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Correlation of Stool Frequency and Abdominal Pain Measures With Simple Endoscopic Score for Crohn's Disease.

BACKGROUND
The Crohn's Disease Activity Index (CDAI) has been criticized for being weakly correlated with bowel inflammation. We assessed correlation between Simple Endoscopic Score for Crohn's Disease (SES-CD) and individual CDAI items stratified by disease location to better understand this relationship.


METHODS
We pooled patient-level data from 3 placebo-controlled Crohn's disease (CD) trials that tested adalimumab, upadacitinib, and risankizumab. Disease location was defined as ileum only, colon only, or ileocolonic based upon colonoscopy at study entry. Pearson correlation coefficients and linear regression assessed correlations between items of the CDAI and SES-CD.


RESULTS
A total of 353 patients were included (20.7% ileal, 30.6% colonic, 48.7% ileocolonic disease). Crohn's Disease Activity Index and SES-CD scores were moderately correlated (R = 0.33; P < 0.001). Among CDAI items, the strongest correlations with SES-CD were seen with very soft or liquid stool frequency (SF) and patient-reported outcome 2 (PRO2; which includes SF and abdominal pain score; both R = 0.36; P < 0.001); these correlations were numerically stronger in colonic disease (SF: R = 0.46; P < 0.001; PRO2: R = 0.44; P < 0.001) than in ileal disease (SF: R = 0.14; P = 0.23; PRO2: R = 0.21; P = 0.07), although a test for interaction was not significant. In adjusted linear regression models, the proportion of mucosa that was inflamed and the proportion of mucosa with ulceration were positively correlated, whereas the presence of strictures was inversely correlated with SF.


CONCLUSIONS
The SF item of the CDAI is moderately correlated with SES-CD and independently correlated with mucosal ulceration, inflammation, and strictures. Understanding why bowel inflammation as measured endoscopically does not correlate more strongly with patients' symptoms could help develop scales that link CD pathology to patient experience.


INTRODUCTION
Crohn's disease (CD) is a chronic inflammatory disease that most commonly involves the ileum and/or colon. Crohn's disease is diagnosed based on a combination of symptoms, along with endoscopic, radiologic, and histologic findings. The main symptoms of CD are abdominal pain (AP) and diarrhea, with many patients also experiencing extraintestinal symptoms including fatigue, joint pain, weight loss, and ocular and dermatologic manifestations. Treatment goals include resolution of symptoms and reduction of bowel inflammation, the latter being targeted with the hope of preventing future symptomatic relapse and progressive bowel damage. 1,2 Placebo-controlled randomized clinical trials, which are the gold standard for testing the efficacy and safety of novel therapies, require valid outcome measures that can accurately and reliably differentiate efficacious treatments from placebo. For decades, the Crohn's Disease Activity Index (CDAI) was used to define disease activity in clinical trials. 3,4 The CDAI is a composite index composed of 8 items: the number of liquid or very soft stools per day (referred to as stool frequency [SF] hereafter), AP, general well-being, anemia, physical examination findings (presence of fistulas, fissure, fever, and extraintestinal manifestations), presence of an abdominal mass, body weight, and treatment (use of opiates or other agents for diarrhea). Thus, it is neither a patient-reported outcome (PRO) nor a biomarker of inflammation. Although the CDAI has been used successfully to demonstrate the efficacy of numerous medications that are now the basis of treatment for CD, it has been criticized for its lack of a strong correlation with bowel inflammation as assessed on endoscopy. 5,6 As such, there has been a movement to separate the main symptom features of CDAI into individual PROs including only SF and AP, which can be combined either weighted or unweighted as PRO2 or PRO3 if general well-being is also included. 7 As a requirement of regulatory authorities, PROs are now widely used in conjunction with an endoscopic measure of bowel inflammation as co-primary outcomes for clinical trials.
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Author contributions: James D. Lewis is the primary author of the manuscript. All authors contributed to the development of the content. The authors reviewed drafts and approved and maintained control of the final content.
Role of sponsor: Abbvie contributed to the study design, research, analysis, data collection and interpretation, and to the writing, review, and approval of the publication.
The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Scoring for Crohn's Disease (SES-CD) are the 2 most extensively studied colonoscopy indices for CD. However, neither has been fully validated. 8 Given that the SES-CD is easier to implement, correlates strongly with CDEIS, and is likely to be more reliable and responsive than the latter measure, it has become the more commonly used of the 2 indices for clinical research. 8,9 The SES-CD requires evaluation of 4 items (extent of involved mucosa, extent of ulceration of the mucosa, size of ulcers, and presence of strictures) in 5 bowel segments (terminal ileum, right colon, transverse colon, left/sigmoid colon, and rectum). The total SES-CD, which ranges from 0 (no inflammation) to 56 (very high inflammation), is derived by summing the segment scores.
Although intuitively appealing, several questions remain regarding the use of PRO2 or PRO3 measures in combination with SES-CD for CD clinical trials. No standard has been set for how to define endoscopic response or remission using SES-CD or PROs. Many historic clinical trials therefore have used "absence of ulcerations" as an endoscopic outcome measure, although an SES-CD reduction of 50% has more recently been introduced as an alternative endoscopic outcome measure based on post hoc analyses of a clinical trial with infliximab. 10 We hypothesized that the poor correlation of SES-CD with CDAI 5, 6 is due to the inclusion of numerous items of the CDAI that are less strongly correlated with the findings of endoscopic inflammation than are the main symptoms of SF and AP. In addition, we hypothesized that not all items of the SES-CD are equally correlated with symptoms. As such, it may be possible to revise the SES-CD scoring to improve correlation with the main symptoms of CD. Thus, the aims of this study were to assess the correlation of the SES-CD with individual items of the CDAI and to determine which features of the SES-CD correlate most strongly with the clinical symptoms of CD. In addition, we sought to define the correlation of commonly used dichotomous symptombased and endoscopic outcome measures to inform selection of outcomes for clinical trials.

