Treating the outpatient with severe ibd case studies
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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


Case 1 severe ulcerative colitis

Case 1 : Severe Ulcerative Colitis

  • Russ Cohen


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.


Treating the outpatient with severe ibd case studies

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


Treating the outpatient with severe ibd case studies

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.


Case 2 severe crohn s disease

Case #2: Severe Crohn’s Disease

  • Dan Present


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


Case 3 severe fistulous crohn s disease

Case 3: Severe Fistulous Crohn’s Disease

  • Russ Cohen and Dan Present


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


When do you stop therapy

When do you stop therapy?


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