Management of Inflammatory Bowel Diseases (IBD): 2019 & …Management of Inflammatory Bowel Diseases...

Management ofInflammatory Bowel Diseases

(IBD): 2019 & Beyond

Adam C. Ehrlich, MD, MPH

Assistant Professor of Medicine, Section of Gastroenterology

Co-Medical Director, Temple IBD Program

Associate Program Director, Gastroenterology Fellowship

Lewis Katz School of Medicine at Temple University

Advances in Digestive Diseases 2019

June 1, 2019

Disclosures

• Consultant: Level Ex, Vindico Medical Education

• Scientific Advisory Board: Praeventix LLC, Janssen

Topics to Cover

• Management with traditional therapies– 5-ASA withdrawal in CD

– Anti-TNFs in pre-operative period in IBD

– FMT for C difficile in IBD

• Management with recent therapies– Ustekinumab in UC

– Vedolizumab vs adalimumab in UC

– Tofacitinib in UC in real life

• Touch on future therapies

Stopping 5-ASAs in Crohn’s Disease

Patients Starting Biologic Therapy Does

Not Increase the Risk of Adverse Clinical

Outcomes: Analysis of Two National

Population-Based Cohorts

Ryan C. Ungaro, Berkeley N. Limketkai, Camilla Bjørn Jensen, Clara Yzet,Kristine H Allin, Manasi Agrawal, Thomas Ullman, Johan Burisch, Tine Jess,and Jean-Frederic Colombel

Presentation 110, Digestive Disease Week 2019

Background

• 5-ASA has limited efficacy in CD and its use is generally not

recommend by clinical guidelines

• 5-ASA are one of the most commonly used medications in CD

• 5-ASA use poses significant cost and pill burden on patients

• There has been significant research on de-escalation of

immunomodulators and biologics in CD but little to no data on

stopping 5-ASA

• It is unknown if it is safe to stop 5-ASA in CD patients who

require escalation of therapy to anti-TNF agents

Lichtenstein G et al Am J Gastro 2018

Siegel C et al DDW 2017

Torres J et al Gastro 2015

Methods• U.S. Cohort: Truven Health MarketScan Commercial Database

• Over 450 million entries per year from 2007-2016 followed up to 3 years

• CD patients identified using ICD-9 and 10 codes

• Danish cohort: Drawn from 3 nationwide Danish health registers Inpatient and

outpatient data on all Danish patients

•All Danish patients from 1995 -2014 followed up to 9 years

•CD patients identified using ICD-8 and 10 codes

• Inclusion criteria

• Prescribed Anti-TNF with continuation for at least 90 days

• Prescribed 5-ASA for at least 90 days prior to initiating anti-TNF therapy

• Primary Outcome was composite of adverse clinical events defined as:

• Need for new oral steroid therapy (at least 90 days after biologic prescription)

• IBD-related hospitalization (CD diagnosis as primary code)

• IBD-related surgery (small/large bowel surgeries)

•Secondary Outcomes: individual components of the primary composite

• Variable of interest: Discontinuation of 5-ASA

• Defined as discontinuation of 5-ASA within 90 days of starting anti-TNF

Patient CharacteristicsUnited States Cohort Denmark Cohort

Characteristic Continue

5-ASA

(N = 1916)

Stop

5-ASA

(N = 1044)

P value Continue

5-ASA

(N = 112)

Stop

5-ASA

(N = 106)

P value

Age at start of

biologic therapy,

mean years (SD)

41.0 (14.5) 39.3 (14.0) <0.01 41.1 (14.6) 36.2 (13.7) 0.01

Age at CD

diagnosis, mean

years (SD)

N/A N/A 34.5 (14.6) 31.1 (13.1) 0.08

Sex 0.76 0.7

Male 959 (50.1) 529 (50.7) 56 (50) 56 (53)

Female 956 (49.9) 515 (49.3) 56 (50) 50 (47)

Pre-anti-TNF

disease duration,

median years (IQR)

N/A N/A 4.7 (1.4,9.4) 3.2 (0.7, 8.1) 0.02

Pre-anti-TNF 5-ASA

treatment, median

days (IQR)

495

(404, 633)

305

(211,363)

<0.01 844

(476, 1540)

272

(192, 548)

<0.01

Follow-up time from

initiation of anti-TNF

therapy, median

days (IQR)