Clinical Trials Included in the Pooled Analysis
This study pooled patient-level data from 3 placebocontrolled clinical trials: a phase 2 study of risankizumab, 11 a phase 3 study of the effects of adalimumab on mucosal healing (EXTEND), 12, 13 and a phase 2 study of upadacitinib (ABT-494; CELEST; NCT02365649). 14   EXTEND had an open-label induction with adalimumab at Weeks 0 and 2 for all patients before randomizing patients to receive adalimumab or placebo starting at Week 4. The other 2 trials compared drug with placebo from the baseline visit until measurement of primary outcomes. This analysis was limited to patients with SES-CD values for the ileum plus ≥1 colonic segment at baseline, to allow for determination of location of disease, and with a colonoscopy at Week 12 or Week 16 with available data to assess disease activity ( Fig. 1). Missing SES-CD items within a segment were imputed as 0, but patients for whom all SES-CD items for the ileum or entire colon were missing at baseline or follow-up were excluded. Imputation of ≥1 item occurred infrequently (EXTEND trial 0/100 at baseline and 0/100 at follow-up; upadacitinib trial 15/160 at baseline and 17/160 at follow-up; risankizumab trial 8/93 at baseline and 15/93 at follow-up; combined 23/353 at baseline and 35/353 at follow-up). Disease location was defined according to the findings of the colonoscopy before baseline and categorized as ileal, colonic, or both if the SES-CD was >0 for that region. 15 Although the EXTEND trial used the local investigators' prerandomization colonoscopy reading to determine eligibility, these were re-read by a central reader. The centrally read SES-CD values were used for this study. The risankizumab trial used the CDEIS rather than the SES-CD for inclusion criteria.
However, all participants also had SES-CD scores computed by the central reader. These scores were used for this study.
The SES-CD was further categorized into subscores for the individual items (eg, size of ulcers, proportion of mucosa with ulceration, proportion of mucosa inflamed, and strictures) by summing these items across all bowel segments ( Supplementary Fig. 1). The most diseased segment of bowel was that with the highest subscore.
The CDAI scores were computed based on data selfreported by the patient 7 days before the study visit in all trials. When data collection was incomplete, imputation was used if at least 4 days of data were available to estimate the full CDAI by assuming that the average of the recorded days was equal to the missing days. PRO2 measures were based on weighted values for the SF and AP items, which were also used for CDAI.

