Histological Disease Activity Research Articles

Liver inflammation activity in patients with autoimmune hepatitis with normal alanine aminotransferase and immunoglobulin G levels

Background and aimsNormal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. MethodsTwo hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. ResultsOne hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045–1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138–2.014, P = 0.004) were independent factors associated with advanced inflammation. ConclusionsHigh proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Effects of Mirikizumab on Histologic Resolution of Crohn's Disease in a Randomized Controlled Phase 2 Trial

Histologic evaluation of mucosal healing in Crohn's disease (CD) is an evolving treatment target. We evaluated histologic outcomes for mirikizumab efficacy and associations with endoscopic and 1-year outcomes. Biopsies from 1 ileal and 4 colonic segments were evaluated at Weeks 0, 12, and 52 from each 170 SERENITY participants. Criteria for the Weeks 12 and 52 histologic response (a) no epithelial neutrophils or epithelial damage, or (b) >50% decrease in either Robarts Histopathology Index or active Global Histologic Disease Activity Score and remission (no mucosal neutrophils and no epithelial damage) had to be met in all biopsies. Agreement was evaluated between histologic and endoscopic endpoints. Associations between 1-year outcomes and Week 12 histologic and endoscopic response were evaluated. At Week 12, 1000 mg mirikizumab resulted in greater rates of histologic response (66% vs 27%, P<0.001) and remission (26% vs 6%, P<0.01) than placebo. Rates were numerically similar at 1-year (mirikizumab pooled response: 46-69%, remission: 13-31%). Agreement between Week 12 histologic and endoscopic response was 69% (Cohen's Kappa coefficient (κ)=0.40) and remission was 83% (κ=0.38) in all pooled arms, including placebo. At 1-year, the percentage of participants who received any dose of mirikizumab and achieved endoscopic remission differed by their Week 12 response: histologic (20%), endoscopic (25%), combined histology-endoscopy (45%), or neither (4%) (.003). In a post-hoc analysis of phase 2 data, mirikizumab induced and sustained histologic response and remission in CD over 52 weeks. Early combined histologic-endoscopic response was associated with endoscopic remission after 1 year of treatment with mirikizumab (ClinicalTrials.gov NCT02891226.

Histologic Activity in Inflammatory Bowel Disease and Risk of Serious Infections: A Nationwide Study

Individuals with inflammatory bowel disease (IBD) are at increased risk of serious infections, but whether this risk varies by histologic disease activity is unclear. This was a national population-based study of 55,626 individuals diagnosed with IBD in 1990 to 2016 with longitudinal data on ileocolorectal biopsy specimens followed up through 2016. Serious infections were defined as having an inpatient infectious disease diagnosis in the Swedish National Patient Register. We used Cox regression to estimate hazard ratios (HRs) for serious infections in the 12 months after documentation of histologic inflammation (vs histologic remission), adjusting for social and demographic factors, chronic comorbidities, prior IBD-related surgery, and hospitalization. We also adjusted for IBD-related medications in sensitivity analyses. With histologic inflammation vs remission, there was 4.62 (95% CI, 4.46-4.78) and 2.53 (95% CI, 2.36-2.70) serious infections per 100 person-years of follow-up, respectively (adjusted HR [aHR], 1.59; 95% CI, 1.48-1.72). Histologic inflammation (vs remission) was associated with an increased risk of serious infections in ulcerative colitis (aHR, 1.68; 95% CI, 1.51-1.87) and Crohn's disease (aHR, 1.59; 95% CI, 1.40-1.80). The aHRs of sepsis and opportunistic infections were 1.66 (95% CI, 1.28-2.15) and 1.71 (95% CI, 1.22-2.41), respectively. Overall, results were consistent across age groups, sex, and education level, and remained largely unchanged after adjustment for IBD-related medications (aHR, 1.47; 95% CI, 1.34-1.61). Histologic inflammation of IBD was an independent risk factor of serious infections, including sepsis, suggesting that achieving histologic remission may reduce infections in IBD. The study was approved by the Stockholm Ethics Review Board (approval numbers 2014/1287-31/4, 2018/972-32, and 2021-06209-01).

