Surrogate markers of mucosal healing in inflammatory bowel disease: A systematic review

Table 1 Synthetic presentation of data on fecal marker performance in detecting mucosal healing

Ref.	Study type	Investigated marker	MH definition	CU/CD	Number of patients	AUC	95%CI	Sn (%)	Sp (%)	Cutoff level
E Penna et al[22]	Prospective cohort	FC	SES-CD ≤ 2	CD	65 + 21 individuals in the control group	0.77	0.65-0.88	96	78	155 mcg/g
Hiraoka et al[17]	Prospective cohort	FC	MES = 0	UC	84	0.67	0.56 - 0.78	77	67	180 mcg/g
Hiraoka et al[17]	Prospective cohort	FIT	MES = 0	UC	84	0.62	0.50- 0.74	95	62	NA
Lee et al[23]	Prospective cohort	FC-ELISA; FC-QPOCT	MES = 0; SES-CD < 4	UC + CD	93	0.88	NANA	81.8(ELISA); 85.7 (QPOCT)	100 ELISA; 100 QPOCT	201 mcg/g ELISA; 150.5 mcg/g QPOCT
Urushikubo et al[24]	Cross-sectional, observational	FC	MES = 0; REI = 0; UCEIS = 0	UC	50	0.823; 0.780; 0.777	0.707-0.939; 0.658-0.903; 0.645-0.909	100; 100; 88	62; 70; 71	490 mcg/g; 288 mcg/g; 288 mcg/g
Ryu et al[18]	Retrospective cohort	FIT	MES = 0; UCEIS = 0-1	UC	128	NA	NA	98.0; 94.9	37.4; 38.3	100 ng/mL
Ryu et al[18]	Retrospective cohort	FC	MES = 0; UCEIS = 0-1	UC	128	NA	NA	78.4; 74.6	74.4; 76.5	170 mcg/g
Lin et al[25]	Multicentric prospective cohort	FC	UCEIS < 3; CDEIS < 6	UC + CD	88	0.87; 0.74	NA	88; 50	75; 100	191 mcg/g; 918 mcg/g
Vázquez Morón et al[26]	Prospective cohort	FC	SES-CD ≤ 2	CD	71	NA	NA	95.9	52.3	71 mcg/g
Ryu et al[27]	Retrospective cohort	FIT	MES = 0-1	UC	63	0.81	0.59-0.94	73.33	81.82	< 7 ng/mL
Hassan et al[28]	Prospective cohort	FC	MES = 0-1	UC	44	0.949	0.838-0.992	89.7	93.3	58 mcg/g
Kostas et al[29]	Retrospective cohort	FC	MES = 0-1; absence of mucosal lesions for CD	UC + CD	149	0.956	NA	91.9	87.2	174 mcg/g
Yen et al[21]	Retrospective cohort	FC	MES = 0-1	UC	50	0.812	NA	74.19	84.21	156 mcg/g
Yen et al[21]	Retrospective cohort	iFOBT	MES = 0-1	UC	50	0.906	NA	80.65	100	≤ 43 ng/mL
Kristensen et al[30]	Prospective cohort	FC	MES = 0-1	UC	20	NA	NA	82.4	100	250 mcg/g

UC: Ulcerative colitis; CD: Crohn’s disease; FC: Fecal calprotectin; FIT: Fecal immunoassay test; MES: Mayo endoscopic subscore; UCEIS: Ulcerative colitis endoscopy index of severity; REI: Rachmilewitz endoscopic index; M2-PK: M2 pyruvate kinase, iFOBT: Immune fecal occult blood test; NA: Not available; QPOCT: Quantitative point-of-care test; AUC: Area under the curve; CI: Confidence interval; Sn: Sensitivity; Sp: Specificity.

