Immunomodulators and Biologics Maria T. Abreu, MD University of Miami Miller School of Medicine...

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