B. MD, FACG - American College of Gastroenterologys3.gi.org/meetings/wb2016/16ACG_VGS_Regional_0016.pdfTitle Microsoft PowerPoint - Sun-Hanauer-Traetment Options for Severe IBD Author

Stephen B. Hanauer, MD, FACG

2016 ACG/VGS/ODSGNA Regional Postgraduate CourseCopyright American College of Gastroenterology 1

Current Treatment Options for Patients Hospitalized with Severe UCStephen B. Hanauer, MD, FACGProfessor of MedicineFeinberg School of MedicineMedical Director, Digestive Health Center

Classification of UC Severity

MILD• <4 stools/day

± blood• Normal ESR• No signs of

toxicity

MODERATE• ≥4 stools/day

± blood• Minimal signs

of toxicity

SEVERE• >6 bloody

stools/day• Fever• Tachycardia• Anemia or ESR

FULMINANT• >10 stools/day• Continuous bleeding• Toxicity• Abdominal

tenderness/distension• Transfusion requirement• Colonic dilation on x-ray

Truelove SC, Witts LJ. Br Med J. 1955;2:1041.Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.



Indications for Hospitalization

• Severe luminal disease

• Suspected toxic megacolon

• Failure of outpatient medications

•Venous thrombosis

• Infection

•Medication‐related adverse event

Variable Mild Severe Fulminant

N Stools < 4 > 6 > 10

Blood Intermittent Frequent Continuous

Temp Normal > 37.5 > 37.5

Pulse Normal > 90 > 90

Hgb Normal < 75% nl Transfusion

ESR < 30 > 30 > 30

Xray Thumbprinting Dilation

Exam Tenderness Distension/ tenderness

What Does “Severe” Mean?

Dickinson RJ. Gut. 1985; 26:1380-84.



Mayo Endoscopic Subscore

NormalColon (0)

MildUlcerativeColitis (1)

ModerateUlcerativeColitis (2)

SevereUlcerativeColitis (3)

Endoscopic pictures courtesy of Gil Melmed, Cedars-Sinai Medical Center

Deep Ulcerations



Endoscopic Severity Predicts Colectomy

Severeendoscopic colitis

Moderateendoscopic colitis

Carbonnel F et al. Dig Dis Sci. 1994;39:1550.

100

0

Colectomy (%)

Deep/extensive

ulcers

93%

Mucosaldetachment

30%

Largemucosal

abrasions

26%

Well-likeulcers

17%

93% → colectomy93% → colectomy

100

0Superficial

ulcers

77%

Deep butnonextensive

ulcers

8%

23% → colectomy23% → colectomy

Colectomy (%)

Predicators of Poor Response or Surgery• Stool frequency

• >8 or >5 after 3 days IV rx.

• Percentage bloody stools

• Body temperature > 37.5

• Heart rate >90 bpm

• CRP (>25, >45 mg/L)

• Transverse colon > 5 cm

• Low hemoglobin <10.5 g/dL

• Serum albumin

• ESR > 30 mm/h

• Bandemia

• Prolonged flare

• Active infection

• Hospitalization setting

• Severe endoscopic lesions

• Disease duration

Lindgren SC et al. Eur J Gastroenterol Hepatol 1998;10(10):831-5. Gonzalez-Lama Y et al. Hepatogastroenterol2008;55(86-87):1609-14. Suzuki Y et al Dig Dis Sci 2006;51(11):2031-8. Cacheux W. et al. A,m J Gastroenterol2008;103(3):637-42. Ananthakrishnan AN et al. A, J Gastroenterol 2008;103(11):2789-98.



Management Day 11 2 3

• Check for C difficile

• Abdominal x-ray to rule out dilation

• Complete physical exam for signs or symptoms of DVT, dehydration, sepsis, toxic megacolon

• Pregnancy test if appropriate

• Set patient expectations

• IV steroids for no more than 5 days

• Colorectal surgery consultation

• Patient will be discharged on some form of immune suppression

• IV steroids

• IV fluids if volume depletion but patient can eat if no nausea/ vomiting

• DVT prophylaxis

• No narcotics -if patient having pain suspect toxicity

• Check chemistries, CBC, but also TMPT, PPD, Hep B serologies

Inpatient Medications

•No role for oral 5‐ASA

• IV steroids: 40 mg or 1 mg/kg IV methylprednisolone daily

•No randomized trials comparing different steroid regimens

•Unclear if thiopurine continued or not

•Antibiotics not indicated to treat UC

Often used in toxic settings



93%78%

53%69% 65% 70%

0%20%40%60%80%

100%

Dexa100mg

x3

HC400mg

M-pred40mg

M-pred0.75-1..0

mg/kg

HC 400mg

M-pred64 mg

% R

emis

sion

or

Sub

stan

tial

R

espo

nse

Daily Dose

Outcomes: Severe UC by Day 15

Sood, A et al. J Clin Gastroenterol 2002;35(4):328‐31. Panes, J et al. Gastroenterology 2000;119:903‐8.Mantzaris, GJ et al. Scand J Gastroenterol 2001;36:971‐4. Mantzaris, GJ et al. Am J Gastroenterol 1994;89:43‐6.D’Haens G et al. Gastroenterology 2001;120:1323‐9. Chapman et al. Gut 1986;27:1210‐2

