Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn's disease

Ray K Boyapati; Joana Torres; Carolina Palmela; Claire E Parker; Orli M Silverberg; Sonam D Upadhyaya; Tran M Nguyen; Jean‐Frédéric Colombel

doi:10.1002/14651858.CD012540.pub2

Absetzen von Immunsuppressiva oder der biologischen Therapie bei Patienten mit ruhendem Morbus Crohn

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Referencias

References to studies included in this review

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References to studies excluded from this review

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References to ongoing studies

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otras referencias

NCT01817426. Discontinuation of infliximab therapy in patients with CD during sustained complete remission (STOP IT). clinicaltrials.gov/ct2/show/NCT01817426 (accessed 1 February 2018).

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Lémann 2005

Methods	Randomized, double‐blind, multi‐centre, placebo controlled withdrawal trial (N = 83) 11 sites in France, 1 site in Belgium
Participants	Adults (> 18 years) with CD as diagnosed by established clinical, endoscopic, radiological and histological criteria who had received continuous azathioprine therapy for > 42 months Patients were ineligible if they had: a) experienced a flare‐up while receiving azathioprine; b) had active disease at entry (CDAI score > 150); c) had isolated perianal disease; or d) were treated with azathioprine for the prevention of post‐operative recurrence
Interventions	1:1 randomization ratio Group 1: oral azathioprine once daily at the dose taken prior to study enrolment (n = 40) Group 2: placebo (n = 43) Follow‐up duration: 18 months
Outcomes	Primary outcome: proportion of patients with relapse (defined as CDAI score > 250, a CDAI score 150‐250 on 3 consecutive weeks with an increase of > 75 points from baseline, or the need for surgery) over the 18 month study period
Notes	The definition of relapse was chosen to eliminate small/transient increases of the CDAI score, which could be attributable to a cause other than relapse such as irritable bowel syndrome
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomization using permutation tables of 2 or 4
Allocation concealment (selection bias)	Unclear risk	Not adequately described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The placebo and azathioprine were identical in appearance and taste
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Patients filled out diary cards Biological test results were reviewed by co‐investigators who had no patient contact and recorded results in a separate case report form The endoscopists calculated the CDEIS (it is unclear, but assumed that they were blinded to clinical information)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Drop‐outs were balanced across treatment groups 37/40 in the azathioprine group completed the study compared to 40/43 in the placebo group
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Low risk	The study appears to be free from other sources of bias

O'Donoghue 1978

Methods	Randmized, double‐blind, placebo‐controlled withdrawal trial of azathioprine in CD (N = 51)
Participants	Adults (>18 years) with CD as diagnosed by established criteria who were on azathioprine for > 6 months and had been in clinical remission for > 6 months
Interventions	Group 1: oral azathioprine at the dose taken prior to study enrolment (n = 27) Group 2: placebo (n = 24) Duration of follow‐up: 12 months
Outcomes	Primary outcome: proportion of patients with relapse (defined as a significant deterioration in clinical state requiring change in treatment as judged by two doctors unaware of the patient's treatment) over the 12 month study period
Notes	This represents the first withdrawal trial of azathioprine monotherapy in CD
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study only states the groups were randomly divided, no information on how this was performed
Allocation concealment (selection bias)	Unclear risk	Not adequately described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind trial with control tablets utilized
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not adequately described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Drop‐outs were balanced across treatment groups 21/24 in the azathioprine group completed the study compared to 25/27 in the placebo group
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Low risk	This study appears to be free from other sources of bias

