Remission endpoints in ulcerative colitis: A systematic review

Table 1 Descriptors and intra- and inter-observer variation

Descriptor	Likert scale anchor points	Intra-observer variation(a weighted k)	Inter-observer variation (a weighted k)
Vascular pattern	Normal (1) Patchy loss (3) Obliterated (5)	0.61	0.42
Mucosal erythema	None (1)	0.43	0.35
	Light red (3)
	Dark red (5)
Mucosal surface (Granularity)	Normal (1)	0.45	0.34
	Granular (3)
	Nodular (5)
Mucosal oedema	None (1)	0.43	0.31
	Probable (3)
	Definite (5)
Mucopus	None (1)	0.47	0.4
	Some (3)
	Lots (5)
Bleeding	None (1)	0.57	0.37
	Mucosal (2)
	Luminal mild (3)
	Luminal moderate (4)
	Luminal severe (5)
Incidental friability	None (1)	0.49	0.4
	Mild (2)
	Moderate (3)
	Severe (4)
	Very severe (5)
Contact friability	None (1)	0.34	0.3
	Probable (3)
	Definite (5)
Erosions and ulcers	None (1)
	Erosions (2)	0.65	0.45
	Superficial ulcer (3)
	Deep ulcer (4)
Extent of erosions or ulcers	None (1)	0.6	0.42
	Limited (2)
	Substantial (3)
	Extensive (4)

Table 2 The ulcerative colitis endoscopic index of severity descriptors (maximum score = 8, Scoring is based on the most severe area)

Descriptors	Likert Scale anchor point	Definition
Vascular pattern	0: Normal 1: Patchy obliteration 2: Complete obliteration	Normal vascular pattern with arborisation of capillaries clearly defined, or with blurring or patchy loss of capillary margins Complete obliteration
Bleeding	0: None 1: Mucosa 2: Luminal mild 3: Luminal moderate or severe	Some spots or streaks of coagulated blood on the surface of the mucosa Some free liquid blood in the lumen Frank blood in the lumen ahead of endoscope or visible oozing from a haemorrhagic mucosa
Erosions and Ulcers	0: None 1: Erosions	None Tiny < 5 mm defects in the mucosa, of white or yellow colour with a flat edge
	2: Superficial ulcer	Larger > 5 mm defect in the mucosa, which are discrete fibrin-covered ulcers in comparison with erosions, but remain superficial
	3: Deep ulcer	Deeper excavated defects in the mucosa, with a slightly raised edge

Table 3 Ulcerative colitis disease activity index (maximum score = 12)

Variables	Score	Items
Stool frequency	0	Normal
	1	1-2 stools/d more than normal
	2	3-4 stools/d more than normal
	3	> 4 stools/d more than normal
Rectal bleeding	0	None
	1	Streaks of blood
	2	Obvious blood
	3	Mostly blood
Endoscopic appearance	0	Normal
	1	Mild friability
	2	Moderate friability
	3	Exudation, spontaneous bleeding
Physician global assessment	0	Normal
	1	Mild
	2	Moderate
	3	Severe

Table 4 Validation studies of ulcerative colitis endoscopic index of severity and ul-cerative colitis disease activity index

