clinical parameters correlate with endoscopic activity of

Clinical Gastroenterology and Hepatology 2019;17:1265–1275

Clinical Parameters Correlate With Endoscopic Activity ofUlcerative Colitis: A Systematic Review

Sophie Restellini,*,‡,a Che-Yung Chao,§,a Myriam Martel,k Alan Barkun,*,k

Omar Kherad,¶ Ernest Seidman,* Gary Wild,* Alain Bitton,* Waqqas Afif,*Talat Bessissow,* and Peter L. Lakatos*,#

*Division of Gastroenterology, kDivision of Gastroenterology, Epidemiology and Biostatistics and Occupational Health, McGillUniversity Health Centre, Montreal, Canada; ‡Division of Gastroenterology and Hepatology, Geneva’s University Hospitals,¶Internal Medicine Department, La Tour Hospital, University of Geneva, Switzerland; §Department of Gastroenterology andHepatology, Princess Alexandra Hospital, Brisbane, Australia; #First Department of Medicine, Semmelweis University,Budapest, Hungary

BACKGROUND & AIMS:

aAuthors share co-first authors

Abbreviations used in this papecharacteristic curve; MCSe, Matient-reported outcomes; RB,Colitis Activity Index; SF, stool

Optimal management of patients with ulcerative colitis (UC) requires assessment of diseaseactivity—usually by endoscopy, which is invasive, costly, and not risk free. We performed asystematic review to determine whether clinical symptoms correlate with findings fromendoscopy assessments of patients with UC.

METHODS:
We performed a systematic review of publication databases from January 1980 through July2018 to identify clinical trials and observational studies reporting correlations among symp-toms, disease activity index scores and/or patient reported outcomes (rectal bleeding and/orstool frequency), and endoscopic disease activity. Correlations were ascertained in patientswith active vs inactive disease and by disease extent and treatment type. Risk of bias wasassessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Because of sig-nificant heterogeneity, meta-analysis was not possible. Results were synthesized qualitativelyand systematically.
RESULTS:
Our final analysis included 23 studies (1 randomized trial, 22 observational studies)comprising 3320 patients with UC. The studies used a variety of measures to assess clinicalactivity, endoscopic activity, and measures of correlation (sensitivity, specificity, correlationcoefficients, area under the receiver operator curve). Overall, studies were at moderate-highrisk of bias. Composite clinical measures, including rectal bleeding and stool frequency, hadmoderate to strong correlations with endoscopic disease activity; the absence of rectal bleedingidentified patients with inactive disease with higher levels of sensitivity than normalization ofstool frequency. In general, symptoms correlated more strongly with endoscopic activity inpatients with left-sided colitis than extensive colitis. The effect of different medications on thecorrelation between clinical and endoscopic activity has not been well studied.
CONCLUSIONS:
In a systematic review, we found a moderate to strong correlation between clinical ac-tivity, particularly the combination of rectal bleeding and stool frequency, and endoscopicactivity in patients with UC. Although these clinical assessments could help prioritizepatients for endoscopic evaluation in resource-limited settings, challenges associated withtreating patients based on symptoms alone preclude adaptation of current managementalgorithms.
Keywords: Inflammatory Bowel Disease; IBD; Evaluation; Prognostic Factors.

hip.

r: AUC, area under the receiver operatingyo Clinic endoscopic subscore; PRO, pa-rectal bleeding; SCCAI, Simple Clinicalfrequency; UC, ulcerative colitis.

Most current article

© 2019 by the AGA Institute1542-3565/$36.00

https://doi.org/10.1016/j.cgh.2018.12.021


http://crossmark.crossref.org/dialog/?doi=10.1016/j.cgh.2018.12.021&domain=pdf

What You Need to Know

BackgroundAccurate assessment of disease activity is required tooptimize outcomes of the treat-to-target manage-ment strategy for patients with ulcerative colitis(UC). We performed a systematic review to deter-mine if symptoms of UC correlate with findings fromendoscopy.

FindingsIn an analysis of data from 23 articles, we foundresults of clinical indices used to evaluate UC activityto correlate with endoscopic features. Compositeclinical measures including rectal bleeding and stoolfrequency had moderate to strong correlations withendoscopic disease activity; absence of rectalbleeding identified patients with inactive diseasewith higher levels of sensitivity than normalization ofstool frequency.

Implications for patient careInclusion of clinical activity parameters, such as thecombination of rectal bleeding and stool frequency,might improve assessment of UC activity and prior-itize patients for endoscopic evaluation in resource-limited settings. However, limitations excludeadaptation of symptom-based treatment.

1266 Restellini et al Clinical Gastroenterology and Hepatology Vol. 17, No. 7

Ulcerative colitis (UC) is a chronic relapsing andremitting inflammatory disease of the colon. Ac-

curate assessment of disease activity is a vital process fordisease management and improving long-term outcomes.Although endoscopic assessment provides the mostdefinitive and objective assessment of disease activity,it is invasive, costly, and has limited availability.

Patient-reported outcomes (PRO), symptoms reporteddirectly by the patient without a clinician’s interpretation,are commonly used to provide information about diseaseactivity for chronic disorders. PROs are important de-terminants of the illness experience, particularly from apatient’s point of view. The inclusion of a PRO also ismandated by the Food and Drug Administration for use inclinical trial designs.1 The existing literature suggests thatrectal bleeding (RB) and increased stool frequency (SF)(PRO2) are the most relevant clinical symptoms in UC.2

Indeed, the International Organization For the Study of In-flammatory Bowel Disease Stride guidelines recommendedresolution of PRO2 as a key clinical treatment target.2

Multiple clinical activity scores also have been devel-oped for the assessment of disease activity incorporatingPRO and additional components, including physician’sglobal assessment, noninvasive laboratory tests, and/orendoscopic scores. These include the noninvasive indicesof Seo et al,3 Simple Clinical Colitis Activity Index (SCCAI orWalmsley et al4 score), Pediatric UC Activity Index,5 Lich-tiger et al,6 and Beattie et al 7 scores. In contrast, the Mayoclinical score,8 Rachmilewitz9 score (clinical activity in-dex), UC disease activity index,10 and the Powell–Tuck11/St Mark index consist of composite clinical, physician’sglobal assessment, and endoscopic scores. Table 1 sum-marizes all invasive, noninvasive, and composite indicescurrently available to describe disease activity in UC.

Emerging literature has suggested that in contrast toCrohn’s disease, there may be a better correlation be-tween clinical symptoms and endoscopic assessment inUC, and that endoscopic evaluation contributes littleadditional information to activity assessment.17 Therefore,treating UC patients based on reported symptoms may beacceptable in certain clinical scenarios. However, most ofthe comparisons have been made using a heterogeneouscombination of clinical and endoscopic scores. It is withinthis framework that we aimed to systemically reviewwhether clinical symptoms, and especially the PRO2 score,correlate reliably with endoscopic evaluation for theassessment of disease activity in UC patients.

Methods

Search Strategy

Systematic searches were performed from January1980 to June 2018 using MEDLINE, EMBASE, Scopus,CENTRAL, and ISI Web of knowledge. Citation selectionused a highly sensitive search strategy identifyingstudies with medical subject headings relating to the

following: (1) ulcerative colitis (2) severity of illnessindex, and (3) invasive and noninvasive scoring systems.Recursive searches, cross-referencing, and subsequenthand-searches were completed.

