Prevalence and Correlations of Gastrointestinal Symptoms With Endoscopic and Histologic Mucosal Healing in Crohn's Disease.

To characterize the associations between clinical disease activity with endoscopic and histologic (endohistologic) mucosal healing in Crohn's disease, we performed a secondary analysis of prospectively collected data on 424 ileocolonoscopies from 258 unique adults at a tertiary referral center from 2014 to 2021. One-third of patients (34%, 25/73) in endoscopic-histologic remission reported gastrointestinal symptoms. The 2-item patient-reported outcome measure for abdominal pain and stool frequency correlated weakly with endoscopic (Simple Endoscopic Score for Crohn's Disease; r = 0.17, 95% CI 0.08-0.26, P = 0.0003) and histologic disease activity (Global Histologic Disease Activity Score; r = 0.14, 95% CI 0.03-0.24, P = 0.015). Overall, gastrointestinal symptoms correlate poorly with endohistologic disease activity.

Correlations Between Gastrointestinal Symptoms and Endoscopic-Histologic Disease Activity in Adults with Ulcerative Colitis.

INTRODUCTION: Discordance between gastrointestinal (GI) symptoms and endoscopic inflammation in patients with ulcerative colitis (UC) is known. However, the correlations between symptoms and endoscopic and histologic (endo-histologic) mucosal healing and remains unknown. METHODS: We performed a secondary analysis of prospectively collected clinical, endoscopic, and histologic data on 254 colonoscopies from 179 unique adults at a tertiary referral center from 2014 to 2021. Spearman's rank was used to assess the correlation between patient reported outcomes and objective assessments of disease activity, as measured by validated instruments: Two-item patient-reported outcome measure (PRO-2) for stool frequency and rectal bleeding, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for endoscopic inflammation, and the Geboes score for histologic inflammation. The predictive value of objective assessments of inflammation and clinical symptoms was described using sensitivity, specificity, and positive/negative predictive value. RESULTS: One-quarter (28%, 72/254) of cases were in endo-histologic remission; of these, 25% (18/72) report GI symptoms (22% diarrhea; 6% rectal bleeding). Endo-histologically active disease had higher sensitivity (95% rectal bleeding; 87% diarrhea) and negative predictive value (94% rectal bleeding, 78% diarrhea) for clinically active disease compared to active disease on endoscopic (77%) or histologic assessment only (80%). The specificity of endo/histologic inflammation for GI symptoms was < 65%. PRO-2 was positively correlated with endoscopic disease activity (Spearman's rank 0.57, 95% CI 0.54-0.60, p < 0.0001) and histologic disease activity (Spearman's rank 0.49, 0.45-0.53, p < 0.0001). CONCLUSION: One-quarter of patients with ulcerative colitis in endo-histologic (deep) remission have gastrointestinal symptoms, more commonly with diarrhea than rectal bleeding. Endo-histologic inflammation has high sensitivity (≥ 87%) for diarrhea/rectal bleeding.

Development and Validation of a Test to Monitor Endoscopic Activity in Patients With Crohn's Disease Based on Serum Levels of Proteins.

BACKGROUND & AIMS: Noninvasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS: We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI], using samples from 278 patients with CD from a multinational training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naive patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤2 and ≤1 in each segment, or a total CD endoscopic index of severity score <3) was assessed by using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum C-reactive protein (CRP) and fecal calprotectin. RESULTS: The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% confidence interval, 0.942-0.982) and an AUROC of 0.693 in validation cohort 2 (95% confidence interval, 0.619-0.767), regardless of CD location or phenotype. A cutoff value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cutoff value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P < .001 in validation cohort 1 and 0.624, P = .109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC; P = .147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC; P = .298 in validation cohort 2). CONCLUSIONS: We developed an index called the EHI to identify patients with CD in endoscopic remission based on blood levels of 13 proteins. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice to assess endoscopic activity in patients with CD.

