Are faecal markers good indicators of mucosal healing in inflammatory bowel disease?

Table 1 Studies investigating the correlation between faecal calprotectin concentrations and endoscopic activity in subjects with inflammatory bowel diseases

Ref.	Number of participants		Population	Endoscopic index used	Endoscopic indexcut off	Faecal calprotectincut off (μg/g)	Outcome measures				Correlation
	CD	UC					Sensitivity	Specificity	PPV	NPV	r value	P value
Crohn’s disease studies
Falvey et al[46]	59		Adults	SES-CD	≤ 3	125	71%	71%	85%	50%	0.55%	< 0.0001
						200	60%	79%	88%	45%
Lobatón et al[51]	85		Adults	CDEIS	< 3	274 ELISA	77%	97%	75%	98%	0.784%	< 0.001
					< 3	272 QPOC	79%	97%	76%	98%	0.722%	< 0.001
					0	262 ELISA	75%	76%
					0	200 QPOC	75%	77%
Nancey et al[45]	78		Adults	SES-CD	≤ 2	250	71%	78%	79%	71%	0.53%	< 0.0001
						100	88%	38%	62%	73%
D’Haens et al[47]	87		Adults	CDEIS	≤ 3	< 250	94.1%	62.2%	48.5%	96.6%	0.419%	< 0.001
				SES-CD	0	< 250	51.6%	82.6%	89.2%	38%	0.49%	< 0.001
af Björkesten et al[15]	64		Adults	SES-CD	≤ 2	< 100	81%	74%	-	-	0.56%	< 0.001
						< 94	84%	74%	-	-
				SES-CD	0	< 94	82%	78%	-	-
Aomatsu et al[16]	18		Paediatrics	SES-CD	0	100	94.7%	50%	87.8%	71.4%	0.76%	< 0.01
						150	94.7%	50%	87.8%	71.4%
Sipponen et al[17]	19		Adults	SES-CD	≤ 2	< 100	-	80%	-	-	-	-
Schoepfer et al[21]	122		Adults	SES-CD	≤ 3	< 50	89%	58%	89%	61%	0.75%	< 0.01
						< 70	89%	72%	88%	76%
Langhorst et al[23]	43		Adults	SES-CD		> 6	100%	30%	82.5%	100%	0.35%	< 0.05
						> 48	81.8%	80%	93.1%	57.1%
Schoepfer et al[22]	36		Adults	SES-CD	≤ 19	50	-	-	-	-	-	< 0.0001
Sipponen et al[18]	61		Adults	SES-CD (total)	≤ 3	< 100	-	-	-	-	0.662%	< 0.001
				SES-CD (colon)	≤ 3	< 100	-	-	-	-	0.642%	< 0.001
				SES-CD (ileal)	≤ 3	< 100	-	-	-	-	0.317%	> 0.05
Sipponen et al[19]	15		Adults	CDEIS	≤ 2	< 200	87%	100%	100%	70%	0.831%	< 0.001
Sipponen et al[20]	77		Adults	CDEIS	≤ 2	< 50	91%	44%	76%	73%	0.729%	< 0.001
						< 100	81%	69%	84%	66%
						< 200	70%	92%	94%	61%
Jones et al[24]	164		Adults	SES-CD	≤ 6	≤ 50	-	-	-	-	0.45%	< 0.05
Denis et al[25]	28		Adults	CDEIS	≤ 5	< 50	-	-	-	-	-	0.57
Schoepfer et al[26]	24		Adults	SES-CD	≤ 19	< 50	-	-	-	-	-	0.0001
D'Incà et al[28]	31		Adults	SES-CD		> 80	-	-	-	-	0.48%	0.008
Mixed inflammatory bowel disease population studies
Molander et al[29]	183	69	Mixed	SES-CD; Mayo	≤ 2; ≤ 1	< 100	-	-	-	72%	-	< 0.0001
Vieira et al[30]	38	40	Adults	CDEIS; Mayo	≤ 2; ≤ 2	> 200.01	88.6%	97.1%	97.5%	86.8%	-	0
Schoepfer et al[22]	36	28	Adults	SES-CD; Rachmilewitz	≤ 19; ≤ 4	50	-	-	-	-	-	< 0.0001
Canani et al[50]	26	32	Paediatrics	Saverymuttu	≤ 1	143	-	-	-	-	0.46%	≤ 0.05
Fagerberg et al[31]	27	10	Paediatrics	Saverymuttu		< 85.7	-	-	-	-	0.65%	< 0.001
Silberer et al[32]	21	18	Adults	Stange		18.6	61.5%	95%	-	-	-	< 0.0001
Røseth et al[33]	17	28	Adults	Farup		< 50	0%	100%	-	97.8%	-	-
Bunn et al[34]	2	9	Paediatrics	Saverymuttu			-	-	-	-	0.65%	< 0.05
Ulcerative colitis studies
Falvey et al[46]		38	Adults	Baron	0	125	74%	80%	85%	67%	0.55%	< 0.0001
						200	58%	95%	95%	59%
Nancey et al[45]		55	Adults	Rachmilewitz	≤ 2	250	91%	87%	87%	91%	0.75%	< 0.0001
						100	100%	53%	85%	100%
Kristensen et al[48]		62	Adults	Mayo	0	61 Cal	84.1%	83.3%	92.5%	68.2%		< 0.001
					0	96 BM	90.9%	83.3%	93%	78.9%		< 0.001
					≤ 1	110 Cal	80%	66.6%	69.2%	78%
					≤ 1	259 BM	83.3%	71.9%	73.5%	82.1%
D’Haens et al[47]		39	Adults	Mayo	0	< 250	71%	100%	100%	47.1%	0.56%	< 0.001
Komraus et al[35]		16	Paediatrics	Rachmilewitz		< 50	-	-	-	-	0.52%	0.0391
Aomatsu et al[16]		17	Paediatrics	Matts	≤ 6	100	94.1%	50%	88.9%	66.7%	0.84%	< 0.01
						150	91.2%	87.5%	96.9%	70%
Schoepfer et al[27]		115	Adults	Rachmilewitz	< 4	< 50	93%	71%	91%	81%	0.83%	< 0.001
						< 100	86%	88%	96%	65%
Langhorst et al[23]		42	Adults	Mayo		> 6	100%	6.7%	6.6%	100%	0.49%	< 0.001
						> 48	81.5%	72.3%	84.6%	68.8%
Schoepfer et al[22]		28	Adults	Rachmilewitz	≤ 4	50	-	-	-	-	-	0.0025
Schoepfer et al[26]		12	Adults	Rachmilewitz	≤ 1	< 50	-	-	-	-	-	0.0335
D'Incà et al[28]		46	Adults	Mayo		> 80	-	-	-	-	0.511%	0.001
Hanai et al[36]		31	Adults	Matts	≤ 1		-	-	-	-	0.81%	< 0.001
Røseth et al[37]		62	Adults	Sandborn	≤ 1	< 10	-	34%	-	-	0.57%	< 0.0001
						< 20	-	62%	-	-

