Transcript Treating the refractory inpatient with severe IBD: Case

Treating the outpatient with severe
IBD: Case studies
Daniel H. Present, MD, MACG
Clinical Professor of Medicine
The Mount Sinai School of Medicine
Russell D. Cohen, MD, FACG, AGAF
Professor of Medicine, Pritzker Medical School
Co-Director, Inflammatory Bowel Disease Center
The University of Chicago Medical Center
1
Case 1 : Severe Ulcerative
Colitis
• Russ Cohen
2
New Patient Visit
• 24 yo Black female
• Moved to Chicago from Maryland to pursue career at
Boeing.
• 1 month ago: developed painless BRBPR with mucus:
– Flexible sigmoidoscopy to 60cm: 10cm of proctitis; normal
proximal. Biopsies of the affected area revealed active proctitis,
crypt abscesses, not much chronicity. Proximal biopsies were
normal.
3
What Would YOU Do?
1. Any additional workup at this time?
a. Full colonoscopy?
b. Small bowel imaging?
c. Upper endoscopy?
2. Therapeutic Options:
a.
b.
c.
d.
e.
Mesalamine 1g suppositories qhs?
Mesalamine 4g enemas qhs?
Topical steroids instead?
Oral 5-ASA?
Oral steroids?
4
Initial Clinical Course
•
•
•
•
Starts 5-ASA suppositories
Initially attains remission
Stops suppositories, relapses.
Restart suppositories – not responding, now
worse.
– 5 to 6 blood bowel movements, cramping,
diarrhea
5
What Would YOU Do?
1. Restart 5-ASA 1g suppository; see how
she does.
2. Start 5-ASA enema?
3. Start oral 5-ASA?
4. Start oral steroids?
5. Check stool specs.
6. Start nothing; set up for scope
6
Your Decision…
• She underwent
flexible
sigmoidoscopy
(unprepped) in your
office:
L Colon: Sharp demarcation line
– Limited to 40cm
– Showed moderately
active UC to 30cm
with an abrupt cut-off
to normal mucosa
7
Rectum: Circumferential, Continuous Inflammation
Next Steps:
• Mesalamine enemas started; patient can’t
hold them.
• Oral mesalamine 4.8g started; patient
seemed to worsen.
• Oral prednisone (20mg po bid) started;
patient still without obvious improvement.
8
Why Aren’t the Steroids
Working?
1.
2.
3.
4.
? Too sick
? Infected (ie. C diff)
? Wrong Diagnosis
They are working for his colitis; diarrhea is of
other origin.
–
–
–
–
Celiac?
5-ASA diarrhea?
IBS?
Dietary
9
Acute, Severe Colitis….
• Typically Abrupt
Onset.
– Often can identify a
“trigger”:
• Infection, antibiotic,
major life stress
– “Get Over” the acute
insult.
Cohen RD et al. Am J Gastroenterol 1999;94:1587-92.
Stack WA et al. Aliment Pharmacol Ther 1998;12:973-8
Wenzl HH et al. Z Gastroenterol 1998;36:287-93.
D’Haens G et al. Gastroenterology 2001;120:1323-9
Hyde GM et al. Eur J Gastroenterol Hepatol 1998;10:411-3.
• Often Early in Disease
Course:
– 10% of fulminant
colitics – initial
presentation.
– Median Age  earlymid 30’s
– Disease Duration:
median 4-7 years
10
Options for Severe Colitis
• If responsive to oral steroids:
– Immunomodulators (aza, 6MP) with gradual
taper of steroids
– Infliximab
– Adalimumab
11
Azathioprine or 6-MP in UC
Maintenance of Remission in UC
Steroid-Dependent Active UC
80%
90%
AZA
80%
AZA/6-MP
Placebo
Placebo
60%
Response Rate
Relapse Rate
70%
70%
60%
50%
40%
30%
20%
50%
40%
30%
20%
10%
10%
0%
0%
1.5-2.0 mg/kg/d1
100 mg/d2
100 mg/d2 2.0 mg/kg/d3 2.2mg/k/d4
AZA: azathioprine.
