Controversies in IBD: Resolving clinical ... - Cochrane › sites › ibd.cochrane.org › ... · •Sensitivity analyses based on a ﬁxed-effect model and duration of therapy conducted

Controversies in IBD: Resolving clinical dilemmas using Cochrane reviewsDR. NILESH CHANDE

COORDINATING EDITOR, IBD REVIEW GROUP; UNIVERSITY OF WESTERN ONTARIO, LONDON, ON CANADA

An international organisation that aims to help people make well-informed decisions about healthcare by preparing, maintaining and promoting the accessibility of systematic reviews of the effects of health care interventions

Cochrane IBD review group

o636 authors

o16 editors

o79 published reviews

o50 published protocols

oImpact Factor 2015: 5.357

Cochrane IBD review group

o Co-publication agreements with:

• Inflammatory Bowel Diseases

• American Journal of Gastroenterology

o Concise versions of Cochrane reviews

o Wider dissemination to clinicians

Symposium format

I. Case Study

II. Cochrane Evidence

III. Panel Discussion

Panel members:

Dr. Brian Feagan, University of Western Ontario, London, ON, Canada

Dr. William Sandborn, University of California San Diego, CA, USA

Dr. Fernando Velayos, University of California San Francisco, CA, USA

Agenda

1. 5-ASA for the treatment of Crohn’s disease - Dr. Stephen Hanauer

2. Strategies for detecting colon cancer in patients with inflammatory bowel disease - Dr. James East

3. Biologics for induction and maintenance of remission in Crohn’s disease: a network meta-analysis - Dr.

Pieter Hindryckx

4. Withdrawal of drug therapy in patients with Crohn’s disease - Dr. Jean-Frédéric Colombel

5. Audience Q & A

We would like to sincerely thank the following individuals for the important role they played in

organizing the DDW Cochrane Symposium 2017:

Dr. Ray Boyapati (Monash Health, Clayton, Victoria, Australia; University of Edinburgh, Edinburgh, Scotland)

Dr. William Bye (Prince of Wales Hospital, New South Wales, Australia)

Dr. Leonard Guizzetti (Robarts Clinical Trials Inc, London ON, Canada)

Dr. Vipul Jairath (University of Western Ontario, London ON, Canada)

Orli Silverberg (University of Western Ontario, London ON, Canada)

Dr. Joana Torres (Icahn School of Medicine at Mount Sinai, New York; Hospital Beatriz Angelo, Loures, Portugal)

Sonam Upadhyaya (University of Western Ontario, London ON, Canada)

Special thanks

Interested in Authoring a Cochrane Review?

Interested in Becoming a Peer Reviewer?

Contact Us!

John K. MacDonald, Managing Editor

[email protected]

Tran M. Nguyen, Trial Search Coordinator

[email protected]

For slides from today’s presentation, please visit http://ibd.cochrane.org/

mailto:[email protected]

mailto:[email protected]

http://ibd.cochrane.org/

Case 1

5-ASA for the treatment of Crohn’s Diseaseo42 year old non-smoking male

oRLQ pain and diarrhea for 6 months

oColonoscopy showed ileal Crohn’s disease with

ulceration without stricturing

oMRE showed 10 cm ileal disease

oPatient not keen on steroids or immune suppression

oCan he be treated with 5-ASA?

Case 2

Strategies for detecting colon cancer in patients with inflammatory bowel diseaseo 61 year old male

o Ulcerative pancolitis for 22 years – was well on 5-ASA

o Flare 5 years ago – treated with steroids then transitioned to

infliximab and azathioprine

o Surveillance colonoscopy shows disease remission but scarring from

prior inflammation

o Should chromoendoscopy with targeted biopsies be used rather than

white light with random biopsies?

Case 3

Biologics for induction and maintenance of remission in Crohn’s disease: a network meta-analysiso 25 year old female

o Bloody diarrhea with abdominal pain and weight loss for 3 months

o Colonoscopy shows moderate patchy Crohn’s colitis with rectal sparing

o No extraintestinal features

o Does not want steroids

oWhat treatment do you suggest?