CD: Crohn’s disease; UC: Ulcerative colitis; PPV: Positive predictive value; NPV: Negative predictive value; SES-CD: Simple endoscopic score for Crohn’s disease[54]; CDEIS: Crohn’s disease endoscopic index of severity[55]; ELISA: Enzyme linked immunosorbant assay; QPOC: Quantitative point of care test; Mayo: Mayo endoscopic sub-scoring of ulcerative colitis[56]; Rachmilewitz: Rachmilewitz endoscopic score[57]; Saverymuttu: Non-standard endoscopic scoring system[58]; Stange: Non-standard endoscopic scoring system[59,60]; Farup: Non-standard endoscopic scoring system[61]; Baron: Baron score; Matts: Matts score[62]; Sandborn: Non-standard endoscopic scoring system[63]; Cal: Calpro ELISA: Calpro Calprotectin ELISA, Calpro AS, Norway; BM: BM ELISA, EK-CAL, Buhlmann Laboratories AG, Switzerland; Farmer: Non-standard endoscopic scoring system[64]; Faecal Hb: Faecal haemoglobin; PMN-e: Polymorhonuclear elastase; Hb-Hp: Haemoglobin; Haptoglobin complex; D’Haens: Non-standard histologic scoring system[65]; Fazio: Non-standard histologic scoring system[66]; Floren: Non-standard histologic scoring system[67].