Understanding Determinants of Patient Preferences Between Stool Tests and Colonoscopy for the Assessment of Disease Activity in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Evidence is now available in support of using fecal biomarkers to monitor disease activity in inflammatory bowel disease (IBD). Patient adherence is often cited as a barrier to implementation. We assessed patient determinants for using stool tests to monitor disease activity. METHODS: Prospective interview of IBD patients using an analytic hierarchy matrix survey built to understand preferences for choosing between stool testing or colonoscopy for monitoring disease activity, after considering different test criteria (accuracy, preparation, pain, complications). Theoretical thresholds of misclassification were posed to patients to see how they might consider shifting from colonoscopy to stool testing. RESULTS: A total of 100 patients (n = 51 CD, n = 46 male) were interviewed with median age and disease duration of 44 years (IQR 27-63) and 9 years (IQR 5-21), respectively. Stool-based testing was preferred over colonoscopy by 60% initially; however, a majority of participants changed their choice to colonoscopy after learning more about the diagnostic performance of currently available stool tests for disease monitoring (p < 0.001). Across all sub-groups, accuracy was ranked as the top criterion when choosing between stool-based testing and colonoscopy for disease activity assessments. Most patients were willing to choose stool-based testing over colonoscopy for disease monitoring if the stool test was wrong at most 1 in 20 times (5% misclassification rate). DISCUSSION: Accuracy is the most important criteria for IBD patients when choosing monitoring strategies, and a high degree of confidence is required of stool test results for patients to choose this strategy.

A Serum Biomarker Panel Can Accurately Identify Mucosal Ulcers in Patients With Crohn's Disease.

BACKGROUND: The Endoscopic Healing Index (EHI) is a serum biomarker panel that can predict endoscopic inflammation in Crohn's disease (CD). METHODS: Paired serum samples with endoscopies from adult patients participating in a prospective biobank (June 2014 to December 2018) were analyzed post hoc. Diagnostic performance for EHI was assessed against the individual parameters of the Simple Endoscopic Score for CD using previously identified cutoffs. Confounders for EHI performance were identified using logistic regression. RESULTS: A total of 205 CD patients were included (50% male, median age 37 years). An EHI of 20 points was sensitive for ruling out any ulcers (85%; 95% confidence interval [CI], 77%-91%) and large (5-20 mm) or very large (>20 mm) ulcers (93%; 95% CI, 84%-97%). An EHI of 50 points was specific for ruling in any ulcers (86%; 95% CI, 76%-92%) and large or very large ulcers (87%; 95% CI, 79%-92%). After accounting for total extent of inflamed mucosa, strictures, and disease location, each 20-point increase in EHI was associated with a 1.7-fold increased probability for the presence of large or very large ulcers (adjusted odds ratio, 1.7; 95% CI, 1.1-2.6). CONCLUSIONS: The EHI was independently associated with ulcer size and accurately identified large or very large ulcers. A cutoff of 50 points can reliably rule in mucosal ulcers and allow for treatment adjustment. A cutoff of 20 points can reliably rule out mucosal ulcers and signal completion of treatment adjustment algorithms.

Preserved SARS-CoV-2 Vaccine Cell-Mediated Immunogenicity in Patients With Inflammatory Bowel Disease on Immune-Modulating Therapies.

Immune-modulating medications for inflammatory bowel diseases (IBDs) have been associated with suboptimal vaccine responses. There are conflicting data with SARS-CoV-2 vaccination. We therefore assessed SARS-CoV-2 vaccine immunogenicity at 2 weeks after second mRNA vaccination in 29 patients with IBD compared with 12 normal healthy donors. We observed reduced humoral immunity in patients with IBD on infliximab. However, we observed no difference in humoral and cell-mediated immunity in patients with IBD on infliximab with a thiopurine or vedolizumab compared with normal healthy donors. This is the first study to demonstrate comparable cell-mediated immunity with SARS-CoV-2 vaccination in patients with IBD treated with different immune-modulating medications.

Risk of Relapse in Patients With Ulcerative Colitis With Persistent Endoscopic Healing: A Durable Treatment Endpoint.

BACKGROUND: Deep remission in patients with UC has relied on initial achievement of biochemical, endoscopic, and/or histological remission. We evaluated persistent symptomatic remission and endoscopic healing (EH: Mayo endoscopy score [MES] 0 or 1) on consecutive endoscopic examinations as a durable treatment endpoint. METHODS: In a retrospective cohort study, we estimated and compared cumulative risk of clinical relapse in patients with persistent EH, with and without persistent histological remission and depth of EH, among adults with active UC treated-to-target of symptomatic remission and EH who achieved and maintained symptomatic remission and EH over two serial endoscopic assessments. We also explored risk of relapse in patients with persistent EH whose therapy was de-escalated. RESULTS: Of 270 patients who initially achieved EH with treatment-to-target, 89 maintained symptomatic remission and EH on follow-up endoscopy [interval between EH1 and EH2, 16 months]. On follow-up after EH2 [median, 19 months], 1-year cumulative risk of relapse in patients with persistent EH was 11.5%, and with persistent histological remission was 9.5%. Seventeen patients with persistent EH, who underwent de-escalation of therapy, did not have an increased risk of relapse as compared with patients who continued index therapy [5.3% vs 14%, p = 0.16]. CONCLUSIONS: Patients with active UC treated-to-target of clinical remission, who achieve and maintain symptomatic remission and EH over consecutive endoscopies, have a low risk of relapse, particularly in a subset of patients who simultaneously achieve histological remission. Persistent EH should be examined as a treatment endpoint suggestive of deep remission.