Roblin 2017

Methods	Randomized open‐label trial (N = 81: UC N = 36; CD N = 45)
Participants	Patients with IBD (UC and CD) in deep remission for at least 6 months who were treated with combination therapy (infliximab and azathioprine) for at least one year
Interventions	Cohort A: azathioprine and infliximab continued (usual care) (UC n = 12; CD n = 16) Cohort B: azathioprine dose halved (UC n = 13; CD n = 14) Cohort C: azathioprine stopped (infliximab continued as monotherapy) (UC = 11; CD n = 15)
Outcomes	Primary: clinical relapse (CDAI score > 220 with a delta CDAI > 70 from the previous assessment and/or need to change the original therapeutic regimen because of adverse events or drug intolerance Secondary: infliximab trough levels and anti‐drug antibodies
Notes	Authors were contacted, and they provided information regarding CD‐specific results Patients with CD from cohorts A and C (n = 31) were included in this review
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomised into three parallel groups with randomisation balanced by blocks"
Allocation concealment (selection bias)	Low risk	"The randomisation was not stratified and was centrally performed by an interactive web response system (IWRS)"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label
Incomplete outcome data (attrition bias) All outcomes	Low risk	Drop‐outs were balanced across treatment groups 13/16 in the combination therapy group completed the study compared to 10/15 in the group where azathioprine was stopped
Selective reporting (reporting bias)	Low risk	All primary and secondary outcomes reported CD and UC data not reported separately, however authors supplied this information upon request
Other bias	Unclear risk	Premature stopping of the trial due to slow enrolment

Van Assche 2008

Methods	Randmized, open‐label controlled trial (N = 80)
Participants	Patients (> 16 years) with luminal CD on a combination regimen consisting of infliximab 5 mg/kg IV and an immunosuppressant (azathioprine/6‐mercaptopurine or methotrexate) for at least 6 months Patients must have had full disease control at entry
Interventions	1:1 randomization ratio Group 1: azathioprine and infliximab continued (n = 40) Group 2: placebo with only infliximab continued (n = 40) Duration of follow‐up: 104 weeks
Outcomes	Primary outcome: the proportion of patients who required a change in the dosing interval or completely stopped infliximab therapy due to disease flare (i.e. clinical relapse) Secondary outcomes: infliximab trough levels, adverse events and mucosal healing
Notes	This study was not powered as a non‐inferiority trial; continuation therapy was assumed to be superior. To study non‐inferiority, > 250 patients per treatment arm would be required.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not adequately described (no explicit statement about the method used)
Allocation concealment (selection bias)	Low risk	Centralized randomization was performed
Blinding of participants and personnel (performance bias) All outcomes	High risk	Due to the open‐label design no placebo was given
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcome assessment was not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Drop‐outs were balanced across treatment groups 29/40 in the combination therapy group completed the study compared to 31/40 in the group where azathioprine was stopped
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	This study appears to be free from other sources of bias

Vilien 2004

Methods	Randomized, open‐label, controlled trial (N = 29)
Participants	Patients with quiescent CD who had received a continuous dose of azathioprine for at least 2 years
Interventions	Group 1: azathioprine withdrawal (n = 15) Group 2: continued azathioprine treatment at an unchanged dose (n = 14)
Outcomes	Primary outcome: clinical relapse (defined as a rise in CDAI > 75 with a total CDAI > 150; or, any increased disease activity requiring new medical or surgical treatment) Follow‐up duration was 12 months
Notes	Randomization took place after stratification by azathioprine dose High azathioprine dose was defined as > 1.60 mg/kg/day Low azathioprine dose was defined as < 1.60 mg/kg/day
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated 1:1 randomization
Allocation concealment (selection bias)	Low risk	Randomization was performed centrally
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label trial; participants and personnel not blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of outcome assessment
Incomplete outcome data (attrition bias) All outcomes	Low risk	There was only one drop‐out (in the azathioprine group)
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Low risk	This study appears to be free from other sources of bias

Wenzl 2015

Methods	Randmized, double‐blind, placebo‐controlled withdrawal trial (N = 52)
Participants	CD patients in stable clinical remission (CDAI < 150) on azathioprine for > 4 years
Interventions	1:1 randomization ratio Group 1: placebo (n = 26) Group 2: azathioprine at dose prior to study entry (n = 26) Follow‐up duration: 24 months
Outcomes	Primary outcome: Time interval between first intake of the study drug and disease relapse Secondary outcomes: Disease activity (CDAI), quality of life, and laboratory parameters associated with active disease (CRP, serum hemoglobin, serum albumin, and platelet count)
Notes	Slow recruitment led to premature cessation of the study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization tables were used according to a 1:1 ratio
Allocation concealment (selection bias)	Low risk	Centralized randomization was performed
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind: medicine was provided in identical‐appearing tablets
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not adequately described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Drop‐outs were balanced across treatment groups 19/26 in the azathioprine group completed the study compared to 23/26 in the placebo group
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported
Other bias	Unclear risk	Premature stopping of the trial due to slow enrolment.