Table 2 Synthetic presentation of data on serum marker performance in detecting mucosal healing

Ref.	Study type	Investigated marker	MH definition	CU/CD	Number of patients	AUC	95%CI	Sn (%)	Sp (%)	Cutoff level
Shinzaki et al[40]	Prospective cohort	LRG	Matts = 1-2 (MH); Matts = 1/MES = 0 (complete MH)	CU	129	0.849; 0.759	NA	NA	NA	NA
Dierckx et al[39]	Case control pilot study	GlycA	MES = 0-1; SES-CD ≤ 2	CU + CD	58 + 10 healthy controls	NA	NA	NA	NA	NA
Neubauer et al[36]	Prospective cohort	S-Nampt	MES = 0-1; NA for CD	CU + CD	240 + 40 non-IBD controls	0.768	0.67-0.85	76	75	≤ 1.54 ng/mL
Planell et al[35]	Cross-sectional cohort + case control	HP	MES = 0	UC	126 + 20 healthy controls + 16	0.75	0.64-0.85	63.5	80	-2.9 DCt
Nakov et al[32]	Prospective cohort	TTF3	MES = 0; UCEIS = 0	UC		0.927	0.877-0.976	87.9	86.9	6.74
Budzynska et al[34]	Prospective cohort	NGAL	MES = 0-1; SES-CD = 3-7	UC + CD	120	0.79;0.608	0.65-0.93; NA	96; 48	50; 83	43.6 ng/mL; 72.5 ng/mL
Wakai et al[38]	Retrospective cohort	Serum amyloid A	MES = 0-1	UC	108	0.807	0.748-0.867	72.2	85	< 5.8

UC: Ulcerative colitis; CD: Crohn’s disease; LRG: Leucine-rich alpha-2 glycoprotein; GlycA: Glycoprotein acetylation; Nampt: Nicotinamide phosphoribosyltransferase; HP: Haptoglobin; TFF3: Trefoil factor 3; NGAL: Serum neutrophil gelatinase-associated lipocalin; NA: Not available; SES-CD: Simple endoscopic score for Crohn’s disease; AUC: Area under the curve; CI: Confidence interval; Sn: Sensitivity; Sp: Specificity.

Table 3 Synthetic presentation of data on combined marker performance in detecting mucosal healing

Ref.	Study type	Investigated marker	MH definition	CU/CD	Number of patients	AUC	95%CI	Sn (%)	Sp (%)	Cutoff level
Reinisch et al[43]	Post hoc analysis of clinical trial	FC, CRP and CDAI	CDEIS < 4	CD	244	0.68,	0.62-0.74	74	64	FC < 250 mcg/g, CRP < 5 mg/L, and CDAI < 150
D'Haens et al[41]	Prospective-specimen collection, retrospective–blinded-evaluation	EHI	SES-CD of ≤ 2 and ≤ 1 in each segment	CD	311 in 2 cohorts (116 + 195)	0.962; 0.693	0.942-0.982; 0.619-0.767	97.1; 83.2 (for cutoff of 20)	100; 87.8 (cutoff of 50)	≤ 20
Gubatan et al[42]	Prospective cohort	IL-4 + IL-10/IL-17A + TNF-α	Geboes Histologic Grade of < 3	CU	70	0.641		52.6	75	0.1522
Mavropoulou et al[44]	Prospective cohort	sIL-2R (CU); IL-6 (CD); FC (UC); FC (CD)	MES = 0-1; SES-CD ≤ 3	UC + CD	299 (84 + 145)	0.80; 0.80; 0.92; 0.84	0.68-0.91; 0.71-0.89; 0.86-0.99; 0.76-0.92	63; 69; 91; 70	85; 80; 89; 100	< 646 IU/mL; < 5.5 pg/mL; 340 mg/kg; < 180 mg/kg

EHI: Endoscopic healing index measuring 13 proteins in blood [angiopoietin 1 (ANG1) and 2 (ANG2), carcinoembryonic antigen-related cell adhesion molecule 1, C-reactive protein, serum amyloid A1, interleukin 7, transforming growth factor α, vascular cell adhesion molecule 1, extracellular matrix metalloproteinase inducer, and matrix metalloproteinases 1 (MMP1), 2 (MMP2), 3 (MMP3), and 9 (MMP9)]; UC: Ulcerative colitis; CD: Crohn’s disease; AUC: Area under the curve; CI: Confidence interval; Sn: Sensitivity; Sp: Specificity; SES-CD: Simple endoscopic score for Crohn’s disease; CRP: C-reactive protein; CDAI: Crohn’s disease activity index; sIL-2R: Soluble interleukin 2 receptor; MES: Mayo endoscopic subscore; FC: Fecal calprotectin.