Case 4Withdrawal of drug therapy in patients with Crohn’s disease

o 59 year old non-smoking female with ileal Crohn’s disease for 25 years

o Treated in past with steroids and 5-ASA but required extensive 50 cm

ileocecal resection with anastomosis 10 years ago for stricturing disease

o Flare of symptoms 5 years ago treated with prednisone and azathioprine

o Currently in clinical remission with normal fecal calprotectin and CRP

o Colonoscopy shows no recurrence at anastomosis

o Can this patient stop azathioprine therapy?

5-ASA for the treatment of Crohn’s disease DR. STEPHEN HANAUER

FEINBERG SCHOOL OF MEDICINE, NORTHWESTERN UNIVERSITY, CHICAGO, IL , USA

Background• RCTs investigating the efficacy of aminosalicylates for treatment of mildly to moderately active Crohn’s disease have yielded conflicting results

• A systematic review was conducted to critically examine current available data on the efficacy of sulfasalazine and mesalamine for inducing remission or clinical response in these patients1

• A systematic review to evaluate the efficacy and safety of oral 5-ASA agents for the maintenance of medically-induced remission in Crohn’s disease was also conducted2

1. Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of remission or response in Crohn’s disease. Cochrane Database of Systematic Reviews 2016, Issue 7. Art. No.: CD008870. DOI: 10.1002/14651858.CD008870.pub2. 2.

2. Akobeng AK, Zhang D, Gordon M, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD003715

Objective

To evaluate the efficacy and safety of aminosalicylates compared to placebo, corticosteroids, and other aminosalicylates (alone or in combination with corticosteroids) for treatment of mildly to moderately active Crohn’s disease

Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of remission or response in Crohn’s disease. Cochrane Database of Systematic Reviews 2016, Issue 7. Art. No.: CD008870. DOI: 10.1002/14651858.CD008870.pub2.

Methods

• PubMed, EMBASE, MEDLINE and the Cochrane Central Library were searched from inception to June 2015

• Reference lists from potentially relevant papers and review articles, as well as proceedings from major annual meetings (1991-2015) were handsearched

• RCTs that evaluated the efficacy of sulfasalazine or mesalamine for the treatment of mildly to moderately active Crohn’s disease compared to placebo, corticosteroids, or other aminosalicylates (alone or in combination with corticosteroids) were included


Data collection and analysis

•Data extraction and assessment of methodological quality independently performed; any disagreement resolved by discussion and consensus

•Methodological quality assessed using the Cochrane risk of bias tool

•Overall quality of evidence supporting the outcomes evaluated using GRADE criteria

•Primary outcome measure: induction of remission or response to treatment; secondary outcomes: mean Crohn’s disease activity index (CDAI) scores, adverse events, serious adverse events and withdrawal due to adverse events

•Dichotomous outcomes: pooled risk ratio (RR) and 95% CI calculated using a random-effects model; continuous outcomes: mean difference (MD) and 95% CI calculated using a random-effects model

•Sensitivity analyses based on a fixed-effect model and duration of therapy conducted where appropriate


Main results

20 studies (2367 patients) were included

• 2 studies judged at high risk of bias due to lack of blinding

• 8 studies judged at high risk of bias due to incomplete outcome data (high drop-out rates) and potential selective reporting

• 10 studies were judged to be at low risk of bias


Sulfasalazine vs placebo or corticosteroids

A non-significant trend in favor of sulfasalazine over placebo for inducing remission, with benefit confined mainly to patients with Crohn’s colitis

• 45% (63/141) of sulfasalazine patients entered remission at 17-18 weeks compared to 29% (43/148) of placebo patients (RR 1.38, 95% CI 1.00 to 1.89, 2 studies)

• A GRADE analysis rated the overall quality of the evidence supporting this outcome as moderate due to sparse data (106 events)

• No difference between sulfasalazine and placebo in adverse event outcomes

Sulfasalazine was significantly less effective than corticosteroids and inferior to combination therapy with corticosteroids (RR 0.64, 95% CI 0.47 to 0.86, 1 study, 110 patients)

• 43% (55/128) of sulfasalazine patients entered remission at 17 to 18 weeks compared to 60% (79/132) of corticosteroid patients (RR 0.68, 95% CI 0.51 to 0.91; 2 studies, 260 patients)

• GRADE analysis rated overall quality of evidence supporting this outcome as moderate due to sparse data (134 events)