	Ref.	Patient number	Outcomes
UCEIS
Validity	Corte et al[18]	89	Correlation between UCEIS and outcomes The UCEIS score was directly proportional to requirement of rescue therapy UCEIS ≥ 5 was significantly linked to requiring colectomy 18/54 (33%) patients with UCEIS ≥ 5 compared to 3/33 (9%) with UCEIS ≤ 4 No definition of remission
	Fernandes et al[19]	108	Prediction of outcomes in acute severe colitis UCEIS was applied to score of the rectum and sigmoid, seg-UCEIS Seg-UCEIS predicted to develop steroid-refractory disease and the likelihood of colectomy (seg-UCEIS = 14 had a 17 times higher risk of steroid-refractory disease and a 25 times higher risk of requiring colectomy) Every 1 point increase in the UCEIS or Seg-UCEIS increased the need of colectomy by 2.78 and 1.79 respectively Mayo score did not predict these No definition of remission
	Arai et al[20]	285	Reflection of true UC activity and remission The recurrence rate was directly proportional to the UCEIS score (5.0% for UCEIS = 0, 22.4% for UCEIS = 1, 27.0% for UCEIS = 2, 35.7% for UCEIS = 3, 75% for UCEIS = 4-5) The absence of bleeding and mucosal damage were independent factors for continued clinical remission UCEIS ranged from 0 to 5 when clinical remission, Mayo ≤ 1 UCEIS ≤ 1 for clinical remission, which showed sensitivity of 68% and specificity 57% The expected duration of recurrence is also prolonged when UCEIS ≤ 1
	Kucharski et al[21]	49	Assessment of 9 endoscopic indices correlate well with (1) clinical indices; and (2) histological Geboes Index[22] The UCEIS showed the strongest correlation with the Geboes Index (the coefficient: 0.434 to 0.629) Recommends the UCEIS for the best overall correlations with both clinical and histological indices
Responsiveness	Ikeya et al[23]	41	The ability to detect to change after Tacrolimus remission induction treatment for moderate to severe UC Although Mayo endoscopic score is easy to use, it does not distinguish depth of ulcers unlike UCEIS Despite UCEIS score improved from 7 to 4, Mayo endoscopic score remained at 3 (severe) An improvement of UCEIS ≥ 3 showed close correlation with clinical remission, colectomy-free and relapse free rates Proposed remission (score 0-1), mild (2-4), moderate (5-6), severe (7-8) UCEIS 1 in remission is only from vascular pattern
	Menasci et al[24]	80	Comparison of the global UCEIS score from 5 segments and a traditional method of UCEIS score The regular method of the UCEIS is to score the most inflamed segment of the bowel This was compared with the sum of the score of five colonic segments A very good correlation (Spearman’s r = 0.86, P < 0.0001) for disease with UCEIS score ≤ 5 Less correlation (r = 0.48, P < 0.01) for disease with UCEIS > 5
Reliability	Travis et al[15]		Investigation of intra- and inter-observer consistency assessment 25 readers evaluated 28 videos including 4 duplicates to assess intra-reader reliability The intra and inter-reader reliability ratios for the UCEIS were 0.96 and 0.88 respectively The USCEI revealed a strong correlation with overall assessment of severity without being influenced by knowledge of clinical information No definition of remission
	Feagan et al[25]	281	The effect of centralized review of images on inter-observer variations Patients with UCDAI ≥ 2 were randomised to evaluate the efficacy of delayed mesalamine treatment (4.8 g/d for 10 wk) UCEIS was used as a part of inter-observer agreement study and showed interclass correlation coefficient of 0.83 amongst 7 central readers, which is superior to UCDAI
	Travis et al[26]		Clinical information influences UCEIS score 40 readers evaluated 28 of 44 videos No discrepancy between blinded and unblended readers Intra- and inter-reader variability demonstrated moderate to substantial agreement (κ = 0.47 to 0.74 and κ = 0.40 to 0.50 respectively) UCEIS correlated well with patient-reported symptoms - rectal bleeding, stool frequency and patient functional assessment (rank correlation = 0.76 to 0.82)
UCDAI
Validity	Higgins et al[27]	66	Finding endpoints in disease activity indices for remission and improvement in UC UCDAI < 2.5 for remission, which had a sensitivity and specificity of 0.82 and 0.89 Remission in this study was defined by patients
	Poole et al[28]	126	Establish the relationship between the UCDAI and patient reported EQ-5D The UCDAI with or without endoscopy assessment demonstrated a good correlation with EQ-5D Endoscopy assessment may not link with the disease activity
	Kucharski et al[21]	49	Assessment of 9 endoscopic indices correlate well with (1) clinical indices; and (2) histological Geboes Index (22) The UCDAI showed strong correlations with all 9 endoscopic indices (the coefficient in a range of 0.712 to 0.790) The UCDAI showed the highest correlation amongst clinical activity indices with the Geoboes Index (the Spearman’s coefficient 0.478) Compared to UCEIS, the UCDAI is less correlated with the Geboes Index
Reliability	Feagan et al[25]	281	The effect of centralized review of images on inter-observer variations Patients with UCDAI ≥ 2 were randomised to evaluate the efficacy of delayed mesalamine treatment (4.8 g/d for 10 wk) 31% of patients with UCDAI ≥ 2 enrolled in the RCT initially were considered ineligible by the central readers Inter-observer agreement amongst 7 central readers was good (interclass correlation coefficient: 0.78)

UC: Ulcerative colitis; UCEIS: Ulcerative colitis endoscopic index of severity; Seg-UCEIS: The sum of the rectal and sigmoid segmental UCEIS score; UCDAI: Ulcerative colitis disease activity index; EQ-5D: EuroQoI Five Dimensions Questionnaire; RCT: Randomised control trial.