325 (163, 642) 296 (166, 558) 0.1 199

(101, 410)

142

(82, 336)

0.1

Groups in both cohorts similar in terms of corticosteroid use in prior 90 days, hospitalizations in prior year,history of surgeries, concomitant immunomodulatory therapy, and emergency room visits in prior year

0.00

0.25

0.50

0.75

1.00

Ris

k o

f m

ajo

r ad

ve

rse

ou

tco

me

1044 288 90 32Stop 5-ASA

1916 583 203 85Cont 5-ASA

Number at risk

0 1 2 3Years after initiation of biologic therapy

Cont 5-ASA Stop 5-ASA

0.00

0.25

0.50

0.75

1.00

Ris

k o

f m

ajo

r a

dve

rse

ou

tcom

e

1044 417 173 75Stop 5-ASA

1916 849 388 172Cont 5-ASA

Number at risk



0.00

0.25

0.50

0.75

1.00

Ris

k o

f m

ajo

r a

dve

rse

ou

tcom

e

1044 375 139 58Stop 5-ASA

1916 755 327 141Cont 5-ASA

Number at risk



0.00

0.25

0.50

0.75

1.00

Ris

k o

f m

ajo

r a

dve

rse

ou

tcom

e

1044 318 112 40Stop 5-ASA

1916 641 243 102Cont 5-ASA

Number at risk



C D

B

Log-rank p=0.69 Log-rank p=0.72


Pro

po

rtio

n h

osp

ital

ize

dP

rop

ort

ion

co

mb

ined

fai

lure

s

Years since anti-TNF initiation Years since anti-TNF initiation

Years since anti-TNF initiationYears since anti-TNF initiation

Pro

po

rtio

n n

ee

din

g st

ero

idP

rop

ort

ion

nee

din

g su

rger

y

A

Cumulative rates of adverse events in U.S. cohort

Cumulative rates of adverse events in Danish cohort

CD

Log-rank p=0.85


Pro

po

rtio

n c

om

bin

ed f

ailu

res

Years since anti-TNF initiation

Years since anti-TNF initiationYears since anti-TNF initiation

Pro

po

rtio

n n

ee

din

g st

ero

idP

rop

ort

ion

nee

din

g su

rger

y

A

Pro

po

rtio

n h

osp

ital

ize

d

Years since anti-TNF initiation

Log-rank p=0.01

B

D

Multivariable Analysis

Discontinue versus Continue 5-ASA

aHR (95% CI)* P value

United States Cohort

New Steroid Use 0.87 (0.74 – 1.03) 0.12

Hospitalization 0.87 (0.70 – 1.08) 0.21

Surgery 0.79 (0.49 – 1.29) 0.35

Composite 0.89 (0.77 – 1.03) 0.13

Denmark Cohort

New Steroid Use 1.18 (0.60 – 2.33) 0.63

Hospitalization 2.06 (1.01 – 4.20) 0.05

Surgery 1.13 (0.45 – 2.83) 0.80

Composite 1.13 (0.68 – 1.87) 0.63

Abbreviations: 5-ASA, 5-aminosalicylate; anti-TNF, anti-tumor necrosis factor alpha; aHR, adjustedhazard ratio; CI, confidence interval; IR, incidence rate.*In the U.S. cohort, models adjusted for age, sex, duration of pre-biologic 5-aminosalicylate treatment,

and baseline health care utilization (hospitalization, emergency department visits, corticosteroid use,

gastrointestinal surgery). In the Danish cohort, models adjusted for age, sex, duration of Crohn’s

disease at initiation of biologic therapy, duration of pre-biologic 5-aminosalicylate treatment, and

baseline health care utilization (hospitalization, emergency department visits, corticosteroid use,gastrointestinal surgery)

Multivariable Analysis

Abbreviations: 5-ASA, 5-aminosalicylate; anti-TNF, anti-tumor necrosis factor alpha; aHR, adjustedhazard ratio; CI, confidence interval; IR, incidence rate.*In the U.S. cohort, models adjusted for age, sex, duration of pre-biologic 5-aminosalicylate treatment,

and baseline health care utilization (hospitalization, emergency department visits, corticosteroid use,

gastrointestinal surgery). In the Danish cohort, models adjusted for age, sex, duration of Crohn’s

disease at initiation of biologic therapy, duration of pre-biologic 5-aminosalicylate treatment, and

baseline health care utilization (hospitalization, emergency department visits, corticosteroid use,

gastrointestinal surgery)