Extracellular matrix remodeling proteins as biomarkers for clinical assessment and treatment outcomes in eosinophilic esophagitis

BackgroundEosinophilic esophagitis (EoE) is a chronic progressive inflammatory disease of the esophagus, characterized by extracellular matrix remodeling and fibrotic stricture formation. Disease monitoring requires multiple re-endoscopies with esophageal biopsies. Hence non-invasive methods for determining tissue fibrosis and treatment efficacy are warranted.AimsTo investigate the ability of extracellular matrix proteins in serum as potential biomarkers of tissue remodeling and clinical, endoscopic, and histological disease outcomes in adult EoE patients.MethodsProtein-fingerprint assays were used to measure neo-epitope specific fragments of collagen remodeling, human-neutrophil elastase degraded calprotectin, and citrullinated or non-citrullinated vimentin in the serum of an adult EoE-cohort. Biomarker analysis, symptoms, endoscopic features and histological disease activity (eosinophils(eos) per high-power-field(hpf)) were evaluated at baseline and after six weeks of dietary intervention.ResultsPatients with a baseline (Endoscopic Reference score) EREFS fibrosis subscore ≥ 2 presented with increased fibrolysis of cross-linked type III collagen (CTX-III) (p < 0.01), whereas low CTX-III levels were observed in patients achieving histological remission (< 15 eos/hpf) (vs. no histological remission (p < 0.05). Progression of endoscopic fibrosis after intervention was associated with increased levels of type-III (PRO-C3) and -VI collagen (PRO-C6) formation (all; p < 0.05). A baseline EREFS inflammatory subscore ≥ 2 correlated with higher neutrophilic activity (Cpa9-HNE) at week 6 (p < 0.05). Moreover, increased degradation of type-III (C3M) and -IV (C4M/PRO-C4) collagens were associated with remission of food impaction after intervention (all; p < 0.05).ConclusionSerum extracellular matrix remodeling proteins demonstrated potential as surrogate biomarkers for assessing histological disease remission, endoscopic fibrosis, and remission of symptoms of food impaction after diet intervention in adult EoE patients.

Healing of the epithelial barrier in the ileum is superior to endoscopic and histologic remission for predicting major adverse outcomes in ulcerative colitis.

Achieving endoscopic remission is a key therapeutic goal in patients with ulcerative colitis (UC) that is associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of endoscopic and/or histologic remission against ileal barrier healing for predicting long-term disease behavior in a large cohort of UC patients in clinical remission. At baseline, UC patients in clinical remission underwent ileocolonoscopy with assessment of ileal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity and ileal barrier healing were scored using validated scores. During subsequent follow-up (FU), patients were closely monitored for clinical disease activity and occurrence of major adverse outcomes (MAO) defined as the following: disease relapse; UC-related hospitalization; UC-related surgery; necessity for initiation or dose escalation of systemic steroids, immunosuppressants, small molecules or biological therapy. Of the 73 UC patients included, 67% experienced MAO during a mean FU of 25 months. The probability of MAO-free survival was significantly higher in UC patients with endoscopic and/or histologic remission compared to patients with endoscopically and/or histologically active disease. Ileal barrier healing on endomicroscopy was highly accurate for predicting the further course of UC and outcompeted endoscopic and histologic remission for predicting MAO-free survival. Ileal barrier healing in clinically remittent UC patients can accurately predict future MAO development and is superior in its predictive capabilities than endoscopic and histologic remission. Ileal barrier healing therefore represents a novel and superior surrogate parameter for stratification of UC patients according to their risk for development of complicated disease behavior. https://classic.clinicaltrials.gov/ct2/show/NCT05157750, identifier NCT05157750.

Deep Learning Models Capture Histological Disease Activity in Crohn's Disease and Ulcerative Colitis with High Fidelity.

