Histologic assessments in ulcerative colitis: the evidence behind a new endpoint in clinical trials

Figures & data

Table 1. Definitions of histologic disease activity targets in ulcerative colitis.

Target	Definition	GS	RHI	NHI	IBD-DCA	Reference
Histologic improvement	Neutrophil infiltration in < 5% of crypts; no crypt destruction, erosions, ulcerations, or granulation tissue	≤3.1	Proposed: 6-point reduction or ≤ 9	Proposed: 1-point reduction or ≤ 1	Proposed: D: any, C: ≤2, A: 1	[41,42,44,45]
Histologic remission	Colorectal mucosa without neutrophilic inflammation but with indications of chronicity (quiescent UC)	≤2B.0 or < 2.0	≤3	≤1 or 0	D: any, C: ≤2, A: 0	[27,31,41,45–47]
Histologic normalization	Complete normalization of the colorectal mucosa	0.0, 1.0, 2A.0, 2B.0, 3.0, 4.0, and 5.0	–	–	D = 0, C = 0, A = 0^g	[27,41,48]

Abbreviations: A = activity features; C = chronicity; D = distribution; GS = Geboes score; IBD-DCA = Inflammatory Bowel Disease – Distribution, Chronicity, Activity; NHI = Nancy Histologic Index; RHI = Robarts Histopathology Index; UC = ulcerative colitis.

Figure 1. UC treatment targets.

Abbreviations: PRO = patient-reported outcome; QoL = quality of life.

Figure 2. Timeline of selected UC histology assessments and regulatory guidance.

Abbreviations: EMA = European Medicines Agency; FDA = Food and Drug Administration; IBD-DCA = Inflammatory Bowel Disease-Distribution, Chronicity, Activity.

Table 2. Scoring of selected histologic assessments.

Measure and components	Scoring	Reference
Geboes Grading Scale	The Geboes Grading Scale is a categorical measure ranging from 0–6 based on the highest subscore observed or 0–22 by adding all subscores, with higher scores indicating worse histological disease activity. The worst score from available biopsies is taken.	[55]
Grade 0: Architectural changes	0.0 No abnormality 0.1 Mild abnormality 0.2 Mild/moderate diffuse or multifocal abnormalities 0.3 Severe diffuse or multifocal abnormalities
Grade 1: Chronic inflammatory infiltrate	1.0 No increase 1.1 Mild but unequivocal increase 1.2 Moderate increase 1.3 Marked increase
Grade 2A: Eosinophils in lamina propria	2A.0 No increase 2A.1 Mild but unequivocal increase 2A.2 Moderate increase 2A.3 Marked increase
Grade 2B: Neutrophils in lamina propria	2B.0 No increase 2B.1 Mild but unequivocal increase 2B.2 Moderate increase 2B.3 Marked increase
Grade 3: Neutrophils in epithelium	3.0 None 3.1 < 5% crypts involved 3.2 < 50% crypts involved 3.3 > 50% crypts involved
Grade 4: Crypt destruction	4.0 None 4.1 Probable – local excess of neutrophils in part of the crypts 4.2 Probable – marked attenuation 4.3 Unequivocal crypt destruction
Grade 5: Erosions and ulcerations	5.0 No erosion, ulceration, or granulation 5.1 Recovering epithelium + adjacent inflammation 5.2 Probable erosion – focally stripped 5.3 Unequivocal erosion 5.4 Ulcer or granulation tissue
Robarts Histopathology Index	Robarts Histopathology Index = 1 × chronic inflammatory infiltrate level + 2 × lamina propria neutrophils + 3 × neutrophils in epithelium + 5 × erosion or ulceration. The total Robarts Histopathology Index score ranges from 0–33, with higher scores indicating worse histological disease activity.	[56]
Chronic inflammatory infiltrate level	Weighted: x 1  0 = No increase  1 = Mild but unequivocal increase  2 = Moderate increase  3 = Marked increase
Lamina propria neutrophils	Weighted: x 2  0 = No increase  1 = Mild but unequivocal increase  2 = Moderate increase  3 = Marked increase
Neutrophils in epithelium	Weighted: x 3  0 = None  1 = <5% crypts involved  2 = <50% crypts involved  3 = >50% crypts involved
Erosion or ulceration	Weighted: x 5  0 = No erosion, ulceration, or granulation tissue  1 = Recovering epithelium + adjacent inflammation  1 = Probable erosion – focally stripped  2 = Unequivocal erosion  3 = Ulcer or granulation tissue
Nancy Histological Index	The Nancy Histological Index ranges from 0–4: if ulcerations are present, 4; if clusters of neutrophils are present, 3; if a few neutrophils are present, 2; if moderate increase in chronic inflammatory infiltrate, 1; if no or mild increase in chronic inflammatory infiltrate, 0.	[47]
Chronic inflammatory infiltrate	0 = No or mild increase (no histological significant disease) 1 = Moderate or marked increase (chronic inflammatory infiltrate with no acute inflammatory infiltrate)
Acute inflammatory cells infiltrate	2 = Mild (mildly active disease) 3 = Moderate or severe (moderately active disease)
Ulceration	4 = Present (severely active disease)
Inflammatory Bowel Disease – Distribution, Chronicity, Activity Score	The Inflammatory Bowel Disease – Distribution, Chronicity, Activity Score reports each subscore separately: DX, CX, AX, where X ranges from 0 (no disease activity) to 2 (most severe activity).	[48,57]
Distribution	0 = Normal 1 = Less than 50% of tissue affected at same biopsy location 2 = 50% or more of tissue affected at same biopsy location
Chronicity	0 = Normal 1 = Crypt distortion and/or mild lymphoplasmacytosis 2 = Marked lymphoplasmacytosis and/or marked basal plasmacytosis
Activity	0 = Normal 1 = 2 or more neutrophils in lamina propria in 1 high-power field and/or any number of intraepithelial neutrophils 2 = Crypt abscesses, erosions, and/or ulcers