Sulfasalazine vs placebo

Outcome: Induction of remission (CDAI <150), therapeutic response (Van Hees Index decrease >25%) or clinical improvement


Sulfasalazine vs corticosteroids

Outcome: Induction of remission (CDAI <150)


Low-dose mesalamine

Low dose mesalamine (1-2 g/day) was not superior to placebo for induction of remission

• 23% (43/185) of low dose mesalamine patients entered remission at week 6 compared to 15% (18/117) of placebo patients (RR = 1.46, 95% CI 0.89 to 2.40; n = 302)

• A GRADE analysis indicated overall quality of evidence supporting this outcome was low due to risk of bias (incomplete outcome data) and sparse data (61 events)

• No difference between low dose mesalamine and placebo in the proportion of patients who had adverse events (RR 1.33, 95% CI 0.91 to 1.96; 3 studies, 342 patients) or withdrew due to adverse events (RR 1.21, 95% CI 0.75 to 1.95; 3 studies, 342 patients)


Controlled-release mesalamine (1-2 g/day) vs placeboOutcome: Induction of remission (CDAI <150 + decrease of >50)


High-dose mesalamine•High dose controlled-release mesalamine (4 g/day) was not superior to placebo, inducing a clinically non significant reduction in CDAI (MD -19.8 points, 95% CI -46.2 to 6.7; 3 studies, 615 patients, GRADE = low)

•High dose controlled-release mesalamine was inferior to budesonide (RR 0.56, 95% CI 0.40 to 0.78; 1 study, 182 patients, GRADE = low)

•High dose delayed-release mesalamine (3 to 4.5 g/day) was not superior to placebo for induction of remission (RR 2.02, 95% CI 0.75 to 5.45; 1 study, 38 patients, GRADE = very low)

•No significant difference in efficacy compared to conventional corticosteroids (RR 1.04, 95% CI 0.79 to 1.36; 3 studies, 178 patients, GRADE = moderate) or budesonide (RR 0.89, 95% CI 0.76 to 1.05; 1 study, 307 patients, GRADE = moderate)

• However, these trials were limited by risk of bias (incomplete outcome data) and sparse data (small numbers of events)


Controlled-release mesalamine 4 g/day vs placebo

Outcome: Mean change in CDAI from baseline


Delayed-release mesalamine 3.2 g/day vs placebo

Outcome: Induction of remission (CDAI <150 and decrease >70)


Delayed-release mesalamine 3-4.5 g/day vs corticosteroids


Outcome: Induction of remission (CDAI <150 with or without decrease of at least 60 points)

Mesalamine 4-4.5 g/day vs budesonide

Outcome: Induction of remission (CDAI <150


Oral 5-aminosalicylic acid for maintenance of medically-induced remission in CD

12 Studies (2146 participants) compared 5-ASA to placebo

• 7 studies judged to be at low risk of bias

• 5 were judged to have an unclear risk of bias

There was no statistically significant difference in relapse rates at 12 months

• 53% (526/998) of 5-ASA patients (dose 1.6 g to 4 g/day) relapsed at 12 months compared to 54% (544/1016) of placebo patients (RR 0.98, 95% CI 0.91 to 1.07; 11 studies; 2014 patients; moderate-quality evidence)

• Sensitivity analyses based on an available case analysis and a random-effects model had no impact on the results

• One study found no difference in relapse rates at 24 months. Fifty-four per cent (31/57) of 5-ASA patients (dose 2 g/day) relapsed at 24 months compared to 58%(36/62) of placebo patients (RR 0.94, 95% CI 0.68 to 1.29, 119 patients; low-quality evidence)

• One pediatric study found no statistically significant difference in relapse rates at 12 months

Akobeng AK, Zhang D, Gordon M, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD003715

5-ASA vs placebo

Akobeng AK, Zhang D, Gordon M, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD003715

Outcome: Relapse of CD

Conclusions• Sulfasalazine is only modestly effective with a trend towards benefit over placebo and is inferior to corticosteroids for the treatment of mildly to moderately active Crohn’s disease

• High dose mesalamine (3.2-4 g/day) is not more effective than placebo for inducing response or remission