Trial Selection, Patient Population, andInclusion–Exclusion Criteria

To be included, studies were required to meet thefollowing criteria: (1) fully published studies comparingPRO2 (rectal bleeding and stool frequency, or otherclinical scores) with endoscopy; (2) a diagnosis of UCestablished by clinical, endoscopic, and/or histologiccriteria; (3) endoscopic assessments of UC patients per-formed at the same time as patient symptom assessmentusing a score; and (4) observational design (prospectiveor post hoc analysis of prospectively obtained cohort) orinterventional design (randomized or nonrandomized).

Trials comprising only pediatric patients or inpatientswere excluded. Guidelines, retrospective case series, casereports, or proceedings from consensus conferences alsowere excluded.

Choice of Outcomes

The primary outcome measure was the correlationbetween PRO2, represented by the presence or absence

June 2019 Clinical Parameters and Mucosal Healing in UC 1267

of RB and/or changes in SF with endoscopic activityin UC.

We assessed secondarily the correlation betweenclinical score and endoscopic activity for patients withactive vs inactive disease, localization of the disease, andmedications used.

Data Analysis

Definitions used for endoscopic activity or remission,clinical activity or remission, and PRO2 are summarizedin Table 1.

Given the heterogeneous nature of the collected in-formation, the results were analyzed principally in aqualitative fashion.

Studies assessed the scale validity to a clinical orendoscopy outcome by reporting sensitivity or speci-ficity. Other studies reported the Pearson or Spearmancorrelation coefficients that measure the strength of as-sociation between the clinical or endoscopic scales andthe direction of the relationship, whereas other studiesalso assessed the correlation between the scales.

The reported comparisons and outcomes were ex-pected to vary in each study, precluding performing ameta-analysis.

Validity Assessment

Two investigators (S.R. and C.-Y.C.) assessed citationeligibility for each publication, with discrepanciesresolved by a third independent reviewer (P.L.L.).

Quality Assessment

Two authors (S.R. and C.-Y.C.) assessed the quality ofincluded studies using the Quality Assessment of Diag-nostic Accuracy Studies 2 tool (Figure 1). Any disagree-ments were resolved through discussion with a thirdsenior author (P.L.L.).

Results

Included Studies

Of 3449 citations, 23 studies (1 randomizedcontrolled trial and 22 observational studies) fulfilledour inclusion criteria (n ¼ 3320 patients) (Figure 2,Preferred Reporting Items for Systematic Reviews andMeta-Analyses diagram). The indication for endoscopywas for the assessment of active disease in 18 studies.

Clinical scales for UC activity assessment includedSCCAI, partial Mayo, Rachmilewitz,9 Seo et al3 index, andPRO2 (rectal bleeding and increased stool frequency).Endoscopic scales as comparators comprised the Ulcer-ative Colitis Colonoscopic Index of Severity,15 Mayo,8

Rachmilewitz,9 St Mark’s index,11 Baron et al,18 and Ul-cerative Colitis Endoscopic Index of Severity.14

Comparison methods between clinical and endoscopicscores were conducted using correlation coefficient in 18studies, while agreement coefficient and area under thereceiver operating characteristic curve (AUC) weredetermined in 1 and 2 studies, respectively.

Study Quality Assessment: Quality Assessmentof Diagnostic Accuracy Studies-2

Selected studies showed a high applicability concernin patient selection (ie, moderate to severe disease)because only active or newly diagnosed UC patients withactive disease were included. The risk of bias was un-clear for patient selection, index test, reference standard,and flow and timing. High risk was found for the latter in1 study in which not all of the initial patients wereincluded in the final analysis.

Association Between Clinical Symptoms andEndoscopy in the Different Study Populations

Patient-reported outcomes 2: rectal bleeding and stoolfrequency. Overall, 4 studies provided information onPRO2 and other clinical indices (Lewis et al,19 Dhandaet al,20 Azzolini et al,12 and Seo et al3) and all showedthat the PRO2 correlation with endoscopic disease ac-tivity was stronger or at least comparable with estab-lished clinical indices with a Spearman correlationcoefficient varying from 0.64 to 0.89 (P < .01). Two posthoc analyses of clinical trials (Jharap et al,21 Jairathet al1) and 1 prospective cohort study (Colombel et al22)compared PRO2 independently of composite clinicalindices with endoscopic assessment. These studies alsoshowed that PRO2 correlated well and had comparablediagnostic performance with clinical indices in assessingendoscopic activity (sensitivity, 0.21–0.62; specificity,0.77–0.98; AUC, 0.62–0.9). Table 2 contains the completedetails of the included studies.

The study by Jairath et al1 showed that the combineduse of RB and SF had a superior AUC than using theseitems separately (AUC, 0.9 vs 0.78–0.85). Similarly,Jharap et al21 also suggested higher specificity usingcombined RB and SF score (specificity, 0.98 vs0.59–0.94).

Insufficient data were available to compare thediagnostic capacity of RB vs SF. However, Jharap et al21

described that RB was associated with a lack of ulcerhealing whereas stool frequency may remain increaseddespite mucosal healing. Colombel et al22 similarly re-ported that endoscopically inactive disease was associ-ated with the absence of RB but not with completenormalization of SF. When identifying UC patients withinactive disease, RB scores were superior to SF scoresand the combination (sensitivity/specificity: Mayo Clinicendoscopic subscore [MCSe], 0/1; RB, 0.77/0.81; SF,0.62/0.95; RB þ SF, 0.54/0.95; MCSe, 0; RB, 0.87/0.66;SF, 0.76/0.83; RB þ SF, 0.68/0.86). Across different

Table 1. Summary of Invasive Noninvasive and Composite Indices Available to Access Disease Activity in Ulcerative Colitis

Parameters assessed Scoring system

Activity score thresholds

Remission Mild Moderate Severe

Noninvasiveindices

ECCI (Azzolini etal12)

Serum albumin bloody stoolNocturnal bowel movementsFever

Severity scale not available

Lichtiger et al6

indexDiarrhea frequencyNocturnal diarrheaVisible blood (% of movements)Fecal incontinenceAbdominal pain/crampingWell-beingAbdominal tendernessNeed for antidiarrheal medications

Cumulative score �3 4–8 9–14 >14

PRO-213 Rectal bleeding over past weekStool frequency over past week

Cumulative score <8 8–13 14–34 >35

Rachmilewitz9

score (CAI)Bowel movement frequencyBlood in stoolsPhysician rating of disease activityAbdominal pain/crampsTemperatureEIMsLaboratory findings (ESR,hemoglobin)

Cumulative score 0–4 5–10 11–17 >17

SCCAI (Walmsleyet al4)

Bowel movement frequency (day)Bowel movement frequency (night)Urgency of defecationBlood in stoolWell-beingExtracolonic features

Cumulative score �2<2.5

3–20

Seo et al3 index Bowel movement frequencyBlood in stoolESRHemoglobinAlbumin

Cumulative score <108<120

<150 150–220 >220

Invasive indicesMayo endoscopy

score8Mucosal appearance at

endoscopyStepwise score of escalating

severityNormal/inactive

mucosalappearance

1 (erythema, decreasedvascular pattern, mildfriability)

