Mucosal healing in inflammatory bowel disease: Maintain or de-escalate therapy

Table 1 Studies concerning the achievement of mucosal healing

Ref.	Design	No. of patients	Drugs (dose)	Time of endoscopy	Endoscopic index	Definition of MH	Results
5-ASA
Vecchi et al[43]	RCT, mc	130 UC	5-ASA 4 g p.o. vs 2 + 2 g and enema	6 wk	Rachmilewitz	< 4	58% vs 71%
Mansfield et al[44]	RCT, db, mc	50 UC	Balsalazide 6.75 g vs SASP 3 g	8 wk	4 point score	Score 0	27% vs 25%
Kruis et al[45]	RCT, db, mc	321 UC	5-ASA 0.5 g × 3 vs 1 g × 3 vs 1.5 g × 3	8 wk	Rachmilewitz	Histology improvement	53% vs 84% vs 70%
Hanauer et al[47]	RCT, db, mc	391 UC	Asacol 4.8 g vs 2.4 g	6 wk	No score	Normal endoscopy	84% vs 67% (in moderate UC)
ASCEND 1 and 2
Kamm et al[48]	RCT, db, mc	343 UC	Mesalamine MMX 4.8 g vs 2.4 g vs plc	8 wk	Mod. Sutherland index	< 1	77% vs 69% vs 46%
MMX
Kruis et al[46]	RCT, db, mc	380 UC	5-ASA 3 g vs 1 g × 3	8 wk	Rachmilewitz	< 4	71% vs 70%
Steroids
Ardizzone et al[49]	RA, sc	157 UC	Systemic steroids 40-60 mg	3 mo	Mod. Baron score	Score 0	38%
Sandborn et al[50]	RTC, db, mc	672 UC	Budesonide MMX 9 mg vs 6 mg vs plc	8 wk	UCDAI mucosal appearance	0	27% vs 16% vs 17%
CORE
Van Assche et al[51]	RTC, db, mc	282 UC	BDP 5 mg/d vs PD 40 mg/d (tap.)	4 wk	DAI subscore	0	23% vs 21%
Immunomodulators
D’Haens et al[60]	PA, sc	15 CD	AZA 2 mg/kg	26 wk	Rutgeerts score	Ri 0	40%
Ardizzone et al[52]	RCT, sc	72 UC	5-ASA vs AZA	3 mo and 6 mo	Baron score	Improving mean Baron index	At 3 mo: 2.3 vs 1.1
							at 6 mo: 2.2. vs 0.9
Mantzaris et al[61]	RCT, sc	57 CD	AZA 2-2.5 mg/kg vs budesonide 6-9 mg	52 wk	CDEIS	CDEIS < 4	83% vs 24%
Laharie et al[62]	RTC, sc	51 CD	MTX 15-25 mg/wk vs AZA 2-3 mg/kg vs IFX 5 mg/kg		CDEIS	CDEIS < 4	11% vs 50% vs 60%
Rispo et al[53]	PA, sc	104 UC	AZA or 6-MP	104 wk	Mayo	Mayo 0-1	36%
Biologics
Colombel et al[63]	RCT, db, mc	508 CD	AZA 2.5 mg/kg vs IFX 5 mg/kg vs AZA 2.5 mg/kg + IFX 5 mg/kg	26 wk	No score	Absence of ulcers	16% vs 30% vs 44%
SONIC
Reinisch et al[54]	RCT, db, mc	390 UC	ADA 160/80/40 mg vs 80/40 mg vs plc	8 wk	Mayo	Mayo 0-1	47% vs 37% vs 41%
ULTRA 1
Sandborn et al[55]	RCT, db, mc	518 UC	ADA 160/80/40 mg vs plc	8 wk and 52 wk	Mayo	Mayo 0-1	18% vs 10% (Sustained MH)
ULTRA 2
Rutgeerts et al[64]	RCT, db, mc	135 CD	ADA only induction (plc in maintenance) vs ADA continuous	12 wk and 52 wk	CDEIS	CDEIS 0	Baseline CDEIS ≤ 9: Continuous at 12 wk 40%, at 52 wk 30%.
EXTEND
							Baseline CDEIS < 9: Continuous at 12 wks 16% at 52 wk 19%
Laharie et al[58]	RA, mc	63 UC	IFX 5 mg/kg	6-52 wk	Mayo	Mayo 0-1	48%
Feagan et al[56]	RCT, db, mc	746 UC	Vedolizumab every 8 wk vs Vedolizumab every 4 wk vs plc	6 wk and 52 wk	Mayo	Mayo 0-1	6 wk: VDZ 41% vs placebo 24%;
GEMINI							52 wk: 56% vs 51% vs 20%
Sandborn et al[59]	RCT, db, mc	774 UC	Golimumab 400/200 mg vs 200/100 mg vs plc	6 wk	Mayo	Mayo 0-1	17.9% vs 17.8% vs 6.4%
PURSUIT