Table 5 Definitions of remission in ulcerative colitis

Guidelines	Definition
FDA[5]	Clinical remission Mayo score of ≤ 2 with no individual subscore > 1 Rectal Bleeding subscore = 0 Stool Frequency subscore = 0 (at least one point decrease in Stool Frequency subscore from baseline and achieved 1 is considered) Endoscopy subscore = (Mayo score: 0 or 1, UCDAI = 0) Clinical response Reduction in Mayo score ≥ 3 and ≥ 30% from baseline with Rectal Bleeding subscore ≤ 1 Corticosteroid-free remission Clinical remission in patients using oral corticosteroids at baseline who have discontinued them and are in clinical remission at the end of the study
World Gastroenterology Organisation	Clinical remission UCDAI ≤ 2 (2010 World Gastroenterology Organisation Practice Guideline)[50] Corticosteroid-free remission Decreasing the frequency and severity of recurrence and reliance on corticosteroids
International Organisation for the Study of IBD	End points = induction of remission = mucosal healing[12] The absence of friability, blood, erosions and ulcers in all visible segments No mention of clinical symptoms
American College of Gastroenterology	No clear definition[51]
British Society of Gastroenterology	No clear definition[52]
European Crohn’s and Colitis Organisation	Remission[53] A complete resolution of symptoms and endoscopic mucosal healing Not been a fully validated definition of remission Suggest the best way forward is a combination of Stool Frequency ≤ 3 No rectal bleeding Normal or quiescence mucosa at endoscopy Clinical response Clinical and endoscopic response depending on the activity index Generally, a decrease in the activity index > 30% plus a decrease in the rectal bleeding and endoscopic subscores

UCDAI: Ulcerative colitis disease activity index; IBD: Inflammatory bowel disease; FDA: Food and Drug Administration.

Table 6 Clinical studies measured with the ulcerative colitis endoscopic index of severity

Ref.	Year	Type of study	Drug/subject of study	Entry criteria	Primary endpoint	Secondary endpoint	Remission/clinical improvement	Length of study
Hartman et al[54]	2016	Randomised, double-blind, placebo-controlled study	AVX-470, oral	36 patients with Mayo score 5-12 and Mayo ES ≥ 2	Not set, but implies clinical response at week 4	Not set	Remission was not defined. Clinical response Mayo reduction ≥ 3	4 wk
Lin et al[55]	2015	Prospective, multi-centre study	Faecal calprotectin	52 patients with UC	N/A	N/A	Endoscopic remission: UCEIS < 3	N/A
Magro et al[56] ACERTIVE study	2016	Cross-sectional multi-centre study	Faecal calprotectin/ lipocalin	371 patients Mayo partial score < 2, montreal classification < 2			Remission: UCEIS ≤ 1 Mucosal healing: Mayo ES = 0

UCEIS: Ulcerative colitis endoscopic index of severity; UC: Ulcerative colitis; ES: Endoscopic subscore; N/A: Not available.

Table 7 Randomised clinical trials measured with the ulcerative colitis disease activity index