Table 3. Histologic disease activity endpoints in clinical trials of treatments for UC.

Treatment, Stage, Trial(s)	Endpoints	Clinical, Endoscopic, and Histologic Results Percent change from placebo (95% CI) unless otherwise indicated	Ref.
Cobitolimod Phase 2b CONDUCT (NCT03178669)	Primary  Clinical remission (MS): RBS = 0, SFS ≤ 1, MES ≤ 1 Secondary  Endoscopic improvement: MES ≤ 1  Histologic improvement: NHI ≤ 1	Week 6 (2 × 250-mg dose)  Clinical remission: 3.8 (1.5–9.5)  Endoscopic improvement: 1.5 (0.8–2.8)  Histologic improvement: 0.8 (0.4–1.6)  Values presented as odds ratio (80% CI)	[67]
Etrasimod Approved ELEVATE UC 12 (NCT03996369), ELEVATE UC 52 (NCT03945188)	Primary  Clinical remission (MS): RBS = 0, SFS ≤ 1, MES ≤ 1 Secondary  Endoscopic improvement: MES ≤ 1  Endoscopic normalization: MES = 0  Mucosal healing: MES ≤ 1, GS < 2	Week 12  Clinical remission: 19.8% (12.9–26.6)  Endoscopic improvement: 21.2% (13.0–29.3)  Endoscopic normalization: 10.2% (4.7–15.7)  Mucosal healing 16.9% (10.8–23.0) Week 52  Clinical remission: 25.4% (18.4–32.4)  Endoscopic improvement: 26.7% (19.0–34.4)  Endoscopic normalization: 20.4% (13.8–27.0)  Mucosal healing: 18.4% (11.4–25.4)	[68]
Filgotinib* Approved SELECTION (NCT02914522)	Primary  Clinical remission (MS): RBS = 0, SFS ≤ 1, MES ≤ 1 Secondary  Endoscopic remission: MES = 0  Histologic remission (GS): Grade 0 ≤ 0.3, Grade 1 ≤ 1.1, Grade 2A ≤ 2A.3, Grade 2B = 2B.0, Grade 3 = 3.0, Grade 4 = 4.0, and Grade 5 = 5.0	Week 58 (200-mg dose)  Clinical remission: 26.0% (16.0–35.9)  Endoscopic remission: 9.5% (1.8–17.1)  Histologic remission: 24.9% (14.6–35.2)	[69]
Guselkumab Phase 2b QUASAR (NCT04033445)	Secondary  Clinical remission (MS): RBS = 0, SFS ≤ 1, MES ≤ 1  Endoscopic improvement: MES ≤ 1  Endoscopic normalization: MES = 0  Histo-endoscopic improvement: MES ≤ 1, GS ≤ 3.1	Week 12 (200-mg dose)  Clinical remission: 16.3% (6.3–26.3)  Endoscopic improvement: 18.3% (7.5–29.0)  Endoscopic normalization: 11.3 (2.6–20.0)  Histo-endoscopic improvement: 12.1% (2.8–21.4)	[70]
Mirikizumab Approved LUCENT-1 (NCT03518086), LUCENT-2 (NCT03524092)	Primary  Clinical remission (MS): RBS = 0, SFS ≤ 1, MES ≤ 1 Secondary  Endoscopic remission: MES ≤ 1  Histologic improvement (GS, not reported): GS ≤ 3.1 (neutrophil infiltration in < 5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue)  Histologic remission (GS): GS ≤ 2B.0 (no lamina propria neutrophils; no neutrophils in the surface or crypt epithelium; no crypt destruction; and no erosions, ulcerations, or granulation tissue)  Histo-endoscopic improvement: endoscopic remission (MES ≤1) plus histologic improvement  Histo-endoscopic remission: endoscopic remission (MES ≤ 1) plus histologic remission	Week 12  Clinical remission: 11.1% (3.2–19.1)  Endoscopic remission: 15.4% (6.3–24.5)  Histologic remission: 13.7% (8.6–18.7)  Histo-endoscopic improvement: 13.4% (5.5–21.4) Week 52 (week 40 of maintenance)  Clinical remission: 23.2% (15.2–31.2)  Endoscopic remission: 28.5% (20.2–36.8)  Histologic remission: 22.5% (14.5–30.5)  Histo-endoscopic remission: 19.9% (12.1–27.6)	[71,72]
