. 2025 Mar 13;19(4):jjaf040. doi: 10.1093/ecco-jcc/jjaf040

Table 2.

Studies of biologic and small molecule therapies using novel IBD objectively measured outcomes in UC.

Study	Treatment	Key study details and findings
Histological activity, including histological remission alone and composite endpoints of HEMI and HEMR
VARSITY⁷⁶ Histological remission was a prespecified endpoint in an RCT in the Phase 3 VARSITY study	Vedolizumab vs adalimumab	Histological remission = GS < 2 or RHI score ≤ 2 at week 14 and week 52 (prespecified exploratory endpoints)Statistically significant higher remission rates were observed with vedolizumab vs adalimumab at week 14 and week 52 on the GS and RHI.Histological remission (GS < 2) vedolizumab vs adalimumab Week 14: 16.7% vs 7.3%; difference 9.4% (95% CI, 4.9%-13.9%); P < .0001 Week 52: 29.2% vs 8.3%; difference 20.9% (95% CI, 15.6%-26.2%); P < .0001 Histological remission (RHI score ≤ 2) vedolizumab vs adalimumab Week 14: 25.6% vs 16.1%; 9.5% (95% CI, 3.8%-15.2%); P = .0011 Week 52: 37.6% vs 19.9%; difference 17.6% (95% CI, 11.3%-23.8%); P < .0001
LUCENT I and II⁷⁷Histological and histological-endoscopic endpoints were included at outcomes in Phase 3 induction and maintenance trials	Mirikizumab	Histological remission = GS < 2Endoscopic remission = MES of 0 or 1 (excluding friability)HEMI = histological improvement + endoscopic remissionHEMR = histological remission + endoscopic remissionAt week 12, mirikizumab vs placebo Histological remission: 29% vs 16%; common risk difference 13.7%; P < .001 HEMI: 27% vs 14%; common risk difference 13.4%; P < .00001 HEMR: 22% vs 11%; common risk difference 11.3%; P < .001 At week 40, mirikizumab vs placebo Histological remission: 49% vs 25%; common risk difference 22.5%; P < .001 HEMI: 48% vs 22%; common risk difference 23.9%; P < .001 HEMR: 43% vs 22%; common risk difference 19.9%; P < .001 Histological remission, HEMI, and HEMR at week 12 were associated with corticosteroid-free remission, clinical remission, and symptomatic remission at week 40
ELEVATE UC 52 and ELEVATE UC 12⁴⁸Histological-endoscopic were included as outcomes endpoints for Phase 3 trials	Etrasimod	HEMR = Histological remission (GS < 2) + endoscopic remission MES ≤ 1, without friabilityIn ELEVATE UC 52 Week 12: 21% (58/274) patients treated with etrasimod vs 4% (6/135) patients treated with placebo achieved HEMR; difference 16.9% (95% CI, 10.8-23.0); P < .0001 Week 52: Difference between etrasimod vs placebo on HEMR of 18.4% (95% CI, 11.4-25.4); P < .0001 ELEVATE UC 12 at week 12 16% (36/222) patients treated with etrasimod vs 9% (10/112) patients treated with placebo achieved HEMR; difference 7.4% (95% CI, 0.5-144); P = .036
GEMINI I and LTS⁷⁸Study carried out at University Hospitals Leuven using biopsy samples from patients enrolled in the Phase 3 GEMINI I study and its open-label long-term extension study at that center	Vedolizumab	Histological mucosal healing = GS 0 or 1 and Endoscopic mucosal healing = MES of 0 or 122 patients treated with vedolizumab achieved mucosal healing, and of these 12 (55%) also showed histological healing, that is, HEMR at the timepoints studied (3/6 at week 6, 2/3 at week 12, and 7/12 at week 52)
UNIFI Phase 3 clinical trials pooled analysis to examine clinical relevance of histological improvements alone and with endoscopic improvement⁷⁹	Ustekinumab	Histologic improvement = GS ≤ 3.1Endoscopic improvement = MES of 0 or 1.HEMI = histologic + endoscopic improvementClinical remission = Mayo score ≤ 2 points, with no individual subscore > 1 At week 8, following ustekinumab induction Patients with histologic improvement (283/816) ~20 times more likely to achieve week 8 clinical remission vs those without histologic improvement (OR 19.9; 95% CI, 10.7-39.5) Patients with histologic improvement at week 8 were ~12 times more likely to have endoscopic improvement vs patients without histologic improvement (OR 11.9 [95% CI, 8.0-17.9]) At week 44 Clinical remission at week 44 was achieved in 54% (76/140) patients with histological improvement at week 8 after ustekinumab induction vs 40% (49/124) in patients without histological improvement at week 8 (P = .0191) Considering patients with positive outcomes at week 44, 61% (56/92) patients with HEMI after induction achieved clinical remission, vs 34% (24/71) of patients with histologic improvement alone after induction (P = .0009)
U-ACHIEVE induction and U-ACCOMPLISH indication and U-ACHIEVE⁴² pooled analysis to examine to assess the clinical relevance of achieving HEMI and HEMR	Upadacitinib	HEMI = GS ≤ 3.1 and MES of 0 or 1HEMR = GS < 2 and MES of 0CS-free remission = 90-day CS-free clinical remission (total Mayo score ≤ 2 no subscore > 1)The proportion of patients who achieved CS-free remission at week 52 among patients with no HEMI (n = 197) was 6%, with HEMI without HEMR (n = 78) was 80%, and with HEMR (n = 45) was 89% (P < .001 comparison vs no HEMI for both HEMI without HEMR and HEMR)
Intestinal ultrasound