• However, trials assessing the efficacy of high dose mesalamine (4 to 4.5 g/day) compared to budesonide yielded conflicting results and firm conclusions cannot be made

• Future large randomized controlled trials are needed to provide definitive evidence on the efficacy of aminosalicylates in active Crohn’s disease

• No evidence to suggest that oral 5-ASA preparations are superior to placebo for maintenance of medically-induced remission

• Additional randomized trials may not be justified

Comments

Trials performed in 1970s-1990s• No endoscopic assessments or confirmation of active disease

• No central reading

• CDAI or HBI as primary endpoints

Maintenance trials were not “randomized-responders”• Biologic trials that did not randomize responders were, similarly, negative

Why are clinicians reporting that patients are doing well on 5-ASAs? Does it work in a subgroup of patients? (e.g. superficial disease)

• Khanna et al. Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial. Lancet 386(10006):1825-34.

- Open-label cluster randomized controlled trial (NCT01030809)- Community gastroenterology practices in Belgium and Canada randomly assigned to

either early combined immunosuppression or conventional management - Up to 60 adult patients per practice with Crohn’s disease were followed for 2 years- Primary outcome: patients in corticosteroid-free remission at 12 months

• Guizzetti et al. Development of Clinical Prediction Models for Surgery and Complications in Crohn’s Disease, 2017 (under review)

-Development of prediction models for CD-related surgery, CD-related complications (first CD-related surgery, hospitalization or complication within 24 months) based on the REACT data

Slide currently unavailable

Slide currently unavailable

Strategies for detecting colon cancer in IBDDR. JAMES EAST

CONSULTANT GASTROENTEROLOGIST, UNIVERSITY OF OXFORD, OXFORD, UK

IBD surveillance guidelines= chromoendoscopy

Meta-analysis chromoendoscopy studiesSCENIC guidelines

1.8 (1.2-2.6)

Laine L et al. Gastroenterology 2015;148:639-651 Vu JX et al. Best Pract Res Clin Gastroenterol 2016;30:949-958

Chromoendoscopy in “real life”

Mooiweer E et al. Am J Gastroenterol 2015;110:1014-21

SCENIC1.8 (1.2-2.6)

Dysplasia risk by lesion morphology

>

Combined

Blonski (2008)

Goldstone (2011)

Jess (2006)

Kisiel (2012)

Medlicott (1997)

Odze (2004)

Pekow (2010)

Rozen (1995)

Rubin (1999)

Vieth (2006)

0 20 40 60 80 100CRC progress (per 1000 patient years)

Wanders LK et al. Clin Gastroenterol Hepatol 2014;12:756-64 Choi CH et al. Am J Gastroenterol 2015; 110:1461–71

Field cancerization in IBD

Choi CR et al. Nat Rev Gastroenterol Hepatol 2017;14:218-229

Participants: Patients of any age with IBD selected for CRC surveillance, based solely on the duration and extent of disease

Types of studies: RCTs, cohort and case-control studies

Intervention: Any form of CRC surveillance aimed at early detection

Primary outcome(s): Proportion of patients with a colorectal cancer diagnosis

12896 records identified

9499 records after duplicates removed

9499 records screened

9460 records excluded

39 full text articles assessed

34 records excluded with reasons

5 studies included in meta-analysis

Systematic review: Strategies for detecting colon cancer in IBD

Does colonoscopic surveillance in IBD prevent colorectal cancer?

Bye B et al. Cochrane Database of Systematic Reviews (update in progress 2017)

Outcome: Proportion of patients with CRC

Does colonoscopic surveillance in IBD prevent CRC death?


Outcome: Proportion of patients who died from CRC

Colitis-associated cancer stages


Outcome: Proportion of patients with Duke’s stage C or D

Key message

• In IBD colonoscopic surveillance reduces the risk of colorectal canceror colorectal cancer-related death by roughly half

Personalised care in IBD: the interface

between science and practice

Oxford IBD Masterclass 2017

11th -12th September

Examination Schools Oxford UK

Joining forces with Oxford Centre for Personalised Medicine

Biologic drugs for the treatment of Crohn’s disease: a network meta-analysis

DR. PIETER HINDRYCKX

DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY HOSPITAL OF GHENT, GHENT, BELGIUM; ROBARTS CLINICAL TRIALS INC, LONDON ON, CANADA

We want an agent that:

Works fast

Has a sustained effect

Has few (or even better, negligible) adverse events

Does not pose long-term risks such as serious

infections or cancer

What can we offer to the patient?