6-MP: 6-mercaptopurine
1)Jewell
DP, Truelove SC. Br Med J. 1974;4:627-630. 2) Hawthorne AB, et al. Br Med J. 1992;305:20-22.
3) Ardizzone S, et al. Gut. 2006;55:47-53. 4) Mantzaris et al. Am J Gastroenterol. 2004;99:1122-1128.
6-MP Maintenance in UC
UC – Maintenance Therapy n=83
Probability of Remission
Maintenance
1.0
.8
.6
.4
.2
0
0
20
40
Months
George J et al. Amer J Gastroenterol 1996; 91:1711
60
Infliximab in UC:
Clinical Remission
ACT 1
IFX 10 mg/kg
†
45
Percent of Patients
IFX 5 mg/kg
39
40
†
†
34
32
35
30
†
40
37
35
25
20
16
15
Placebo
15
10
5
0
Percent of Patients
Placebo
ACT 2
IFX 5 mg/kg
IFX 10 mg/kg
‡
‡
36
34
‡
‡
28
30
26
25
20
15
10
11
6
5
0
8 Weeks
30 Weeks
8 Weeks
30 Weeks
†P
‡P
Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.
.002 vs placebo
.003 vs placebo
Infliximab in UC:
Mucosal Healing
ACT 1
†
70
Percent of Patients
IFX 5 mg/kg
62
60
59
†
†
50
49
34
30
25
20
10
IFX 5 mg/kg
‡
70
†
50
40
Placebo
IFX 10 mg/kg
Percent of Patients
Placebo
ACT 2
60
IFX 10 mg/kg
‡
‡
62
60
‡
50
46
40
31
57
30
30
20
10
0
0
8 Weeks
30 Weeks
8 Weeks
30 Weeks
Mucosal healing = endoscopic subscore of 0
P<.001 vs placebo
or 1
P .009 vs placebo
†
‡
Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.
Infliximab in UC
Corticosteroid Discontinuation
at Week 30
ACT 1
Placebo
IFX 5 mg/kg
IFX 10 mg/kg
Placebo
†
24
25
19
20
IFX 5 mg/kg
15
10
10
5
0
IFX 10 mg/kg
‡
30
Percent of Patients
Percent of Patients
30
ACT 2
27
25
‡
18
20
15
10
5
3
0
†P=.030
Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.
‡P
vs placebo
.010 vs placebo
Infliximab, Azathioprine, or Infliximab + Azathioprine for the
Treatment of Moderate to Severe Ulcerative Colitis:
“UC SUCCESS Trial”
Randomization of Patients
Visits
AZA + PBO
(2.5 mg/kg) (n=79)
IFX (5 mg/kg) + PBO
(n=78)
IFX+AZA
(n=80)
Week 0
Week 2
Week 6
Week 8
Possible escape* (blinded)
Week 14
Week 16
Primary Evaluation
*Subjects not achieving ≥1 point improvement in partial Mayo score
Panaccione et al. DDW 2011 Abstract #835
Infusions ABSTRACT
ONLY
Infliximab, Azathioprine, or Infliximab + Azathioprine for the
Treatment of Moderate to Severe Ulcerative Colitis:
“UC SUCCESS Trial”
Week 16 Steroid Free Remission*
50%
40%
40%
30%
P = 0.032 vs. AZA
P = 0.017 vs. IFX
24%
22%
20%
10%
0%
Aza (n=76)
IFX (n=77)
Both (n=78)
* Total Mayo score < 2, no subscore >1, no steroids.
