Predictors and outcomes of achieving histological remission in ulcerative colitis treated to endoscopic healing

SUMMARY

Background:

Clinical remission is the recommended treatment target in ulcerative colitis. The predictors and outcomes of achieving histologic remission within a treat-to-target paradigm are not well established.

Aim:

We evaluated the predictors and outcomes of achieving histologic remission in patients with ulcerative colitis treated-to-target of endoscopic healing (modified Mayo endoscopy score 0 or 1).

Methods:

We conducted a retrospective cohort study in adults with active ulcerative colitis (modified Mayo endoscopy score 2 or 3), whose treatment was iteratively optimized to achieve endoscopic healing. We identified predictors of achieving histologic remission, and outcomes (risk of symptomatic relapse, and ulcerative colitis-related hospitalization and/or surgery) of achieving histologic remission vs. persistent histologic activity, using Cox proportional hazard analysis.

Results:

Of 411 patients with clinically active ulcerative colitis, 270 patients achieved endoscopic healing. Of 270 patients, 55% simultaneously achieved histologic remission. Depth of endoscopic healing at final endoscopic assessment was the only independent determinant of histologic remission (modified Mayo endoscopy score 0 vs. 1: odds ratio, 0.31 [95% confidence intervals, 0.18–0.52]). Over 28 months, achieving histologic remission was associated with a lower risk of clinical relapse (1-year cumulative risk: 18.7% vs 29.5%; adjusted hazard ratio, 0.56 [0.37–0.85]), and lower risk of hospitalizations (hazard ratio, 0.44 [0.20–0.94]). The incremental benefit of achieving histologic remission was observed only in patients achieving Mayo endoscopy score 1, but not Mayo endoscopy score 0.

Conclusions:

In patients with active ulcerative colitis treated-to-target of endoscopic healing, 55% simultaneously achieve histologic remission. Histologic remission, particularly in patients achieving modified Mayo endoscopy score 1, was associated with favorable outcomes. Treating to a target of histologic remission over endoscopic healing requires prospective evaluation.

INTRODUCTION

Clinical remission, a composite outcome defined by a (PRO, patient reported outcome) of resolution of rectal bleeding and near normalisation of stool frequency and endoscopic healing based on MES 0 or 1, is the recommended treatment target in patients with UC, based on recent guidelines¹. Approximately 50–60% patients with EH achieve histologic remission, whereas others have persistent histological activity². Histologic remission, regardless of clinical and endoscopic activity, may have superior long-term outcomes^3–5, warranting its examination as a treatment target in patients with UC⁶. However, there are few studies specifically evaluating whether achievement of histologic remission among patients with active UC treated to a target of clinical remission has incremental benefit in clinical outcomes, especially in patients who have achieved MES 0. Furthermore, the feasibility and predictors of achieving histologic remission in the current treat-to-target paradigm remain uncharacterized.

Hence, we conducted a retrospective cohort study in patients with active UC who were treated-to-target of clinical remission comprised of both PRO remission and EH to (I) identify the feasibility and predictors of histologic remission during routine care, and to (II) analyze whether histologic remission provides incremental benefit in the likelihood of achieving relevant outcomes, including symptomatic relapse, hospitalization and surgery.

METHODS

Study Setting

We performed a retrospective cohort study in UC patients followed at the University of California San Diego (UCSD), a tertiary care IBD referral center. This study was approved by the UCSD Institutional Review Board (IRB# 191127) and funded by Janssen, who provided input in study design. All decisions were at the final discretion of the study team.

Inclusion and Exclusion Criteria

Eligible patients had (a) a diagnosis of UC based on standard clinical, endoscopic and histologic criteria, (b) were seen and followed at UCSD, for at least six months between 2012 – 2019, (c) underwent at least 2 endoscopic evaluations, with the first evaluation showing endoscopically active disease, and (d) subsequently underwent UC-directed therapy with an intent to achieve a treatment target of both PRO remission and EH.

Patients were excluded if they had Crohn’s disease or IBD unclassified, if they did not have active disease at initial assessment, or did not achieve PRO remission and EH at follow-up endoscopic evaluation.