Table 2 Studies investigating the correlation between faecal lactoferrin concentrations and endoscopic activity in subjects with inflammatory bowel diseases

Ref.	Number of participants		Population	Endoscopic index used	Endoscopic indexcut off	Faecal lactoferrincut off (μg/mL)	Outcome measures				Correlation
	CD	UC					Sensitivity	Specificity	PPV	NPV	r value	P value
Crohn’s disease studies
Sipponen et al[17]	19		Adults	SES-CD	≤ 2	< 7.25	-	80%	-	-	-	-
Pfefferkorn et al[38]	54		Paediatrics	Unique score		≥ 7.25	100%	43%	70%	100%	-	< 0.001
						≥ 60	84%	74%	81%	77%
Sipponen et al[18]	61		Adults	SES-CD (total)	≤ 3	< 7.25	-	-	-	-	0.705%	< 0.001
				SES-CD (colon)	≤ 3	< 7.25	-	-	-	-	0.627%	< 0.001
				SES-CD (ileal)	≤ 3	< 7.25	-	-	-	-	0.18%	> 0.05
Sipponen et al[19]	15		Adults	CDEIS	≤ 2	< 10	77%	100%	100%	58%	0.865%	< 0.001
Sipponen et al[20]	77		Adults	CDEIS	≤ 2	< 10	66%	92%	94%	59%	0.773%	< 0.001
						< 7.25	71%	83%	89%	60%
Jones et al[24]	164		Adults	SES-CD	≤ 6	< 7.25	-	-	-	-	0.48%	< 0.05
Langhorst et al[23]	43		Adults	SES-CD		> 7.25	81.8%	60%	87.1%	50%	0.42%	< 0.01
						> 7.05	81.8%	60%	87.1%	50%
Schoepfer et al[22]	36		Adults	SES-CD	≤ 19	7	-	-	-	-	-	< 0.0001
Schoepfer et al[26]	24		Adults	SES-CD	≤ 19	< 7	-	-	-	-	-	0.0008
D'Incà et al[28]	31		Adults	SES-CD			-	-	-	-	0.192%	0.545
Mixed inflammatory bowel disease population studies
Vieira et al[30]	38	40	Adults	CDEIS; Mayo	≤ 2; ≤ 2	4-8	93.2%	76.5%	83.7%	89.7%	-	0
Schoepfer et al[22]	36	28	Adults	SES-CD; Rachmilewitz	≤ 19; ≤ 4	7	-	-	-	-	-	< 0.0001
Silberer et al[32]	21	18	Adults	Stange		6.64	33.3%	95%	-	-	-	0.0059
Ulcerative colitis studies
Langhorst et al[23]		42	Adults	Mayo		> 7.25	88.9%	66.7%	82.8%	76.9%	0.56%	< 0.001
						> 7.05	92.6%	66.7%	83.3%	83.3%
Schoepfer et al[22]		28	Adults	Rachmilewitz	≤ 4	7	-	-	-	-	-	0.078
Schoepfer et al[26]		12	Adults	Rachmilewitz	≤ grade 1	< 7	-	-	-	-	-	0.7815
D'Incà et al[28]		46	Adults	Mayo			-	-	-	-	0.354%	0.023

CD: Crohn’s disease; UC: Ulcerative colitis; PPV: Positive predictive value; NPV: Negative predictive value; SES-CD: Simple endoscopic score for Crohn’s disease[54]; CDEIS: Crohn’s disease endoscopic index of severity[55]; Mayo: Mayo endoscopic sub-scoring of ulcerative colitis[56]; Rachmilewitz: Rachmilewitz endoscopic score[57]; Stange: Non-standard endoscopic scoring system[59,60].