IV Corticosteroids: Effective in Severe UC

IV Corticosteroids: Effective in Severe UC

Management Day 3

Travis S. Gut. 1996; 38:905-910.Ho GT. Aliment Pharmacol Ther. 2004; 19:1079-87.

•Travis or Ho Index used to predict likelihood of colectomy

•Consider flex sig to rule out CMV

•Re check C. difficile toxin



• had an 85% risk of medical failure.

Predictors of IV Steroid Failure

Travis et al, 1996• 85% failure rate on

day 3 if:– >8 BM/d or – CRP>45mg/l

• 60% failure rate on day 7 if:– >3 BM/d or– Blood still visible

• Higher failure rate if: – Severe ulcerations

present on sigmoidoscopy

Over first 3 days Points

Mean # BMs 4–6 1

Mean # BMs 6–8 2

Mean # BMs >9 4

Albumin <3.0 g/dL 1

Colonic dilatation 4

Travis S, et al. Gut. 1996;38:905.Ho GT, et al. Aliment Pharmacol Ther. 2004;19:1079.

Ho et al, 2004

Failure of Medical TherapyScore 0–1 = 11%Score 2–3 = 43%Score ≥4 = 85%

C. difficile Infection

• IBD patients higher risk for infection

•C. diff positive hospitalized UC patients

Longer hospital stay, more aggressive disease 20% colectomy rate

OR 4.7 for death if C. diff positive

•As infection tends to be more severe, treatment with vancomycin recommended at first line

14Berg AM, et al. Inflamm Bowel Dis. 2013 Jan;19(1):194-204.



Unique Risk Factors for CDI in IBD Patients

• Younger age

• No antibiotic exposure

• Outpatient acquisition

• More commonly seen in UC than Crohn’s colitis

Berg AM, et al. Inflamm Bowel Dis. 2013 Jan;19(1):194-204.

Pseudomembranes Rarely Seen in IBD Patients

Issa M, Vijayapal A, Graham MB, et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007 Mar;5(3):345‐51.



CDI‐IBD Patients Have Worse Outcomes• Population based retrospective study based on discharge

diagnosis (2003)

• Primary outcome: in‐hospital mortality

• CDI‐IBD 2804, CDI 44,400, IBD 77,366

• Compared to non IBD CDI patients; IBD patients with CDI had:

2x greater mortality

6x more likely to undergo bowel surgery

3x longer length of stay

3x more likely to require TPN

2x more likely to require blood transfusionsAnanthakrishnan AN, McGinley EL, Binion DG. Excess hospitalization burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut. 2008 Feb;57(2):205-10

Cytomegalovirus in Severe UC

• Immunosuppressed patients at risk for CMV infection

•Testing can be serologic, histologic

• Serum CMV IgM and IgG

•Biopsy with H+E, immunohistologic stains

•ACG guidelines suggest treatment with gancyclovir and reducing immune suppressing medications*

Kandiel A, Lashner B. Am J Gastroenterol. 2006:101(12):2857-65. Maconi G, et al. Dig Liver Dis. 2005;37(6):418-23.Kornbluth A, et al. Am J Gastroenterol. 2010 Mar;105(3):501-23.

*No evidence of benefit



Day 4

Adequate Response

•Continue IV steroids until clinical remission

Formed bowels

No blood

No urgency

•Transition to oral steroids & discharge

Inadequate Response

•Colectomy

Safest

• Infliximab

•Cyclosporine

•Monitor until clinical remission

The CYSIF Study

CsA vs Infliximab in IV Steroid-Refractory UC

Laharie D, et al. Lancet. 2012;380(9857):1909-15.

Response Rates at Day 7

CsA

Pati

ents

(%)

Infliximab

84%

020406080

100 86%

N=111 (55 CsA; 56 infliximab)



Accelerated induction dosing of infliximab compared with standard dosing in acute severe UC

• Gibson et al, ClinGastroenterol Hepatol 13:330‐335;2014

(Accelerated dosing = 5 mg/kg at median day 0>7>24)

“Real Life”: CSA vs. Infliximab ?

