Immunomodulators and Biologics

Maria T. Abreu, MD

University of Miami Miller School of Medicine

Miami, Florida

Management of Post-Operative Recurrence of IBD

David T. Rubin, MD, AGAFAssociate Professor of Medicine

Co-Director, Inflammatory Bowel Disease CenterUniversity of Chicago Medicine

IBD

Induction of remission

Maintenance of remission off steroids

and/orMucosal healing

(histology)

Maintenance of remission

What do we know: Guiding principles

Combination therapy is better than monotherapy

Early therapy is better than late therapy (esp Crohn’s disease)

Well timed surgery is ok

Indications for Surgery

Crohn’s disease: Obstruction Medically refractory disease Hemorrhage/transfusion requirements High grade dysplasia or cancer Growth delay Fistula/abscess

Ulcerative colitis: Medically refractory disease/fulminant disease High grade dysplasia or cancer Hemorrhage/transfusion requirements Perforation

Chimeric monoclonal antibody (75% humanIgG1 isotype)

Infliximab

IgG1

Mouse HumanPEG, polyethylene glycol.

Humanized Fab’fragment (95% humanIgG1 isotype)

Certolizumab Pegol

PEG

PEG

VHVL

CH1

No Fc

Human recombinant antibody (100% humanIgG1 isotype)

Adalimumab

IgG1

First-line Biologic Agents for the Treatment of CD

SONIC

• Moderate-to-severe CD in patients with no prior exposure to biologic agents or immunomodulators• Excluded intermediate TPMT activity• Average disease duration 2.3 years

• 1° endpoint: Induction + maintenance of steroid-free remission

• 2° endpoint: Mucosal healing

AZA 2.5mg/kg IFX 5mg/kg IFX + AZA

Clinical Remission Without Corticosteroids at Week 26

SONIC 9

Primary Endpoint

30

45

57

0

20

40

60

80

100

Pro

po

rtio

n o

f P

atie

nts

(%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.009 p=0.022

52/170 75/169 96/169

Colombel, J.F., et al., N Engl J Med. 362(15): p. 1383-95.

Cumulative Probability of Surgeryin Crohn’s Disease

Mekhjian HS et al. Gastroenterol. 1979;77(4 pt 2):907-913.

Pati

en

ts*

(%)

0

20

40

60

80

100

0 5 10 15 20 25 30 35Years After Onset

Preoperative Corticosteroids Increase Risk of Postoperative Complications in IBD

Minor Complications

Major Complications*

CS 3.69 (1.24–10.97) 5.54 (1.12–27.26)

CS <20 mg 2.56 (0.68–9.61) 6.28 (0.97–40.36)

CS 30–40 mg 3.12 (0.93–10.49) 5.87 (0.90–38.23)

CS >40 9.16 (1.51–55.42) 18.94 (1.72–207.34)

6-MP/AZA 1.68 (0.65–4.27) 1.2 (0.37–3.94)

6-MP <1.5 mg/kg 1.49 (0.56–3.98) 1.12 (0.32–3.93)

6-MP>1.5 mg/kg 4.50 (0.46–44.51) 1.89 (0.32–3.93)

• 159 IBD patients (71 UC, 88 CD) undergoing elective bowel surgery

Aberra FN et al. Gastroenterology. 2003;125:320.

*Major complications include sepsis, pneumonia, peritonitis, abscess, wound infection

CS, corticosteroids; 6-MP, 6-mercaptopurine; AZA, azathioprine

TNF Use Prior to Surgery

• Postoperative infections– CD1: Mayo Clinic

• 52 IFX vs 218 no IFX • OR 0.9 (95% CI 0.4–1.9)1

– UC2: Mayo Clinic • 47 IFX vs. 254 no IFX • OR 2.7 (95% CI 1.1–6.7)

– UC3: Cleveland Clinic • Pelvic sepsis • 46 IFX vs. 46 no IFX • OR 13.8 (1.8–105)

1. Colombel JF et al. Am J Gastroenterol. 2004;99:878. 2. Selvasekar CR et al. J Am Coll Surg. 2007;204:956.

3. Mor IJ. Dis Col Rectum. 2008;51:1202.

CD

UC

?