Routine clinical practice

All patients with IBD at UCSD are treated by an IBD team following unified evidence-based guidelines. Patients with UC are treated-to-target of EH consisting of serial endoscopic evaluation every 4–6 months, followed by stepwise treatment intensification in the presence of moderate to severe endoscopic activity (MES 2 or 3), and interval re-evaluation. All endoscopies follow a standard biopsy protocol. For disease activity assessment, a minimum of two biopsies are obtained from the worst area of the right and left colon (colonoscopy) or from the recto sigmoid (flexible sigmoidoscopy). If performed for dysplasia surveillance, then biopsies are obtained from the cecum/ascending, transverse, descending, and rectosigmoid colon. 1 of 5 pathologists blinded to all clinical information reviewed slides, and a single gastroenterologist (SJ) blinded to other clinical data at the time of review, assigned a histologic classification (described below).

Data Abstraction

A single reviewer (SJ) abstracted data using a standardized form. In addition to exposure and outcome variables (see below), the following items were abstracted: date of birth, age at cohort entry, sex, body mass index, smoking status, age at disease onset, disease duration, disease location, smoking status, clinical and endoscopic disease activity, treatment at initial and follow-up evaluations, date of endoscopy, degree of EH, and degree of histologic activity at time of active UC and of clinical remission, and treatment modifications needed to achieve remission EH.

Definitions

Clinically active disease was defined as rectal bleeding (RBS >0) and 3–4 stools above normal (stool frequency score [SFS], 2 to 3); endoscopically active disease was defined as MES 2 or 3. Most endoscopies rated the presence of any friability as MES 2, consistent with the modified MES; however, in 12 patients the presence of mild friability was classified by the endoscopist as MES 1. Symptomatic remission was defined as resolution of rectal bleeding (RBS 0) and near-normalization of stool frequency (SFS 0 or 1), with absence of corticosteroids. EH was defined as MES 0 or 1; complete endoscopic remission as MES 0, mild endoscopic activity as MES 1. Histologic remission was defined as either complete mucosal normalization or chronic architectural changes with complete absence of neutrophils in the epithelium and ≤ 1 neutrophil per high power field in the lamina propria. Histologic activity was defined as architectural changes with superimposed acute infiltrate characterized as mild (neutrophilic cryptitis), moderate (neutrophilic cryptitis and neutrophilic crypt abscesses), or severe (the presence of ulcer), similar to the established Nancy histologic index⁷. To evaluate how our pragmatic definition of histologic remission compared to the validated Geboes score, a single expert gastrointestinal pathologist (MV) blinded to the initial clinical pathology read re-evaluated the biopsy slides from 38 patients, and scored them using the validated Geboes score⁸. Individual components of the Geboes score were recorded: structural (architectural change) (Grade 0), chronic inflammatory infiltrate (Grade 1), lamina propria eosinophils (Grade 2A), lamina propria neutrophils (Grade 2B), neutrophils in the epithelium (Grade 3), crypt destruction (Grade 4), and erosions or ulceration (Grade 5). Histologic remission by Geboes score was defined as (1) <2B.1 (no increase in neutrophils in the lamina propria) and (2) <3.1 (no neutrophils in the epithelium), in the segment with highest activity of a patient, as has been performed in similar prior investigations⁵. We analyzed the correlation between our pragmatic definition of histologic remission vs. the Geboes score.

Exposure and Outcomes

Aim I.

To identify the predictors of achieving histologic remission in patients with UC treated-to-target of EH. The primary outcome was achieving histologic remission. Covariates of interest were age at diagnosis, age at cohort entry, disease duration, endoscopic disease extent and activity at time of active disease, MES at time of final assessment, smoking, treatment modifications to achieve EH, and time to achieve EH from time of baseline activity. Treatment modifications were categorized as (a) modification of index therapy (either dose optimization, and/or adding topical therapy in patients being treated with oral 5-ASA (5-aminosalicylic acid)), or (b) switching to a different medication. Corticosteroids was not classified as a treatment modification, given they were for symptom control but not for achieving endoscopic targets.