Table 3 Studies investigating the correlation between other faecal marker concentrations and endoscopic activity in subjects with inflammatory bowel diseases

Ref.	Number of participants		Population	Endoscopic index used	Endoscopic indexcut off	Faecal marker measured	Faecal marker cut off	Outcome measures				Correlation
	CD	UC						Sensitivity	Specificity	PPV	NPV	r value	P value
Nancey et al[45]	78		Adults	SES-CD	≤ 2	Neopterin	200 pmol/g	74	73	73	74	0.47	< 0.001
							150 pmol/g	80	65	68	78
		55	Adults	Rachmilewitz	≤ 2	Neopterin	200 pmol/g	74	100	100	73	0.72	< 0.001
							150 pmol/g	84	100	100	78
Nakarai et al[39]		152	Mixed	Mayo	0	Faecal Hb	< 100 ng/mL	92	71	37	97	0.5409	< 0.0001
						Faecal Hb	< 60 ng/mL	94	74	40	98
				Mayo	≤ 1	Faecal Hb	< 100 ng/mL	60	87	85	64
						Faecal Hb	< 60 ng/mL	58	90	88	64
Langhorst et al[23]	43		Adults	SES-CD		PMN-e	< 0.062 μg/mL	81.8	70	90	54.8	0.32	< 0.05
		42	Adults	Mayo		PMN-e	< 0.062 μg/mL	70.4	66.7	79.2	55.6	0.36	< 0.05
Silberer et al[32]	21	18	Adults	Stange		PMN-e	0.124	79.5	95	-	-	-	< 0.0001
						Lysozyme	1.3	47.5	95	-	-	-	< 0.0001
						α1-AT	158	20	95	-	-	-	-
						Faecal Hb	1.8	61.5	95	-	-	-	-
						Hb-Hp	0.8	64.1	95	-	-	-	-
Moran et al[40]	7	21	Mixed	Farmer		α1-AT	≤ 0.58 mg/g	-	-	-	-	0.83	0.001
Cellier et al[41]	95		Adults	CDEIS		α1-AT		-	-	-	-	0.26	0.001

CD: Crohn’s disease; UC: Ulcerative colitis; PPV: Positive predictive value; NPV: Negative predictive value; SES-CD: Simple endoscopic score for Crohn’s disease[54]; CDEIS: Crohn’s disease endoscopic index of severity[55]; Mayo: Mayo endoscopic sub-scoring of ulcerative colitis[56]; Rachmilewitz: Rachmilewitz endoscopic score[57]; Stange: Non-standard endoscopic scoring system[59,60]; Farmer: Non-standard endoscopic scoring system[64]; Faecal Hb: Faecal haemoglobin; PMN-e: Polymorhonuclear elastase; Hb-Hp: Haemoglobin and Haptoglobin complex.

Table 4 Studies investigating the correlation between FC concentrations and histologic activity in subjects with inflammatory bowel diseases

Ref.	Number of participants		Population	Histology index used	Histology indexcut off	Faecal calprotectincut off (μg/g)	Outcome measures				Correlation
	CD	UC					Sensitivity	Specificity	PPV	NPV	r value	P value
Crohn’s disease studies
Sipponen et al[18]	61		Adult	D'Haens (ileocolonic)		< 100	-	-	-	-	0.563	< 0.01
				D'Haens (ileal)		< 100	-	-	-	-	0.311	> 0.05
Sipponen et al[19]	15		Adult	D'Haens (pretreatment colonic)		< 200	-	-	-	-	0.522	0.046
				D'Haens (posttreatment colonic)		< 200	-	-	-	-	-	> 0.05
				D'Haens (ileal)		< 200	-	-	-	-	-	> 0.05
Canani et al[50]	26		Paediatric	Saverymuttu	≤ 1	143	-	-	-	-	0.681	< 0.0001
Kaiser et al[42]	32		Adult	Unique score	0	< 50	-	-	-	-	0.412	< 0.05
D'Incà et al[28]	31		Adult	Fazio		> 80	81%	80%	95%	-	0.117	0.545
Fagerberg et al[43]	22		Paediatric	Unique score		< 50	95%	93%	95%	93%	-	< 0.00001
Mixed inflammatory bowel disease population studies
Vieira et al[30]	38	40	Adult	Unique score		> 200	77%	100%	100%	68%	-	0
Canani et al[50]	26	32	Paediatric	Saverymuttu	≤ 1	143	94%	64%	81%	87%	0.655	< 0.05
D'Incà et al[28]	31	46	Adult	Fazio; Floren (SES-CD; Mayo)	> 80	79	74%	92%	-	-	-
Fagerberg et al[31]	27	10	Paediatric	Saverymuttu	≤ 2	< 50	93%	73%	90%	80%	0.75	< 0.001
						< 85.7	93%	82%	93%	82%
				Saverymuttu			-	-	-	-	0.79	< 0.001
Kolho et al[44]	9	16	Paediatric	Farup		50	-	-	69%	100%	-	-
						100	-	-	72%	96%	-	-
Bunn et al[53]	2	9	Paediatric	Saverymuttu	≤ 6	6.3	100%	80%	-	-	0.74	< 0.01
Ulcerative colitis studies
Canani et al[50]		32	Paediatric	Saverymuttu	≤ 1	143	-	-	-	-	0.661	< 0.0001
D'Incà et al[28]		46	Adult	Floren		> 80	78%	70%	90%	-	0.323	0.042
Kaiser et al[42]		27	Adult	Unique score		< 50	-	-	-	-	0.311	0.14
Røseth et al[37]		62	Adult	Farup	≤ 1	< 10	-	50%	-	-	0.70	< 0.0001
						< 20	-	81%	-	-