Panaccione et al. DDW 2011 Abstract #835
ABSTRACT
ONLY
Co-administration of
Immunosuppressants: Dramatically
Lower anti-Infliximab antibody rates
• “SONIC” Crohn’s Disease Trial:
• Infliximab alone: 14% anti-Infix antibodies
• Infliximab + Aza: 1% anti-Infix antibodies
• “UC-Success” Ulcerative Colitis Trial:
• Infliximab alone: 14% anti-Infix antibodies
• Infliximab + Aza: 1% anti-Infix antibodies
Adalimumab in Moderate to Severe UC
20%
18.5% *
16%
12%
9.2%
10.0%
8%
4%
0%
Placebo
Adalimumab 80/40
Adalimumab 160/80
• 8 week trial: Doses given weeks 0,2,6.
•Primary endpoint: Clinical Remission (Mayo score < 2; no subscore >1).
• * p=0.031 vs. placebo.
• SAE: 7.6%, 3.8%, 4.0% respectively. 2 malignancies: both in placebo (basal cell;
breast)
Reinisch W et al. Gut ;2011 (online Jan 5, 2011: 10.1136/gut.2010.221127)
Adalimumab: Induction of Clinical Remission
in Moderate to Severe UC (DDW 2011)
Clinical Remission
Week 8: Remission
* p=0.019 vs. placebo.
• 8 week endpoint (52 week trial): Doses given weeks 0,2,6.
• 494 Patients: moderate to severe UC
• Primary endpoints: Clinical Remission at weeks 8 and 52.
• Response rates: 34.6% placebo vs. 50.4% ADA (p<0.001)
Sandborn W et al. DDW 2011, abstract #744.
ABSTRACT
ONLY
Adalimumab: Mucosal Healing in Moderate
to Severe UC (DDW 2011)
Clinical Remission
Week 8
* p=0.032
• 8 week endpoint (52 week trial): Doses given weeks 0,2,6.
• 494 Patients: moderate to severe UC
• Primary endpoints: Clinical Remission at weeks 8 and 52.
Sandborn W et al. DDW 2011, abstract #744.
ABSTRACT
ONLY
Back to the case:
• Patient started on infliximab and
azathioprine.
• Initially also on topical therapies.
• Steady response; steroids successfully
tapered.
• Subsequent colonoscopy revealed no active
disease, although chronic mucosal changes
and pseudopolyps characterized rectum – to
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–distal L colon.
Case #2: Severe Crohn’s Disease
• Dan Present
24
New Patient Appointment
• 30 yo W Male
• 10- yr history of vague crampy abd pain,
intermittent but became more persistent.
• Recalls going to the local ER about 8 years ago
while in college and subsequently having
“intestine xrays where I had to drink barium”
which suggested possible Crohn’s disease. Thinks
he had a colonoscopy and “didn’t show anything”
25
but didn’t know if the ileum was intubated.
Current Symptoms
• Post-prandial watery bowel movements.
• Admits that he has lost about 20lbs in the
past few months due to “it hurts when I eat
too much.”
• Fatigued.
• Vague joint pains.
• Asks if he can step outside to smoke a
cigarrette…
26
WHAT WOULD YOU DO?
1. Order a colonoscopy?
2. Order small bowel imaging?
a. If so, which one?
3. Start mesalamine 4g
4. Start metronidazole 500mg tid?
5. Start anti-TNF?
27
Diagnostic Workup
• SBFT: Multiple strictures of the distal
jejunum, mid- and distal ileum, with normal
intervening mucosa. Active inflammation. No
proximal dilation.
• Colonoscopy: colon normal; ileum: narrowed;
some ulcerations.
• Bx: Ileum: Ileitis c/w Crohn’s. Colon: normal
• Diagnosed with “Crohn’s disease”
28
Now, What Would YOU Do?
1.
2.
3.
4.
5.
6.
7.
Mesalamine 4g
Budesonide CIR 9mg
Prednisone 40mg
6MP initiation
Anti-TNF
Natalizumab
Surgery
29
Clinical Course
• Budesonide 9mg started
– Plan is to decrease by 3mg every 3 weeks.