Aim II.

To explore how achieving histologic remission affects clinical outcomes, we assessed for clinical relapse, defined as RBS >0 with SFS 2 or 3. Endoscopic or biochemical activity was not included into the definition of clinical relapse. Secondary outcomes were time to UC-related emergency room visit or hospitalization and time to UC-related surgery. Subgroup analyses on future clinical outcomes were stratified by degree of EH (MES 0 vs. MES 1), by degree of histologic remission (normalization vs chronic architectural changes vs acute inflammatory infiltrate) and by historic disease severity based on treatment with 5-ASA (low risk disease) vs. treatment with anti-metabolite, biologic agents and/or targeted immunosuppressive agents (high risk disease).

Statistical Analyses

For patients with active disease, we calculated treatment modifications required to achieve the EH target and identified the proportion of patients who achieved histologic remission or who had persistent histologic activity.

Subsequently, (Aim I) demographic, clinical, treatment and endoscopic factors in patients achieving histologic remission were compared to those with persistent histologic activity utilizing chi square or t tests to examine the prevalence of clinical factors. Logistic regression evaluated factors independently associated with histologic remission.

(Aim II) We evaluated the association between histologic remission and clinical outcomes in patients with UC treated-to-target of EH using time-to-event survival analysis. Follow up time began at attainment of clinical remission (symptomatic and endoscopic remission). To evaluate the independent effect of histologic remission on risk of symptomatic relapse, multivariate Cox proportional hazard analyses was performed with adjustment for covariates including age at diagnosis, age at cohort entry, disease duration, baseline disease severity (as previously described), baseline endoscopic disease extent and activity, degree of EH, treatment modifications and time to achieve EH. We performed secondary analyses using univariate time-to-event analysis with log-rank tests and Cox proportional hazard analysis to evaluate associations between histologic remission and time to UC-related hospitalization and surgery. Subgroup analyses based on degree of EH and disease severity were performed using univariate time-to-event and Cox proportional hazard analysis. Agreement between histologic remission and MES 0 disease was determined through calculation of kappa statistic, with interpretation of agreement cut-off values as previously described by Landis and Koch⁹. Correlation analysis between our pragmatic definition of histologic remission and the Geboes score-defined remission was performed using Spearman’s correlation coefficient¹⁰.

All hypothesis testing was performed using a 2-sided p-value with statistical significance threshold <.05. All statistical analyses were performed using RStudio (Version 1.1.456, Boston, MA).

RESULTS

Patient Characteristics

We identified 411 patients with clinically and endoscopically active UC who underwent iterative treat-to-target interventions. Of these, 270 patients (65.7%) successfully achieved clinical remission over a median of 11 months (interquartile range [IQR], 6–11); 110 patients (40.7%) achieved MES 0 and 160 patients (59.3%) achieved MES 1. Overall, 141 patients (34.3%) were unable to achieve EH despite treat-to-target interventions.

Treatment modifications required to achieve endoscopic healing

During the course of their treat-to-target interventions, patients were treated with 5-ASA (n=119), anti-metabolites (n=101), tumor necrosis factor-α (TNFα) antagonists (n=116), vedolizumab (n=61), or tofactinib (n=9). To achieve EH, 82.2% (n=222) required at least one treatment modification over baseline. Of the 222 patients who underwent treatment modifications, 37% patients (n=83) required dose optimization (34.7% optimized once, 2.7% with multiple dose optimizations). Approximately 85% patients (n=189) required switching therapies at least once, including 16.2% patients (n=36) required switching therapies twice, and 2.7% patients (n=6) changed drugs three times or more. The prevalence of moderate to severe endoscopic disease activity in patients in symptomatic remission, and consequent treatment modification to achieve EH was low (<5%).