2012 BMJ Publishing Group Ltd & British Society of Gastroenterology

AGENT CLINICAL TRIALS (date of publication)

Infliximab Targan et al. (1997); ACCENT-1 (2002); SONIC (2010); Step-up Top-down (2008)

Adalimumab CLASSIC-1 (2006); CLASSIC-2 (2007); CHARM (2007); EXTEND (2012)

Certolizumab pegol Schreiber et al. (2005); PRECISE-1 (2008); PRECISE-2 (2010)

Natalizumab Ghosh et al. (2003); ENACT-1 (2005); ENACT-2 (2005); ENCORE (2007)

Vedolizumab GEMINI-2 (2013); GEMINI-3 (2014)

Ustekinumab UNITI-1 (2016); UNITI-2 (2016); IM-UNITI (2016)

What evidence do we have for decision-making?

INCLUDED STUDIES: RCTs that assess the efficacy and safety of conventional dose regimens of infliximab, adalimumab, certolizumab pegol, natalizumab, vedolizumab or ustekinumabcompared to placebo or another active treatment for induction or maintenance of remission in CD

Biologic drugs for induction and maintenance of remission in Crohn's disease: a network meta-analysis

Hindryckx et al. Cochrane Database Syst Rev. In preparation

CLINICAL RESPONSE CLINICAL REMISSION

Induction of response (CDAI-100) and remission (CDAI<150)


Vedolizumab for CD in TNF antagonist failures

Sands et al. Gastroenterology 2014

Ustekinumab for CD in TNF antagonist failures

Feagan et al. NEJM 2016

Maintenance of remission (CDAI<150)


Immunogenicity Rates of Biologic Drugs in CD

Key reference Monotherapy Combination therapy

INFLIXIMAB SONICCOMMIT

14.6%20%

0.9%4%

ADALIMUMAB DIAMOND 13.2% 4%

CERTOLIZUMAB PEGOL

PRECISE-1PRECISE-2

10%12%

4%2%

NATALIZUMAB ENACT-1ENACT-2

13%11%

3%3%

VEDOLIZUMAB GEMINI 3%* 4%*

USTEKINUMAB IM-UNITI 2.3%

*abstract only data, no separate analysis for CD

Adverse events


Serious infections

Infection risk associated with biologic drugs for CDAGENT SERIOUS INFECTIONS OPPORTUNISTIC INFECTIONS

Individual RCTs Meta-analyses Safety registries Individual RCTs Meta-analyses Safety registries

TNF ANTAGONISTS No association Possible risk increaseNo association in most recent meta-analyses (Bonovas et al. 2016; Shah et al. 2017; Wheat et al. 2017).Risk increase in largest meta-analysis in RA (RR 1.31; 95%CI 1.34-1.69)

Risk increaseENCORE (RR 1.64; 95% CI 1.17, 2.31)TREAT (RR 1.43; 95% CI 1.11, 1.84)

No association Risk increaseFord et al. 2013 (RR 2.05; 95% CI 1.10-3.85); Bonovas et al. 2016 (RR 1.90; 95%CI 1.21-3.01)

Suggestive of risk increase (TREAT), supporting data from large cohorts such as SABER (HR 1.6, 95% CI 1.0 to 2.6)

ANTI-INTEGRINS No association No association No association(limited data from the VedolizumabGlobal Safety Database)

No association No association (limited data)

No association(limited data)

USTEKINUMAB No association No association(data mainly in psoriasis)

No association(only data in psoriasis)

No association No association (data mainly in psoriasis)

No association(only data in psoriasis)

Colombel et al. Gut 2017

Risk of serious infections associated with vedolizumab for UC and CD: Data from an integrated safety analysis of six trials

Risk of serious infections associated with ustekinumab or TNF antagonists in psoriasis

Kalb et al. JAMA Dermatol. 2015

Disease activity

Concomitant use of immunosuppressives (CS!!)