Histological disease activity in inflammatory bowel disease [IBD] is associated with clinical outcomes and is an important endpoint in drug development. We developed deep learning models for automating histological assessments in IBD. Histology images of intestinal mucosa from phase 2 and phase 3 clinical trials in Crohn's disease [CD] and ulcerative colitis [UC] were used to train artificial intelligence [AI] models to predict the Global Histology Activity Score [GHAS] for CD and Geboes histopathology score for UC. Three AI methods were compared. AI models were evaluated on held-back testing sets, and model predictions were compared against an expert central reader and five independent pathologists. The model based on multiple instance learning and the attention mechanism [SA-AbMILP] demonstrated the best performance among competing models. AI-modelled GHAS and Geboes subgrades matched central readings with moderate to substantial agreement, with accuracies ranging from 65% to 89%. Furthermore, the model was able to distinguish the presence and absence of pathology across four selected histological features, with accuracies for colon in both CD and UC ranging from 87% to 94% and for CD ileum ranging from 76% to 83%. For both CD and UC and across anatomical compartments [ileum and colon] in CD, comparable accuracies against central readings were found between the model-assigned scores and scores by an independent set of pathologists. Deep learning models based upon GHAS and Geboes scoring systems were effective at distinguishing between the presence and absence of IBD microscopic disease activity.

Crohn’s Disease Features in Anastomotic Biopsies from Patients With and Without Crohn’s Disease: Diagnostic and Prognostic Value

Endoscopic evidence of disease activity is a critical predictor of clinical relapse in patients with Crohn’s disease (CD), and histologic disease activity is evolving as a similarly important end point for patient management. However, classical morphologic features of CD may overlap with postoperative inflammatory changes, confounding the evaluation of anastomotic biopsies. There is a clear unmet need for better characterization of diagnostic and clinically significant histologic features of CD in these surgically altered sites. We evaluated ileocolonic and colocolonic/rectal anastomotic biopsies performed at 3 academic institutions in patients with and without CD. The biopsies were blindly assessed for CD histologic features and correlated to clinical and endoscopic characteristics. In CD patients, the presence of each feature was correlated with the subsequent clinical exacerbation or relapse. We obtained anastomotic biopsies from 208 patients, of which 109 were operated on for CD and 99 for another indication (neoplasia [80%], diverticular disease (11%), and other [9%]). Mean time since surgery was 10 years (0-59; 14 years for CD [1-59], 6 years for non-CD [0-33]). Endoscopic inflammation was noted in 52% of cases (68% for CD and 35% for non-CD). Microscopic inflammation was present in 74% of cases (82% for CD and 67% for non-CD). Only discontinuous lymphoplasmacytosis (P < .001) and pyloric gland metaplasia (P = .04) occurred significantly more often in CD patients. However, none of the histologic features predicted clinical disease progression. In subset analysis, the presence of histologic features of CD in nonanastomotic biopsies obtained concurrently in CD patients was significantly associated with relapse (P = .03). Due to extensive morphologic overlap between CD and postoperative changes and the lack of specific histologic features of relapse, biopsies from anastomotic sites are of no value in predicting clinical CD progression. Instead, CD activity in biopsies obtained away from anastomotic sites should be used for guiding endoscopic sampling and clinical management.

Urine L-selectin reflects clinical and histological renal disease activity and treatment response in lupus nephritis across multi-ethnicity.

There is an urgent need for novel biomarkers in lupus nephritis (LN). We report a non-invasive urinary biomarker, L-selectin, in two independent multi-ethnic cohorts. uL-selectin was tested cross-sectionally in a Chinese cohort (n=255) and a US cohort (n=219) of SLE patients and controls using ELISA. A longitudinal cohort includes 20 active Chinese LN patients. uL-selectin was significantly increased in active LN patients compared to active non-renal SLE, inactive LN, inactive non-renal SLE, chronic kidney disease patients, and healthy controls. uL-selectin positively correlated with global and renal disease activities as well as histological activity index and chronicity index (CI). Low uL-selectin was an independent predictor for high CI. During follow-up, uL-selectin levels decreased significantly in the complete renal remission group. uL-selectin is a novel biomarker of disease activity and renal histopathology in LN across multiple ethnicities. It also reflects treatment response in LN patients during follow up.