2 (marked erythema, absentvascular pattern, friability,erosions)

3 (spontaneous bleeding,ulceration)

Rachmilewitz9

endoscopyscore

Granulation, vascular pattern,vulnerability of mucosa, andmucosal damage

Cumulative score with differentweightings given according tonumber, longitudinal extent, anddescriptors

<4 4–6 6–9 9–12

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UCEIS14 Vascular pattern, bleeding,erosions, and ulcer

Cumulative score with eachparametergraded on a scale of 1–4

Score of 1 on allparameters

�3 for vascular pattern andbleeding, with �2 forerosions and ulcers

UCCI15 Vascular pattern, edema,granularity, erythema,ulcerations, bleeding-friability,stricture, loss ofhaustral folds, rigidity,pseudopolyps and gradingof segment and globalendoscopic activity

Cumulative score with eachparametergraded on a scale of 0–2 (forvascularpattern, granularity andbleeding-friability),0–1 (for edema, erythema,stricture,loss of haustral folds, rigidityand pseudopolyps),0–4 (for ulceration), and 0–4 (forgrading of segment and globalendoscopic activity)

Severity scale not available

Composite scores:PRO andinvestigatorassessments

Full Mayoscore8

Stool frequencyRectal bleedingPhysician rating of disease activityMucosal appearance at

endoscopy

Cumulative score 0–2 3–5 6–10 11–12

Powell-Tucket al11 index(St Mark’sindex)

Well-beingAbdominal painBowel movement frequencyStool consistencyBleedingAnorexiaNausea/vomitingAbdominal tendernessEye, joint, mouth, or skin

complicationsTemperatureMucosal appearance at

endoscopy

Cumulative score �3 4–10 11–14 >14

UCDAI10 Stool frequencyRectal bleedingPhysician rating of disease activityMucosal appearance at

endoscopy

Cumulative score 0–2 3–8 9–12 UCDAI10

CAI, clinical activity index; EIM, extraintestinal manifestations; ESR, erythrocyte sedimentation rate; PRO, patient-reported outcomes; SCCAI, Simple Clinical Colitis Activity Index; UCCI, Ulcerative Colitis Colonoscopic Index ofSeverity; UCDAI, Ulcerative Colitis Disease Activity Index; UCEIS, Ulcerative Colitis Endoscopic Index of Severity.Adapted from Laurent Peyrin-Biroulet et al.16

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Figure 1. Study qualityassessment using theQuality Assessment ofDiagnostic AccuracyStudies 2 tool.


definitions of mucosal healing (MCSe � 1, 0, or 0 plusinactive histology), a larger subset of patients reportedincreased SF (0.39, 0.25, and 0.27, respectively)compared with RB (0.24, 0.13, and 0.1, respectively). Incontradiction, Dhanda et al20 found that SF contributedto higher variance for total Mayo score than RB.

Active vs inactive disease. Overall, 8 studies onlyincluded patients with active disease (Lewis et al,19

Dhanda et al,20 Jharap et al,21 Scaioli et al,23 Seo et al,3

Achitei et al,24 Mirpour et al,25 Jairath et al1), whereas15 studies included patients with both active and inac-tive disease (Bodelier et al,26 Schoepfer et al,27 Pagniniet al,28 Beattie et al,7 Azzolini et al,12 Hirai et al,29 Lan-ghorst et al,30 Arai et al,31 Higging et al,32 Ricanek et al,33

Samuel et al,34 Taleban et al,35 Falvey et al,36 Chen et al,37

and Colombel et al22). Unfortunately, the published datado not provide information for active vs inactive diseaseseparately. No study examined only patients inremission.

All of these studies consistently showed a good cor-relation between noninvasive indices and endoscopyresults in studies of active patients only, or in studieswith both active patients and patients in remission.However, 2 studies (Pagnini et al28 and Hirai et al29)suggested that the correlation between clinical andendoscopic indices might be stronger among patientswith lower levels of disease activity. For example, inHirai et al29 the correlations between the clinical indicesand endoscopic indices were weaker (Spearman corre-lation coefficient, 0.29–0.47) when the disease activity inthe UC patients was high, whereas with a decrease indisease activity after treatment, the positive correlations

Figure 2. Prisma diagram.

among indices was stronger (Spearman correlation co-efficient, 0.53–0.84). See Supplementary Table 1 fordetailed data on referenced studies.

Localization. The majority of studies included pa-tients with variable disease extent. Four studies (Dhandaet al,20 Jharap et al,21 Beattie et al,7 and Scaioli et al2015) excluded patients with proctitis only. Only 2studies specifically analyzed the correlation of clinicalindices and endoscopic activity between various diseaselocalizations (Seo et al3 and Taleban et al35). In Seo et al3

the Spearman correlation between clinical indices andthe Baron et al18 index for combined locations was 0.352(P < .001) for SF, 0.624 (P < .001) for RB, and 0.688 (P< .001) for the Seo et al3 index. The best correlation wasobtained for the Baron et al18 score with left-sided colitis(SF, 0.503, P < .05; RB, 0.723, P < .001; and Seo et al1

index, 0.688, P < .001). Taleban et al35 consistentlyfound a superior correlation between SCCAI and endo-scopic disease activity in UC with left-sided diseasecompared with patients with extensive colitis (r ¼ 0.73vs 0.45; P ¼ .005) (Supplementary Table 1).

Ulcerative colitis medications. No study compared thecorrelation between clinical and endoscopic indicesspecific to different treatment regimens.

Discussion

This systematic narrative review aimed to compre-hensively examine the use of clinical indices, includingPRO2, compared with endoscopic assessment of UCdisease activity: it has shown a consistent correlation

Table 2. Rectal Bleeding, Stool Frequency, and Association With Mucosal Healing

Study; country; N Clinical and endoscopic scales used Analysis method

Results

Correlation Sensitivity/specificity/AUC

Azzolini et al,12 2005; Italy;n ¼ 137

Clinical: SF and RBEndoscopic: self-developed endoscopic

activity score

Correlation Total daily SF: Spearman correlationcoefficient, 0.57 (P < .001)

Night time SF: Spearman correlationcoefficient, 0.60 (P < .001)

Rectal bleeding: Spearman correlationcoefficient, 0.64 (P < .001)

Colombel22 2017; United States;n ¼ 103

Clinical: SF and RBEndoscopic: Mayo

Sensitivity/specificity SF: sensitivity, 0.62; specificity, 0.95RB: sensitivity, 0.77, specificity, 0.81

Dhanda et al,20 2012; UnitedKingdom; n ¼ 134

Clinical: SF and RB, pMayoEndoscopic: Mayo

Correlation RB þ SF to Mayo: Spearman correlationcoefficient,0.89 at week 4, and 0.90 at week 8

Jairath et al,1 2015; UnitedKingdom; n ¼ 181

Clinical: SF and RBEndoscopic: endoscopy subscore of UCDAI

(for derivation cohort)Baron et al18 (for validation cohort)

AUC For derivation cohort and endoscopicremission (�1 point)

AUC for SF, 0.74AUC for RB, 0.62AUC for RB þ SF, 0.74For validation cohort and endoscopic

remission (�1 point)AUC for SF, 0.85AUC for RB, 0.78AUC for RB þ SF, 0.90

Jharap et al,21 2015; UnitedStates; n ¼ 470

Clinical: SF and RBEndoscopic: Mayo

Sensitivity/specificity Mucosal healing at 8 wkSF: sensitivity, 0.21 (0.15–0.27); specificity,

0.97 (0.93–0.99)RB: sensitivity, 0.72 (0.65–0.78); specificity,

0.73 (0.66–0.78)RB þ SF: sensitivity, 0.18 (0.13–0.23);

specificity, 0.98 (0.96–1.0)Mucosal healing at 52 wkSF: sensitivity, 0.30 (0.23–0.36); specificity,



specificity, 0.98 (0.93–1.0)Lewis et al,19 2008; United

States; n ¼ 105Clinical: SF and RBEndoscopic: Mayo

Correlation sensitivity/specificity

RB þ SF to Mayo: Spearman correlationcoefficient, 0.88 (P < .01)

Disease remission (n ¼ 75)RB þ SF (threshold of 1.5): sensitivity, 0.65;

specificity, 0.81

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Tab

le2.