Biologic without Immunomodulator

Biologic with Immunomodulator

aHR (95% CI)* P value aHR (95% CI)* P value

United States

Steroid 0.83 (0.67 – 1.02) 0.08 0.96 (0.72 – 1.28) 0.78Hospitalization 0.69 (0.52 – 0.92) 0.01 1.23 (0.87 – 1.76) 0.25

Surgery 0.41 (0.19 – 0.87) 0.02 1.44 (0.75 – 2.76) 0.27Composite 0.80 (0.66 – 0.96) 0.02 1.08 (0.84 – 1.37) 0.55

DenmarkSteroid 2.15 (0.91 – 5.09) 0.08 0.07 (0.01 – 0.42) 0.003Hospitalization 2.07 (0.77 – 5.56) 0.15 3.29 (0.83 – 13.00) 0.09

Surgery 3.15 (0.79 – 12.58) 0.10 0.96 (0.09 – 10.69) 0.98

Composite 1.43 (0.73 – 2.79) 0.33 0.81 (0.31 – 2.09) 0.66

Conclusions

• In two national databases, CD patients on 5-ASA for at least 90 days and startedon anti-TNF who then discontinued 5-ASA medications did not have anincreased rate of adverse clinical events (new corticosteroid use, IBD-relatedhospitalization or surgery)

• After adjusting for potential confounders, there was no significant difference inthe risk of adverse clinical events when comparing CD patients whodiscontinued or continued 5-ASA after initiation of anti-TNF

• These results suggest that CD patients may safely discontinue 5-ASA afterstarting biologic therapy but should be validated in a prospective study

Prospective Cohort of Ulcerative Colitis

and Crohn’s Disease Patients

Undergoing Surgery to Identify Risk

Factors for

Post-Operative INfection I (PUCCINI)

Benjamin Lee Cohen, Phillip Fleshner, Sunanda V. Kane, Hans H. Herfarth, Nicole Palekar, Francis A. Farraye, Jonathan A. Leighton, Jeffry Katz, Russell D. Cohen, Mark Edward Gerich, Raymond K. Cross, Peter D.R. Higgins, Andrew Tinsley, Sarah Camille

Glover, Corey A. Siegel, Jaime L. Bohl, Heba Iskandar, Samantha Raymond, Ruiqi Huang, Mayte Suarez-Farinas, Bruce E. Sands

Presentation 415a, Digestive Disease Week 2019

Redacted at request of authors

Jessica R. Allegretti, Jonathan Hurtado, Madeline Carrelas, Jenna Marcus, Emily Phelps, Wing Fei Wong, Julian R. Marchesi, Benjamin H. Mullish, Julie A.K. McDonald, Alexandros Pechlivanis,

Grace F. Barker, Jesus Miguens Blanco, Sashidar Sagi, Matthew Bohm, Collen Kelly, Zain Kassam, Ari Grinspan, and Monika Fischer

The ICON Study: Inflammatory Bowel

Disease and Recurrent Clostridium

difficile Infection: Outcomes after Fecal

Microbiota Transplantation


• Prevalence is 2.5-8 fold higher then non-IBD patients

• 10% lifetime risk

• 4.5-fold higher risk of recurrence

• Patients with UC are at the highest risk

CDI in IBD

Sequela of CDI in IBD

• Exacerbations of IBD

• Increased hospitalizations

• Increased LOS

• Escalation in IBD therapy

• Colectomy

• Higher mortality rates

• Failure of CDI medical therapy

• More CDI recurrences

• Increased health care costs.

• Distinguishing active infection from flare

• Choice and duration of antibiotic therapy

• Escalation or de-escalation of immunosuppression

• Where to position FMT

• Lack of prospective data

– Need to extrapolate from non-IBD data

Treatment of CDI in IBD: Challenges

How Effective is FMT for Recurrent CDI in IBD patients?

3 retrospective studies to date:

Study N Inclusion Delivery CDI Cure Rate

IBD FlareRate*

Khalili et al. 35 (22 UC, 13CD)

≥ 2 Episodes

Capsule (77%)Colo (23%)

97% 54%

Newman et al.