Ref.	Year	Drug	Entry criteria	Primary endpoint	Secondary endpoint	Remission/clinical improvement	Length of study
Randomised clinical trials - to induce remission
Mesalazine (5-ASA)
Marteau etal[58]	2005	Pentasa (PR + PO vs PO alone)	UCDAI: 3-8	Remission at week 4	Remission rate at week 8 Improvement at week 4 and 8	Remission: UCDAI ≤ 1 Clinical improvement: A decrease of UCDAI ≥ 2	8 wk
D’Haens etal[59]	2006	SPD476 - MMX mesalazine	UCDAI: 4-10 + endoscopic score ≥1 PGA score ≤ 2	Remission	Change in UCDAI, FS, histology at week 8 Change in symptoms	Remission: UCDAI ≤ 1 (with RB 0, SF ≤ 1 ) at week 8	8 wk
Sandborn etal[60]	2007	MMX Multi Matrix System mesalazine	UCDAI: 4-10 + endoscopic score ≥1 PGA score ≤ 2	Clinical/endoscopic remission at 8 wk	Proportion of clinical improvement Proportion of patients as treatment failure Change in: RB, SF, FS	Clinical remission: UCDAI ≤ 1 Endoscopic remission: UCDAI endoscopic subscore ≤ 1 Clinical improvement: A decrease of UCDAI ≥ 3 Treatment failure: Unchanged or worsened UCDAI	8 wk
Lichtenstein et al[61]	2007	SPD476 - MMX mesalazine OD vs BD	UCDAI: 4-10	Clinical and endoscopic remission at week 8	Comparison of remission rate at week 8	Clinical remission: UCDAI ≤ 1 with RB/SF/EI = 0	8 wk
Kamm et al[62,63] MEZAVANT study	2007 2009	MEZAVANT MMX Mesalamine	Mild - mod UC: UCDAI 4-10 + endoscopic subscore ≥ 1, PGA ≤ 2	Clinical + Endoscopic remission at week 8	Clinical remission Clinical improvement Change in UCDAI	Clinical + endoscopic remission: UCDAI ≤ 1 + subscore RB/SF = 0, No mucosal friability + a ≥ 1 reduction in EI Clinical improvement: Decrease in UCDAI ≥ 3	8 wk
Ito et al[64]	2010	Asacol vs PentasaTime-dependent vs pH dependent Mesalamine	UCDAI: 3-8 and blood stool score ≥ 1	To demonstrate Asacol over Pentasa AND the decrease in UCDAI	Macroscopic changes	Remission: UCDAI ≤ 2 and no blood diarrhoea Clinical improvement: UCDAI decreased by ≥ 2	8 wk
Hiwatashi etal[65]	2010	Mesalazine - dose study	UCDAI: 6-8	Change in UCDAI at week 8	Remission, improvement, efficacy	Remission: UCDAI ≤ 1 Efficacy: Decrease of UCDAI ≥ 2	8 wk
Flourié et al[66] MOTUS study	2013	Mesalazine, Pentasa OD or BD in total of 4 g/d	UCDAI: 3-8	UCDAI ≤ 1 after 8 wk	Complete remission (UCDAI = 0) at 8 wk UCDAI decreased by ≥ 2 at 8 wk Clinical remission at week 4, 8, 12 Mucosal healing at 8 wk	Complete remission: UCDAI = 0 Endoscopic remission: UCDAI endoscopic subscore: 0 or 1 Clinical remission: UCDAI ≤ 1	12 wk
Probert et al[42] PINCE study	2013	Mesalazine (pentasa) enema	UCDAI: 3-8	Remission rate (UCDAI < 2) at 4 wk	Remission rate at 8 wk, improvement at week 2, 4 and 8 Time to cessation of RB QoL (EQ-5D)	Remission: UCDAI ≤ 1 Clinical improvement: UCDAI decreased by ≥ 2	8 wk
Sun et al[67]	2016	Mesalazine (modified-release vs enteric-coated tablets)	UCDAI: 3-8 + bloody stool score > 1	The decrease in UCDAI	Remission rate Efficacy rate	Remission: UCDAI ≤ 2 + bloody stool 0 Clinical improvement: A decrease of UCDAI ≥ 2	8 wk
Suzuki etal[68]	2016	pH dependent release mesalamine, asacol dose	UCDAI: 6 - 10 Rectal bleeding score ≥ 1	Decrease in UCDAI		Remission: UCDAI ≤ 2 Rectal bleeding score: 0 Improvement UCDAI decreased by ≥ 2	8 wk
Thiazole compounds
Mantzaris etal[69]	2004	Azathioprine alone (2.2 mg/kg) vs combination with olsalazine (0.5 g TID)	Steroid-dependent remission	Relapse rate	Time to relapse Time to discontinuation Severity of relapse	Remission: UCDAI ≤ 1 Relapse: New symptoms + UCDAI > 3	2 yr