Statistical Analysis
Descriptive data were summarized as percentage, mean, and standard deviation. Correlations were determined using Week 12/16 data unless otherwise indicated. This time point was used rather than the baseline colonoscopic finding to have greater range of endoscopic scores as all patients had active disease at baseline. The Pearson correlation coefficient and 95% confidence interval (CI) were used to assess the correlation between the CDAI and its individual items with the SES-CD. Pearson correlation coefficients were also computed for the individual items of the SES-CD with SF and AP items from CDAI. Correlation coefficients are described as weak, moderate, or strong, as per Cohen. 16 Linear regression was used to identify independent correlations with SF and AP and to assess whether the location of the disease in the bowel influenced the correlation between SES-CD and symptoms. Subgroup analyses were conducted among patients without prior bowel resection surgery and those without concomitant corticosteroid use at baseline. Additional analyses examined the correlation of categorically defined outcomes using CDAI, PRO2, and SES-CD. The following clinical outcomes were assessed: CDAI remission: CDAI <150; remission based on PRO2 components (referred hereafter as PRO2 remission): SF ≤2.8 and AP ≤1.0, both not higher than baseline in patients with SF ≥4.0 or AP ≥2.0 at baseline 17 ; resolved diarrhea: SF ≤2.8 and AP not higher than baseline (analyzed in patients with SF ≥4.0 at baseline); resolved AP: AP ≤1.0 and SF not higher than baseline (analyzed in patients with AP ≥2.0 at baseline); dichotomous endoscopic outcomes included endoscopic remission: SES-CD ≤4.0 and ≥2-point reduction vs baseline and no subscore >1.0 in any individual variable 17 ; endoscopic response: SES-CD reduction >50% from baseline or endoscopic remission. Correlations were assessed by computing the sensitivity, specificity, and C-statistic for each clinical outcome, with endoscopic remission and response as the gold standard.

RESULTS
A total of 476 patients were enrolled in the 3 trials; of these, 6 dropped out of the EXTEND trial before randomization, 52 lacked sufficient baseline data to characterize disease location, and 65 had missing endoscopic data at Week 12 or Week 16, resulting in a total of 353 patients who received active drug or placebo being included in this study (Fig. 1). Of these, 73 (20.7%) had isolated ileal disease, 108 (30.6%) had isolated colonic disease, and the remaining 172 (48.7%) had ileocolonic disease ( Table 2). Disease duration was a median (interquartile range) of 9.7 (5.0-17.0) years. The mean (SD) CDAI and SES-CD at baseline were 306.1 (68.7) and 15.3 (8.4), respectively. Concomitant therapy at the time of enrollment included systemic corticosteroids in 34%, thiopurines in 15%, and methotrexate in 11% of patients. Prior use of anti-tumor necrosis factor (TNF) biologics was reported in 293 (83.0%) patients, and 107 (30.3%) had prior surgery.
Subgroup analyses of patients without prior bowel resection and without current corticosteroid use demonstrated qualitatively stronger correlations between CDAI or individual items of CDAI with SES-CD among patients with ileal disease but not among those with colonic disease relative to the overall population (Supplementary Tables 1-3). The highest correlation coefficients in the no surgery population were again SF (R = 0.41; 95% CI, 0.30 to 0.51; P < 0.001) and PRO2 (R = 0.40; 95% CI, 0.29 to 0.50; P < 0.001). For the population not taking corticosteroids, the results were similar.
To explore whether the correlation of SES-CD with SF and AP was related to specific aspects of SES-CD, correlations were computed at Week 12/16 with the items of the SES-CD and with the worst bowel segment score ( Table 5). The correlations of each item of the SES-CD (other than strictures) with SF were highly similar to each other (R = 0.33-0.37; P < 0.001 for all comparisons) and similar to the overall SES-CD (R = 0.36; P < 0.001). Likewise, the correlations of each item of the SES-CD (other than strictures) with AP were highly similar to each other (R = 0.19-0.21; P < 0.001 for all comparisons). The most severely damaged bowel segment score was not more strongly correlated with SF and AP than SES-CD or individual item scores, other than strictures.
Similar to the correlations of SES-CD with SF or AP (and combined measure, PRO2), repeating the analysis stratified by disease location demonstrated stronger correlations between SES-CD items and SF among those with isolated colonic disease than in the pooled analysis (R = 0.40-0.45; P < 0.001 [other than strictures]) and correlations comparable to the full SES-CD (R = 0.46; P < 0.001); the individual items were not significantly associated with SF or AP in those with isolated ileal disease (Supplementary Table 4). The test for interaction was only statistically significant for the correlation of the most severely damaged segment of bowel and SF (P = 0.04). A subgroup analysis limited to those without prior surgery resulted in slightly higher overall correlations between SES-CD items and SF or AP. Again, the highest correlations were seen for SF in those patients with isolated colonic disease analysis (R = 0.42-0.49; P < 0.001 [other than strictures]) and were comparable to the full SES-CD (R = 0.48; P < 0.001) (Supplementary Table 5). Tests of interaction by disease location were not statistically significant.