• 6MP 75mg started (pt weight 75kg)
– Increased to 100mg after 2-3 weeks.
– (TPMT genotype was wildtype)
• Although pt felt better on 9mg budesonide,
he could not decrease the dose to 6mg
without relapse
30
At this point
•
•
•
•
WBC 3,500 Polys: 80%, Bands 2%
Hgb 12.5
Platelet count: 200,000
LFT’s: normal
• 6TG: 325
6MMP 5,000
31
What Would YOU Do?
1. Switch from budesonide to prednisone
40mg
2. 6MP dose increase
3. Anti-TNF
4. Natalizumab
5. Surgery
32
You start an anti-TNF:
1. And stop the 6-MP?
2. And decrease dose of the 6-MP?
3. With same dose of 6-MP?
33
Combination Therapy Increases
Efficacy
P<0.001 vs. aza
P=0.022 vs. ifx
P<0.001 vs. aza
P=0.055 vs. ifx
Columbel JF et al. N Engl J Med 2010;362:1383-95.
Minimal Improvement
• Is seen on the infliximab
• Suspecting a need for surgery, you order at
CT enterography: inflammation,
– Still a substantial amount of SB activity,
multiple strictures but none are obviously
obstructive.
35
What Would YOU Do?
1. Switch from budesonide to prednisone
40mg
2. 6MP dose increase
3. Switch Anti-TNF
4. Natalizumab
5. Surgery
36
Decide to try Natalizumab
•
•
•
•
JC virus antibody status: negative
Patient stops 6MP
Starts natalizumab 300mg IV q 28 days
Able to slowly wean off of Entocort over 3
months
• 6 months out: well on natalizumab
37
Case 3: Severe Fistulous Crohn’s
Disease
• Russ Cohen and Dan Present
38
Presentation To Your Office
• 45 yo W M with fistulous Crohn’s disease
to the perineal area for 10 years.
• Colonoscopies to the ileum have always
showed normal TI, normal colon, other than
the distal rectum, which has some small
ulcerations, and a anorectal stricture.
• Now with increased fistula discharge and
increased difficulty in passing BM
39
Medications
•
•
•
•
Prednisone 25mg po qd
Mesalamine 4.8 g qd
Previously on short-term antibiotics
Had previous fistulotomy 6-years ago
40
Physical Exam
• Abdominal exam: all normal
• Perianal exam- multiple draining perianal
fistulas with mild fluctuance; previous
fistula sites seen, as well as previous
fistulotomy site.
• Attempted rectal examination – stricture too
tight to allow introduction of finger-tip.
41
When do you call…
The surgeon?
– Trial of antibiotics
first?
– Trial of
immunomodulators
first?
– Trial of anti-TNF first?
42
When do you order…
• Imaging?
CT?
MRI?
Dynamic proctography?
from: radiologyassistant.nl
43
Start antibiotics, sent to surgeon
• Orders MRI Pelvis to determine if fistulas
connected to main cavity.
• Examination under anesthesia
– Dilation of the stricture (Hegar)
– Flex sig to 25cm: only distal rectal disease.
– Multiple fistulas emanating from a single fistula
orifice on each side of the dentate line.
• Fistulectomy x2, seton placed x2
44
Patient now sits in front of you..
• With 2 setons coming out their bottom
• Wanting to know, “What ya gonna do?”
45
What You Gonna Do?
1.
2.
3.
4.
5.
6.
7.
Continue 5-ASA ?
Continue Steroids ?
Start antibiotics?
Start 6MP/ Azathioprine?
Start MTX?
Start anti-TNF?
Start natalizumab?
46
What you did…
• Patient started on azathioprine and
infliximab.
• Visits back to the surgeon after each
induction dose of infliximab to evaluate
need for setons (eventually removed).
• Patient well on azathioprine and infliximab
47
When do you stop therapy?
48