Ozanimod Approved True North (NCT02435992)	Primary  Clinical remission (MS): RBS = 0, SFS ≤ 1, MES ≤ 1 Secondary  Endoscopic improvement: MES ≤ 1  Histologic remission: GS < 2  Mucosal healing: Endoscopic improvement plus histologic remission	Week 10  Clinical remission: 12.4% (7.5–17.2)  Endoscopic improvement: 15.7% (9.7–21.7)  Histologic remission: 10.8% (5.8–15.8)  Mucosal healing: 8.9% (4.9–12.9) Week 52  Clinical remission: 18.6% (10.8–26.4)  Endoscopic improvement: 19.4% (11.0–27.7)  Histologic remission: 17.3% (9.6–24.9)  Mucosal healing: 15.6% (8.2–22.9)	[73]
Risankizumab Phase 3 INSPIRE (NCT03398148), COMMAND (NCT03398135)	Primary  Clinical remission (MS): RBS = 0, SFS ≤ 1, MES ≤ 1 Secondary  Endoscopic improvement: MES ≤ 1  Histo-endoscopic improvement: MES ≤ 1, GS ≤ 3.1	Week 12  Clinical remission: 14.1%  Endoscopic improvement: 24.4%  Histo-endoscopic improvement: 16.8% Week 52 (180-mg dose, not placebo adjusted)  Clinical remission: 40%  Endoscopic improvement: 51%  Histo-endoscopic improvement: 43% CI not reported	[74]
Upadacitinib Approved U-ACHIEVE (NCT02819635), U-ACCOMPLISH (NCT03653026)	Primary  Clinical remission (MS): RBS = 0, SFS ≤ 1, MES ≤ 1 Secondary  Endoscopic improvement: MES ≤ 1  Endoscopic remission: MES = 0  Histologic improvement: any decrease in GS  Histo-endoscopic mucosal improvement: MES ≤ 1, GS ≤ 3.1  Mucosal healing: MES = 0, GS < 2	Week 8 (U-ACCOMPLISH)  Clinical remission: 29.0% (23.2–34.7)  Endoscopic remission: 15.9% (11.4–20.3)  Endoscopic improvement: 35.1% (28.6–41.6)  Histologic improvement: 37.9% (29.8–46.1)  Mucosal healing: 11.3% (7.2–15.3) Week 52 (30-mg dose)  Clinical remission: 39.0% (29.7–48.2)  Endoscopic remission: 19.4% (11.7–27.2)  Endoscopic improvement: 46.3% (36.7–55.8)  Mucosal healing: 13.6% (6.6–20.6)	[75]
Ustekinumab Approved UNIFI (NCT02407236)	Primary  Clinical remission: MS ≤ 2 (no subscores > 1) Secondary  Endoscopic improvement: MES ≤ 1  Histologic improvement: < 5% neutrophils in epithelium, no crypt destruction, and no erosions, ulcerations, or granulations  Histo-endoscopic healing: Endoscopic improvement and histologic improvement	Week 8 (130-mg dose)  Clinical remission: 10.3% (5.7–14.9)  Endoscopic improvement: 12.5%  Histologic improvement: 16.1% (9.0–23.3)  Histo-endoscopic healing: 11.4% Week 44 (90 mg every 12 weeks)  Clinical remission: 14.5% (5.5–23.6)  Endoscopic improvement: 15.0%  Histologic improvement: 20.9% (10.8–30.9)  Histo-endoscopic healing: 14.9% (5.7–24.2)  CI not reported for endoscopic improvement (Weeks 8 and 44) and histo-endoscopic healing (Week 8)	[76,77]
Vedolizumab Approved VARSITY (NCT02497469)	Primary  Clinical remission: MS ≤ 2 (no subscores > 1) Secondary  Mucosal healing: MES ≤ 1  Histologic remission (GS): GS < 2  Histologic remission (RHI): RHI ≤ 2	Week 52  Clinical remission: 8.8% (2.5–15.0)  Mucosal healing: 11.9% (5.3–18.5)  Histologic remission (GS): 20.9% (15.6–26.2) Histologic remission (RHI): 17.6% (11.3–23.8)  Values presented as percent difference from adalimumab treatment group	[46]