IFX, infliximab; OR, odds ratio; CI, confidence interval

Disability

Post-op Ileocecectomy is the Perfect Opportunity for Prevention!

DiseasePrevention

Prevention ofSymptomatic Disease

Prevention ofComplications

Prevention ofRelapse

Health SubclinicalInflammation

SymptomaticInflammation

Complications

Recurrence After Surgery in Crohn’s Disease

Rutgeerts P et al. Gastroenterol. 1990;99(4):956-963.

Years

Pat

ient

s (%

)

Survival without surgery

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Survival without symptoms

Survival withoutlaboratory recurrence

Survival withoutendoscopic lesions

N=89

Risk Stratification for Recurrence in Post-operative Crohn’s disease

SmokingPerforating-type of

diseaseSmall bowel diseaseIleocolonic disease

Perianal fistulasDuration of diseaseAge? Clear margins? Length of resection?Type of anastomosis

Greenstein AJ et al. Gut. 1988;29(5):588-592. Bernell O et al. Ann Surg. 2000;231(1):38-45. Bernell O et al. Br J Surg. 2000;87(12):1697-1701. D'Haens GR et al. Gut. 1995;36(5):715-717. Lautenbach E et al. Gastroenterol.1998;115(2):259-267. Moskovitz D et al. Int J Colorectal Dis. 1999;14(4-5):224-226. Kono T et al. Dis Colon Rectum 2011 May;54(5):586-92.

The Neo-TI: The Rutgeerts’ ScorePatients should be scoped 6 months after surgery

to re-stratify risk

Normal ileal mucosa

Rutgeerts 0

<5 aphthous ulcers

Rutgeerts 1

>5 aphthous ulcers, normal intervening mucosa

Rutgeerts 2

Ulceration without normal intervening mucosa

Severe ulceration with nodules, cobblestoning, or stricture

Rutgeerts 3 Rutgeerts 4

The neo-terminal ileum is not the anastomosis!

• Suture-related trauma• Marginal ulcerations/ischemia

Symptoms after Crohn’s Surgery are Not Always Inflammatory!

Symptom/Cause TreatmentsPost-operative pain Limited analgesia, regional

anesthesia when possible

Post-resection “diarrhesis” (rapid transit due to absence of obstruction and muscular hypertrophy)

Anti-diarrheals

Bile salts Bile acid sequestrant

Narcotic bowel NO narcotics!

Bacterial overgrowth antibiotics

Clinical Recurrence Endoscopic recurrence

Placebo 25% – 77% 53% - 79%

5 ASA 24% - 58% 63% - 66%

Budesonide 19% - 32% 52% - 57%

Nitroimidazole 7% - 8% 52% - 54%

AZA/6MP 34% – 50% 42 – 44%

Infliximab 0% 9.1%

Regueiro M. Inflamm Bowel Dis. 2009 Oct;15(10):1583-90.

Medical Prevention of Clinical and Endoscopic Recurrence of Crohn’s Disease

Endoscopic Clinical

Thiopurines for the prevention of postoperative recurrence in Crohn’s disease: meta-analysis

Peyrin-Biroulet L et al. Am J Gastroenterol. 2009 Aug;104(8):2089-96.

Metronidazole/azathioprine combination therapy for post-operative recurrence

– High risk pts (n=81) = (age <30, smokers, steroids <3 months, second resection, perforated/abscess)

– N=40 metronidazole 250 mg TID 3 months + AZA 2–3 tabs– N=41 metronidazole 250 mg TID 3 months + placebo

D'Haens GR et al. Gastroenterology. 2008 Oct;135(4):1123-9.