56 (28 UC, 28 CD)

Failureafter one extended course of antibiotics

colonoscopy 85.7% 25%

Fischer et al. 67(32 UC, 35 CD)

≥3 Episodes

colonoscopy 79% 17.9%

* Or treatment escalation

Baseline

Stool Tests: -Microbiome analysis

(16S)

-Fecal Calprotectin

-Metabolomic Profiling

-Banked Samples

Blood Tests: -CBC, CRP, albumin, Cr

-Metabolomic Profiling

(LCMS)

-Banked Samples

Clinical Data: -Diarrheal Symptoms

-IBD Activity Scores

-Changes in IBD

therapy

-Need for surgery

Week 8

Cdiff testing by EIA and PCR

Fecal Calprotectin

Key inclusion criteria:

Confirmed recurrent CDI

(2 episodes or more)

Confirmed diagnosis of IBD

with colonic involvement

Open label trial at 4 sites around the US

Variable N=37

Female % (n) 56.8% (21)

Avg. Age 37.6 (range 20-76)Crohn’s % (n) 37.8% (14)

Colonic 21.4% (3)Ileo-colonic 64.3% (9)Unknown 14.3% (2)

UC % (n) 62.2% (23)Proctitis 8.7% (2)Left-sided 17.4% (4)Pancolitis 69.6% (16)Unknown 4.3% (1)

Race% (n)

White 91.9% (34)

Black or African American 5.4% (2)

Asian 2.7% (1)

Avg Baseline Calprotectin 1804.8 +/-2307.7

Avg Baseline CRP 5.1 +/- 9.1

Avg Daily BMs at Baseline 4.9 +/- 3.4

Avg Baseline Bristol Score 5.5 +/- 1.0

CDI Recurrence Rates

BWH

Subject ID

Week 1 Week 8 Week 12

Toxin PCR Toxin PCR Toxin PCR

101 neg pos neg pos neg pos

102 neg neg neg neg neg neg




106 pos pos

106B neg neg neg neg neg neg

107 neg pos neg pos neg neg


Indiana

Subject ID



201 neg pos







208 neg pos neg neg neg neg

209 neg Pos




212 pos pos

212B neg pos neg neg neg neg


Mt. Sinai

Subject ID




302 pos pos


303 neg neg neg pos neg neg




307 neg pos neg neg neg pos




Brown

Subject ID



401 neg neg neg pos

402 neg neg neg neg




Success rate: 34/37 = 92%

Crohn’s Disease Outcomes

Harvey Bradshaw Index

Site/Subject Diagnosis Baseline Week 1 Week 8 Week 12 Outcomes

ICON 101 Crohn’s 6 1 2 2 Improved


ICON 106 Crohn’s 12 4 N/A N/A N/A

ICON 106B Crohn’s N/A 4 4 7 Improved

ICON 107 Crohn’s 1 3 (flare) 0 0 No Change

ICON 201 Crohn’s 5 2 Lost to follow-

up

Lost to follow-

up

N/A





ICON 207 Crohn’s 7 10 (flare) 11 (flare) 4 Improved


ICON 212B Crohn’s N/A 0 1 4 Improved


ICON302B Crohn’s N/A 1 2 2 No Change

ICON 305 Crohn’s 6 8 (flare) 4 5 No Change

ICON 310 Crohn’s 1 0 0 0 No Change

Partial Mayo Score

Site/Subject Diagnosis Baseline Week 1 Week 8 Week 12 Outcomes

ICON 102 Ulcerative Colitis 1 1 0 0 No Change

ICON 103 Ulcerative Colitis 2 3 3 5 De Novo Flare

ICON 104 Ulcerative Colitis 6 6 2 2 Improved


ICON 205 Ulcerative Colitis 4 7 (flare) 4 0 Improved


ICON 209 Ulcerative Colitis 6 6 N/A N/A N/A

ICON 209B Ulcerative Colitis N/A 2 3 2 Improved











ICON 401 Ulcerative Colitis 7 3 N/A 3 Improved

ICON 402 Ulcerative Colitis 2 1 N/A 0 Improved




Ulcerative Colitis Outcomes

• FMT is safe and effective for patients with IBD-CDI

• FMT failures are lower then previously reported (92% success)

– done earlier (1st recurrence)

• Only one patient (2.7%) experienced a de novo flare

Conclusions

Efficacy and Safety of Ustekinumabas Maintenance Therapy in Ulcerative Colitis:

Week 44 Results From UNIFI

W.J. Sandborn, B.E. Sands, R. Panaccione, C.D. O’Brien, H. Zhang, J. Johanns, L. Peyrin-Biroulet, G. van Assche, S. Danese, S. Targan,

M.T. Abreu, T. Hisamatsu, P. Szapary, C. Marano


UNIFI Induction Data

Sands BE, et al. UEGW 2018

Conclusions

• UST effective for maintenance in UC patients who respond to induction

• Overall remission at week 44: 44% (~all in CSF remission as well)

• Non-biologic failure patients do better

• Potential for q12w dosing (instead of q8w for biologic naïve)

• No new safety signals

Vedolizumab Shows Superior Efficacy Versus Adalimumab: Results of VARSITY – the First Head-to-Head Study of Biologic Therapy for

Moderate-to-Severe Ulcerative Colitis

Bruce Sands, Laurent Peyrin-Biroulet, Edward Loftus, Silvio Danese, Jean-Frederic Colombel, Brihad Abhyankar, Jingjing Chen, Raquel

Rogers, Richard Lirio, Jeffrey Bornstein, Stefan Schreiber

Presentation 416a, Digestive Disease Week 2019

Conclusions

• Vedolizumab superior to adalimumab in key endpoints of clinical remission and mucosal healing at end of 1 year

• Most of benefit occurs in TNF naïve patients

• Major limitations are lack of dose intensification and presence of TNF exposed patients

• Important first step in comparative effectiveness

Real-World Effectiveness of Tofacitinib in Ulcerative Colitis:

A Multi-Centre Study

Anish Patel1, Marc Fenster2, Geoffrey Bader1, Christina Dimopoulos2, Parakkal Deepak3, Ryan Ungaro2, Matthew Ciorba3, Andrew Yarur5,Robert Hirten2, George Christophi3, Aava Khatiwada3, Bixuan Lin5,

Jean-Frederic Colombel2, Christina Ha4, Benjamin Cohen2, Joel Pekow6, Poonam Beniwal-Patel5, Gaurav Syal4


Background

• Multi-center retrospective cohort study across six tertiary

IBD centers

• Study Criteria– Inclusion: UC diagnosis treated with on-label 10mg induction dosing

– Exclusion: Crohn’s disease or IBD-undetermined

• Primary outcome– clinical response (>50% reduction in symptoms by physician global

assessment (PGA)) at week 8

• Secondary outcomes– clinical remission (resolution of symptoms by PGA) at week 8 and 16

– clinical response/remission at week 8 and 16 stratified by prior biologic

exposure

– corticosteroid-free (CSF) response/remission at weeks 8 and 16

• Patients with therapy discontinuation prior to 8 or 16 week

endpoints consideration non-responder

Methods

Results

246 patients

225 patients

184 patients

21 patients excluded

- Did not receive 10mg BID induction dose

41 patients excluded

- Did not have 8 weeks of follow-up

Baseline Characteristics

Conclusions

• Tofacitinib is effective at inducing short-term

clinical response/remission in a real-world

clinical setting by week 8

• Increase remission rates at 16 weeks compared

to 8 weeks though most who respond do so by 8

weeks

• Prior biologic exposure is associated with

decreased rates of clinical response/remission

One Line Highlights for Future Therapies

• Mirikizumab (anti-IL23) effective in Phase 2 trial in CD and UC

• ABX464 (increase miRNA124) effective in Phase 2a trial in UC

• Etrasimod (S1P modulator) effective in Phase 2 trial in UC

• Upadacitinib (JAK-1 inhibitor) effective in Phase 2 trial in CD and UC

Overall Summary

• Stopping 5-ASA when starting anti-TNF in CD does not result in worse outcomes compared to continuing 5-ASA

• No evidence for increased peri-operative infections in IBD patients on anti-TNF undergoing surgery

• FMT safe and effective for CDI in IBD patients

Overall Summary

• Ustekinumab effective for maintenance in UC in patients who respond during induction

• Vedolizumab superior to adalimumab in UC in first head-to-head trial comparing biologics with some notable limitations

• Tofacitinib effective in real-world analysis in UC

Thank you!

[email protected]

@AdamEhrlichMD

Management of Inflammatory Bowel Diseases (IBD): 2019 & …Management of Inflammatory Bowel Diseases...

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