RCT: Randomized controlled trial; MH: Mucosal healing; 5-ASA: 5-aminosalicylic acid; mc: Multicenter; db: Double-blind; sc: Single-centre; RA: Retrospective analysis; AZA: Azathioprine; CDEIS: Crohn’s Disease Endoscopic Index of Severity; UC: Ulcerative colitis; CD: Crohn’s disease; MMX: Multi Matrix System; IFX: Infliximab; MTX: Methotrexate; PA: Prospective analysis; BDF: Beclomethasone dipropionate.

Table 2 Studies concerning withdrawal of immunomodulators

Ref.	Design	Disease n. patients	Intervention	Surveillance	Evaluation	Main outcome	Results	Predictive factors
Fraser et al[65]	RA, sc	272 CD	Continue AZA vs discontinue AZA	-	Clinical assessment	Cumulative remission rate	At 1 yr 95% vs 63%,	Risk factors for relapse: Female sex (only CD) and higher WBC; no differences for treatment duration of AZA
		346 UC					at 2 yr 90% vs 44%,
							at 3 yr 69% vs 34%,
							at 4 yr 63% vs 28%,
							at 5 yr 62% vs 25%
Lobel et al[66]	RA, sc	61 UC	Continue 6-MP vs discontinue 6-MP	Median f-u: 40 mo (range 4-344)	Clinical and endoscopic assessment	Median time to relapse (wk)	58 wk vs 24 wk	No significant risk factors for relapse were found
							Relapse at 1 yr: 43% vs 77%
Lémann et al[67]	RCT, db, mc	83 CD	Continue AZA vs placebo	18 mo	Clinical assessment	Relapse rate	8% vs 21%	Risk factors for relapse: CRP > 20 mg/L, time steroid-free < 50 mo, Hb < 12 g/dL
Van Assche et al[73]	RCT, db, mc	80 CD	Continue IFX + IS vs IFX + stop IS	104 wk	Clinical and endoscopic assessment	Median CRP;	1.6 mg/L vs 2.8 mg/L;	Not significant P-value for endoscopic features in either groups
						Median TL;	2.8 μg/mL vs 1.6 μg/mL;
						Median SES-CD;	1 vs 2.5
						AE rate;	7.5% vs 7.5%;
						12-mo relapse	58% vs 72.7%
Cassinotti et al[68]	RA, mc	127 UC	AZA discontinuation	Median f-u: 55 mo (range 1-182)	Clinical assessment	Cumulative relapse rate	At 1 yr 35%,	Risk factors for relapse: Short treatment duration of AZA
							at 2 yr 49%,
							at 3 yr 59%,
							at 4 yr 61%,
							at 5 yr 65%
Treton et al[69]	PA, mc	66 CD	AZA discontinuation	Median f-u: 54 mo	Clinical assessment	Cumulative relapse rate	At 1 yr 14%,	Risk factors for relapse: Higher WCB count
							at 3 yr 53%,
				(IQR 20-69)			at 5 yr 62%
Kennedy et al[70]	RA, mc	129 CD	Thiopurine discontinuation	12 mo and 24 mo	Clinical assessment	Cumulative relapse rate	CD at 12 mo: Severe 8.5%, moderate 14%; at 24 mo: Severe 12%, moderate 27%.	Risk factors for relapse: Elevated CRP (only in CD), higher WBC count (only in UC)
		108 UC					UC at 12 mo: Severe 0%, moderate 12%; at 24 mo: Severe 3%, moderate 22%
Moreno-Rincón et al[71]	RA, mc	102 UC	Thiopurine	Median f-u: 27 mo (IRQ 9-75)	Clinical assessment	Cumulative relapse rate	At 1 yr: 18.8%,	Risk factors for relapse: Biological remission, thiopurine treatment duration, pancolitis, time from diagnosis until the starting of thiopurines, number of relapse before the withdrawal
			discontinuation				at 3 yr: 36.5%,
							at 5 yr: 43%
Qiu et al[72]	PA, sc	109 CD	Thiopurine	Median f-u: 46 mo (IQR 27-67)	Clinical and endoscopic assessment	Cumulative relapse rate	45% endoscopic flare, 37% clinical flare, 16% surgery, 23% hospitalization	Risk factors for relapse: Prior bowel complication, perianal disease at diagnosis, CRP > 3 mg/L
			discontinuation

RCT: Randomized controlled trial; UC: Ulcerative colitis; CD: Crohn’s disease; mc: Multicenter; db: Double-blind; sc: Single-centre; AZA: Azathioprine; RA: Retrospective analysis; PA: Prospective analysis; IRQ: Interquartile range; CRP: C-reactive protein.

