Treating the outpatient with severe IBD: Case studies

Daniel H. Present, MD, MACGClinical Professor of Medicine

The Mount Sinai School of Medicine

Russell D. Cohen, MD, FACG, AGAFProfessor of Medicine, Pritzker Medical School

Co-Director, Inflammatory Bowel Disease CenterThe University of Chicago Medical Center

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Case 1 : Severe Ulcerative Colitis

• Russ Cohen

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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.

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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. Mesalamine 1g suppositories qhs?b. Mesalamine 4g enemas qhs?c. Topical steroids instead?d. Oral 5-ASA? e. 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

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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

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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

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L Colon: Sharp demarcation line

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.

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Why Aren’t the Steroids Working?

1. ? Too sick2. ? Infected (ie. C diff)3. ? Wrong Diagnosis4. They are working for his colitis; diarrhea is of

other origin.– Celiac?– 5-ASA diarrhea?– IBS?– Dietary

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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

Cohen RD et al. Am J Gastroenterol 1999;94:1587-92.Stack WA et al. Aliment Pharmacol Ther 1998;12:973-8Wenzl HH et al. Z Gastroenterol 1998;36:287-93. D’Haens G et al. Gastroenterology 2001;120:1323-9Hyde GM et al. Eur J Gastroenterol Hepatol 1998;10:411-3. 10

Options for Severe Colitis

• If responsive to oral steroids:– Immunomodulators (aza, 6MP) with gradual

taper of steroids– Infliximab– Adalimumab

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Azathioprine or 6-MP in UC

AZA

Placebo

AZA/6-MP

Steroid-Dependent Active UCMaintenance of Remission in UC

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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.

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AZA: azathioprine.

6-MP: 6-mercaptopurine

UC – Maintenance Therapy n=83

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

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Infliximab in UC: Clinical Remission

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Infliximab in UC: Mucosal Healing

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

Infliximab in UC Corticosteroid Discontinuation

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Infliximab, Azathioprine, or Infliximab + Azathioprine for the Treatment of Moderate to Severe Ulcerative Colitis:

“UC SUCCESS Trial”

Panaccione et al. DDW 2011 Abstract #835

Possible escape* (blinded)

IFX (5 mg/kg) + PBO(n=78)

AZA + PBO(2.5 mg/kg) (n=79)

IFX+AZA(n=80)

Randomization of Patients

VisitsWeek 0

Week 2

Week 6

Primary Evaluation

Infusions

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

Week 8

ABSTRACT ONLY

Aza (n=76) IFX (n=77) Both (n=78)0%

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Week 16 Steroid Free Remission*

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

P = 0.032 vs. AZAP = 0.017 vs. IFX

Infliximab, Azathioprine, or Infliximab + Azathioprine for the Treatment of Moderate to Severe Ulcerative Colitis:

“UC SUCCESS Trial”

Panaccione et al. DDW 2011 Abstract #835ABSTRACT

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

Placebo Adalimumab 80/40 Adalimumab 160/800%

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• 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)

• 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)

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

Week 8: Remission

Adalimumab: Mucosal Healing in Moderate to Severe UC (DDW 2011)

• 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.

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

ONLY

Week 8

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. 23

Case #2: Severe Crohn’s Disease

• Dan Present

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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” but didn’t know if the ileum was intubated. 25

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 4g4. Start metronidazole 500mg tid?5. Start anti-TNF?

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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”

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Now, What Would YOU Do?

1. Mesalamine 4g2. Budesonide CIR 9mg3. Prednisone 40mg4. 6MP initiation5. Anti-TNF6. Natalizumab7. Surgery

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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

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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

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What Would YOU Do?

1. Switch from budesonide to prednisone 40mg

2. 6MP dose increase3. Anti-TNF4. Natalizumab5. Surgery

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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?

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P<0.001 vs. azaP=0.055 vs. ifx

P<0.001 vs. azaP=0.022 vs. ifx

Columbel JF et al. N Engl J Med 2010;362:1383-95.

Combination Therapy Increases Efficacy

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.

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What Would YOU Do?

1. Switch from budesonide to prednisone 40mg

2. 6MP dose increase3. Switch Anti-TNF4. Natalizumab5. Surgery

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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

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Case 3: Severe Fistulous Crohn’s Disease

• Russ Cohen and Dan Present

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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

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Medications

• Prednisone 25mg po qd• Mesalamine 4.8 g qd• Previously on short-term antibiotics• Had previous fistulotomy 6-years ago

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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.

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When do you call…

The surgeon?– Trial of antibiotics

first?– Trial of

immunomodulators first?

– Trial of anti-TNF first?

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When do you order…

• Imaging?

CT?

MRI?

Dynamic proctography?

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from: radiologyassistant.nl

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

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Patient now sits in front of you..

• With 2 setons coming out their bottom• Wanting to know, “What ya gonna do?”

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What You Gonna Do?

1. Continue 5-ASA ?2. Continue Steroids ?3. Start antibiotics?4. Start 6MP/ Azathioprine?5. Start MTX?6. Start anti-TNF?7. Start natalizumab?

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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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When do you stop therapy?

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