Utility of Geboes score for assessing histological activity in ulcerative colitis

Introduction and Aim: Diagnosis of UC is challenging and calls for an integrated clinical, endoscopic, serological, and histological examination. Although inexpensive and non-invasive, endoscopic findings do not always correlate with disease activity, as demonstrated by traditional histopathological examination. Materials and Methods: This retrospective study was conducted between January 2014 and December 2019. Specimens of patients diagnosed with UC that were received in the Department of Pathology were included. An experienced pathologist assessed the histological disease activity using the Geboes score. The Mayo endoscopic subscore was recorded for endoscopic activity. Results thus obtained were entered into MS Excel and analysis was done using SPSS version 25.0. Results: Of the 123 cases of UC, (age, 14 to 74 years; males: 60.2%, females: 39.8%) majority had endoscopic findings of erythema and edema (n=20) with the least common finding being ileocolitis (n=1). Mayo subscore was available in 24 cases (ranging from 1 to 3; Mayo subscores of 1, 2, and 3 in 1, 14 and 9 cases respectively). Active colitis was noted in 78% (96/123) of the patients while the remaining 22% (27/123) of patients had inactive colitis. Only 24 cases had both Mayo subscore and Geboes score correlation. Fourteen cases had a Mayo subscore of 2 and a Geboes score ranging from 2A to 5.2; 9 cases had a Mayo subscore of 3 and a Geboes score ranging from 4.1 to 5.2. Conclusion: Assessment of histological disease activity by Geboes score provides useful information in routine reporting of biopsy specimens of cases of Ulcerative colitis

Histological Disease Activity as Predictor of Clinical Relapse, Hospitalization, and Surgery in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

The clinical impact of histological remission on short- and long-term clinical outcomes in patients with inflammatory bowel disease (IBD) is not well established. We assessed risk of clinical relapse, hospitalization, and need for surgery in patients achieving histological remission in comparison with active histological disease. A systematic review was conducted using MEDLINE, Scopus, Cochrane CENTRAL, EMBASE, and conference abstracts from inception to November 2022. Our main outcome was the rate of clinical relapse in patients with IBD who reached histological remission vs patients with active histological disease. Secondary outcomes were clinical complications of IBD such as hospitalization and need for surgery. The endpoints were investigated at 2 time points, 6 to 12 months (short term) and >12 months (long term). Short-term outcome analysis showed that the risk of clinical relapse was significantly higher in ulcerative colitis patients with active histological disease in comparison with patients at histological remission (risk ratio [RR], 2.41; 95% confidence interval [CI], 1.69-3.44; P < .01). The risk of hospitalization in ulcerative colitis patients was not significant among the 2 groups (RR, 4.22; 95% CI, 0.91-19.62; P = .07). Long-term outcome analysis demonstrated that the risk of clinical relapse (RR, 2.07; 95% CI, 1.55-2.76; P < .01), need for surgery (RR, 3.14; 95% CI, 1.53-6.45; P < .01), and hospitalization (RR, 2.52; 95% CI, 1.59-4.00; P < .01) was significantly higher in patients with active histological disease. Histological remission in IBD represents an important therapeutic goal that is not yet routinely pursued in clinical practice. In our study, patients who achieved histological remission have more favorable outcomes than those with active histological disease in ulcerative colitis.

Eosinophilic Esophagitis Histologic Scoring System: Correlation with Histologic, Endoscopic, and Symptomatic Disease and Clinical Use.