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos
estudios en curso

Study	Reason for exclusion
Amiot 2016	Reduced dose (not withdrawal) of therapy
Begun 2016	Case report
Benitez 2015	Letter (not study)
Bodini 2015	No control (usual care)
Bortlik 2015a	No control (usual care)
Bortlik 2015b	No control (usual care)
Bortlik 2016	No control (usual care)
Bots 2016a	No control (usual care)
Bots 2016b	No control (usual care)
Bouhnik 1996	Retrospective study
Brooks 2017	No control (usual care)
Chaparro 2015	Letter (not study)
Chauvin 2014	Retrospective study
Chen 2015a	No control (usual care)
Chen 2015b	No control (usual care)
Cortes 2016	No control (usual care)
Crombe 2010a	Pediatric study
Crombe 2010b	Pediatric study
Crombe 2011	Pediatric study
Dai 2014	No control (usual care)
de Lima 2016	CD specific data unavailable
De Suray 2012a	No control (usual care)
De Suray 2012b	No control (usual care)
Domenech 2005	Retrospective study
Duricová 2015	No control (usual care)
Echarri 2013	No control (usual care)
Farkas 2014	No control (usual care)
Feagan 2015a	< 6 months of treatment prior to withdrawal
Feagan 2015b	< 6 months of treatment prior to withdrawal
Fischer 2014	Retrospective study
Gallego 2015	Retrospective study
Grossi 2015a	No control (usual care)
Grossi 2015b	Pediatric study
Helwig 2016	No control (usual care)
Helwig 2017	Review article
Hlavaty 2016b	Retrospective study
Iborra 2016a	Retrospective study
Iborra 2016b	Retrospective study
Iimuro 2011	Retrospective study
Kang 2016	Pediatric study
Kennedy 2016	Retrospective study
Kierkus 2015	Pediatric study
Kim 1999	Retrospective study
Louis 2012	No control (usual care) In the STORI trial (N =115), infliximab was withdrawn from patients with quiescent CD who were receiving combination therapy (infliximab and an immunosuppressant). After 2 years of follow up, approximately 50% of patients relapsed.
Molander 2014	No control (usual care)
Molander 2015	No control (usual care)
Molander 2016	No control (usual care)
Molnar 2013	No control (usual care)
Monterubbianesi 2015	Retrospective study
Monterubbianesi 2016a	Retrospective study
Monterubbianesi 2016b	Retrospective study
Nuti 2010a	Pediatric study
Nuti 2010b	Pediatric study
Paul 2015	Reduced dose (not withdrawal) of therapy
Qiu 2015a	No control (usual care)
Qiu 2015b	No control (usual care)
Rismo 2013	< 6 months of treatment prior to withdrawal
Schnitzler 2009	No control (usual care)
Seirafi 2011a	No control (usual care)
Seirafi 2011b	No control (usual care)
Squires 2015	No control (usual care)
Thomsen 2015	No control (usual care)
Treton 2009	No control (usual care)
Waugh 2010a	Retrospective study
Waugh 2010b	Retrospective study
Wynands 2008	Pediatric study
Zelinkova 2013	No control (usual care)

Characteristics of ongoing studies [ordered by study ID]

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estudios incluidos
estudios excluidos

NCT01817426

Trial name or title	Discontinuation of infliximab therapy in patients With CD during sustained complete remission (STOP IT)
Methods	Prospective, double‐blind, 2‐arm RCT Intervention Model: Parallel Assignment Masking: Triple (Participant, Care Provider, Investigator) Primary Purpose: Treatment
Participants	Patients with luminal Crohn's disease in sustained complete remission on infliximab
Interventions	Arm 1: infliximab at an unchanged dose Arm 2: placebo
Outcomes	Primary outcome: proportion of patients who maintain remission (CDAI < 150)
Starting date	Start date: November 2012 Estimated end date: November 2016
Contact information	Sine Schnoor Buhl MD, [email protected] Mark Ainsworth MD PhD DMSc, [email protected]
Notes	NCT01817426 The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.

