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

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.