The eosinophilic esophagitis histologic scoring system (EoEHSS) was developed to enhance the diagnostic standard of peak eosinophil count (PEC) in evaluating disease activity in EoE. (1) Correlate the EoEHSS and PEC to measures of symptomatic and endoscopic disease activity, (2) Correlate EoEHSS grade and stage subcomponents to clinical, radiology, and endoscopic markers of fibrotic disease, (3) Evaluate EoEHSS remission in asymptomatic patients with PEC < 15 eosinophils per high powered field (eos/hpf). Secondary analysis of prospective cohort data of 22 patients with EoE that underwent dietary therapy and endoscopy at 3 time points. Active disease was defined by EoEHSS grade or stage > 0.125, symptomatic disease by EoE symptom activity index > 20, endoscopic disease by endoscopic reference score > 2, and histologic disease by PEC ≥ 15 eos/hpf. EoEHSS remission was defined by esophageal inflammation (EI) grade of 0-1, EI stage of 0, total grade ≤ 3, and total stage ≤ 3. EoEHSS grade and stage did not correlate with symptomatic disease but did with endoscopic and histologic disease. PEC showed similar correlation pattern. Abnormal grade and stage had strong sensitivity (87-100%) but poor specificity (11-36%) to detect symptomatic, endoscopic, and histologic disease activity. Lamina propria fibrosis was evaluated in 36% of biopsies and did not correlate with minimum esophageal diameter. Out of 14 patients who were in complete symptomatic, endoscopic, and histologic remission, 8 met criteria for EoEHSS remission. The positive and negative correlations of EoEHSS to specific measures of symptomatic, histologic, and endoscopic activity suggest that it provides complementary information in EoE.

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

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. 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. 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). 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.

Can Nonalcoholic Steatohepatitis Be Surgically Cured?: Liver Histologic Comparison After Metabolic Surgery Versus Usual Care.

To compare histologic outcomes in patients with fibrotic nonalcoholic steatohepatitis (NASH) and obesity after metabolic surgery versus nonsurgical care. There are no published data comparing the effects of metabolic surgery versus nonsurgical care on histologic progression of NASH. Repeat liver biopsies were performed in patients with body mass index >30kg/m 2 at a US health system whose baseline liver biopsy between 2004 and 2016 confirmed a histologic diagnosis of NASH including the presence of liver fibrosis, but without cirrhosis. Baseline characteristics of liver histology for patients who underwent simultaneous liver biopsy at the time of metabolic surgery were balanced with a nonsurgical control group using overlap weighting methods. The primary composite endpoint required both resolution of NASH and improvement of at least 1 fibrosis stage in the repeat liver biopsy. A total of 133 patients (42 metabolic surgery and 91 nonsurgical controls) had a repeat liver biopsy with a median interval of 2 years. Overlap weighting provided balance for baseline histologic disease activity, fibrosis stage, and time interval between liver biopsies. In overlap-weighted patients, 50.1% in the surgical and 12.1% in the nonsurgical group met the primary endpoint (odds ratio=7.3; 95% CI, 2.8-19.2, P <0.001). NASH resolution and fibrosis improvement occurred in 68.5% and 64.1% of surgical patients, respectively. Surgical and nonsurgical patients who met the primary endpoint lost more weight than their counterparts who did not meet the primary endpoint [mean weight loss difference in the surgical group: 12.2% (95% CI, 7.3%-17.2%) and in the nonsurgical group: 11.6% (95% CI, 6.2%-16.9%)]. Among patients with fibrotic noncirrhotic NASH, metabolic surgery resulted in simultaneous NASH resolution and fibrosis improvement in half of patients.

Risk of colorectal neoplasia according to histologic disease activity in patients with inflammatory bowel disease and colonic post-inflammatory polyps.

While post-inflammatory polyps (PIPs) have historically been a risk factor for colorectal neoplasia (CRN), histologic activity may explain this association. We aimed to assess the impact of histologic activity on CRN occurrence in IBD patients with colonic PIPs. Patients with PIPs on surveillance colonoscopy at Saint-Antoine hospital between 1 January 1996 and 31 December 2020 were included and subsequent colonoscopies were assessed. Histologic IBD activity was assessed by the Nancy histologic index. Survival and Cox regression analysis were performed to assess the strength of the association of PIPs and other patient variables with progression to CRN. A total of 173 patients with at least two surveillance colonoscopies with PIPs at index colonoscopy were compared to a similar group of 252 patients without PIPs. In survival analysis, the presence or PIPs at index colonoscopy did not impact the risk of CRN in patients with histological inflammation (p = 0.83) and in patients without histological inflammation (p = 0.98). The risk of CRN was associated with increasing Nancy index score of 3 or 4 (HR: 4.16; 95% CI 1.50-11.52 and HR: 3.44; 95% CI 1.63-7.24), age (HR per 10-year increase: 1.37; 95% CI 1.13-1.66) and first-degree family history of colorectal cancer (HR: 5.87; v 1.31-26.26), but not PIPs (HR: 1.17; 95% CI 0.63-2.17). After controlling for histologic activity, PIPs do not increase the risk of CRN in IBD patients. Histologic activity rather than PIPs should be considered in the risk assessment of CRN.