NCT02177071

Trial name or title	A prospective randomized controlled trial comparing infliximab‐antimetabolites combination therapy to antimetabolites monotherapy and infliximab monotherapy in Crohn's disease patients in sustained steroid‐free remission on combination therapy (SPARE)
Methods	Prospective, open‐label, three‐arm RCT
Participants	Patients with luminal CD in steroid‐free remission for at least 6 months who have received combination therapy with infliximab and anti‐metabolites for at least 1 year N = 300 (100 per arm)
Interventions	Study treatment: Infliximab; 6‐mercaptopurine, azathioprine or methotrexate Arm 1: combination therapy with infliximab and anti‐metabolite continued Arm 2: discontinue infliximab, continue anti‐metabolite Arm 3: discontinue anti‐metabolite, continue infliximab
Outcomes	Co‐primary outcome: clinical relapse rate at 2 years; mean remission duration within 2 years
Starting date	Study duration: 2 + 2 years Enrollment: 2 years + 1 year Follow‐up: 2 years Start date: October 2015 Estimated end date: January 2020
Contact information	Edouard Louis PhD, [email protected]
Notes	NCT02177071

Data and analyses

Open in table viewer

Comparison 1. Usual care versus immunosuppressive withdrawal after monotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse at 12, 18 or 24 months Show forest plot	4	215	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.24, 0.72]
Open in figure viewer Analysis 1.1 Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 1 Relapse at 12, 18 or 24 months.
2 New CD‐related complications Show forest plot	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.06, 2.08]
Open in figure viewer Analysis 1.2 Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 2 New CD‐related complications.
3 Adverse events Show forest plot	3	186	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.67, 1.17]
Open in figure viewer Analysis 1.3 Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 3 Adverse events.
4 Serious adverse events Show forest plot	2	134	Risk Ratio (M‐H, Random, 95% CI)	3.29 [0.35, 30.80]
Open in figure viewer Analysis 1.4 Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 4 Serious adverse events.
5 Withdrawal due to adverse events Show forest plot	2	135	Risk Ratio (M‐H, Random, 95% CI)	2.59 [0.35, 19.04]
Open in figure viewer Analysis 1.5 Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 5 Withdrawal due to adverse events.

Open in table viewer

Comparison 2. Usual care versus immunosuppressive withdrawal after combination therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse at 12 or 24 months Show forest plot	2	111	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.68, 1.52]
Open in figure viewer Analysis 2.1 Comparison 2 Usual care versus immunosuppressive withdrawal after combination therapy, Outcome 1 Relapse at 12 or 24 months.
2 Adverse events Show forest plot	2	111	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.44, 2.81]
Open in figure viewer Analysis 2.2 Comparison 2 Usual care versus immunosuppressive withdrawal after combination therapy, Outcome 2 Adverse events.
3 Serious adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.3 Comparison 2 Usual care versus immunosuppressive withdrawal after combination therapy, Outcome 3 Serious adverse events.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 1 Relapse at 12, 18 or 24 months.

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Analysis 1.2

Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 2 New CD‐related complications.

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Analysis 1.3

Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 3 Adverse events.

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Analysis 1.4

Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 4 Serious adverse events.

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Analysis 1.5

Comparison 1 Usual care versus immunosuppressive withdrawal after monotherapy, Outcome 5 Withdrawal due to adverse events.

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Analysis 2.1

Comparison 2 Usual care versus immunosuppressive withdrawal after combination therapy, Outcome 1 Relapse at 12 or 24 months.

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Analysis 2.2

Comparison 2 Usual care versus immunosuppressive withdrawal after combination therapy, Outcome 2 Adverse events.

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Analysis 2.3

Comparison 2 Usual care versus immunosuppressive withdrawal after combination therapy, Outcome 3 Serious adverse events.

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Summary of findings for the main comparison. Usual care compared to immunosuppressive withdrawal after monotherapy for patients with quiescent Crohn's disease