CD: Crohn’s disease; UC: Ulcerative colitis; PPV: Positive predictive value; NPV: Negative predictive value; SES-CD: Simple endoscopic score for Crohn’s disease[54]; Mayo: Mayo endoscopic sub-scoring of ulcerative colitis[56]; Saverymuttu: Non-standard endoscopic scoring system[58]; Farup: Non-standard endoscopic scoring system[61]; D’Haens: Non-standard histologic scoring system[65]; Fazio: Non-standard histologic scoring system[66]; Floren: Non-standard histologic scoring system[67].

Table 5 Studies investigating the correlation between faecal lactoferrin concentrations and histologic activity in subjects with inflammatory bowel diseases

Ref.	Number of participants		Population	Histology index used	Histology indexcut off	Faecal lactoferrincut off(μg/mL)	Outcome measures				Correlation
	CD	UC					Sensitivity	Specificity	PPV	NPV	r value	P value
Crohn’s disease studies
Sipponen et al[18]	61		Adults	D'Haens (ileocolonic)		< 7.25	-	-	-	-	0.543	< 0.01
				D'Haens (ileal)		< 7.25	-	-	-	-	0.291	> 0.05
Sipponen et al[19]	15		Adult	D'Haens (pretreatment colonic)		< 10	-	-	-	-	0.482	0.069
				D'Haens (posttreatment colonic)		< 10	-	-	-	-	-	> 0.05
				D'Haens (ileal)		< 10	-	-	-	-	-	> 0.05
D'Incà et al[28]	31		Adult	Fazio			77%	80%	95%	-	0.477	0.009
Mixed inflammatory bowel disease studies
Vieira et al[30]	38	40	Adults	Unique score		4-8	90%	92%	96%	83%	-	-
D'Incà et al[28]	31	46	Adults	Fazio; Floren (SES-CD; Mayo)		7	76%	67%	90%	-	-	-
Ulcerative colitis studies
D'Incà et al[28]		46	Adults	Floren		7	75%	60%	87%	92%	0.544	0.0001

CD: Crohn’s disease; UC: Ulcerative colitis; PPV: Positive predictive value; NPV: Negative predictive value; SES-CD: Simple endoscopic score for Crohn’s disease[55]; Mayo: Mayo endoscopic sub-scoring of ulcerative colitis[57]; D’Haens: Non-standard histologic scoring system[66]; Fazio: Non-standard histologic scoring system[67]; Floren: Non-standard histologic scoring system[68].

Table 6 Studies investigating the correlation between other faecal marker concentrations and histologic activity in subjects with inflammatory bowel diseases

Ref.	Number of participants		Population	Histology index used	Histology indexcut off	Faecal marker measured	Faecal marker cut off	Outcome measures				Correlation
	CD	UC						Sensitivity	Specificity	PPV	NPV	r value	P value
Crohn’s disease studies
Kaiser et al[42]	32	27	Adults	Unique score	0	S100A12		-	-	-	-	0.44	< 0.01
	32					S100A12	0.8	81	100	-	-	0.451	0.01
		27				S100A12	0.8	91	100	-	-	0.44	< 0.025

CD: Crohn’s disease; UC: Ulcerative colitis; PPV: Positive predictive value; NPV: Negative predictive value.