Disease- and Treatment-related Complications in Older Patients With Inflammatory Bowel Diseases: Comparison of Adult-onset vs Elderly-onset Disease.

BACKGROUND: The incidence and prevalence of inflammatory bowel diseases (IBD) in older adults are rising. There is a limited comparative assessment of risk of disease- and treatment-related complications in older patients (older than 60 years) with adult-onset (age at disease onset, 18-59 years; AO-IBD) vs elderly-onset IBD (age at disease onset, older than 60 years; EO-IBD). We compared clinical outcomes in older patients with IBD with AO-IBD vs EO-IBD. METHODS: We conducted a retrospective cohort study comparing risk of disease-related complications (IBD-related surgery, hospitalization, treatment escalation, clinical flare, or disease complication) and treatment-related complications (serious infection, malignancy, or death) in older patients with AO-IBD vs EO-IBD through Cox proportional hazard analysis, adjusting for age at cohort entry, disease phenotype, disease duration, prior surgery and/or hospitalization, medication use, disease activity at cohort entry, and comorbidities. RESULTS: We included 356 older patients with IBD (AO-IBD, 191 patients, 67 ± 5 y at cohort entry; EO-IBD, 165 patients, 72 ± 8 y at cohort entry). No significant differences were observed in the risk of disease-related complications in older patients with prevalent vs incident IBD (adjusted hazard ratio [aHR], 0.85; 95% CI, 0.58-1.25), although risk of IBD-related surgery was lower in older patients with prevalent IBD (aHR, 0.47; 95% CI, 0.25-0.89). Older patients with prevalent IBD were significantly less likely to experience treatment-related complications (aHR, 0.58; 95% CI, 0.39-0.87). CONCLUSION: Patients with AO-IBD have lower risk of treatment-related complications as they age compared with patients with EO-IBD, without a significant difference in risk of disease-related complications.

Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn's disease.

BACKGROUND: Biologic therapies in patients with Crohn's disease often yield low clinical and endoscopic remission rates. After multiple failed therapies, combining two biologic therapies is possibly the sole medical alternative to recurrent surgery. However, data on this approach are limited. AIMS: To assess the efficacy and safety of concomitant use of two biologic therapies in the largest cohort to date of refractory Crohn's disease patients. METHODS: Data were extracted from Crohn's disease patients started on dual biologic therapy at two referral centres. Biologics utilised include infliximab, adalimumab, vedolizumab, ustekinumab, certolizumab and golimumab. The primary outcome was endoscopic improvement (>50% reduction in Simplified Endoscopic Score-Crohn's disease [SES-CD] or explicitly stated). Endoscopic remission (SES-CD < 3 or stated), clinical response (Crohn's disease-patient-reported outcome-2 score [PRO2] reduced by 8), clinical remission (PRO2 < 8), and C-reactive protein (CRP) were also assessed. RESULTS: A total of 22 patients with 24 therapeutic trials of dual biologic therapy were identified. The majority of patients had prior surgical resections (91%), stricturing (59%) or penetrating (36%) phenotype, and perianal fistulas (50%). Median number of prior failed biologics was 4. Endoscopic improvement occurred in 43% of trials and 26% achieved endoscopic remission. Fifty per cent had clinical response and 41% achieved clinical remission. There were significant post-treatment reductions in median SES-CD (14.0 [12.0-17.5] to 6.0 [2.5-8.0], P = 0.0005], PRO-2 (24.1 [20.3-27.0] to 13.4 [4.6-21.8], P = 0.002] and CRP (17.0 [11.0-24.0] to 9.0 [4.0-14.0], P = 0.02). Presence of perianal fistulas decreased from 50% to 33%. Adverse events occurred in 13% of trials. CONCLUSION: Dual biologic therapy was associated with clinical, biomarker and endoscopic improvements in selected patients with refractory Crohn's disease who failed multiple biologics. Further studies are needed to validate this approach.