Courtesy of Russ Cohen

Infliximab Cyclosporin

• Outpatient

• Inpatient

• IV steroid responsive

• Already failed/allergic to azathioprine or 6‐MP

• Renal disease, hypertension, seizures, advanced age: ok

• Reliable

• Inpatient only

• IV steroid refractory

• Has not failed / allergic to azathioprine / 6‐MP

• Does not have renal disease, hypertension, seizures, advanced age.

• Must be very very reliable.



•Never together

•Often send patient to surgery instead

• Some Exceptions:

1. Cyclosporin: effective, but then has allergic reaction to azathioprine / 6‐MP (wash out for 48‐72 hours?)

2. Cyclosporin: intolerable side‐effect (wash out for 48‐72 hours)

3. Infliximab: failure / allergic reaction; wash out (variable)

• Don’t forget PCP prophylaxis!

BOTH Cyclosporin and Infliximab?

Switching Therapy & Other Considerations

•Patients who fail a rescue therapy should undergo colectomy

•With infliximab consider fecal loss and re‐dosing (accelerated induction)

• Switching from one rescue therapy to another has only 30% success rate but SAE rate of 20%, with death rate as high as 2%

Maser EA, et al. Clin Gastroenterol Hepatol. 2008;6(10):1112-6. Leblanc S, et al. Am J Gastroenterol. 2011;106(4):771-7.



Oral tacrolimus

Open label German study 72% remission

at 2 weeks

Open label German study 72% remission

at 2 weeks

RCT vs placebo in Japan 50% at 2

weeks in treatment arm vs 13% placebo

RCT vs placebo in Japan 50% at 2

weeks in treatment arm vs 13% placebo

Other Therapies

Adalimumab

Not studied in hospital setting and not recommended

Not studied in hospital setting and not recommended

Schmidt KJ, et al. Aliment Pharmacol Ther. 2013;37(1):129-3.Ogata H, et al. Inflamm Bowel Dis. 2012;18(5):803-8.

Tofacitinib

Not studied in hospital setting and

not yet approved

Not studied in hospital setting and

not yet approved

Ulcerative Colitis:Indications for Surgery

• Failure to control severe attacks or toxic megacolon

•Acute complications

•Chronic symptoms despite medical therapy

•Medication side effects without disease control

•Dysplasia or Cancer



Assessing Causality of Perioperative IBD Medications and Complications: Confounders

• Severity of IBD

• Nutritional status

• Concomitant therapies

• Emergent vs Elective Surgery

• Different pre-operative drug window

• Different procedures

• Different expertise of surgeons

Preparing Patients for Surgery:Loeb’s Laws

•The Golden Rule: Don't do to the patient what you wouldn't like done to yourself.

• If what you are doing is working, keep doing it.

• If what you do is not working, stop (and do something else).

•Time is on the doctor’s side.

•Never call a surgeon.

Unless obstruction, abscess, megacolon, strategic fistula

Slightly Modified



RespondersResponders

Switch to oral corticosteroidsAdd AZA or 6-MP or 5-ASA

Switch to oral corticosteroidsAdd AZA or 6-MP or 5-ASA

Assess response at 3 daysAssess response at 3 days

Total or subtotal colectomy with end ileostomy


Management of the Patient with Severe UC Patient admitted with severe ulcerative colitisPatient admitted with severe ulcerative colitis

Conduct:• Assays of stool samples for C. difficile

and bacterial pathogens• Abdominal X-ray• Flexible sigmoidoscopy• Chest X-ray and tuberculosis testing

Treat with intravenous corticosteroidsTreat with intravenous corticosteroids

Non-respondersNon-responders

Surgery or second-line medical therapy

Surgery or second-line medical therapy



Non-respondersNon-responders

If cyclosporine: switch to oral cyclosporine then initiate AZA or 6-MP

If infliximab: additional induction does at 2 and 6 weeks, then maintenance therapy

If cyclosporine: switch to oral cyclosporine then initiate AZA or 6-MP

If infliximab: additional induction does at 2 and 6 weeks, then maintenance therapy

RespondersRespondersAssess response at 5-7

daysAssess response at 5-7

days

Intravenous cyclosporine or infliximab

Intravenous cyclosporine or infliximab

Bitton A, et al. Am J Gastroenterol. 2012 Feb;107(2):179-94.

B. MD, FACG - American College of Gastroenterologys3.gi.org/meetings/wb2016/16ACG_VGS_Regional_0016.pdfTitle Microsoft PowerPoint - Sun-Hanauer-Traetment Options for Severe IBD Author

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