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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

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treating the outpatient with severe ibd case studies

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

new patient visit
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.
what would you do
What Would YOU Do?
  • Any additional workup at this time?
    • Full colonoscopy?
    • Small bowel imaging?
    • Upper endoscopy?
  • Therapeutic Options:
    • Mesalamine 1g suppositories qhs?
    • Mesalamine 4g enemas qhs?
    • Topical steroids instead?
    • Oral 5-ASA?
    • Oral steroids?
initial clinical course
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
what would you do1
What Would YOU Do?
  • Restart 5-ASA 1g suppository; see how she does.
  • Start 5-ASA enema?
  • Start oral 5-ASA?
  • Start oral steroids?
  • Check stool specs.
  • Start nothing; set up for scope
your decision
Your Decision…
  • She underwent flexible sigmoidoscopy (unprepped) in your office:
    • Limited to 40cm
    • Showed moderately active UC to 30cm with an abrupt cut-off to normal mucosa

L Colon: Sharp demarcation line

Rectum: Circumferential, Continuous Inflammation

next steps
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.
why aren t the steroids working
Why Aren’t the Steroids Working?
  • ? 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
acute severe colitis
Typically Abrupt Onset.

Often can identify a “trigger”:

Infection, antibiotic, major life stress

“Get Over” the acute insult.

Often Early in Disease Course:

10% of fulminant colitics – initial presentation.

Median Age  early- mid 30’s

Disease Duration: median 4-7 years

Acute, Severe Colitis….

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.

options for severe colitis
Options for Severe Colitis
  • If responsive to oral steroids:
    • Immunomodulators (aza, 6MP) with gradual taper of steroids
    • Infliximab
    • Adalimumab
azathioprine or 6 mp in uc
Azathioprine or 6-MP in UC

80%

70%

60%

50%

40%

30%

20%

10%

0%

Maintenance of Remission in UC

Steroid-Dependent Active UC

90%

AZA

AZA/6-MP

80%

Placebo

Placebo

70%

60%

Response Rate

50%

Relapse Rate

40%

30%

20%

10%

0%

2.0 mg/kg/d3

2.2mg/k/d4

100 mg/d2

1.5-2.0 mg/kg/d1

100 mg/d2

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
6-MP Maintenance in UC

UC – Maintenance Therapy n=83

1.0

.8

.6

.4

.2

0

Probability of Remission

Maintenance

0 20 40 60

Months

George J et al. Amer J Gastroenterol 1996; 91:1711

infliximab in uc clinical remission
Infliximab in UC: Clinical Remission

ACT 1

ACT 2

†P.002 vs placebo‡P.003 vs placebo

Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.

infliximab in uc mucosal healing
Infliximab in UC: Mucosal Healing

ACT 1

ACT 2

Mucosal healing = endoscopic subscore of 0 or 1

†P<.001 vs placebo‡P.009 vs placebo

Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.

infliximab in uc corticosteroid discontinuation at week 30
Infliximab in UC Corticosteroid Discontinuation at Week 30

ACT 1

ACT 2

†P=.030 vs placebo‡P.010 vs placebo

Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.

slide17
Infliximab, Azathioprine, or Infliximab + Azathioprine for the Treatment of Moderate to Severe Ulcerative Colitis:“UC SUCCESS Trial”

Randomization of Patients

AZA + PBO

(2.5 mg/kg) (n=79)

IFX (5 mg/kg) + PBO

(n=78)

IFX+AZA(n=80)

Visits

Week 0

Week 2

Week 6

Possible escape* (blinded)

Week 8

Week 14

Primary Evaluation

Week 16

*Subjects not achieving ≥1 point improvement in partial Mayo score

Infusions

ABSTRACT ONLY

Panaccione et al. DDW 2011 Abstract #835

slide18
Infliximab, Azathioprine, or Infliximab + Azathioprine for the Treatment of Moderate to Severe Ulcerative Colitis:“UC SUCCESS Trial”

P = 0.032 vs. AZA

P = 0.017 vs. IFX

* Total Mayo score < 2, no subscore >1, no steroids.

ABSTRACT ONLY

Panaccione et al. DDW 2011 Abstract #835

co administration of immunosuppressants dramatically lower anti infliximab antibody rates
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
Adalimumab in Moderate to Severe UC

*

  • 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
Adalimumab: Induction of Clinical Remission in Moderate to Severe UC (DDW 2011)

Week 8: Remission

* p=0.019 vs. placebo.

Clinical Remission

  • 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)

ABSTRACT ONLY

Sandborn W et al. DDW 2011, abstract #744.

adalimumab mucosal healing in moderate to severe uc ddw 2011
Adalimumab: Mucosal Healing in Moderate to Severe UC (DDW 2011)

Week 8

*p=0.032

Clinical Remission

  • 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.

ABSTRACT ONLY

Sandborn W et al. DDW 2011, abstract #744.

back to the case
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 –distal L colon.
new patient appointment
New Patient Appointment
  • 30 yo W Male
  • 10- yr history of vague crampyabd 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” but didn’t know if the ileum was intubated.
current symptoms
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…
what would you do2
WHAT WOULD YOU DO?
  • Order a colonoscopy?
  • Order small bowel imaging?
    • If so, which one?
  • Start mesalamine 4g
  • Start metronidazole 500mg tid?
  • Start anti-TNF?
diagnostic workup
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”
now what would you do
Now, What Would YOU Do?
  • Mesalamine 4g
  • Budesonide CIR 9mg
  • Prednisone 40mg
  • 6MP initiation
  • Anti-TNF
  • Natalizumab
  • Surgery
clinical course
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
at this point
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
what would you do3
What Would YOU Do?
  • Switch from budesonide to prednisone 40mg
  • 6MP dose increase
  • Anti-TNF
  • Natalizumab
  • Surgery
you start an anti tnf
You start an anti-TNF:
  • And stop the 6-MP?
  • And decrease dose of the 6-MP?
  • With same dose of 6-MP?
combination therapy increases efficacy
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
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.
what would you do4
What Would YOU Do?
  • Switch from budesonide to prednisone 40mg
  • 6MP dose increase
  • Switch Anti-TNF
  • Natalizumab
  • Surgery
decide to try natalizumab
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
presentation to your office
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
medications
Medications
  • Prednisone 25mg poqd
  • Mesalamine 4.8 g qd
  • Previously on short-term antibiotics
  • Had previous fistulotomy 6-years ago
physical exam
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.
when do you call
When do you call…

The surgeon?

  • Trial of antibiotics first?
  • Trial of immunomodulators first?
  • Trial of anti-TNF first?
when do you order
When do you order…
  • Imaging?

CT?

MRI?

Dynamic proctography?

from: radiologyassistant.nl

start antibiotics sent to surgeon
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
patient now sits in front of you
Patient now sits in front of you..
  • With 2 setons coming out their bottom
  • Wanting to know, “What yagonna do?”
what you gonna do
What You Gonna Do?
  • Continue 5-ASA ?
  • Continue Steroids ?
  • Start antibiotics?
  • Start 6MP/ Azathioprine?
  • Start MTX?
  • Start anti-TNF?
  • Start natalizumab?
what you did
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
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