Transcript Pro: All medications may be stopped for Crohn’s disease

Prevention of Postoperative
Crohn’s disease
Miguel Regueiro, M.D.
Professor of Medicine
Associate Chief for Education
Clinical Head and Co-Director, IBD Center
University of Pittsburgh School of Medicine
50-65% of CD pts still go to
surgery despite earlier and
more IMM/antiTNF usage
IN 2014:
CD treatment relies on initiation of
med rx in response to ds – in
many, the tissue damage may be
irreversible…therefore…
Surgery is still required in
IBD
…and should not be considered a
failure…..it is how we medically
prevent/manage postop CD that is
the trick.
The Natural Course of postop CD
Recurrence is clinically silent initially
Histologic
Within
1 week
Endoscopic
Radiologic
70-90%
by 1 yr
Tissue
damage
Clinical
30% 3 yr
60% 5 yr
Surgery
[1] D’Haens G, Geboes K, Peeters M, et al. Gastroenterology 1998;114:262-267.
[2] Olaison G, S medh K, Sjodahl R. Gut 1992;33:331-335.
[3] Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:956-983.
[4] Sachar DB. Med Clin North Am 1990;74:183-188.
Surgical
50% by 5 yrs
• i0:
no lesions
• i1:
< 5 aphthous lesions
• i2:
> 5 aphthous lesions with normal intervening
mucosa
• i3:
diffuse aphthous ileitis with diffusely inflamed
mucosa
• i4:
diffuse inflammation with large ulcers,
nodules, and/or narrowing
Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:956-983.
>70% of Pts Have i2,3,4 Recurrence 1 Year
after Surgery – Rutgeerts et al Gastro 1990
i1
i0 and i1 remission
-low likelihood of
progression
i4
i,3
i2,i3,i4 recurrence
Likely progression
to another surgery
Algorithm for post-op CD management
More Questions than Answers
5-ASA?
Antibiotics?
Steroids?
6MP/AZA?
What about anti-TNFs/Biologics?
How should we follow these patients?
When to Colonosocope?
Are there predictors of disease recurrence?
Medications for Preventing
Postoperative Crohn’s
Disease
Summary of Postop RCTs
5ASA, Nitroimidazoles, AZA/6MP
Postop
Prevention
RCTs
Clinical Recurrence
Endoscopic recurrence
Placebo
25% – 77%
53% - 79%
5 ASA
24% - 58%
63% - 66%
Budesonide
19% - 32%
52% - 57%
7% - 8%
52% - 54%
34% – 50%
42 – 44%
Nitroimidazole
AZA/6MP
Regueiro M. Inflammatory Bowel Diseases. 2009
Out of these options…the
best seems to be….
Metronidazole 250mg TID x 3 m then AZA 2.5mg/kg
100
90
80
% Patients
70
60
50
AZA
Placebo
69
p=0.05
44
40
30
20
10
0
Endoscopic recurrence at 1 year
D’Haens G, Norman M, Van Assche G, et al. Gastroenterology 2007;132:289
Limitation of the studies:
the best we can expect are
endoscopic recurrence rates
of ~45%
This means that despite
postop meds, nearly half of
CD pts will have also have a
clinical recurrence and require
future surgery
What about
Postop antiTNF?
Recently: A lot of
discussion and focus on
postop antiTNFs – is it
worth the hype?
Pittsburgh Likes Hype
RCT: Infliximab Prevents
Crohn’s Disease Recurrence
after Ileal Resection
Regueiro M, Schraut W, Baidoo L, Kip KE,
Sepulveda AR, Pesci M, Harrison J, Plevy SE.
Gastroenterology 2009;136:441-50.
• Randomized, two-armed, double-blind, placebocontrolled trial
• Sample size power calculation
– Assuming 80.0% recurrence in placebo
group, 20.7% recurrence in infliximab group
24 total pts needed (2-sided type I error rate
of 0.05)
• 24 patients randomly assigned to infliximab
5mg/kg or placebo within 4 weeks of surgery
(0,2,6, and every 8 weeks for one year)
Infliximab (n=11)
90
Placebo (n=13)
84.6
80
% patients
70
60
50
Infliximab vs placebo
p=0.0006
40
30
20
10
0
9.1
1/11
11/13
Recurrence
Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4.
% patients
90
80
70
60
50
40
30
20
10
0
81.8
Infliximab (n=11)
Placebo (n=13)
30.8
30.8
23.1
7.7
9.1 7.7
9.1
0
0
1
0
2
3
Endoscopic grade 1 year after surgery
4
This is only one small study, we
need more data….