Biopsies from ulcer edge yield higher histological activity scores than biopsies from non-ulcerated mucosa in active ulcerative colitis.

The appropriate location for biopsy collection in ulcerative colitis is unknown. We aimed to determine the location for biopsy collection in the presence of ulcers which yields the highest histopathological score. This prospective cross-sectional study enrolled patients with ulcerative colitis and ulcers in the colon. Biopsy specimens were obtained at the edge of the ulcer; at a distance of one open forceps (7-8 mm) from the ulcer edge; at a distance of three open forceps (21-24 mm) from the ulcer edge; further referred to as locations 1, 2 and 3 respectively. Histological activity was assessed using Robarts Histopathology Index and the Nancy Histological Index. Statistical analysis was performed using mixed effects models. A total of 19 patients were included. Decreasing trends with distance from the ulcer edge (P < 0.0001) were observed. Biopsies procured from the edge of the ulcer (location 1) yielded a higher histopathological score compared to biopsies procured at locations 2 and 3 (P ≤ 0.001). Biopsies from the ulcer edge yield higher histopathological scores than biopsies next to the ulcer. In clinical trials with histological endpoints, biopsies should be obtained from the ulcer edge (if ulcers are present) to reliably assess histological disease activity.

Composite Assessment Using Intestinal Ultrasound and Calprotectin Is Accurate in Predicting Histological Activity in Ulcerative Colitis: A Cohort Study.

Beyond endoscopic remission, histological remission in ulcerative colitis (UC) is predictive of clinical outcomes. Intestinal ultrasound (IUS) may offer a noninvasive surrogate marker for histological activity; however, there are limited data correlating validated ultrasound and histological indices. Our aim was to determine the correlation of IUS activity in UC with a validated histological activity index. Twenty-nine prospective, paired, same-day IUS/endoscopy/histology/fecal calprotectin (FC) cases were included. Intestinal ultrasound activity was determined using the Milan Ultrasound Criteria, histological activity using the Nancy Histological Index, endoscopic activity using Mayo endoscopic subscore and Ulcerative Colitis Endoscopic Index of Severity, and clinical activity using the Simple Clinical Colitis Activity Score. Histological activity demonstrated a significant linear association with overall IUS activity (coefficient 0.14; 95% CI, 0.03-0.25; P = .011). Intestinal ultrasound activity was also significantly associated with endoscopic activity (0.32; 95% CI, 0.14-0.49; P < 0.001), total Mayo score (0.31; 95% CI, 0.02-0.60; P = .036) but not FC (0.10; 95% CI, -0.01 to 0.21; P = .064) or clinical disease activity (0.04; 95% CI, -0.21 to 0.28; P = .768). A composite of IUS and FC showed the greatest association (1.31; 95% CI, 0.43-2.18; P = .003) and accurately predicted histological activity in 88% of cases (P = .007), with sensitivity of 88%, specificity 80%, positive predictive value 95%, and negative predictive value 57%. Intestinal ultrasound is an accurate noninvasive marker of histological disease activity in UC, the accuracy of which is further enhanced when used in composite with FC. This can reduce the need for colonoscopy in routine care by supporting accurate point-of-care decision-making in patients with UC.

The urotensin-II receptor: A marker for staging and steroid outcome prediction in ulcerative colitis.