53

69

3.4

34

44

22

0

20

40

60

80

Month 3 Month 12 No lesions at Month 12

Placebo

Combination therapyp=0.11

p=0.048

p=0.03

% p

atie

nts

with

end

osco

pic

recu

rren

ce (

>i2

) po

st s

urge

ry

0

10

20

30

40

50

60

70

80

90

Endoscopic Recurrence

% p

atie

nts

Infliximab (n=11) Placebo (n=13)

Infliximab vs placebop=0.0006

Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4. Regueiro M et al. 2009 Feb;136(2):441-50.e1; quiz 716.

1/11 11/13

Post-operative Endoscopic RecurrenceInfliximab vs. Placebo

Assess risk of recurrence

Low Moderate HighDon’t Know

Therapy? Start therapy Start therapy ?

Thiopurine + MTX

TNF + IMM

Colonoscopy at 6 months

Colonoscopy at 6 months

Colonoscopy at 6 months

Colonoscopy at 3-6 months

Metronidazole at dischargeMetronidazole at discharge

i0-i1 i2-i4 i0-i1 i2-i4 i0-i1 i2-i4

Follow up

TreatmentEscalate

Rx Change dose/ optimization

4 weeks4 weeks

Metronidazole at discharge

Proposed Algorithm for Prevention of Post-Op Recurrence in Crohn’s

Ulcerative colitis

Early mucosal healing a favorable prognostic factor in UC

Infliximab-treated patientsP<0.0001

Patie

nts

in C

ortic

oste

roid

-fre

e re

mis

sion

%

Week 8 endoscopic score

ACT 1 and ACT 2

Colombel JF et al. Gastroenterology. 2011 Jun 29. [Epub ahead of print].

Week 8 endoscopy

Can Surgery for UC be Prevented?Mucosal Healing and Time to Colectomy in Infliximab-Treated Patients

1 = MILD 2 = MODERATE 3 = SEVERE0 = NORMAL

Colombel JF, Rutgeerts P, Reinisch W, et al. Gastroenterology. 2011 Oct;141(4):1194-201

Ulcerative Colitis: Ileo-pouch Anal Anastomosis

Colectomy

J pouch

Cuff/Anal Transition zone

Better Outcomes at High Volume Hospitals

OR = 1.18 (0.99–1.41)

Kaplan GG et al. Gastroenterology. 2008;134:680.

Per

cen

t

50

40

30

20

10

0

35.4

25.6

OR = 2.42 (1.26–4.63)

4.0 0.7

Mortality Complications

Low volume High volume

“Complications” of the Ileal Pouch

Compliments of Bo Shen, MD

Surgical/MechanicalSurgical/

MechanicalInflammatory/

InfectiousInflammatory/

Infectious FunctionalFunctional Dysplasia/NeoplasiaDysplasia/Neoplasia

Systemic/MetabolicSystemic/Metabolic

- Afferent limb syn.- Efferent limb syn.- Strictures- Leaks- Fistulae- Sinuses- Abscess- Adhesions- Re-operation

- Afferent limb syn.- Efferent limb syn.- Strictures- Leaks- Fistulae- Sinuses- Abscess- Adhesions- Re-operation

- Pouchitis- Crohn’s dis.- Cuffitis- Small bowel bacterial overgrowth- CMV - C. difficile - Polyps

- Pouchitis- Crohn’s dis.- Cuffitis- Small bowel bacterial overgrowth- CMV - C. difficile - Polyps

- Irritable pouch syn.- Pelvic floor dysfunction- Poor pouch compliance- Pseudo- obstruction

- Irritable pouch syn.- Pelvic floor dysfunction- Poor pouch compliance- Pseudo- obstruction

- Anemia- Osteoporosis- Vitamin B12 deficiency- Malnutrition- Fertility- Sexuality

- Anemia- Osteoporosis- Vitamin B12 deficiency- Malnutrition- Fertility- Sexuality