Prospective observational study⁸⁰	Standard of care	BWT assessed by intestinal US and vascularization within the affected bowel wall areas was assessed by DCSThe percentage of patients with increased BWT was reduced significantly from 89.3% of 224 patients at baseline to 32% at week 12 (n = 178) in the sigmoid colon and from 83.0% at baseline to 37.6% at week 12 in the descending colonImprovements in vascularization observed were maintained up to week 12 in both the sigmoid and descending colon
Longitudinal prospective study⁸¹	Tofacitanib	BWT measured by intestinal USBWT was shown to be significantly lower in patients with endoscopic improvement compared with patients without endoscopic improvement after 8 weeks of tofacitinib treatment (analysis of 27 patients)
Prospective pilot study⁸²	Vedolizumab	Vascularization of the bowel wall was assessed with high-frequency ultrasound using DCS in 18 patients at baseline and 14 weeks after vedolizumab treatmentNine of 18 patients (11 with CD, 7 UC) responded to vedolizumab treatment and had a significant decrease in bowel wall vascularization
Composite endpoint of deep remission
Post hoc analysis GEMINI 1⁸³	Vedolizumab	Four deep remission endpoints were defined from high to low stringency:1. Endoscopic remission + symptom improvement: MES = 0; RB = 0; decrease or no change in baseline SF score4. Endoscopic + symptomatic improvement: MES ≤ 1; RB = 0; SF = ≤1Vedolizumab Q8W treatment group (n = 122 patients) or vedolizumab Q4W group (n = 125) had significantly higher deep remission rates than the placebo group (n = 126) at week 52, regardless of deep remission definition. Most stringent definition of deep remission—(1) endoscopic remission and symptomatic improvement: vedolizumab Q8W 27.0% or Q4W 28.0% vs placebo 8.7% (P < .0001 for both comparisons) Least stringent definition of deep remission—(4) endoscopic and symptomatic improvement: Q8W 43.4% or Q4W 43.2% vs placebo 15.9% (P < .0001 for both)
Multicenter, observational, prospective study⁸⁴	Adalimumab	Deep remission (evaluated as a secondary endpoint) = clinical remission (pMS ≤ 2 plus blood-in-the-stool assessment at value 0) + mucosal healing (MES of 0 or 1)Deep remission was achieved in 43.4% (23/53) and 58.5% (31/53) of patients at week 8 and week 52 of adalimumab treatment, respectively
Retrospective review of VICTORY Consortium data⁸⁵	Vedolizumab	Deep remission = clinical remission (complete resolution of all UC-related symptoms) + endoscopic remission (MES of 0)Among 321 patients (71% anti-TNFα experienced, median follow-up 10 months), overall cumulative rates of deep remission were 14% at 6 months and 30% at 12 months of vedolizumab treatment
Multicenter, retrospective, observational cohort study using propensity score weighted comparisons⁸⁶	Vedolizumab vs TNFα-antagonists	Deep remission = clinical remission (resolution of diarrhea, RB and urgency) + endoscopic remission (MES of 0 or 1)CS-free deep remission = no CS within 1 month of clinical remission + endoscopic remissionAnalyzed 454 vedolizumab-treated and 268 anti-TNFα-treated patients with UC. Vedolizumab-treated patients were more likely to achieve deep remission (HR 1.7 [95% CI, 1.0-2.8]; P = .06) and CS-free deep remission (HR 2.8 [95% CI, 1.5-5.3]) than anti-TNFα-treated patients
Composite endpoint of disease clearance
VARSITY, post hoc analysis of Phase 3 trial⁸⁷	Vedolizumab vs adalimumab	Disease clearance = a composite outcome based on clinical remission (pMS ≤ 2 and no individual subscore > 1 excluding sigmoidoscopy subscore) + endoscopic improvement (MES of ≤1) + absence of active histologic disease (RHI < 5)More patients treated with vedolizumab than adalimumab achieved disease clearance at week 52 (vedolizumab: 112/383, 29.2% [95% CI, 24.7-34.1] vs adalimumab: 63/386, 16.3% [95% CI, 12.8-20.4])
Multicenter retrospective real-world cohort.⁸⁸	Multiple treatments, most commonly Thiopurines, infliximab, Vedolizumab, and adalimumab	Disease clearance = clinical remission (pMS ≤ 2, with no subscore > 1) + endoscopic remission (MES = 0) + histological remission (NI = 0)22.1% (109/494) of patients had disease clearance after inductionPatients with disease clearance had a significantly lower risk of negative outcomes vs those without disease clearance; negative outcomes were any escalation of medical therapy, UC‐related hospitalization, UC‐related surgery, colorectal dysplasia/neoplasia, and death (HR 0.22 [95% CI, 0.10-0.48]; P < .001), hospitalization (HR 0.20 [95% CI, 0.09-0.45]; P < .001), and surgery (HR 0.14 [95% CI, 0.03-0.59]; P = .007)

Abbreviations: BWT, bowel wall thickness; CD, Crohn’s disease; CI, confidence interval; DCS, Doppler color signal; GS, Goebes Score; HEMI, histologic endoscopic mucosal improvement; HEMR, histologic endoscopic mucosal remission; HR, hazard ratio; IBD, inflammatory bowel disease; MES, Mayo Endoscopic Score; NI, Nancy index; OR, odds ratio; pMS, partial Mayo score; Q4W, every 4 weeks; Q8W, every 8 weeks; RCT, randomized controlled trial; RHI, Robarts Histology Index; TNFα, tumor necrosis factor alpha, UC, ulcerative colitis; US, ultrasound.