Con

tinue

d

Study;

coun

try;

NClinical

anden

dos

copic

scales

used

Ana

lysismetho

d

Res

ults

Correlatio

nSen

sitiv

ity/spec

ificity/AUC

Seo

etal,3

1998

;Ja

pan

;N

¼96

Clinical:SFan

dRB

End

osco

pic:

Baron

etal

18

Correlatio

nClinical

indices

andBaron

etal

18(com

bined

loca

tions

)SF:

Spea

rman

correlationco

efficien

t,0.35

2(P

<.001

)RB:Spea

rman

correlationco

efficien

t,0.62

4(P

<.001

)Baron

etal

18with

distal

colitis

SF:

0.23

4(P

¼NS)

RB:0.60

6(P

<.001

)Baron

etal

18with

left-sided

colitis

SF:

0.50

3(P

<.05)

RB:0.72

3(P

<.001

)Baron

etal

18an

dpan

colitis

SF:

0.21

9(P

¼NS)

RB:0.51

2(P

<.01)

AUC,area

under

curve;

pMay

o,partia

lMay

o;RB,rectal

bleed

ing;

SF,

stoo

lfreque

ncy;

UCDAI,UlcerativeColitisDisea

seActivity

Index

.


between clinical scores, including patient-reported out-comes of RB and SF, with endoscopic disease activity inthe UC population. The diagnostic performance betweenestablished clinical indices and RB/SF also seem to becomparable, suggesting that the assessment of UC pa-tients could be simplified to the use of these 2 param-eters only. A recent meta-analysis by Narula et al17 alsohas shown that normalization of these 2 outcomes in-dicates a low likelihood of disease activity, potentiallyrendering endoscopic assessment unnecessary incertain situations. This meta-analysis included a posthoc analysis of 4 randomized controlled trials and aprospective cohort study published before February2017. A combined RB and SF subscore of 0 identifiedpatients in endoscopic remission with a pooled sensi-tivity value of 36% (95% CI, 22%–54%), a specificityvalue of 96% (95% CI, 91%–98%), a positive likelihoodratio of 8.4 (95% CI, 5.5–12.8), and a negative likelihoodratio of 0.66 (95% CI, 0.53–0.84). This study, however,was limited by the significant heterogeneity among theincluded studies and potential uncontrolled biasesbecause most of the data were obtained from post hocanalyses. Furthermore, discrepancy between RB and SFalso was identified in this meta-analysis, showing thatthe presence of RB is unlikely in the setting of endo-scopic remission, whereas SF may not necessarilynormalize. The physiological nature of this discrepancyremains unexplained. This potentially could be relatedto persistent histologic disease activity, altered intesti-nal permeability, or concomitant irritable bowel syn-drome.38 In addition, this also may be associated withaltered colonic physiology in the setting of chronicinflammation. Long-standing UC can result in fibro-muscular proliferation, submucosal fibrosis and redu-plication of the muscularis mucosa, as well as changesto the neuromuscular components, which in turn lead tomorphologic changes and intestinal dysmotility.39 Therealso may be a time lag between mucosal healing andresolution of symptoms. Although the results of thisnarrative review support the combined use of these 2PRO parameters, their diagnostic yield individually re-mains to be validated. Finally, all of the PRO studies seta stringent cut-off point of no RB and SF when corre-lating with endoscopic remission. On the other hand,these studies lack sufficient granularity to comparevarying levels of specific PRO cut-off points with thedegree of endoscopic activity other than that there is apositive correlation. There also were no data showingwhat degree of PRO score change would reflect clini-cally significant improvement in endoscopic inflamma-tion and thus could be targeted to guide treatmentoptimization.

Even though the heterogeneous nature of theincluded studies reported in this article precluded amore rigorous statistical analysis being performed, thediagnostic performance of PRO2 and clinical indices re-mains consistent across various patient populations,different clinical settings, and levels of disease activity.


The results of this review also are strengthened by theinclusion of a large number of relevant and up-to-dategood-quality studies.

Indeed, several studies did show that endoscopicassessment contributed little to the variance of diseaseactivity in factor analysis.20,32 Therefore, use of nonin-vasive markers may lead to more efficient and poten-tially more cost effective clinical management strategies,as well as having a beneficial impact on clinical trials.

Whether disease location influences the diagnosticaccuracy of noninvasive indices remains to be deter-mined. The existing literature is insufficiently robust toaddress this issue. In addition, some of the clinicalindices have shown strong construct validity, test–retestreliability, and responsiveness to change7,40; furtherstrengthening their use in clinical practice.

However, despite the consistent correlation betweenPRO measures and endoscopic activity, treating UC pa-tients according to symptomatology alone may not ach-ieve optimal clinical outcomes. First, a subset of patientswith endoscopic activity would not show significantchanges in RB and SF, therefore this would lead toundertreatment of this particular population, or viceversa lead to overtreatment of patients. Furthermore,cumulative evidence in recent years has shown potentialsuperior outcomes with histologic remission over endo-scopic mucosal healing and perhaps this will be consid-ered as the ultimate treatment target in the future.Histologic disease activity such as basal plasmocytosishas been shown to be associated independently withclinical relapse and risk of colectomy.41,42 In addition,resolution of histologic inflammation may lead to areduction in hospitalization, corticosteroid use, surgicalintervention, and even colorectal malignancy risks.43

Further definitive and longitudinal comparison of out-comes between histologic and endoscopic remission aswell as correlation between PRO measures and histologicremission are eagerly awaited; this should assist us indetermining the optimal treatment target and whetherPRO can be used as a surrogate tool in the treatmentalgorithm. Finally, because there are multiple immuno-modulatory agents targeting various inflammatorypathways currently available for the treatment of UC,optimal timing to assess treatment response for eachclass may not be identical and needs to be determinedfurther.

Fecal calprotectin has been shown to be a reliablenoninvasive independent biomarker for assessing UC dis-ease activity, mucosal healing, and possibly histologicremission.44,45 Therefore, perhaps the diagnostic accuracyof PRO could be strengthened further with the combineduse of calprotectin testing. Currently, there are limited datain directly comparing the combined use of PRO and cal-protectin as a potential surrogate marker for endoscopicassessment. Future analysis could assist in advancing theuse of noninvasive tools in determining disease activity.