Table 3 Studies concerning withdrawal of biologic therapies

Ref.	Design	Disease n. patients	Drugs and intervention	Surveillance	Evaluation	Main outcome	Main findings	Predictive factors
Waugh et al[74]	PA, mc	48 CD	IFX discontinuation	Median f-u: 4.1 yr (IQR 0.5-6.7)	Clinical assessment	Cumulative relapse rate	50% relapse rate at a median of 477 d; 35% remain in remission without treatment	Probably 35% in deep remission are different genetic-kind of CD
Louis et al[75]	PA, mc	115 CD	IFX + IMM (IFX discontinuation)	30 mo after withdrawal	Clinical and endoscopic assessment	Cumulative relapse rate	At 1 yr: 44%,	Risk factors for relapse: Male sex, absence of surgical resections, CDEIS > 0, IFX TL > 2 mg/L, CS use between 6 and 12 mo before baseline, WBC count > 6000/mmc, Hb ≤ 14.5 g/dL, CRP ≥ 5 mg/L and fecal calprotectin ≥ 300 μg/g
							at 2 yr: 52%
Steenholdt et al[76]	RA, sc	53 CD	IFX discontinuation	1 yr and 2 yr	Clinical assessment	Cumulative remission rate (no need to restart IFX, no need of CS, no surgery)	at 1 yr:	Risk factors for relapse: Long disease duration (only in CD)
		28 UC					61% CD, 75% UC
							at 2 yr:	(univariate)
							20% CD, 40% UC
Molnár et al[77]	PA, mc	121 CD	Anti-TNF discontinuation	1 yr	Clinical assessment	Cumulative relapse rate	45%	Risk factors for relapse: Smoking, using CS at the start
								of anti-TNF, previous biological therapy, elevated CRP level at the
								start of anti-TNF and a dose intensification in the first yr of anti-TNF (univariate)
Farkas et al[78]	PA, mc	51 UC	IFX discontinuation	1 yr	Clinical assessment	Cumulative relapse rate (need to restart IFX)	35%	Risk factors for relapse: Previous biological therapy
Rismo et al[25]	PA, sc	37 CD	Anti-TNF discontinuation	1-44 mo (range)	Clinical assessment	Cumulative relapse rate	74%	Risk factors for relapse: Elevated mucosal TNF and IL17 expression
Molander et al[79]	PA, sc	17 CD	Anti-TNF discontinuation	12 mo	Clinical and endoscopic assessment	Cumulative remission rate	67% clinical remission,	No significant risk factors for relapse were found
		30 UC
		5 IBDU					85% endoscopic remission
Brooks et al[80]	PA, mc	86 CD	Anti-TNF discontinuation	Median f-u: 495 d (365-2160)	Clinical, endoscopic and radiologic assessment	Whole cohort relapse rate;	At 90 d: 4.7%,	Risk factors for relapse: Montreal location and previous anti-TNF therapy
							at 180 d: 18.6%,
						Endoscopic cohort	at 365 d: 36%;
							6.3%, 12.5%, 31.3%
Chauvin et al[81]	RA, sc	92 CD	IFX + IMM (IFX discontinuation)	Median f-u: 47.1 mo (4.4-110.2)	Clinical assessment	Cumulative relapse rate	Cumulative: 72%,	Risk factors for relapse: Smoking, previous antimetabolite failure, perianal disease (multivariate)
							at 1 yr: 30%,
							at 2 yr: 48%
Dai et al[82]	PA, sc	109 CD	IFX discontinuation	12 mo	Clinical and endoscopic assessment	Cumulative relapse rate (need to restart IFX)	Pt achieved clinical remission: 13.9%	No significant risk factors for relapse were found.
		107 UC						MH doesn’t not predict sustained clinical remission
							Pt achieved full remission: 6.5%
							Pt achieved MH: 10%
Ben-Horin et al[83]	RA, mc	30 CD	Anti-TNF discontinuation	Median f-u: 12 mo	Clinical and endoscopic assessment	Cumulative relapse rate	Detectable drug: 80%,	Risk factors for relapse: Detectable drug levels
		18 UC					undetectable drug: 30%
Papamichael et al[84]	PA, sc	100 CD	IFX discontinuation	Median f-u: 9.7 yr	Clinical assessment	Cumulative remission rate	Cumulative: 52%,	At the univariate analysis were associated with a SCR: Age at diagnosis ≥ 25 yr, disease duration from diagnosis to start of IFX < 1 years, MH at the IFX dis., IFX TC < 6 mg/mL at the IFX dis., positive serum VCAM-1 at the IFX dis.
							at 1 yr 96%,
							at 2 yr 93%,
							at 3 yr 88%,
							at 4 yr 80%,
							at 5 yr 73%
Bortlik et al[85]	PA, sc	61 CD	IFX discontinuation	Median f-u: 28 mo (7-47)	Clinical assessment	Cumulative relapse rate	At 6 mo 18%,	Risk factors for relapse: Ileal disease
							at 12 mo 41%,
							at 24 mo 49%.
							With MH: 18%, 36%, 60%
Monterubbianesi et al[86]	RA, sc	58 CD	Anti-TNF discontinuation	5 yr	Clinical and endoscopic assessment	Cumulative relapse rate	At 1 yr 31%,	MH doesn’t not predict sustained clinical remission
							at 2 yr 48%
							at 5 yr 65%
Bodini et al[87]	RCT, sc	9 CD	Anti-TNF discontinuation; maintenance with AZA vs 5-ASA	Median f-u: 48 wk (20-78)	Clinical assessment	Cumulative relapse rate	AZA 0% vs 5-ASA 30%	Patients in therapy with 5-ASA have an earlier recurrence
		6 UC
Ampuero et al[88]	RA, sc	75 CD	IFX + IMM (IFX dis vs IMM dis.)	12 mo	Clinical and endoscopic assessment	Cumulative relapse rate	30.9% vs 20%	Risk factors for relapse: CRP > 5 mg/L, younger age at diagnosis