Predictors of histologic remission

Of 270 patients successfully treated to EH, 149 patients (55.2%) patients also achieved histologic remission, while 121 patients (44.8%) had persistent histologic activity. Among patients achieving histologic remission, 28 patients (18.8%) had complete normalization and 121 patients (81.2%) had architectural changes. Among patients with persistent histologic activity, the prevalence of mild, moderate and severe histologic activity was 77 patients (63.6%), 33 patients (27.3%) and 11 patients (9%), respectively [Figure 1].

Figure 1.

Degree of histologic remission achieved in patients with ulcerative colitis treated to target of clinical remission

The prevalence of histologic remission was higher in patients with MES 0, compared to those with MES 1 (79/149 [52.7%] vs. 70/149 [47.9%]) with no significant differences observed for other characteristics [Table 1]. Agreement between the achievement of histologic remission and MES 0 disease was fair (kappa, 0.27) [Supp Table 1]. On univariate and multivariable analysis, only degree of endoscopic activity (MES 0 vs MES 1) at time of final assessment was associated with histologic remission (OR, 3.27 [95% CI, 1.92–5.69]) after controlling for other covariates [Table 2].

Table 1.

Characteristics of patients with ulcerative colitis treated-to-target of clinical remission comparing patients with histologic remission vs persistent histologic activity

	Histologic Remission n=149 (55.2%)	Histologic Activity n=121 (44.8%)	p-value
Age at visit, mean (SD)	46.1 (16.5)	45.5 (16.5)	0.77
Age at diagnosis, mean (SD)	33.0 (14.5)	33.4 (15.5)	0.93
Sex, male, frequency (%)	75 (50.3%)	60 (49.6%)	1.00
Current smoking, frequency (%)	21 (14.1%)	15 (12.4%)	0.68
Disease duration, years, median (IQR)	12.2 (9.4)	11.5 (9.0)	0.35
Pancolitis, frequency, (%)	57 (38.3%)	61 (50.4%)	0.06
Disease severity			0.81
• Low-risk disease (No prior or current use of biologic or immunosuppressive use), frequency, (%)	81 (54.4%)	64 (52.9%)
• High-risk disease (Prior or current use biologic or immunosuppressive use), frequency, (%)	68 (45.6%)	57 (47.1%)
Degree of endoscopic healing, frequency, (%)			<0.001
• Mayo end 0	79 (52.7%)	31 (25.6%)
• Mayo 1	70 (46.9%)	90 (74.4%)

Table 2:

Predictors of achieving histologic remission in patients with UC, treated-to-target of clinical remission

Predictive factors	OR	95% Confidence Interval
Baseline Predictors
Age at cohort entry (per 1y)	1.14	0.81–1.61
Age at diagnosis	.98	.96–1.01
Female Gender	.85	.50–1.43
Current smoking (yes vs. no)	1.03	0.49–2.37
Baseline endoscopic activity (MES 3 vs MES 2)	1.25	0.72–2.18
Baseline disease extent (pancolitis vs no pancolitis)	0.72	0.48–1.07
Baseline disease severity (Biologic/immunosuppressive use vs ASA)	1.06	.77–1.48
Predictors at Follow-up
Degree of EH (MES 0 vs. MES 1)	3.27	1.92–5.69
Number of treatment modifications required to achieve EH	1.05	0.77–1.43
Time required to achieve EH (per 1y)	1.00	0.98–1.02

We compared the performance of our pragmatic definition of histologic remission against the validated Geboes score in a random sample of 38 patients. Approximately 58% patients within this subset had histologic remission per our scoring methodology. Our definition of histologic remission had a very strong correlation to Geboes score-defined histologic remission (r=0.85, CI [0.73–0.92]).

Clinical outcomes in patients achieving histologic remission

Clinical relapse (Primary outcome):

Over a median follow-up of 28 months (IQR 13–44), 34.8% of patients treated to clinical remission experienced symptomatic relapse with a cumulative risk at 1 year of 23.7%. Patients with histologic remission vs histologic activity experienced one year actuarial estimates of 8.7% and 29.5% (HR, 0.52 [95% CI, 0.35–0.79]) [Figure 2].

Figure 2.