Relation Between Dichotomous Outcome Measures
The association between dichotomous CDAI and symptom-defined outcomes and dichotomous endoscopic outcomes was relatively poor and comparable across each of the indices examined, with both endoscopic remission and response (Supplementary Table 6). The highest sensitivity was CDAI-defined remission with endoscopic remission (62%; 95% CI, 48.5% to 75.5%) whereas the highest specificity was PRO2 remission with endoscopic response (87%; 95% CI, 83.2% to 91.3%). The C-statistic ranged from 0.60 (resolution of AP for    endoscopic response) to 0.68 (resolution of diarrhea for endoscopic response).

DISCUSSION
The CDAI has been used for decades to study the effectiveness of medical therapies for treating patients with CD. However, it is a composite measure that includes patientreported symptoms, hematocrit, and physical examination findings. The CDAI has fallen out of favor for use in clinical trials due to a weak correlation with objective measures of inflammation in general and endoscopically defined inflammation, in particular. However, the relationship between mucosal lesions and clinical symptoms is complex, likely influenced by multiple factors, and has been inadequately studied. One contributor is likely the properties of the instruments that have been used to define this relationship. In this study, we demonstrated that the SF item of the CDAI is most strongly and consistently correlated with bowel inflammation as measured by the SES-CD, and the correlation is stronger among patients with colonic disease than in those with isolated ileal disease, but even in this population the correlation was only modest. Additionally, each of the items of the SES-CD with the notable exception of strictures correlates similarly with SF. However, neither resolution of diarrhea nor remission defined by the PRO2 was strongly associated with SES-CD-defined endoscopic remission or response when pooled across all patients.
There are many possible explanations for the weak to moderate correlations that were observed between symptoms, particularly AP, and SES-CD. Pain is a complex phenomenon with many potential causes, some of which will differ from those that cause diarrhea. AP in patients with CD can result from noninflammatory processes including irritable bowel syndrome, the effects of surgery on bowel motility, submucosal fibrosis, adhesions, and stricture formation, the latter being more relevant in the small intestines than in the colon. The transmural nature of CD could result in inflammation of enteric neurons in  the absence of significant mucosal inflammation. 6 Whether AP would correlate better with other measures of bowel damage, including cross-sectional imaging or biomarkers, needs to be determined. Another relevant source of the low correlation between symptoms and endoscopically defined disease activity is the nature of the tools available to measure endoscopic inflammation. A previous study that evaluated the operating properties of the individual SES-CD items demonstrated that some of the items, in particular the stricture item, had poor interrater reliability. 18 In the current study, the items of the SES-CD other than strictures each correlated nearly identically with SF and AP in unadjusted analyses. However, in linear regression models, the proportion of mucosa with inflammation, the proportion of mucosa with ulceration, and the presence of strictures were independently associated with SF. In contrast, none of the SES-CD items were independently associated with AP after adjusting for potential confounders. There is substantial overlap of the inflammation and ulceration items of the SES-CD. For example, one cannot have ulceration without inflammation, and the larger the ulcers, the greater the proportion of the mucosa that will be inflamed and ulcerated. This suggests that the SES-CD could be simplified by excluding ≥1 items without compromising the performance of the measure. Whether additional items could be added to the SES-CD or existing items modified to improve the correlation with symptoms should be a focus of future investigation. Nevertheless, endoscopic scores, including the SES-CD, usually correlate better with other objective signs of inflammation, such as biomarkers, which points toward the fact that PROs as currently captured in clinical trials are only modestly reflective of underlying inflammation.
