Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

Table 1 Prognostic indicators of response to anti-tumor necrosis factor treatment in ulcerative colitis

At initiation of treatment	During treatment
Clinical and epidemiological parameters
Severity of the disease	Early clinical response
Younger age
Duration of colitis < 3 yr
Extensive colitis
Laboratory indicators
CRP	Low CRP at week 12
Hemoglobin	Drop of serum CRP
Serum albumin	Fecal calprotectin
Immunological and genetic markers
p-ANCA	Gene expression profiling
Pre-treatment mucosal TNF-α expression	Percentages of regulatory T cells
Mucosal expression of IL-17 and IFN-γ
Genetic polymorphisms
Endoscopic findings
	Mucosal healing
Treatment-related factors
Pharmacological history	Number of IFX infusions
Exposure to immunosuppressants	Co-administration of immunosuppressants
Response to prior treatment with infliximab	Escalation of anti-TNF therapy
	IFX trough levels
	Antibodies against anti-TNF

CRP: C-reactive protein; p-ANCA: Perinuclear antineutrophil cytoplasmatic antibodies; TNF:Tumor necrosis factor; IL: Interleukin; INF: Interferon; IFX: Infliximab.

Table 2 Clinical trials that reported prognostic indicators for response to anti- tumor necrosis factor treatment in Ulcerative Colitis

Ref.	Type of study	No. of patients	Anti-TNF drug	Response endpoints	Predictor of response
Arijs et al[26]	Cohort		IFX	Endoscopic and histological healing	Mucosal gene expression signature
Armuzzi et al[31]	Retrospective	88 (78.4% IFX experienced)	ADA	Clinical remission (4-54 wk)	Short-term clinical remission
					Low CRP at week 12
					(remission at week 54)
					1Previous immunosupressant use (lower long-term remission rates)
Armuzzi et al[27]	Prospective	126	IFX	Steroid–free clinical remission	Thiopurine-naïve status
				Mucosal healing	Combination treatment
				Colectomy (12 mo)	CRP drop to normal
Ben–Horin et al[10]	Retrospective	62 (CD/UC)	IFX	Loss or response	1Low trough levels
					Anti-infliximab antibodies
Cesarini et al[39]	Retrospective	41 (secondary loss of response)	IFX	Clinical remission	Rapid clinical response to optimization
				Colectomy–free (52 wk)
Colombel et al[3]	Prospective (ACT trials)	728	IFX	Clinical remission	Mucosal healing at week 8
				Clinical response	(predictive of long-term outcome)
				Colectomy
De Vos et al[32]	Prospective	53	IFX	Mayo clinical score	Fecal Calprotectin
				Endoscopic remission
Fasanmade et al[23]	Retrospective	728	IFX	Trough levels	1Serum albumin concentration
				Clinical response
Ferrante et al[21]	Cohort	121	IFX	Colectomy-free survival (33 mo)	Short term clinical response
					CRP > 5 mg/L
					1Previous iv treatment with steroids/cyclosporin
Ferrante et al[18]	Cohort	100	IFX	Early clinical response	Younger age
					pANCA-/ACSA+
Garcia-Bosch et al[28]	Retrospective	48	ADA	Clinical response (partial Mayo score)	Response to prior treatment with infliximab
				Colectomy (week 54)	Early response to adalimumab
Gonzalez-Lama et al[20]	Retrospective	47	IFX	Clinical response	1Disease extent
				Steroid-free remission
				Colectomy
Gustavsson et al[35]	Placebo controlled trial	45	IFX	Colectomy (3 yr f-up)	Mucosal healing at 3 mo
Jakobovits et al[19]	Retrospective	30	IFX (not standard induction regimen 0-2-6)	Colectomy	1Younger age at diagnosis
Jürgens et al[13]	Retrospective	90	IFX	Clinical response	CAI-disease activity
				Clinical remission (week 14)	ANCA seronegativity
					IL23R genotype
Lee et al[22]	Retrospective	134	IFX	Clinical response	Haemoglobin > 11.5
				Clinical remission	CRP > 3
					Immunomodulator-naïve status
					Response at week 2
					Mucosal healing
Kohn et al[36]	Open label	83 severe colitis	IFX	Colectomy/Death	1Single infusion
				> 2 mo after first infusion
				(median f-up 23 mo)
Li et al[34]	Prospective?	17	IFX	CRP	Changes in percentages of Foxp3(+) Tregs (mucosal and systemic)
		24		Clinical response
				Endoscopic healing
McDermott et al[30]	Retrospective	23 (86% infliximab experienced)	ADA	Failure (discontinuation of ADA)	1Short–term failure
				Colectomy (follow-up 22 mo)	(increased risk for colectomy)
Olsen et al[24]	Retrospective	59	IFX	UCDAI	Mucosal TNF-a mRNA expression
Oussalah et al[14]	Retrospective	191	IFX (≥1 infusion)	Primary non-response	1Indication for acute severe colitis
				Colectomy	Hb ≤9.4 g/dL
				Infliximab optimization	Non-response
				Hospitalization (median 18 mo)
Park et al[15]	Retrospective	89	IFX	Clinical response	1Mayo score≥11)
				Clinical remission	CMV infection (within prior 3 mo)
				Colectomy
Reinisch et al[17]	Prospective (ULTRA 1)	390 (anti-TNF naïve)	ADA	Clinical remission at week 8	1Mayo score≥10
					CRP = 10 mg/L
Rismo et al[25]	Prospective	74	IFX	UCDAI	Mucosal gene expression signature (Th1 and Th17 related cytokines)
Rostholder et al[38]	Retrospective observational	56	IFX	Clinical remission	Escalation of infliximab therapy
Sandborn et al[16]	Prospective (ACT1&2)	630	IFX	Colectomy (54 wk)	1Concomitant steroidsCRP≥2 mg/dLDisease duration < 3 yrMayo≥10
Seow et al[40]	Cohort	115	IFX	Clinical remission Endoscopic improvement Colectomy	Trough levels
Steenholdt et al[41]	Retrospective	106 (CD/UC)	IFX	Loss of response	1Trough levelsAnti-infliximab antibodies
Taxonera et al[29]	Retrospective	30 (IFX experienced)	ADA	Clinical response at week12 Colectomy (follow-up 48 wk)	Short–term response at week-12 (Associated with less withdrawal and colectomy rates)
Toedter et al[33]	Prospective (ACT-1)	48	IFX	Clinical response	Mucosal gene expression signature

¹Italics correspond to prognostic factors for adverse outcome. IFX: Infliximab; ADA: Adalimumab; UCDAI: Ulcerative colitis disease activity index; HACA: Human anti-chimeric antibodies; CRP: C-reactive protein.