD patient in whom AZA/6-MP treatment fails, how would you initiate anti-TNF therapy?
A. Discontinue AZA/6-MP, and then initiate anti-TNF therapy
B. Continue AZA/6-MP indefinitely in combination with anti-TNF therapy
C. Continue AZA/6-MP for a period of time while starting anti-TNF therapy, and then discontinue it
5
Audience Question 2
For a CD patient in whom AZA/6-MP treatment fails, how would you initiate anti-TNF therapy?
33%
30%
37% A. Discontinue AZA/6-MP, and then initiate anti-TNF therapy
B. Continue AZA/6-MP indefinitely in combination with anti-TNF therapy
C. Continue AZA/6-MP for a period of time while starting anti-TNF therapy, and then discontinue it
6
Case Study: TimPresentation to PCP
•18-year-old male high school student – Abdominal pain, 6-month duration– Weight loss, 10 pounds
PCP, primary care physician.
•3 to 4 loose stools per day, some urgency – Doesn’t smoke cigarettes– Takes ibuprofen for prior basketball injury
• 400 mg 3 or 4 times per day
– No family history of CD
7
TimExamination and Referral
• Physical examination– Tenderness and fullness in right lower quadrant– Small perianal skin tags
• Referred to gastroenterologist for diagnostic testing– MRE– Colonoscopy
CRP, C-reactive protein; MRE, magnetic resonance elastography; WBC, white blood cell.
• Laboratory results– Hemoglobin 8.7 g/dL– WBC 10 х 109/L– Platelets 454,000 (normal range, 120,000-400,000)– CRP 25 mg/L (normal level, <4.0)
8
MRE Results
• Long segment of terminal ileal inflammation
• Some proximal colon thickening
9
Colonoscopy Results
• Colitis in ascending colon
• Distorted ileocecal valve precluding intubation of the ileum
10
TimDiagnosis
•Moderate-to-severe CD of the ileum and colon with perianal involvement
11
Natural History of CD
Patients at risk (N) over time → 2,002 552 229 95 37
0
2400 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228
100
90
80
70
60
50
40
30
20
10
PenetratingPenetrating
Cu
mu
lati
ve P
rob
abil
ity,
%
Months
High potential
Low potential
Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244-250.
StricturingStricturing
InflammatoryInflammatory
12
a One patient lost to follow-up.Faubion, et al. Gastroenterology. 2001;121:255-260.
CorticosteroidsShort- and Long-Term Efficacy in CD
30-day response (N=74)
1-year response(N=74)a
Complete 58%
(n=43)
Prolonged response
28%(n=21)
None 16%
(n=12)
Corticosteroid dependence
32%(n=24)
Surgery38%
(n=28)
Partial26%
(n=19)
13
Therapy for Active Crohn’s DiseaseCorticosteroids
Pat
ien
ts i
n R
emis
sio
n,
%
0
80
60
40
20
Greenberg 19941 N=258
P<0.001
Thomsen 19982
N=182P<0.001
Rutgeerts 19943 N=176P<0.12
62
1. Greenberg GR, et al. N Engl J Med. 1994;331:836-841; 2. Thomsen OO, et al. N Engl J Med. 1998;339:370-374; 3. Rutgeerts P, et al. N Engl J Med. 1994;331:842-845.
Placebo
Budesonide 9 mg/d
Mesalamine 4 g/d
Prednisolone 40 mg/d
20
51
66
36
53
14
Maintenance of Remission in CDAZA
80
60
40
20
0
Pat
ien
ts N
ot
Fai
lin
g T
rial
, %
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
100
P=0.001
AZA 2.5 mg/kg per day (n=33)Placebo (n=30)
Duration of Trial, monthsa Remission induced by prednisolone tapered over 12 weeks.Candy S, et al. Gut. 1995;37:674-678.
a
15
IFX
Monoclonal antibody
Adalimumab
Anti-TNF AgentsStructure
MurineHuman
IgG1Fc
Fab
Certolizumab pegol
PEG
PEGylated humanizedPEGylated humanizedFab′ fragment containingFab′ fragment containing2x20 kDa PEG molecules2x20 kDa PEG molecules
Fab, fragment antigen binding; Fc, fragment crystallizable; IgG, immunoglobulin G; IFX, infliximab; PEG, polyethylene glycol.Hanauer SB. Presented at: Advances in Inflammatory Bowel Diseases Crohn’s and Colitis Foundation’s Research and Clinical Conference; Hollywood, FL; December 4-7, 2008. http://vid.imedex.com/pdf/5477/hanauer.pdf.