Unless otherwise indicated, values represent least squares mean percent change from placebo (95% CI). GS subscores: Grade 0 = architecture changes; Grade 1 = chronic inflammatory infiltrate; Grade 2A = lamina propria eosinophils; Grade 2B = lamina propria neutrophils; Grade 3 = epithelium neutrophils; Grade 4 = crypt destruction; Grade 5 = erosion and ulceration.

Abbreviations: CI = confidence interval; GS = Geboes score; MS = Mayo score; MES = Mayo (or mucosal) endoscopic subscore; NHI = Nancy histological index; RBS = rectal bleeding subscore; RHI = Robarts histopathology index; SFS = stool frequency subscore.

*Filgotinib is approved in the European Union, Great Britain, and Japan.

Figure 3. Potential association of histological remission with clinical outcome.

Table 4. Selected studies analyzing associations between histologic remission and clinical outcomes.

Study description	Clinical outcomes assessed	Histologic definition	Endoscopic definition	Summary findings	Ref
British single-center prospective long-term observational study (enrolled 2007–2008 and followed for median of 72 months) of patients with UC (N = 91)	Corticosteroid use Hospitalization Colectomy	‘No significant inflammation’ in Truelove and Richards’ index	Endoscopic remission: Baron score ≤ 1 without mucosal friability	Histologic remission was associated with corticosteroid use (HR 0.42, 95% CI 0.2–0.9, p = 0.02) and hospitalization (HR 0.21, 95% CI 0.1–0.7, p = 0.02) but not colectomy.	[26]
American single-center prospective study (2009–2013) of 889 biopsies from patients with UC (N = 281)		Complete resolution of neutrophil-associated inflammation	Endoscopic remission: MES ≤ 1	3-year rates of corticosteroid use, hospitalization, and colectomy were lower in patients achieving histologic remission (n = 99) vs those with histologic disease activity (n = 182) (p < 0.001, p = 0.047, and p = 0.46, respectively).	[79]
HAYABUSA Japanese multicenter open-label RCT of patients with UC (enrolled 2014–2017) in remission treated with and/or discontinuing infliximab (N = 95)	Relapse (CAI >5)	Histologic normalization: no acute inflammatory changes (NHI ≤2)	Endoscopic remission: MES = 0	Histologic normalization and low CRP levels were factors associated with a lower risk of relapse after de-escalation of infliximab treatment (In terms of maintaining remission at Week 48: NHI ≥ 2 vs NHI < 2: OR 0.14, 95% CI 0.01–1.37, p = 0.091; baseline CRP level: OR 1.7 × 10^−5, 95% CI 0.00–0.64, p = 0.041).	[80]
Retrospective single-center cohort study (followed for at least 6 months between 2012 and 2019) of American patients with active UC (N = 411)	Relapse (RBS >0 with SFS 2 or 3) Hospitalization Colectomy	Either complete mucosal normalization or chronic architectural changes with no epithelial neutrophils and ≤ 1 neutrophil/high power field in lamina propria (GS < 2B.1 and < 3.1)	MES = 0	Histologic remission was associated with lower risk of relapse (HR 0.56, 95% CI 0.37–0.85) and hospitalization (HR 0.44, 95% CI 0.20–0.94) over 28 months.	[81]