Endoscopic and clinical assessment also may havebeen limited by interobserver variability. Sigmoidoscopy

was often the main endoscopic assessment, which maynot be representative of the entire colon, although thedistal colon tends to be more severe such as in thosewith concurrent primary sclerosing cholangitis or onrectal topical therapy.

Conclusions

Clinical assessment and patient-reported outcome,especially with the normalization of rectal bleedingand stool frequency, may be helpful in determining UCdisease remission. Therefore, the use of endoscopicevaluation may be prioritized in select clinical situa-tions, particularly those in which access is limitedowing to resource- or patient-related matters.Although the ultimate treatment target in UC is to beelucidated, the inherent challenges associated withtreating patients according to symptomatology alonepreclude its adaptation in the current managementalgorithm.

Supplementary Material

Note: To access the supplementary material accom-panying this article, visit the online version of ClinicalGastroenterology and Hepatology at www.cghjournal.org,and at https://doi.org/10.1016/j.cgh.2018.12.021.

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http://www.cghjournal.org


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9. Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid)versus sulphasalazine in the treatment of active ulcerative coli-tis: a randomised trial. BMJ 1989;298:82–86.

10. Sutherland LR, Martin F, Greer S, et al. 5-Aminosalicylic acidenema in the treatment of distal ulcerative colitis, procto-sigmoiditis, and proctitis. Gastroenterology 1987;92:1894–1898.

11. Powell-Tuck J, Day DW, Buckell NA, et al. Correlations betweendefined sigmoidoscopic appearances and other measures ofdisease activity in ulcerative colitis. Dig Dis Sci 1982;27:533–537.

12. Azzolini F, Pagnini C, Camellini L, et al. Proposal of a newclinical index predictive of endoscopic severity in ulcerativecolitis. Dig Dis Sci 2005;50:246–251.

13. Peyrin-Biroulet L, Panes J, Sandborn WJ, et al. Defining diseaseseverity in inflammatory bowel diseases: current and future di-rections. Clin Gastroenterol Hepatol 2016;14:348.

14. Travis SP, Schnell D, Krzeski P, et al. Developing an instrumentto assess the endoscopic severity of ulcerative colitis: the Ul-cerative Colitis Endoscopic Index of Severity (UCEIS). Gut 2012;61:535–542.

15. Thia KT, Loftus EV Jr, Pardi DS, et al. Measurement ofdisease activity in ulcerative colitis: interobserver agreementand predictors of severity. Inflamm Bowel Dis 2011;17:1257–1264.

16. Peyrin-Biroulet L, Panes J, Sandborn WJ, et al. Defining dis-ease severity in inflammatory bowel diseases: current andfuture directions. Clin Gastroenterol Hepatol 2016;14:348–354.e17.

17. Narula N, Alshahrani AA, Yuan Y, et al. Patient-reported out-comes and endoscopic appearance of ulcerative colitis-a sys-tematic review and meta-analysis. Clin Gastroenterol Hepatol2019;17:411–418.

18. Baron JH, Connell AM, Lennard-Jones JE. Variation betweenobservers in describing mucosal appearances in proctocolitis.Br Med J 1964;1:89–92.

19. Lewis JD, Chuai S, Nessel L, et al. Use of the noninvasivecomponents of the Mayo score to assess clinical response inulcerative colitis. Inflamm Bowel Dis 2008;14:1660–1666.

20. Dhanda AD, Creed TJ, Greenwood R, et al. Can endoscopy beavoided in the assessment of ulcerative colitis in clinical trials?Inflamm Bowel Dis 2012;18:2056–2062.

21. Jharap B, Sandborn WJ, Reinisch W, et al. Randomised clinicalstudy: discrepancies between patient-reported outcomes andendoscopic appearance in moderate to severe ulcerative colitis.Aliment Pharmacol Ther 2015;42:1082–1092.

22. Colombel JF, Keir ME, Scherl A, et al. Discrepancies betweenpatient-reported outcomes, and endoscopic and histologicalappearance in UC. Gut 2017;66:2063–2068.

23. Scaioli E, Scagliarini M, Cardamone C, et al. Clinical applicationof faecal calprotectin in ulcerative colitis patients. Eur J Gas-troenterol Hepatol 2015;27:1418–1424.

24. Achitei D, Gologan E, Stefanescu G, et al. Clinical, biological andepidemiological aspects of inflammatory bowel diseases inNorth-East Romania. Rev Med Chir Soc Med Nat Iasi 2013;117:16–22.

25. Mirpour S, Rabie R, Mirpour K, et al. Evaluation of relationshipbetween clinical and colonoscopic features in patients withactive ulcerative colitis. Indian J Gastroenterol 2007;26:74–76.

26. Bodelier AG, Jonkers D, van den Heuvel T, et al. High per-centage of IBD patients with indefinite fecal calprotectin levels:

additional value of a combination score. Dig Dis Sci 2017;62:465–472.

27. Schoepfer AM, Beglinger C, Straumann A, et al. Ulcerativecolitis: correlation of the Rachmilewitz endoscopic activityindex with fecal calprotectin, clinical activity, c-reactiveprotein, and blood leukocytes. Inflamm Bowel Dis 2009;15:1851–1858.

28. Pagnini C, Menasci F, Festa S, et al. Application of clinical in-dexes in ulcerative colitis patients in regular follow-up visit:correlation with endoscopic ’mucosal healing’ and implicationfor management. Preliminary results. Eur Rev Med PharmacolSci 2015;19:3674–3681.

29. Hirai F, Matsui T, Aoyagi K, et al. Validity of activity indices inulcerative colitis: comparison of clinical and endoscopic indices.Dig Endosc 2010;22:39–44.

30. Langhorst J, Elsenbruch S, Koelzer J, et al. Noninvasive markersin the assessment of intestinal inflammation in inflammatorybowel diseases: performance of fecal lactoferrin, calprotectin,and PMN-Elastase, CRP, and clinical indices. Am J Gastro-enterol 2008;103:162–169.

31. Arai M, Naganuma M, Sugimoto S, et al. The ulcerativecolitis endoscopic index of severity is useful to predictmedium- to long-term prognosis in ulcerative colitis pa-tients with clinical remission. J Crohns Colitis 2016;10:1303–1309.

32. Higgins PD, Schwartz M, Mapili J, et al. Is endoscopy necessaryfor the measurement of disease activity in ulcerative colitis? AmJ Gastroenterol 2005;100:355–361.

33. Ricanek P, Brackmann S, Perminow G, et al. Evaluation ofdisease activity in IBD at the time of diagnosis by the use ofclinical, biochemical, and fecal markers. Scand J Gastroenterol2011;46:1081–1091.

34. Samuel S, Bruining DH, Loftus EV, et al. Validation of the ul-cerative colitis colonoscopic index of severity and its correlationwith disease activity measures. Clin Gastroenterol Hepatol2013;11:49–U178.

35. Taleban S, Stewart KO, Li DK, et al. Clinical activity and qualityof life indices are valid across ulcerative colitis but not Crohn’sdisease phenotypes. Dig Dis Sci 2016;61:2627–2635.

36. Falvey JD, Hoskin T, Meijer B, et al. Disease activity assessmentin IBD: clinical indices and biomarkers fail to predict endoscopicremission. Inflamm Bowel Dis 2015;21:824–831.