Age

Comorbidity

Nutritional status

Bowel surgery

Intensity of drug exposure

Potential confounding factors for serious infection in CD that may determine the infection risk for biologic drugs

Hindryckx et al. Clin pharmacol Ther, in preparation

Risk of Malignancy with TNF Antagonists in CD

Reference Agent Type of study Monotherapy Combination therapy

Long et al. 2012 TNF ANTAGONISTS

Retrospective cohort and nested case-control studies

NMSC: no associationMelanoma: possible association (2-fold risk)

NMSC: 4-fold risk

Osterman et al. gastroenterology 2014)

ADALIMUMAB Pooled analysis of 6 clinical trials

No increased risk 5-fold risk of NMSC3-fold risk of other malignancies8-fold risk of lymphoma

Chen et al. 2016 TNF ANTAGONISTS

Overview of systematic reviews and meta-analyses

Only one of the meta-analyses in CD has found an association with riskof lymphoma (SIR, 3.23; 95%CI 1.5–6.9)

No separate analysis

Conclusions

TNF antagonists Anti-integrins Ustekinumab

Works fast (within 6 weeks)

+ + (in biologic-naïvepatient)

+

Has a sustainedeffect

+ + (3-year data)1 + (2-year data)2

Has few adverse events

+ + +

Does not pose long-term risks

(infections, cancer)

+/- (monotherapy <> combination therapy)

? ?

1Vermeire et al. J Crohns Colitis 20172Sandborn et al. ECCO 2017

Withdrawal of drug therapy in patients with quiescent Crohn’s disease

DR. JEAN-FRÉDÉRIC COLOMBEL

DIRECTOR OF THE IBD CENTER, ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, USA

Withdrawal of drug therapy (IS and biologics) in CD

• The feasibility of de-escalation of therapy once remission is achieved is a common question encountered in clinical practice, driven by patient and clinician concerns around safety, adverse events, cost and national regulations

• Withdrawal of immunosuppressive and biologic drugs in patients with quiescent CD could limit adverse events and reduce healthcare costs

• Alternatively, ceasing these drug therapies may result in negative outcomes such as disease relapse, drug desensitization, bowel damage and need for surgery

What are the consequences of stopping a drug (IS or biologics) once remission is

achieved?

Stopping therapy: possible scenarios

Monotherapy

Stop IS

Stop Anti-TNF-α

Combination therapy

Stop IS

Stop Anti-TNF-α

Boyapati R, Torres J, Palmela C, Parker CE, Silverberg OM, Upadhyaya SD, Khanna R, Jairath V, Feagan BG, Colombel JF. Withdrawal of drug therapy for patients with quiescent Crohn's disease (Protocol). Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD012540. DOI: 10.1002/14651858.CD012540.

Cochrane Review: Withdrawal of drug therapy for patients with quiescent Crohn's disease

Inclusion criteria

• Adults (age >18 years) with CD who achieved remission (as defined by the study) while receiving immunosuppressive or biologic drugs administered alone or in combination

• Minimum duration of six months after drug discontinuation

• Received a minimum treatment duration of 6 months

Types of studies

• Randomized controlled trials (RCTs)

• Controlled clinical trials

• Prospective cohort studies

Primary outcome

• Proportion of patients who relapse following discontinuation of immunosuppressive or biologic drugs, administered alone or in combination

• The comparison was usual care (continuing therapy)


9103 records identified

5414 records after duplicates removed

5414 records screened

5341 records excluded

73 full text articles assessed

68 records excluded with reasons

PRISMA flow diagram

5 studies included in meta-analysis


Stopping Immunossupressives(monotherapy)

Immunosuppressive withdrawal after monotherapy vs usual care

Relapse at 12-24 months

Adverse Events


Stopping Immunossupressives(combination therapy)

Immunosuppressive withdrawal after combination therapy vs usual care

Relapse at 24 months

Adverse Events


Stopping biologics

Stopping biologics in CD

• There are no prospective controlled studies or randomized controlled studies on stopping biologics in CD

• There are no studies specifically assessing anti-TNF-α withdrawal after a period of monotherapy (variable rates of combination therapy among studies)

STORI: Infliximab diSconTinuation in Crohn's disease patients in stable Remission on combined therapy

Prospective, multicentre cohort study in 20 centres

N=115 CD patients in remission on IFX and AZA, 6-MP or MTX ◦ At least 1 year on IFX/AZA and ≥6 months steroid-free remission

IFX stopped and patients followed every 2 months for ≥1 year(median: 28 months)

Primary endpoint: time to relapse after withdrawal of IFX

Louis E, et al. Gastroenterology 2012;142:63–70

Time to relapse after IFX withdrawal (STORI trial)

Louis E, et al. Gastroenterology 2012;142:63–70.