Retrospective long-term single-center study (2005–2013 and followed for up to 60 months) of American patients with UC (N = 646)	Relapse (SCCAI >2 with subscore > 1 for SF, RB, and/or medication escalation)	Histologic normalization: normal mucosa with no architectural changes Histologic quiescence: No active inflammation but architectural changes	Endoscopic healing: MMDAI ≤ 1	Histologic normalization was associated with relapse-free survival versus histologic quiescence (HR 4.31, 95% CI 1.48–12.46, p = 0.007) and histologic disease activity (HR 6.69, 95% CI 2.16–20.62, p = 0.01).	[82]
Retrospective single-center study (2005 to date of last follow-up occurring after 2010) of American patients with UC (N = 495)	Dysplasia		N/A	The risk of developing dysplasia (a precursor to neoplasia) was lower in patients achieving histologic normalization versus histologic quiescence (HR 0.32, 95% CI 0.13–0.81) and histologic disease activity (HR 0.52, 95% CI 0.25–1.10).	[83]
UNIFI phase 3 RCT assessing ustekinumab treatment in patients with moderately-to-severely active UC (N = 2630)	Clinical remission Corticosteroid-free remission	Histologic improvement: <5% neutrophils in epithelium, no crypt destruction, and no erosions, ulcerations, or granulations	Endoscopic improvement: MES ≤ 1	Histo-endoscopic mucosal healing after induction was associated with a 20% to 30% increase in clinical remission and corticosteroid-free remission at Week 44 compared to patients with either histologic or endoscopic improvement alone. Clinical remission: Histologic improvement (p = 0.0009) Endoscopic improvement (p = 0.093) Corticosteroid-free remission: Histologic improvement (p = 0.0028) Endoscopic improvement (p = 0.0628)	[44]
LUCENT-1 and −2 phase 3 RCTs assessing mirikizumab treatment in patients with moderately-to-severely active UC (LUCENT-1: N = 1162; LUCENT-2 N = 544)		Histologic improvement: GS ≤ 3.1 Histologic remission: GS ≤ 2B.0	Endoscopic remission: MES ≥ 1	Histologic improvement at Week 12 in LUCENT-1 was significantly associated with clinical remission and symptomatic remission at Week 40 in LUCENT-2 (OR 1.61, 95% CI 1.06–2.44, p = 0.0238; and OR 1.67, 95% CI 1.06–2.64, p = 0.0260; respectively). Achieving histologic remission at Week 12 in LUCENT-1 was significantly associated with corticosteroid-free remission, clinical remission, and symptomatic remission at Week 40 in LUCENT-2 (OR 1.54, 95% CI 1.01–2.35, p = 0.0435; OR 1.60, 95% CI 1.05–2.44, p = 0.0293; and OR 1.82, 95% CI 1.12–2.94, p = 0.0144; respectively).	[84]

Abbreviations: CAI = Clinical Activity Index; CI = confidence interval; CRP = C-reactive protein; GS = Geboes score; HR = hazard ratio; MES = Mayo endoscopic score; MMDAI = modified Mayo disease activity index; N = number of patients; n = number of patients in subgroup; N/A, not applicable: NHI = Nancy histological index; OR = odds ratio; RB = rectal bleeding; RBS = rectal bleeding score; SCCAI = Simple Clinical Colitis Activity Index; SF= stool frequency; SFS = stool frequency score; UC = ulcerative colitis.

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