RCT: Randomized controlled trial; UC: Ulcerative colitis; CD: Crohn’s disease; mc: Multicenter; db: Double-blind; sc: Single-centre; AZA: Azathioprine; RA: Retrospective analysis; PA: Prospective analysis; IRQ: Interquartile range; CRP: C-reactive protein; IFX: Infliximab; 5-ASA: 5-aminosalicylic acid; MH: Mucosal healing; TL: Trough level; CS: Costicosteroid; TNF: Tumor necrosis factor; IL: Interleukin; IMM: Immunomodulator.

Table 4 Synopsis on relapse rates with or without withdrawal of immunomodulator or biologics

Drugs	Overall patients number	Relapse at 1 yr	Relapse at 2 yr	Relapse at 5 yr
Immunomodulator	659 CD, 744 UC
Maintenance	Mixed	6%	10%[65]	48%[65]
Median (range)		(range 5-43)[65-67]
	Only CD	6%[67]
	Only UC	43%[66]
De-escalation	Mixed	20.50%	44%	63.50%
Median (range)		(range 12-37)[65,68-71]	(range 25-56)[65,68,70]	(range 43-75)[65,68-71]
	Only CD	18%	39%[70]	62%[69]
		(range 14-22)[69,70]
	Only UC	19%	37%	54%
		(range 12-35)[68,70,71]	(range 25-49)[68,70]	(range 43-65)[68,71]
Anti-TNF	605 CD, 216 UC
Maintenance	Mixed	49%	72%
Median (range)		(range 23-75)[58,95]	(range 36-83)[58,73,95]
	Only CD	75%[95]	77.5%[73,95]
			(range 72-83)
	Only UC	23%[58]	36%[58]
De-escalation	Mixed	35%	48.5%	46%
Median (range)		(range 4-45)[76-80,82,84-86]	(range 7-80)[76,84-86]	(range 27-65)[84,86]
	Only CD	37.5%	48.50%	46%
		(range 4-45)[76,77,80,84-86]	(range 7-80)[76,84-86]	(range 27-65)[84,86]
	Only UC	30% (range 25-35)[76,78]	60%[76]
Combination therapy	362 CD
Anti-TNF de-escalation	262 CD	31%	50%
		(range 30-44)[75,81,88]	(range 48-52)[75,81]
Immunomodulator de- escalation	100 CD	20%[88]	58%[73]

UC: Ulcerative colitis; CD: Crohn’s disease.