37. Chen JM, Liu T, Gao S, et al. Efficacy of noninvasive evalu-ations in monitoring inflammatory bowel disease activity: aprospective study in China. World J Gastroenterol 2017;23:8235–8247.

38. Tomita T, Kato Y, Takimoto M, et al. Prevalence of irritablebowel syndrome-like symptoms in Japanese patients withinactive inflammatory bowel disease. J Neurogastroenterol Motil2016;22:661–669.

39. Torres J, Billioud V, Peyrin-Biroulet L, et al. Ulcerative colitis as asole mucosal disease: another misunderstanding? Gut 2012;61:633.

40. Higgins PD, Leung J, Schwartz M, et al. The quantitative vali-dation of non-endoscopic disease activity indices in ulcerativecolitis. Aliment Pharmacol Ther 2007;25:333–342.

41. Bitton A, Peppercorn MA, Antonioli DA, et al. Clinical, biological,and histologic parameters as predictors of relapse in ulcerativecolitis. Gastroenterology 2001;120:13–20.

42. Bessissow T, Lemmens B, Ferrante M, et al. Prognostic value ofserologic and histologic markers on clinical relapse in ulcerative



























































































































































colitis patients with mucosal healing. Am J Gastroenterol 2012;107:1684–1692.

43. Bryant RV, Winer S, Travis SP, et al. Systematic review: histo-logical remission in inflammatory bowel disease. Is ’complete’remission the new treatment paradigm? An IOIBD initiative.J Crohns Colitis 2014;8:1582–1597.

44. Lin JF, Chen JM, Zuo JH, et al. Meta-analysis: fecal calprotectinfor assessment of inflammatory bowel disease activity. InflammBowel Dis 2014;20:1407–1415.

45. Mak WY, Buisson A, Andersen MJ Jr, et al. Fecal calprotectin inassessing endoscopic and histological remission inpatients with ulcerative colitis. Dig Dis Sci 2018;63:1294–1301.

Reprint requestsAddress requests for reprints to: Peter Lakatos, MD, PhD, FEBG, AGAG,Inflammatory Bowel Disease Centre, McGill University, McGill UniversityHealth Centre, Montreal General Hospital, 1650 Cedar Avenue, D16.173.1,Montreal, Quebec, H3G 1A4 Canada. e-mail: [email protected] [email protected]; fax: (514) 934-4452.

Conflicts of interestThe authors disclose no conflicts.

FundingSupported by a salary provided by a Canada Research Chair in immune-mediated intestinal diseases and the B Kaufman endowed IBD Chair atMcGill University (E.S.).

















mailto:[email protected]

mailto:[email protected]

Supplementary Table 1. Summary of the Included Studies

Study,country, study

type, NPatient inclusions/exclusions;

enrollment duration, moDiseaseactivity

Localization atbaseline, Mayoclassification;comparisonbetween

localization,yes or no

Clinical andendoscopicscales used PRO2

Outcomeassessment Results

Achitei et al,23

2013;Romania;N ¼ 555

Inclusions: all hospitalized UCExclusions: NAEnrollment: 36

Active disease E1–E2–E3No

pMayoeMayo

No Correlation Clinical score correlation between pMayoand eMayo: Pearson, 0.73

Arai et al,30

2016;Japan; N ¼ 285

Inclusions: UC with colonoscopyExclusions: infectious, radiation or ischemic

colitis, Crohn’s disease,Behcet’s disease

Enrollment: 11 mo

Active andinactivedisease

E1–E2–E3No

pMayoUCEIS

No Correlation Spearman correlation between pMayo andUCEIS,

0.637

Azzolini et al,12

2005; Italy;N ¼ 137

Inclusions: consecutive UC scheduled forcolonoscopy (active disease orsurveillance) with biochemical andphysical examination within 1 mo

Exclusions: incomplete colonoscopy,testing interval >1 mo, severe UC

Enrollment: 50 mo


E1–E2–E3No

PRO2SCCAIECCISelf-developed

endoscopicactivity score

Yes Correlationsensitivity/specificity/AUC

Spearman correlation between clinical scoreand self-developed endoscopic activityscore

PRO2:Total daily stool frequency, 0.57Night time stool frequency, 0.6Rectal bleeding, 0.64SCCAI, 0.68ECCI, 0.81AUC SCCAI and severe endoscopic disease

(threshold > 10), 86.07AUC ECCI and severe endoscopic disease

(threshold > 10), 93.24Considering 55 points the cut-off sensitivity,

81%Bodelier et al,25

2017; TheNetherlands;N ¼ 80

Inclusions: CD/UCa

Exclusions: IPAAEnrollment: 6 mo

Active þ inactivedisease

E1–E2–E3No

SCCAIMayo endoscopic

score

No Sensitivity/specificity

SCCAI vs eMayo (n ¼ 34 with endoscopicscore)

Sensitivity, 0.82Specificity, 0.60

Chen et al,36

2017; China;N ¼ 45

Inclusions: IBD (CD þ UC) with completecolonoscopy

Exclusions: indeterminate colitis,pregnancy, infection, malignancy,rheumatic disease, recent surgery (1 mo),trauma and NSAID (3 mo)

Enrollment: not statedOnly UC data were useda


E1–E2–E3No

Rachmilewitz9

clinical scoreMayo

No Correlationsensitivity/specificity

AUC

For detection of endoscopically activedisease

Spearman correlation coefficient, 0.776Sensitivity, 60.6%Specificity, 100%

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Colombel et al,22

2017; UnitedStates;N ¼ 103

Inclusions: UC with complete centrally readileocolonoscopy

Exclusions: biologic within 3 mo, pregnant,breastfeeding, infectious colitis, blood-borne infection

Enrolment: 21 mo


E1–E2–E3No

PRO2 eMayo Yes Sensitivity/specificity

For eMayo ¼ 0:SF: sensitivity, 76.3%; specificity, 83.1%RB: sensitivity, 86.8%; specificity, 66.2%RB þ SF: sensitivity, 68.4%; specificity,

86.2%For eMayo � 1:SF: sensitivity, 62.3%; specificity, 95.2%RB: sensitivity, 77%; specificity, 81%RB þ SF: sensitivity, 54.1%; specificity,

95.2%Dhanda et al,20

2012; UnitedKingdom;post hocfrom RCT;N ¼ 134

Inclusions: moderate - severe UC Mayo �6 þ steroid refractory assessed at weeks4 and 8

Exclusions: proctitis/standard clinical trialsEnrollment: 17 mo

Active disease E2–E3No

PRO2 pMayoeMayo

Yes CorrelationLinear

regression

Clinical remission (8 wk): correlationRho ¼ 0.89 at week 4 and 0.9 at week 8

Falvey et al,35

2015; NewZealand;N ¼ 65

Inclusions: all UC requiring colonoscopyExclusions: IBD-U, NSAID use, concurrent

significant luminal disease, advancedpolyposis, cancer, previous colectomy,incomplete examination

Enrollment: 17 mo


E1–E2–E3No

SCCAIModified Baron

et al18

No CorrelationSensitivity/

Specificity/AUC

Spearman rank correlation, 0.44 (0.27–0.59)AUC Baron et al18 < 1, 0.71SCCAI (threshold, 3.5): sensitivity, 0.59;

specificity, 0.88

Higging et al,31


Inclusions: UC planed for endoscopy (activeor surveillance)