Urotensin-II receptor- (UTR) related pathway exerts a key-role in promoting inflammation. The aim was to assess the relationship between UTR expression and clinical, endoscopic and biochemical severity of ulcerative colitis (UC), exploring its predictivity of intravenous (iv) steroid administration therapeutic outcome. One-hundred patients with first diagnosis of UC and 44 healthy subjects were enrolled. UTR expression was assessed by qPCR, Western Blot (WB) and immunohistochemistry (IHC). Clinical, endoscopic and histological activity of UC were evaluated by using Truelove and Witts (T&W) severity index, Mayo Endoscopic Score (MES), and Truelove and Richards Index (TRI). The partial and full Mayo scores (PMS and FMS) were assessed to stage the disease. The UTR expression, resulted higher in the lesioned mucosa of UC patients in comparison to healthy subjects (p < .0001 all). Direct relationship between UTR (mRNA and protein) expression and disease severity assessment (T&W, PMS, MES and TRI) was highlighted (p < .0001 all). UTR expression resulted also higher in the 72 patients requiring iv steroids administration compared to those who underwent alternative medications, (p < .0001). The 32 steroid-non-responders showed an increased UTR expression (WB, IHC and qPCR from lesioned mucosa), compared to 40 steroid-responders (p: .0002, .0001, p < .0001 respectively). The predictive role of UTR expression (p < .05) on the negative iv steroids administration therapeutic outcome was highlighted and ROC curves identified the thresholds expressing the better predictive performance. UTR represents a promising inflammatory marker related to clinical, endoscopic, and histological disease activity as well as a predictive marker of steroid administration therapeutic outcome in the UC context.

Correlation Between the Nancy Histopathology Index and Markers of Disease Activity in Pediatric Ulcerative Colitis.

The Nancy Histological Index (NHI) was developed to assess histological disease activity in adult ulcerative colitis (UC) patients. However, data in pediatrics is limited. Our aim was to determine whether the NHI correlates with different indices of disease activity in pediatric UC patients. We retrospectively reviewed the NHI in rectal biopsies from 61 pediatric UC patients (median age 14.3 years), of whom 34 (55.7%) were newly diagnosed. The median Pediatric Ulcerative Colitis Activity Index (PUCAI) score among participants was 30 (interquartile range 5-55). Most patients exhibited an NHI of 3 (41/61, 67.2%) or 4 (8/61, 13.1%), reflecting moderate-severe histologic inflammation. A moderate positive correlation was identified between the NHI and PUCAI, fecal calprotectin, and Mayo endoscopic scores ( r = 0.60, 0.54, and 0.56 respectively, P ≤ 0.001), but not with CRP or albumin. These results indicate that the NHI has a modest correlation with clinical, laboratory and endoscopic indices of disease activity in pediatric UC patients.

P268 Development and validation of a novel composite index for the assessment of endoscopic and histologic disease activity in pouchitis: The Atlantic pouchitis index.

Abstract Background Several instruments have been used in clinical trials of pouchitis to define eligibility criteria and outcome measures but have not been formally validated. A need remains for a validated pouchitis instrument that is suitable for use in novel drug development. We developed and internally validated the novel composite Atlantic pouchitis index (API) for the assessment of endoscopic and histologic disease activity in patients with pouchitis. Methods Paired baseline and week 10 endoscopic videos and histologic images were obtained from 98 patients with chronic antibiotic-refractory pouchitis who participated in a randomised placebo-controlled trial of alicaforsen enema (ClinicalTrials.gov identifier: NCT02525523). For each pair, 4 endoscopists and 3 pathologists scored 59 items. These items included 51 component items from 11 indices (4 endoscopic, 4 histologic, 3 composite) identified in a prior systematic review and 8 additional items identified in a prior Research and Development/University of California Los Angeles appropriateness methodology exercise. The reliability of all measures was assessed using intraclass correlation coefficients (ICCs) and interpreted according to Landis and Koch benchmarks (slight, 0.00-0.20; fair, 0.21-0.40; moderate, 0.41-0.60; substantial, 0.61-0.80; almost perfect, 0.81-1.00). Responsiveness was evaluated using the area under the receiver operating characteristic curve (AUC). The API was developed using linear regression with a 100-mm visual analogue scale (VAS) of pouchitis activity as an anchor. Results Among all measures assessed for reliability and responsiveness, the simple endoscopic score for Crohn’s disease (SES-CD) and the Robarts histopathology index (RHI) were selected for inclusion in the API. The total API score ranges from 0 to 69, with higher scores indicating more severe disease activity, and can be calculated as API = (3 × SES-CD [0 to 12]) + (1 × RHI [0 to 33]). The API demonstrated almost perfect intra-rater reliability (ICC, 0.88 [95% CI: 0.81, 0.92]), substantial inter-rater reliability (ICC, 0.72 [95% CI: 0.60, 0.79]), and a high correlation with the VAS (r = 0.84 [95% CI: 0.76, 0.89]). Index responsiveness in detecting meaningful improvements in disease activity was higher for the API (AUC, 0.95 [95% CI: 0.89, 0.98]) than for existing endoscopic indices (∆AUC, 0.09-0.24; P≤0.005) (Table). Conclusion The novel API is a composite index of endoscopic (SES-CD) and histologic disease activity (RHI) that is reliable and significantly more responsive than existing endoscopic pouchitis scoring systems. The API is a promising tool for use in clinical trials of novel therapies for pouchitis. Further validation is needed in independent datasets.