Cumulative risk of clinical relapse in patients with ulcerative colitis treated-to-target of clinical remission, by histologic activity at time of endoscopic healing

On Cox proportional hazard analysis, achieving histologic remission was independently associated with 45% lower risk of symptomatic relapse, after adjusting for covariates (adjusted HR, 0.55 [95% CI, 0.36–0.85]) [Table 3].

Table 3:

Predictors of clinical relapse in patients with UC, treated-to-target of clinical remission

	Hazard Ratio	95% Confidence Interval
Histologic Remission (vs. persistent histologic activity)	0.55	0.36–0.85
Age at Cohort Entry	1.11	.76–1.62
Age at Diagnosis (per 1y)	1.00	.97–1.03
Female Gender	0.96	0.62 – 1.48
Disease Duration (per 1y)	1.16	.85–1.57
Baseline endoscopic activity (MES 3 vs MES 2)	0.87
Baseline disease extent (pancolitis vs no pancolitis)	1.20	.86–1.68
Baseline disease severity (Biologic/immunosuppressive use vs ASA)	0.89	.67–1.18
Degree of EH (MES 0 vs. MES 1)	0.74	.46–1.18
Number of treatment modifications required to achieve EH	.95	.73–1.24
Time required to achieve EH (per 1y)	1.01	.99–1.18

On stratified analysis, we observed that the incremental benefit of achieving histologic remission was restricted to a subset of patients with MES 1 (1-year cumulative risk of relapse in patients with histologic remission vs. histologic activity: (20.3% vs, 33.7, HR 0.44 [0.26–0.76]), but not in patients who achieved MES 0: (17.2% vs, 17.3, HR, 0.91 [0.41–1.99]) [Figure 3a and 3b]. In contrast, the benefit of achieving histologic remission was apparent both in patients with mild disease at baseline (1-year cumulative risk of relapse in patients with histologic remission vs. persistent histologic activity: 16.0% vs 29.2%; HR, 0.50 [0.29–0.86]) and moderate-severe disease at baseline (21.7% vs. 30.0%; HR, 0.56 [0.30–1.0]) [Figure 3c and 3d]. We did not find that degree of endoscopic healing (MES 1 vs MES 0), regardless of underlying histologic activity, was associated with any significant difference in relapse rate [Supp Fig 1]. Additionally, we did not find that degree of histologic healing (complete normalization vs architectural changes) was associated with any significant difference in relapse rate. On sensitivity analysis excluding 12 patients with any friability classified originally as MES 1 (which would be re-classified as MES 2 with modified MES), overall results were unchanged.

Figure 3.

Cumulative risk of clinical relapse in patients with ulcerative colitis treated-to-target of clinical remission, by histologic activity in (a) modified Mayo endoscopic score, MES 0 (b) MES 1 (c) mild disease severity at baseline (d) moderate-to-severe disease at baseline

Hospitalization and/or surgery (Secondary outcome):

In patients treated to EH, the cumulative risk of hospitalization and surgery at 1-year was 6.6% and 0.9%, respectively. Achieving histologic remission was associated with a lower risk of hospitalization (1-year cumulative risk, 3.9% vs 9.7%; HR, 0.44 [0.21–0.91]) [Supp Fig 2]. After adjusting for key covariates, histologic remission was independently associated with 56% lower risk of hospitalizations (HR, 0.44 [0.20–0.94]). In contrast, degree of EH regardless of histologic activity, was not associated with risk of hospitalization (1-year cumulative risk: 7.0% vs. 6.3%; HR 1.05 [0.51–2.96]) [Supp Fig 1B]. Achieving histologic remission was not associated with any difference in risk of surgery, although the number of surgical events was very low in both groups.

DISCUSSION

While treating to a target of clinical remission is an attractive goal, there is increasing interest in achieving the more rigorous goals of endoscopic remission (MES 0) and histologic remission. While histologic remission has been previously associated with improved clinical outcomes, few studies have longitudinally evaluated the benefits of achieving histologic remission in patients with previously active disease in the context of a treat-to-target of EH paradigm. Furthermore, there has been limited assessment of the feasibility and predictors of achieving histologic remission in patients treated to conventional target of EH.