Some CDAI items are only weakly linked to inflammation and/or are heavily influenced by other confounding variables. For example, although weight loss is a manifestation of uncontrolled inflammation in patients with active CD, treatment with corticosteroids may offset this effect without having a strong benefit on endoscopically defined disease activity. Likewise, hematocrit is affected by blood volume status, blood loss from causes other than CD such as menstruation, and bone marrow suppression from immunosuppressive drugs. The original selection of the CDAI items was based upon regression of items generated by clinicians with physician assessment of clinical disease activity as a gold standard, as opposed to endoscopic assessment of bowel inflammation. We found that PRO2, which only includes CDAI-derived SF and AP items, correlated as well as CDAI with SES-CD. Importantly, PRO2 is substantially easier to implement and relies exclusively on patients' symptoms, making it more practical for use in clinical trials and possibly routine clinical practice. However, it must be acknowledged that the correlation with endoscopic findings was qualitatively stronger in those patients with colonic disease, and PRO2 is not designed to be used in patients with an ostomy, such that generalizability to all patients remains a challenge.
The correlation of SF with SES-CD was numerically larger among patients with colonic disease, and to a lesser extent ileocolonic disease, than in those with isolated ileal disease. Although the test for statistical interaction was not significant (Supplementary Table 4), this is typically an underpowered test. These results are similar to those of Cellier, who studied the CDEIS. 6 The stronger correlation in those with colonic disease may reflect the colon's role in water absorption or merely the greater extent of mucosal involvement due to the relative size of the colon compared with the ileum. Alternatively, there is a smaller range of SES-CD values for isolated ileal disease, which could limit the strength of the correlation. Finally, only a limited portion of the ileum is visualized during colonoscopy, and as such there is a greater risk of misclassification of disease activity in the ileum.
Another novel observation was that endoscopic remission and response were similarly associated with improvement in symptoms. A major limitation of the SES-CD has been the lack of a definition for clinically meaningful improvement. These findings suggest that endoscopic response could be viewed as an equally important outcome measure as endoscopic remission for clinical trials, although additional studies of long-term outcomes with endoscopic response vs remission, as defined by the SES-CD, are needed.
This study has several strengths, including pooling patientlevel data from 3 placebo-controlled trials, use of centrally read colonoscopies resulting in lower intra-and interobserver variability, and the ability to stratify analyses by disease location. Setting an arbitrary cut-point for SF to define remission may have been problematic, particularly among patients with prior bowel resection surgery. In theory, change in the SF score may be a better way to define clinical response than using a fixed cutpoint, assuming that the increased SF is a consequence of active bowel inflammation. However, the change in SES-CD correlated poorly with change in CDAI at 12/16 weeks in this study. It is generally perceived that symptoms improve before mucosal changes of CD. It is possible that the correlation of changes in SF and AP with changes in the SES-CD would be stronger at a later time point and that 12/16 weeks is too early to meaningfully look for endoscopic improvement. Furthermore, combining data from trials testing 3 drugs following various modes of action could also play a role due to differences in the kinetics of symptomatic vs mucosal improvements between those compounds. Despite the use of central reading, ~10% of endoscopic exams had at least 1 item missing. Given the small number of patients to whom this applied, it is unlikely that these factors significantly biased the results.

CONCLUSIONS
In conclusion, this analysis of 3 clinical trials demonstrated that the SF item of the CDAI is most strongly and consistently correlated with bowel inflammation, as measured by the SES-CD, particularly in those with colonic disease, although even these correlations were only modest. Additionally, the total SES-CD and the 3 items of SES-CD other than strictures had comparable correlations with patients' symptoms. The proportion of the mucosa with inflammation, the proportion with ulceration, and presence of strictures were independently associated with SF, whereas none of the SES-CD items were significantly associated with AP in multivariable regression. Similarly, endoscopically defined response and remission were comparably correlated with patients' symptoms. Improved knowledge of why bowel inflammation as measured endoscopically does not correlate more strongly with patients' symptoms and outcomes could help to optimize endoscopic scoring systems and further develop alternative measurement modalities that better connect the underlying pathology of Crohn's disease to the patient's experience.

SUPPLEMENTARY DATA
Supplementary data are available at Inflammatory Bowel Diseases online.