- Dysplasia- Cancer

- Dysplasia- Cancer

Risk Factors for Pouchitis

• Extensive UC• Backwash ileitis• Primary sclerosing cholangitis• p-ANCA• NOD2/ IL-1 receptor antagonist

polymorphisms• Ex-smoker• NSAIDs• Arthralgias• Family history of Crohn’s disease

Fazio VW et al. Ann Surg. 1995 August; 222(2): 120–127; Schmidt CM et al. Ann Surg. 1998 May; 227(5): 654–665; J L Lohmuller et al. Ann Surg. 1990 May; 211(5): 622–629; Fleshner P et al. Clin Gastroenterol Hepatol. 2007 Aug;5(8):952-8; quiz 887; Achkar JP et al.Clin Gastroenterol Hepatol. 2005 Jan;3(1):60-6; Shen B et al. Am J Gastroenterol. 2005 Jan;100(1):93-101; Le Q et al. Inflamm Bowel Dis. 2012 Mar 29 [Epub ahead of print]

Figure: http://www.webmd.com accessed May, 2012.

Infrequent Relapse

Infrequent Relapse

Frequent Relapse

Frequent Relapse

Antbx-dependentPouchitis

Antbx-dependentPouchitis

Antbx-responsive Pouchitis

Antbx-responsive Pouchitis

RespondedResponded Not RespondedNot Responded

Cipro or Metronidazole x 2 more wksCipro or Metronidazole x 2 more wks

RespondedResponded Not RespondedNot Responded

Cipro+ Metronidazole or Rifaximin or Tinidazole x 4 wks

Cipro+ Metronidazole or Rifaximin or Tinidazole x 4 wks

Antbx-refractoryPouchitis

Antbx-refractoryPouchitis

Not RespondedNot Responded

5-ASA/steroids/Immunomodulators/Infliximab?

5-ASA/steroids/Immunomodulators/Infliximab?

Antibiotics prnAntibiotics prn Probiotics or Antibiotics

Probiotics or Antibiotics

Cipro or Metronidazole x 2 wksCipro or Metronidazole x 2 wks

PouchitisPouchitis

Management of Pouchitis(endoscopic confirmation is preferred)

Can Pouchitis be Prevented?Frequency of Pouchitis with Probiotic

Prophylaxis

10%

40%

0

20

40

60

80

100

VSL3 Placebo

Gionchetti P et al. Gastroenterol 2003 May;124(5):1202-9.

N = 206 grams QD x 12 months

N = 20

P < 0.05%

case

s w

ith fl

are

-up

Key Take Home Messages

IBD

• Stratify patients for disease severity & potential long-term complications

• Combination therapy better than monotherapy for sick patients naïve to both

• Low Absolute risk of IS or Biologic therapy • Vaccines, DXAs and other health

maintenance issues will eventually be used to measure quality

Risks of IBD Therapy

• Non-melanoma skin cancer (NMSC) associated with current or past IS therapy

• No other solid tumors show clear association with IS or anti-TNF therapy

• No clear signal that combination therapy leads to higher risk than monotherapy

• HSTCL occurs AFTER 2 years of thiopurine exposure

• Risk of PML after 2 years on natalizumab about 1 in 100 exposed patients

Management of Post-operative Recurrence in IBD

• Know patient’s risk of recurrence• Confirm endoscopic disease• Ulcerative colitis

– Mucosal healing reduces risk of colectomy– Assess risk of pouchitis– Distinguish pouchitis/Crohn’s/pre-pouch ileitis

• Crohn’s disease (ileo-colonic anastomosis)– Assess colonoscopic recurrence @ 6 months– Prophylaxis vs re-treatment based on risks and treatment

history – Subsequent clinical/endoscopic f/u not defined

Microscopic colitis

• Incidence appears to have stabilized• Consider celiac disease if steatorrhea or

weight loss• Consider drug-induced MC • Treat with bismuth or budesonide

– -Right dose and right duration• Maintenance therapy with budesonide is

effective

Gut microbiota and IBS

• Microbiota in IBS:– Differs from health & may contribute to

pathogenesis– May lead novel diagnostic tests for IBS– May select or predict response to IBS

treatments treatments– Provide potential target in IBS

• Antibiotics, Probiotics, Therapeutic foods