Exclusions: non-native speakers who couldnot understand the consent form,incomplete data, confounding medicalillness, non-UC, cancer

Enrollment: 12 mo


E1–E2–E3No

SCCAISeo et al3 indexSt MarkUCDAI

No Correlation Spearman correlation coefficient between:St Mark and SCCAI, 0.866St Mark and Seo et al,3 0.705UCDAI and SCCAI, 0.8517UCDAI and Seo et al,3 0.7843

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Hirai et al,28

2010; Japan;N ¼ 74

Inclusions: moderate to severe UCExclusions: mild UC, surgeryEnrollment: NA

Active diseasebeforetreatmentand activeand inactiveaftertreatment

Compare activevs nonactiveafter tx

E: NANo

Rachmilewitz9 CAISeo et al3 indexLichtiger et al6

Rachmilewitz9

endoscopicscore

Baron et al18

No Correlation Before treatment:Spearman correlation clinical indices and

Baron et al18:Rachmilewitz9 CAI, 0.39Seo et al,3 0.29Lichtiger et al,6 0.47Spearman correlation clinical indices and

Rachmilewitz9 endoscopic score:Rachmilewitz9 CAI, 0.34Seo et al,3 0.35Lichtiger et al,6 0.33After treatment:Week 4 Spearman correlation clinical

indices and Baron et al18:Rachmilewitz9 CAI, 0.56Seo et al,3 0.29Lichtiger et al,6 0.56Spearman correlation clinical indices and

Rachmilewitz9 endoscopic score:Rachmilewitz9 CAI, 0.66Seo et al,3 0.28Lichtiger et al,6 0.67Week 8 Spearman correlation clinical

indices and Baron et al18:Rachmilewitz9 CAI, 0.76Seo et al,3 0.53Lichtiger et al,6 0.78Spearman correlation between clinical

indices and Rachmilewitz9 endoscopicscore:

Rachmilewitz9 CAI, 0.84Seo et al,3 0.65Lichtiger et al,6 0.80

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Jairath et al,1

2015; UnitedKingdom;post hocfrom RCT;N ¼ 181

Inclusions: adults, documented UC, diseaseextending at least 15 cm from the analverge, mildly to moderately active UCdefined by a modified UCDAI score 4–10with sigmoidoscopy component �2 andrectal bleeding �1

Exclusions: severe UC, previous failure ofcurrent treatment with a dosage ofmesalamine >2 g/d, current diseaserelapse lasting >6 wk; systemicantibiotic therapy for UC, probiotics,antidiarrheals, or a nicotine patch within1 wk; systemic or rectal corticosteroidtherapy within 4 wk; administration ofazathioprine, 6-mercaptopurine, orimmunosuppressive agents within 6 wk;administration of infliximab or otherbiologic treatment within 3 mo; oradministration of any investigational drugwithin 30 d before randomization, historyof colectomy or partial colectomy;colorectal dysplasia; Crohn’s disease;bleeding disorders; toxic megacolon;hypersensitivity to salicylates, aspirin,sulfasalazine, or mesalamine; serumcreatinine level >1.5 times the upper limitof normal or serum aspartatetransaminase, alanine transaminase,total bilirubin, or alkaline phosphataseconcentration >2 times the upper limit ofnormal; a serious underlying conditionother than UC; a history of drug oralcohol abuse; or a stool culture positivefor Clostridium difficile

Pregnant or lactating women also wereexcluded

Enrollment: 18 mo


PRO Endoscopicsubscores ofUCDAI (forderivationcohort)

Baron et al18 (forvalidationcohort)

Yes AUC For derivation cohort and endoscopicremission (0 points):

AUC for SF, 0.74AUC for RB, 0.65AUC for RB þ SF, 0.77For derivation cohort and endoscopic

remission (�1 point):AUC for SF, 0.74AUC for RB, 0.62AUC for RB þ SF, 0.74For validation cohort and endoscopic

remission (0 points):AUC for SF, 0.75AUC for RB, 0.71AUC for RB þ SF, 0.80For validation cohort and endoscopic

remission (�1 point):AUC for SF, 0.85AUC for RB, 0.78AUC for RB þ SF, 0.90

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Jharap et al,21

2015; UnitedStates; posthoc fromRCT;N ¼ 470

Inclusions: moderate-severe UC biologicnaive or not, Mayo � 6 þ endoscopysubscore �2, prior treatment withcorticosteroids and/orimmunosuppressants permitted

Exclusions: colectomy, cyclosporin,mycophenolate, tacrolimus, intravenoussteroids, enemas, suppositories,fulminant colitis, toxic megacolon,proctitis, indeterminate colitis, Crohn’sdisease, total parenteral nutrition, Cdifficile, infections, Hx or activemalignancy, pregnancy, breastfeeding,bad comorbidities, active alcoholconsumption, or drug consumption

Enrollment: 52 mo


PRO2 eMayo(mucosalhealing ¼ 0 or 0 /1)

Yes Sensitivity /Specificity

Mucosal healing at 8 wk:SF: sensitivity, 0.21 (0.15–0.27); specificity,



specificity, 0.98 (0.96–1.0)Mucosal healing at 52 wk:SF: sensitivity, 0.30 (0.23–0.36); specificity,



specificity, 0.98 (0.93–1.0)

Langhorstet al,29

2008; Germany;N ¼ 42

Inclusions: UCExclusions: NAEnrollment: 18 mo


E1–E2–E3No

Rachmilewitz9 CAIeMayo


Correlation:R ¼ 0.74Rachmilewitz9 CAI to predict active disease

(n ¼ 42): sensitivity, 89.3%; specificity,93.3% (cut-off Rachmilewitz9 > 4 points)

Lewis et al,19

2008; UnitedStates; posthoc fromRCT;N ¼ 105

Inclusions: mild to moderate UCExclusions: infectious colitis, pregnant,

breast feeding, chronic liver disease,NYHA class III þ IV heart failure, activemalignancy, diabetes/use ofcorticosteroids at doses greater than 20mg/d of prednisone

Enrollment: 40 mo


PRO2 pMayoeMayo

Yes Sensitivity /Specificity ofpMayo andMayo fordiseaseremissionand clinicalresponse

CorrelationbetweenpMayo andeMayo,

PRO2 to pMayoand PRO2 toeMayo

Disease activity measure correlation (n ¼ 75)Mayo (12 wk):Spearman correlation coefficient, 0.71 (P <

.01) pMayo (12 wk): Spearmancorrelation coefficient, 0.70 (P < .01)

PRO2 (12 wk): Spearman correlationcoefficient, 0.61 (P < .01)

Between scales correlation:PRO2 to Mayo, correlation coefficient, 0.88

(P < .01)PRO2 to Mayo: correlation coefficient, 0.96

(P < .01)Disease remission (n ¼ 75)Mayo (threshold, 4.5): sensitivity, 0.88;

specificity, 0.78 pMayo (threshold, 2.5):