Usual care compared to immunosuppressive withdrawal after monotherapy for patients with quiescent Crohn's disease
Patient or population: Patients with quiescent Crohn's disease Setting: Outpatient Intervention: Usual care Comparison: Immunosuppressive withdrawal after monotherapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with immunosuppressive withdrawal after monotherapy	Risk with usual care
Relapse at 12, 18 or 24 months	Study population		RR 0.42 (0.24 to 0.72)	215 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	Sparse data (50 events)
	324 per 1,000	136 per 1,000 (78 to 234)
New CD‐related complications	Study population		RR 0.34 (0.06 to 2.08)	135 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{3 4}	Very sparse data (5 events)
	58 per 1,000	20 per 1,000 (3 to 121)
Adverse events	Study population		RR 0.88 (0.67 to 1.17)	186 (3 RCTs)	⊕⊕⊝⊝ LOW ^{2 5}	Sparse data (45 events)
	240 per 1,000	211 per 1,000 (161 to 280)
Serious adverse events	Study population		RR 3.29 (0.35 to 30.80)	134 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{3 4}	Very sparse data (2 events)
	0 per 1,000	0 per 1,000 (0 to 0)
Withdrawal due to adverse events	Study population		RR 2.59 (0.35 to 19.04)	135 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{3 4}	Very sparse data (5 events)
	14 per 1,000	38 per 1,000 (5 to 276)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded one level due to high risk of bias for blinding in one study and unclear risk of bias in three studies in the pooled analysis ² Downgraded one level due to sparse data ³ Downgraded one level due to unclear risk of bias in the two studies in the pooled analysis ⁴ Downgraded two levels due to very sparse data ⁵ Downgraded one level due to unclear risk of bias in the three studies in the pooled analysis

Summary of findings for the main comparison. Usual care compared to immunosuppressive withdrawal after monotherapy for patients with quiescent Crohn's disease

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Summary of findings 2. Usual care compared to immunosuppressive withdrawal after combination therapy for patients with quiescent Crohn's disease

Usual care compared to immunosuppressive withdrawal after combination therapy for patients with quiescent Crohn's disease
Patient or population: Patients with quiescent Crohn's disease Setting: Outpatient Intervention: Usual care Comparison: Immunosuppressive withdrawal after combination therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with immunosuppressive withdrawal after combination therapy	Risk with usual care
Relapse at 12 or 24 months	Study population		RR 1.02 (0.68 to 1.52)	111 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	Sparse data (54 events)
	491 per 1,000	501 per 1,000 (334 to 746)
Adverse events	Study population		RR 1.11 (0.44 to 2.81)	111 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	Sparse data (51 events)
	455 per 1,000	505 per 1,000 (200 to 1,000)
Serious adverse events	Study population		RR 1.00 (0.21 to 4.66)	80 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 3}	Very sparse data (6 events)
	75 per 1,000	75 per 1,000 (16 to 350)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded one level due to high risk of bias for blinding ² Downgraded one level due to sparse data ³ Downgraded two levels due to very sparse data

Summary of findings 2. Usual care compared to immunosuppressive withdrawal after combination therapy for patients with quiescent Crohn's disease

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Table 1. Sensitivity analysis: random effects vs fixed effect modelling

Comparison 1: Usual care versus immunosuppressive withdrawal after monotherapy
Outcome	Random Effects RR (95% CI)	Fixed Effect RR (95% CI)	Impact
1.1 Relapse at 12, 18 or 24 months	0.42 (0.24‐0.72)	0.42 (0.24‐0.72)	No change
1.2 New CD‐related complications	0.34 (0.06‐2.08)	0.34 (0.06‐2.08)	No change
1.3 Adverse events	0.88 (0.67‐1.17)	0.97 (0.71‐1.32)	Minimal
1.4 Serious adverse events	3.29 (0.35‐30.80)	3.29 (0.35‐30.80)	No change
1.5 Withdrawal due to adverse events	2.59 (0.35‐19.04)	3.10 (0.49‐19.41)	Minimal
Comparison 2: Usual care versus Immunosuppressive withdrawal after combination therapy
Outcome	Random Effects RR (95% CI)	Fixed Effect RR (95% CI)
2.1 Relapse at 12 or 24 months	1.02 (0.68‐1.52)	0.99 (0.69‐1.43)	Minimal
2.2 Adverse events	1.11 (0.44‐2.81)	1.04 (0.73‐1.47)	Minimal
2.3 Serious adverse events	No pooling	No pooling	No pooling

Table 1. Sensitivity analysis: random effects vs fixed effect modelling

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Table 2. Definition of remission by study

