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