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sensitivity, 0.71; specificity, 0.84PRO2 (threshold, 1.5): sensitivity, 0.65;

specificity, 0.81Clinical response (n ¼ 75)Mayo (threshold, 3.5): sensitivity, 0.88;

specificity, 0.80 pMayo (threshold, 3.5):sensitivity, 0.88; specificity, 0.87

PRO2 (threshold, 2.5): sensitivity, 0.88;specificity, 0.80

Mirpour et al,24

2007; Iran;N ¼ 88

Inclusions: NAExclusions: NAEnrollment: NA


Self-developedscore (well-being, pain,stool frequency,PR bleed,extraintestinalmanifestations,weight loss,hemoglobin,ESR, age)

Baron et al18

No Correlation Spearman rank correlation, 0.714

Pagnini et al,27

2015; Italy;N ¼ 75

Inclusions: UC: routine clinic visit, clinicalexamination, laboratory tests, and acomplete colonoscopy performed withinan interval of time no longer than 1 mo,complete record of the

clinical and laboratory parametersnecessary for the calculation of theclinical scores, and 1-y follow-updocumentation from the time of the visit

Exclusions: non-UC patients: first visit orsevere flare of disease, no documentedreport of any of the parametersnecessary for the calculation of theclinical scores or with an incompleteendoscopic examination and patientswithout 1-y of documented follow-upevaluation

Enrollment: 48 mo


E1–E2–E3No

SCCAIECCI pMAYOSeo et al3 indexBaron et al18

No CorrelationSensitivity /

Specificity

Correlation R:SCCAI, 0.75ECCI, 0.77 pMayo, 0.77Seo et al3 index, 0.64Mucosal healing: SCCAI: sensitivity, 87.9;

specificity, 76.5ECCI: sensitivity, 86.2; specificity, 82.4

pMayo: sensitivity, 0.81; specificity, 82.4Seo et al3 index: sensitivity, 79.3; specificity,

82.4

Ricanek et al,32

2011; Norway;N ¼ 61

Inclusions: newly diagnosed, treatment-naive UC

Exclusions: infection, microscopic colitis,malignancy

Enrollment: 31 mo


E1–E2–E3No

SCCAI eMayo No Linearregression

Linear regression, 3.17 (95% CI, 1.17–5.17;P ¼ .002)

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Inclusions: all UCExclusions: indeterminate/Crohn’s/

infectious colitis, colorectal neoplasia,poor bowel preparation, failed to captureendoscopy image

Enrollment: 7 mo


E1–E2–E3No

SCCAIRachmilewitz9 score

(CAI)UCCIS (self-

developedscore)

No Correlation Pearson or Spearman correlation coefficientas appropriate between SCCAI andUCCIS, 0.62

Rachmilewitz9 CAI and UCCIS, 0.52

Scaioli et al,45

2015; Italy;N ¼ 121

Inclusions: consecutive UC patientsattending outpatient clinic, E2 or E3, UCdiagnosis for 6 mo or more, age 16–89 y,complete colonoscopy with intubation ofthe cecum/informed consent/fecalsample

Exclusions: UC proctitis, Crohn’s,microscopic or IBD-U, infectious colitis,malignancy, pregnancy, colorectalsurgery, NSAIDs

Enrollment: 19 mo


SCCAI eMayo No Correlation Spearman rank, 0.78

Schoepferet al,26

2009;Switzerland;N ¼ 134

Inclusions: UC planed for endoscopy (activeor surveillance), duration >3 mo,complete colonoscopy (with intubationof cecum, intubation of terminal ileumnot mandatory) including biopsies(at least 6 colonic biopsy specimens fromUC-affected colon and rectum), informedconsent, age 18–85 y, fecal samplesdelivered from 3 to 1 d beforecolonoscopy

Exclusions: incomplete colonoscopy,infectious enterocolitis, colorectalcancer, Crohn’s disease, IBD-U, urinaryincontinence, inability to collect fecalsamples, pregnancy, history colonicresection, regular intake of aspirin and/orNSAID (2 tablets/wk)

Enrollment: 26 mo


E1–E2–E3No

Rachmilewitz9 score(CAI)

Rachmilewitz9

endoscopicscore


Spearman rank, 0.672Endoscopically active disease:Rachmilewitz9 clinical activity:

sensitivity, 0.81;specificity, 0.52

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Seo et al,3 1998;Japan;N ¼ 96

Inclusions: active UC flareExclusions: NAEnrollment: 108 mo

Active disease E1–E2–E3Yes: different

resultsdescribedbetweenlocations

PRO2Seo et al3 indexBaron et al18

Yes Correlation Clinical indices and Baron et al18 (combinedlocations):

SF: Spearman correlation coefficient, 0.352(P < .001)

RB: Spearman correlation coefficient, 0.624(P < .001)

Seo et al3 index: Spearman correlationcoefficient, 0.688 (P < .001)

Baron et al18 with distal colitis:SF, 0.234 (P ¼ NS)RB, 0.606 (P < .001)Seo et al3 index, 0.634 (P < .001)Baron et al18 with left-sided colitis:SF, 0.503 (P < .05)RB, 0.723 (P < .001)Seo et al3 index: 0.688 (P < .001)Baron et al18 and pancolitis:SF, 0.219 (P ¼ NS)RB, 0.512 (P < .01)Seo et al3 index, 0.614 (P < .01)

Taleban et al,34

2016; Romania;N ¼ 199

Inclusions: all UC with results of endoscopyand clinical data within 1 mo of eachother

Exclusions: NAEnrollment: NA


E1–E2–E3No

SCCAI eMayo No Correlation Spearman rank correlation:Overall localizations, 0.55SCCAI and pancolitis, 0.45SCCAI and left disease, 0.73SCCAI and proctitis, 0.58

Turner et al,7

2009;Canada;N ¼ 86

Inclusions: adult UC patients, undergoingcomplete C-scope, newly diagnosed,flare or routine endoscopic follow-upevaluation

Exclusions: proctitisEnrollment: NA


E2–E3No

pMayoRachmilewitz9

Lichtiger et al6

Seo et al3 indexSCCAIECCIBaron et al18 for

correlationeMayo to defineremission


Pearson correlation coefficient clinical scorevs Baron et al18:

pMayo, 0.69Rachmilewitz,9 0.79Lichtiger et al,6 0.69Seo et al,3 0.72SCCAI, 0.74ECCI, 0.80Total of 33 patients with clinical-endoscopic

remission (PGA þ eMayo score 0 or 1):sensitivity, 0.85; specificity, 0.91

AUC, area under curve; CAI, clinical activity index; CD, Crohn’s disease; C-scope, colonoscopy; ECCI, Endoscopic-Clinical Correlation Index; eMayo, endoscopic Mayo; ESR, erythrocyte sedimentation rate; Hx, history; IBD,inflammatory bowel disease; IBD-U, inflammatory bowel disease unclassified; IPAA, ileal pouch-anal anastomosis; NA, not available; NSAID, nonsteroidal anti-inflammatory drug; NYHA, New York Heart Association; PGA,physician’s global assessment; pMayo, partial Mayo; PR bleed, per rectum bleed; PRO, patient-reported outcome; RCT, randomized controlled trial; SCCAI, Simple Clinical Colitis Activity Index; tx, treatment; UC, ulcerativecolitis; UCEIS, Ulcerative Colitis Endoscopic Index of Severity.aOnly UC data were used for this narrative review.

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