Schreiber etal[70]	2007	Tetomilast - Thiazole compound	UCDAI: 4-11	Clinical improvement: UCDAI decreased by ≥ 3 at 8 wk	Remission Clinical improvement at week 4 IBDQ-32 score Proportion of pts with improved Flexible Sigmoidscopy score Time to clinical improvement Time to remission	Clinical improvement: UCDAI decreased by ≥ 3 Remission: UCDAI ≤ 1	8 wk
Steroids
Travis et al[71] CORE II study	2012	Budesonide MMX	UCDAI: 4-10	Clinical/endoscopic remission at week 8	Clinical improvement Endoscopic improvement at week 8	Clinical/endoscopic Remission: UCDAI ≤ 1 + RB/SF/EI = 0 Clinical improvement: A decrease of UCDAI ≥ 3 Endoscopic improvement: A decrease of EI ≥ 1	8 wk
Probiotics
Vernia etal[72]	2000	Sodium Butyrate	Mild-moderate UC	Remission or marked improvement		Remission: UCDAI ≤ 2 Positive response: Decrease of UCDAI ≥ 2	6 wk
Mahmood etal[73]	2005	Human recombinant trefoil factor 3 enema	UCDAI: >3	Remission at week 2	Clinical significant improvement in clinical and histological scores at 2 and 4 wk	Remission: UCDAI ≤ 1 without RB Clinical improvement: A decrease of UCDAI >3	4 wk
Lichtenstein et al[74]	2007	Bowman-Birk inhibitor concentrate - soy extract with high protease inhibitor activity	UCDAI: 4-10	Remission at week 8		Remission: UCDAI ≤ 1 + no RB or SF Clinical improvement: UCDAI decrease ≥ 1
Tursi et al[75]	2009	VSL #3 (probiotic)	UCDAI 3-8, endoscopic subscore ≥ 3	Decrease in UCDAI of ≥ 50%	Activity of relapsing UC Remission Improvement Change in objective and subjective symptoms	Remission: UCDAI ≤ 2	8 wk
Sood et al[76]	2009	VSL #3 probiotic	UCDAI 3-9 with endoscopic subscore ≥ 2	Clinical improvement at week 6	Clinical remission	Clinical remission: UCDAI ≤ 2 Clinical improvement: A decrease UCDAI by 50%	12 wk
Tamaki etal[77]	2016	Bifidobacterium longum 536 (probiotic)	UCDAI 3-9	Change in UCDAI	Remission Improvement of Objective and subjective symptoms Endoscopic improvement in Mayo subscore	Remission: UCDAI ≤ 2	8 wk
Helminth therapy Garg etal[78]	2014	Helminth Trichuris suis ova	UCDAI of ≥ 4	Clinical improvement	Clinical remission	Clinical improvement: Decrease in the UCDAI of ≥ 4 Clinical remission: UCDAI of ≤ 2	12 wk
Nicotine therapy
Ingram etal[79]	2005	Nicotine enema 6 mg/d	Confirmed UC with inflamed mucosa grade > 2	Clinical remission	Improvement in the UCDAI	Clinical remission: UCDAI EI ≤ 1 and No RB for 1 wk	6 wk
Randomised clinical trials - to maintain remission
Lichtenstein et al[80-82] and Zakko etal[83]	2010 2012 2015 2016	Mesalamine granules 1.5 g/d, OD	Previously achieved remission with steroids for > 1 mo and < 12 mo	Percentage of patients relapse-free at 6 mo	Mean changes from baseline at month 6	Relapse: UCDAI RB ≥ 1 and EI ≥ 2 Remission: UCDAI RB = 0, EI < 2	6 mo
Bokemeyer et al[43] and Dignass etal[84]	2009 2011	Mesalazine, Pentasa OD or BD in total of 2 g/d	Clinical remission: UCDAI < 2	To demonstrate OD is not inferior to BD	Time to relapse between 2 groups UC-DAI total and subscores between 2 groups	Remain in remission UCDAI ≤ 2	12 mo

RB: Rectal bleeding; SF: Stool frequency; EI: Endoscopic index/subscore; OD: Once daily; BD: Twice daily; TID: Three times daily; UCDAI: Ulcerative colitis disease activity index; QoL: Quality of life.