In this cohort study of well-characterized patients with active UC treated systematically to a target of EH, we made several important observations. First, through the longitudinal treat-to-target EH paradigm involving iterative treatment modification with optimization of index therapy and switching to alternative therapies, we were able to measure achievement of EH in 2/3^rd patients with active UC over a median follow-up of 11 months. Conversely, despite treatment modifications, one third of patients with active UC were unable to achieve currently recommended treatment target representing an important therapeutic gap.

Second, of the patients who achieved EH, approximately 55% simultaneously achieved histologic remission; this rate was higher in patients with complete endoscopic remission (MES 0, 72%) relative to those with mild endoscopic activity at time of symptomatic remission (MES1, 44%). Importantly, the only factor associated with achieving histologic remission in the treat-to-target paradigm was degree of endoscopic healing (MES 0 vs. MES 1) at time of endoscopic reassessment. Third, both high and low risk patients who achieved histologic remission in the treat-to-target framework had significantly lower risk of clinical relapse and hospitalization on follow-up, after adjusting for key covariates. The potential benefit of achieving histologic remission was strongest in patients achieving MES 1, and was not significant in patients achieving MES 0. Achieving MES 0 was itself associated with lower risk of relapse, as compared to MES 1, regardless of histologic activity status.

These findings have important implications for practice. While there is considerable interest in targeting histologic remission in patients with UC, prior studies have not evaluated the feasibility of achieving this target in routine clinical practice. Though earlier studies have evaluated associations between histologic remission and improved clinical outcomes, our study follows patients with active UC who undergo iterative treatments in attempt to reach EH and who may or may not achieve concurrent histologic remission, allowing us to evaluate the feasibility and outcomes of such an approach in a real-world context. Given this approach, we found that despite iterative treatment modifications, we were unable to achieve EH in one third of patients with current treatment strategies. Of the patients who achieved EH, 41% achieved complete endoscopic remission, and only 55% simultaneously achieved histologic remission. Prevalence of histologic remission was higher in patients achieving endoscopic remission relative to those with persistent endoscopic activity. Achievement of MES 0 disease did not ensure histologic remission, with 28% of patients demonstrating persistent histologic activity, similar to proportions of persistent histologic activity among complete endoscopic healing noted in other cohorts^{5, 11}.

Predicting which baseline patient factors may be associated with successful achievement of histologic remission have previously been uncharacterized. We found that beyond degree of endoscopic healing, no conventional demographic or clinical factors could identify which patients treated-to-target of EH would achieve histologic remission. While prior studies have not evaluated factors associated with achieving histologic remission, they have not identified any systematic differences in patients who achieve histologic remission vs. persistent histologic activity after achieving EH^{2, 3, 5}. We show in this cohort that conventional baseline factors do not determine if patients are able to achieve histologic remission. This circumstance highlights potential challenges in trying to prescriptively target histologic remission, as it may be hard to achieve and predict beyond the association we observed between MES 0 and histologic remission. Future studies that identify thus far uncharacterized biologic characteristics of patients that are likely to achieve histologic remission, beyond EH, with effective therapies are warranted.

By specifically focusing on outcomes of achieving histologic remission in patients treated-to-target of EH, we have attempted quantify the incremental benefit of histologic remission. Importantly, we observed that achieving histologic remission may be most relevant in patients who have mild endoscopic activity, whereas its benefit in patients who achieve complete endoscopic remission may have less impact on shorter terms outcomes, requiring a longer time horizon of follow up to identify benefit. However, prior studies have demonstrated benefit of achieving histologic remission, even in patients who achieve complete endoscopic remission^12–16. These differences may be related to variability in patient characteristics including the proportion of patients with high-and low-risk disease and the accuracy of diagnosing MES 0 vs. MES 1 in different studies.

Although the degree of histologic remission has been previously associated with clinical outcomes³, we did not find any significant differences in clinical relapse rates among patients with mucosal normalization compared to those with persistent architectural distortion, likely due to the small number of patients who achieved complete normalization in our cohort (n=28, 18.8%).