Study	Length of remission prior to drug withdrawal	Definition of remission prior to drug withdrawal
Roblin 2017	Minimum 6 months	CDAI ≤ 150 and fecal calprotectin levels < 250 μg/g
Lémann 2005	Mean 62 months (standard deviation 26 months); Minimum 42 months	Clinical remission (CDAI ≤ 150) and no need for medical/surgical therapy in the previous 42 months
O'Donoghue 1978	Minimum 6 months	Clinical remission not otherwise specified
Van Assche 2008	Minimum 6 months	Clinical response to infliximab and disease control
Vilien 2004	Not specified	Clinical remission: physician's global assessment
Wenzl 2015	Minimum 12 months	Clinical remission, no need for new medical therapy in the previous 12 months

Table 2. Definition of remission by study

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Comparison 1. Usual care versus immunosuppressive withdrawal after monotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse at 12, 18 or 24 months Show forest plot	4	215	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.24, 0.72]

2 New CD‐related complications Show forest plot	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.06, 2.08]

3 Adverse events Show forest plot	3	186	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.67, 1.17]

4 Serious adverse events Show forest plot	2	134	Risk Ratio (M‐H, Random, 95% CI)	3.29 [0.35, 30.80]

5 Withdrawal due to adverse events Show forest plot	2	135	Risk Ratio (M‐H, Random, 95% CI)	2.59 [0.35, 19.04]

Comparison 1. Usual care versus immunosuppressive withdrawal after monotherapy

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Comparison 2. Usual care versus immunosuppressive withdrawal after combination therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse at 12 or 24 months Show forest plot	2	111	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.68, 1.52]

2 Adverse events Show forest plot	2	111	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.44, 2.81]

3 Serious adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 2. Usual care versus immunosuppressive withdrawal after combination therapy

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Referencias

References to studies included in this review

Lémann 2005 {published data only}

O'Donoghue 1978 {published data only}

Roblin 2017 {published data only}

Van Assche 2008 {published data only}

Vilien 2004 {published data only}

Wenzl 2015 {published data only}

References to studies excluded from this review

Amiot 2016 {published data only}

Begun 2016 {published data only}

Benitez 2015 {published data only}

Bodini 2015 {published data only}

Bortlik 2015a {published data only}

Bortlik 2015b {published data only}

Bortlik 2016 {published data only}

Bots 2016a {published data only}

Bots 2016b {published data only}

Bouhnik 1996 {published data only}

Brooks 2017 {published data only}

Chaparro 2015 {published data only}

Chauvin 2014 {published data only}

Chen 2015a {published data only}

Chen 2015b {published data only}

Cortes 2016 {published data only}

Crombe 2010a {published data only}

Crombe 2010b {published data only}

Crombe 2011 {published data only}

Dai 2014 {published data only}

de Lima 2016 {published data only}

De Suray 2012a {published data only}

De Suray 2012b {published data only}

Domenech 2005 {published data only}

Duricová 2015 {published data only}

Echarri 2013 {published data only}

Farkas 2014 {published data only}

Feagan 2015a {published data only}

Feagan 2015b {published data only}

Fischer 2014 {published data only}

Gallego 2015 {published data only}

Grossi 2015a {published data only}

Grossi 2015b {published data only}

Helwig 2016 {published data only}

Helwig 2017 {published data only}

Hlavaty 2016b {published data only}

Iborra 2016a {published data only}

Iborra 2016b {published data only}

Iimuro 2011 {published data only}

Kang 2016 {published data only}

Kennedy 2016 {published data only}

Kierkus 2015 {published data only}

Kim 1999 {published data only}

Louis 2012 {published data only}

Molander 2014 {published data only}

Molander 2015 {published data only}

Molander 2016 {published data only}

Molnar 2013 {published data only}

Monterubbianesi 2015 {published data only}

Monterubbianesi 2016a {published data only}

Monterubbianesi 2016b {published data only}

Nuti 2010a {published data only}

Nuti 2010b {published data only}

Paul 2015 {published data only}

Qiu 2015a {published data only}

Qiu 2015b {published data only}

Rismo 2013 {published data only}

Schnitzler 2009 {published data only}

Seirafi 2011a {published data only}

Seirafi 2011b {published data only}

Squires 2015 {published data only}

Thomsen 2015 {published data only}

Treton 2009 {published data only}

Waugh 2010a {published data only}

Waugh 2010b {published data only}

Wynands 2008 {published data only}

Zelinkova 2013 {published data only}

References to ongoing studies

NCT01817426 {published data only}