#24
The Pittsburgh Postop Bus
PO- Endo Recur
antiTNF
Control
Sorrentino1 (MTX/IFX v
5ASA 2yr)
0%
100% (5ASA)
Regueiro2 (IFX vs PBO
RCT 1 yr)
9%
85% (PBO)
Yoshida3 (IFX vs PBO
Open 1 yr)
21%
81% (5ASA)
Armuzzi8 (IFX vs AZA
Open 1 yr)
9%
40% (AZA)
10%
N/A
Papamichael5 (ADA 6m)
0%
N/A
Savarino6 (ADA 3yr)
0%
N/A
21%
N/A
De Cruz9 (ADA vs AZA
6mos)
6%
38% (AZA)
Savarino10 (ADA vs AZA
vs 5ASA 2 yrs)
6%
65% (AZA), 83%(5ASA)
Fernandez-Blanco 4 (ADA)
Aguas7 (ADA 1 yr)
Anti-TNF Postop References
1. Sorrentino et al. Arch Intern Med 2007
2. Regueiro et al. Gastroenterol 2009
3. Yoshida et al. Inflamm Bowel Ds 2011
4. Fernandez-Blanco et al. Gastroenterol 2010A
5. Papamichael et al. JCrohnsColitis 2012
6. Savarino et al. Europ Journal Gastro Hep 2012
7. Aguas et al. World J Gastro 2012
8. Armuzzi et al. JCrohnsColitis 2013
9. DeCruz et al. Gastro 2012A
10. Savarino et al. Am Journal Gastro 2014
Antitumor necrosis factor [alpha] is more
effective than conventional medical therapy
for the prevention of postoperative
recurrence of Crohn's disease: a metaanalysis.
Nguyen, Douglas; Solaimani, Pejman; Nguyen, Emily; Jamal,
Mohammad; Bechtold, Matthew
European Journal of Gastroenterology & Hepatology.
26(10):1152-1159, October 2014.
Clinical Remission 1 yr postop
Endoscopic Remission 1 yr postop
Histologic Remission 1 yr postop
Comparison of the effectiveness of infliximab and adalimumab in preventing
postop recurrence in patients with Crohn’s disease (Tursi A et al. Tech Coloproctol 2014)
What about long-term
postoperative Crohn’s ds?
Most studies stop at one year
Infliximab Maintenance Prevents
Endoscopic and Surgical Crohn’s
Disease Recurrence:
Long-term Outcomes from the Randomized
Controlled Postoperative Prevention Study
Regueiro M, Kip K, Baidoo L, Swoger J, Schraut
W. Clinical Gastroenterology and Hepatology
2014
Long-term outcomes in patients assigned to placebo or infliximab after surgery
1 year
End RCT
Time 0
S
u
r
g
e
r
y
IFX (11)
PBO (13)
Figure 1
IFX
Status
> 5 years
After Surgery
Long-term outcomes in patients assigned to placebo or infliximab after surgery
1 year
End RCT
Time 0
S
u
r
g
e
r
y
IFX (11)
Recurrence (1)
Remission (10)
IFX
Status
> 5 years
After Surgery
Cont. IFX (3)
No Recurrence*
No Surgery
Stop IFX (8)
Recurrence (8)
Surgery (5)
PBO (13)
*1 IFX patient i3 at 1 year after surgery, remained i3 through 6 years
+All 5 patients had been i3 or i4 and all progressed to surgery
^This pt had been i1 at end of RCT but progressed to i4 and another surgery
Figure 1
Long-term outcomes in patients assigned to placebo or infliximab after surgery
1 year
End RCT
Time 0
S
u
r
g
e
r
y
IFX
Status
> 5 years
After Surgery
Start IFX (12)
Recurrence (5)+
Surgery (5)
Recurrence and
Surgery^
IFX (11)
PBO (13)
Recurrence(11)
Remission (2)
No IFX (1)
*1 IFX patient i3 at 1 year after surgery, remained i3 through 6 years
+All 5 patients had been i3 or i4 and all progressed to surgery
^This pt had been i1 at end of RCT but progressed to i4 and another surgery
Figure 1
How should we manage a
Crohn’s ds pt who recently had
surgery?
Take into account risk factors for
postop recurrence
• Relative Risk Factors
– Early age of surgery (<30)
– Short time to first surgery
– Ileocolonic disease
• Active cigarette smoking
• Progressed to surgery despite
immunomodulators
• Penetrating (fistulizing) disease
• History of prior resection
My Approach – Almost All of
my patients start a med after
surgery
…but NOT necessarily an antiTNF
- take into account Risk Factors
for Recurrence
Risk of Post-Op Recurrence
Low
Moderate
High
No Meds
6MP or AZA
± metronidazole
Anti-TNF
Colonoscopy 6-12
months post-op
Colonoscopy 6-12
months post-op
No
Recurrence
Recurrence
No
Recurrence
Recurrence
Colonoscopy
every 1-3 yrs
Immunomodulator
or anti-TNF
Colonoscopy
every 1-3 yrs
 anti-TNF or
Δ biologics
Long-standing
<10yrs
Penetrating
CD, long
CD,
stricture
disease,
1st surgery,
or
> inflammatory
2 short
surgeries
stricture
CD
Coming Next Year
The PREVENT Study
Thank you!
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