There are several strengths to our study. First, by anchoring our study on patients with active UC who are treated-to-target of EH, we were able to review incremental benefits of simultaneously achieving histologic remission in the context of current practice recommendations. Second, while this was a retrospective study, our endoscopic and biopsy sampling protocols and treatment approach was standardized with a small group of experts managing all patients with IBD. Third, we systematically examined the feasibility of treat-to-target in clinical practice, and attempted to identify predictors of achieving histologic remission, neither of which have been previously investigated.

There are important limitations to our study. First, we did not use a validated histologic scoring system⁷, due to the retrospective nature of the study. However, histologic assessment was blinded and pathologists modeled their interpretations on the established Nancy index. Furthermore, we evaluated the performance of our pragmatic histologic remission and found a very strong correlation with validated Geboes score-defined remission among a subset of randomly selected patients in our cohort⁵. While Geboes score and other histologic indices have proven utility in clinical trials, our definition of defining histologic remission as the absence of neutrophils from the lamina propria and epithelium may be more generalizable to routine clinical practice. Second, due to small number of events, we were unable to accurately estimate the impact of incrementally achieving histologic remission on risk of surgery or dysplasia. Third, we are unable to contextualize our findings against treating to a target of symptomatic remission alone, or to a target of symptomatic and biochemical remission. The latter is of particular interest in patients with UC where the combination of symptoms and fecal calprotectin can predict endoscopic activity with high accuracy¹⁷. Because fecal calprotectin was not routinely assessed in our cohort, we were unable to evaluate its association with histologic remission. However, we expect similar findings in this cohort – the majority of patients achieving symptomatic and biochemical remission tend to achieve MES 1, and predictive value of this combination for achieving complete endoscopic remission is low¹⁸. Finally, and most importantly, our findings do not inform feasibility or outcomes of patients treated-to-target of histologic remission, but rather focuses on feasibility and outcomes of patients who achieve histologic remission in the context of conventional treat-to-target practices. Patients who achieve histologic remission in this context (55% of cohort) may be self-selected to be more responsive to therapy, whereas it may not be easy to achieve histologic remission in the remaining 45% patients with persistent histologic activity with iterative treatment modifications. The VERDICT trial (In actiVE ulcerative colitis, a RanDomIzed Controlled Trial for determination of the optimal treatment target; EudraCT Number: 2019–002485-12) comparing treat-to-target to clinical remission vs. EH vs. histologic remission in patients with UC will help to inform the question regarding optimal treatment target⁶.

In conclusion, approximately 2/3^rd patients with active UC can be treated-to-target of EH with iterative treatment modification in routine clinical practice. Of these, ~55% will simultaneously achieve histologic remission, with degree of endoscopic remission most likely to predict histologic remission. Patients who achieve histologic remission in this treat-to-target context have lower risk of clinical relapse and hospitalization, with higher magnitude of benefit in patients with mild endoscopic activity (MES 1). Our findings support examining histologic remission as a treatment endpoint in patients with UC, though caution that this endpoint may be hard to predict and achieve in individual patients.

Supplementary Material

Supp Fig 1

Supplemental Figure 1. (a) Risk of clinical relapse and (b) Risk of hospitalizations in patients with ulcerative colitis treated to modified Mayo endoscopic score MES 0 vs. MES 1

Supp Fig 2

Supplemental Figure 2. Cumulative risk of hospitalization in patients with ulcerative colitis treated to target of clinical remission, by histologic activity at time of endoscopic healing

Abbreviations:

5-ASA

5-aminosalicylic acid

CI

confidence interval

EH

endoscopic healing

HR

hazard ratio

IBD

Inflammatory bowel disease

IQR

interquartile range

IRB

Institutional review board

MES

Mayo endoscopy score

OR

odds ratio

PRO

patient reported outcomes

RBS

rectal bleeding score

SFS

stool frequency score

UC

ulcerative colitis

UCSD

University of California, San Diego