Number at risk:

1

0

Pro

po

rtio

n w

ith

ou

t re

lap

se

0

Months since infliximab withdrawn

115

0.2

0.4

0.6

0.8 43.9% of patientsrelapsed after 1 year 52.2% of patients

relapsed over 2 years

3

100

6

79

9

59

12

49

15

47

18

38

21

32

24

32

27

29

30

15

33

Long-term outcomes after infliximab withdrawal in CDMedian follow up 7 years of the STORI cohort (n=102)

Reenaers C, et al. Presented at DDW. May 2016

Cumulative incidence of starting or restarting a biologic• Cumulative incidence of anti-TNF resumption: 34.3(±9.3)%, 56.0(±9.7)%

and 64.4(±9.5)% respectively 1, 3 and 5 years after IFX withdrawal• 29.0% (95%CI: 20.7-39.6) of the patients were still without biologic

treatment 7 years after IFX withdrawal

Time-to-major complication• 18/102 experienced a severe failure after a median

follow-up of 83.3 months (IQR: 71.1-92.9)• 18.5% (95%CI: 10.2-26.8) major complications 7 years

after IFX withdrawal

Time since infliximab withdrawal (month)

Su

rviv

al w

itho

ut s

eve

re fa

ilure

0 12 24 36 48 60 72 84 96

0.0

0.2

0.4

0.6

0.8

1.0

# at risk 102 100 95 92 83 73 65 40 10

Stopping anti-TNF-α agents in CD:qualitative data – prospective studies

Type of remission Relapse rates at 6 months

(%, average)

Relapse rates at 12 months

(%, average)

Relapse rates at 24 months

(%, average)

Clinical 19.9% 36% 46.4%

Deep 16.7% 31.7% 49.2%

Deep: Clinical remission and endoscopic or radiological or analytical (CRP and/or FC)

FACTORS PREDICTIVE OF RELAPSE

Reflective of disease activity at de-escalation or during follow-up

Elevated inflammatory markers (leucocyte count, CRP, FC) Laboratorial markers suggestive of ongoing inflammation (low hemoglobin) Absence of mucosal healing

Factors reflective of disease poor prognostic features

Smoking Perianal disease Disease location (Ileocolonic disease; colonic vs ileal or ileocolonic disease, extensive colitis

vs limited) Young age at diagnosis

Previous disease course

Prior disease course marked by higher therapeutic requirements (higher steroid use, prior anti-TNF-α course, need for dose-escalation prior to discontinuation, prior immunosuppressive failure )

Other

Male sex (HR 3.7 [1.9-7.4]) Elevated/detectable IFX trough levels

Torres J, Boypati R. et al. Gastroenterology 2015

Conclusions

•Withdrawal of thiopurines in patients with CD in clinical remission is associated with a higher chance of relapse but a potentially lower chance of adverse events

•There is no difference in relapses rates for patients on combination therapy that stop or continue IS

• No studies have assessed anti-TNF-α discontinuation in CD patients in remission in a controlled way

•Data from uncontrolled studies on anti-TNF-α withdrawal suggest that roughly 50% of patients will relapse after 2 year follow-up

The ‘Biocycle’ project Ongoing study

CCFA

Antimetabolites

Anti-TNF-αArm Acontrol

Antimetabolites

New treatment cycle if neededArm B

Anti-TNF-α withdrawal

New treatment cycle if needed

Anti-TNF-αArm C

Antimetabolites withdrawal

Antimetabolites

Anti-TNF-αCombotherapy

Documents

Controversies in IBD: Resolving clinical ... - Cochrane › sites › ibd.cochrane.org › ... · •Sensitivity analyses based on a ﬁxed-effect model and duration of therapy conducted