16
Maintenance of Remission in CD Anti-TNF Therapies
Adalimumab (N=76)
ACCENT, A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen; CHARM, Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance; CLASSIC, Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease; EOW, every other week; PRECiSE, Pegylated Antibody Fragment Evaluation in Crohn’s Disease.1. Hanauer SB, et al. Lancet. 2002;359:1541-1549; 2. Sanborn W, et al. NEJM. 2007;357:228-238; 3. Schreiber S, et al. NEJM. 2007;357:239-250; 4. Colombel, JF et al. Gastroenterol. 2007;132:52-65; 5. Hanauer SB, et al. Gastroenterol. 2006;130:323-333; 6. Sanborn W, et al. Gut. 2007;56:1232-1239.
0
100
80
60
40
20
ACCENT I1
Week 54PRECiSE 12
Week 26PRECiSE 23
Week 26CHARM4
Week 56CLASSIC I5-II6
Week 24
Episodic IFX
(N=110)
Combined IFX
(N=225)
CertolizumabPegol
(N=331)
CertolizumabPegol
(N=215)
Adalimumab (N=172)
Adalimumab(N=157)
Rem
issi
on
, %
33.3
48
29
13.6
3641
20
17
Higher Remission Rates With Shorter Disease Duration
a P=0.002; b P<0.001.CDAI, Crohn’s Disease Activity Index. 1. Sandborn WJ, et al. Presented at: Annual Scientific Meeting of the American College of Gastroenterology; October 12-17, 2007; Philadelphia, PA; 2. Schreiber S, et al. Gastroenterol. 2007;132:A-147.
Pat
ien
ts in
CD
AI R
emis
sio
n
(<15
0) a
t W
eek
26, %
80
0
70
60
50
40
30
20
10
Disease Duration
68
37.1
55
36.4
47
29.1
44
23.5
<1 Year
1 to <2 Years
2 to <5 Years
≥5 Years
Adalimumab
PRECiSE 21
Pat
ien
ts in
CD
AI R
emis
sio
n
(<
150)
at
Wee
k 26
, %2
0
Disease Duration
<2 Years
2 to <5 Years
≥5 Years
70
60
50
40
30
20
10
59a
17
41b
14
40
25
CHARM2
Certolizumab pegol Placebo
n=35
n=19
n=22
n=20
n=45
n=55n=98
n=131
n=39
n=23
n=36
n=233n=57
n=111
18
Early Biologic Trials: 2008
• Top-Down/Step-Up1
– Early combined therapy– Steroid-naïve– Immune modifier-naïve– Duration: 2 years– End point: 104 weeks
• SONIC2
– Not in remission– Some patients on steroids– Duration: 1 year – End points: 26 weeks,
52 weeks
SONIC, Study of Immunomodulator-Naïve Patients in Crohn’s Disease.1. D’Haens G, et al. Lancet. 2008;371:660-667; 2. Sandborn W, et al. Presented at: 2008 American College of Gastroenterology Annual Scientific Meeting and Postgraduate Course. October 3-8, 2008; Orlando, FL.
Steroids steroids AZA IFX
IFX AZA
IFX + AZA
IFX alone
AZA alone
19
Top-Down vs Step-Up TrialClinical Results at 2 Years
a Remission defined as CDAI <150, no steroids, no surgery.D’Haens G, et al. Lancet. 2008;371:660-667.
Weeks
Pat
ien
ts i
n
Rem
issi
on
,a %
0
60
40
20
14 26 52
80
100
78 104
P=0.0001P=0.006
P=0.028P=0.797
P=0.431
Early combined immunosuppression (top-down; n=66)
Conventional management (step-up; n=67)
WeeksP
atie
nts
Giv
en
AZ
A/6
-MP
, %
0
60
40
20
80
100
26 52 78 104
20
SONICCorticosteroid-Free Clinical Remission at Week 26
30.6
44.4
56.8
0
20
40
60
80
100
Pat
ien
ts,
%
AZA + placeboIFX + placeboIFX + AZA
P<0.001
P=0.009 P=0.022
52/170 75/169 96/169
Sandborn W, et al. Presented at: 2008 American College of Gastroenterology Annual Scientific Meeting and Postgraduate Course. October 3-8, 2008; Orlando, FL.
21
Audience Question 3
What would you prescribe as initial treatment for Tim?
A. Mesalamine
B. Budesonide
C. Prednisone
D. AZA/6-MP
E. Anti-TNF therapy
F. AZA/6-MP + anti-TNF combination therapy
G. MTX + anti-TNF combination therapy
22
Audience Question 3
What would you prescribe as initial treatment for Tim?
14%14%13%16%12%15%16% A. Mesalamine
B. Budesonide
C. Prednisone
D. AZA/6-MP
E. Anti-TNF therapy
F. AZA/6-MP + anti-TNF combination therapy
G. MTX + anti-TNF combination therapy
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