P247 Oncostatin M and its receptor are markers of endoscopic and histological disease activity in Inflammatory Bowel Disease

Abstract Background Oncostatin M (OSM) and its receptor (OSMR) have been associated with active disease in patients with inflammatory bowel disease (IBD). This study compared the expression of OSM and OSMR in intestinal tissue according to clinical, endoscopic, and histological disease activity. Methods A multi-centre IBD database containing RNA-sequencing datasets, was used to analyse OSM and OSMR expression in ileal and/or colonic tissue, expressed as transcripts per million (TPM). Clinical scoring systems included the Harvey Bradshaw Index for Crohn’s disease (CD) and partial Mayo score for ulcerative colitis (UC). Endoscopic scoring systems included the simple endoscopic score for CD (SES-CD) and UC endoscopic index of severity (UCEIS). Histological scoring included the modified Naini and Cortina, and Riley scores. Graphs were presented in log transformed TPM+1 values. Results 155 patients (108 CD, 47 UC) and 38 controls were included. For IBD patients, 49% were men, median age was 35 years and intestinal tissue was collected at endoscopy (73%) and surgery (27%). Compared to controls, patients with CD and UC had significantly elevated median expression of OSM (0.08, 0.29 and 0.34 TPM respectively) and OSMR (1.21, 1.69 and 3.53 TPM respectively). OSMR expression was higher in UC patients than CD (p&amp;lt;0.001). There was no difference in OSM or OSMR between Harvey Bradshaw Index categories (0-4 vs 5-7 vs 8-16) or partial Mayo scores (0 vs 1-3 vs 4-7). Endoscopically, OSM was higher for SES-CD scores of 16-51 (1.11 TPM), compared to SES-CD scores of 0-3 (0.14 TPM, p=0.003) and controls (0.08 TPM, p&amp;lt;0.0001). Median OSMR increased non-significantly with increasing SES-CD scores (score 0-3: 1.59 TPM; score 4-15: 1.90 TPM; score 16-51: 2.04 TPM). There was no difference in OSM and OSMR expression between UCEIS scores, but the most severe disease (UCEIS score 5-8) had higher expression than controls for both OSM (3.92 vs 0.08 TPM, p&amp;lt;0.001) and OSMR (6.10 vs 1.21 TPM, p&amp;lt;0.0001). Increasing expression of OSM and OSMR was found with increasing histological scores, see Figure. Using the modified Naini and Cortina score for CD, OSM and OSMR were most expressed in the highest scores compared to the lowest scores (OSM: 1.48 vs 0.09 TPM, p&amp;lt;0.001; OSMR: 5.50 vs 1.27 TPM, p=0.003). For the modified Riley score for UC, both OSM and OSMR were also able to differentiate between the highest and lowest score groups (OSM: 3.14 vs 0.12 TPM, p=0.0001; OSMR: 6.61 vs 1.58 TPM, p&amp;lt;0.0001). Conclusion This study showed that OSM and OSMR expression in intestinal tissue is associated with inflammation both histologically and endoscopically. Further investigations are needed to confirm our observations and explore the OSM pathway’s relevance in intestinal inflammation.