Abstract Background The endoscopic healing index (EHI) is a serum biomarker panel that identifies endoscopic Crohn’s Disease (CD) activity. Endoscopy and biomarkers are limited in assessing small bowel disease compared to magnetic resonance enterography (MRE). The Simplified Magnetic Resonance Index of Activity (MaRIAs) is validated to detect CD activity. Data are lacking on the relationship between EHI with other endpoints. This study performed the first assessment of EHI to diagnose CD-related intestinal inflammation on MRE using the MaRIAs score. Methods Data were extracted on CD patients with EHI within 90 days of MRE. We assessed the diagnostic accuracy of EHI for any (MaRIAs≥1) or severe (MaRIAs≥2) MR inflammation identified on MRE using area under the receiver operator characteristic (AUROC) curve analyses. Proportions with inflammation on MRE were compared between groups above and below the identified EHI and FCAL threshold. Analyses were repeated between EHI and active endoscopy (SES-CD≥5), fecal calprotectin (FCAL>50, >250), and clinical symptoms (CD PRO-2≥8). Results 241 MREs uniquely paired to either EHI or FCAL from 155 patients, mean age was 42 years, 50.3% were female, 83.2% of patients had small bowel involvement, and 29.7% had penetrating disease. The mean time between EHI to MRE was 28 days, and the mean time between FCAL and MRE was 24 days. Both EHI and FCAL had similar accuracy to diagnose inflammation (AUROC: EHI:0.635-0.651, FCAL:0.680-0.708). Optimal EHI values were 42 and 26 for inflammation on MRE and endoscopy, respectively. Patients with EHI≥42 (100% vs. 63%, p=0.002), FCAL>50µg/g (87% vs. 64%, p<0.001) and FCAL>250µg/g (90% vs. 75%, p=0.02) had higher rates of MaRIAs≥1 compared to lower values. EHI differentiated ileitis more than FCAL (delta: 24-25% vs. 11-21%). Patients with low FCAL had high rates (59-69%) of active endoscopic disease, whereas those with low EHI rarely (6%) with endoscopic activity. Patients with FCAL≥50µg/g had higher rates of severe inflammation compared to FCAL<50µg/g (75% vs. 47%, p<0.001) whereas smaller differentiation existed for EHI. In patients with CD PRO-2 scores, clinical remission was not associated with disease activity corresponding to active EHI, endoscopy, or MRE. Conclusion In CD patients predominantly with ileal involvement, EHI>42 and FCAL>50 were both specific to confirm inflammation on MRE. Lower EHI values (<42), but not low FCAL (<50), were associated with lower rates of severe radiologic inflammation. MRE inflammation was frequently present in the presence of low EHI and FCAL with similar proportions of false negative MRE results. However, the absence of endoscopic inflammation was only associated with low EHI, but not low FCAL values.
Introduction: Controversy exists for ustekinumab concentrations needed in Crohn’s disease (CD). No data exist comparing ustekinumab concentrations and validated radiologic outcomes. We characterized these relationships and clarified concentrations needed. Methods: CD patients on maintenance ( > 16 weeks) ustekinumab with both ustekinumab concentrations and simplified magnetic resonance index of activity (sMaRIA) scoring were included. Ustekinumab concentrations were compared between those with and without (1) radiologic remission (sMaRIA < 2), (2) severe radiologic inflammation (sMaRIA < 3) and (3) fecal calprotectin (FCP) biomarker remission (FCP < 50 μg/g). Area under the receiver-operating characteristic (AUROC) curve determined optimal ustekinumab concentrations. Outcomes were compared between patients above and below identified ustekinumab thresholds. Results: Thirty-eight paired ustekinumab concentrations and MRE were included. Ustekinumab concentrations were higher with radiologic remission (11.4 μg/mL vs. 6.4 μg/mL, P=.005) and had good diagnostic accuracy for radiologic remission (AUROC 0.76, 95% CI 0.60 – 0.91) and for absence of severe inflammation (AUROC 0.71, 95% CI 0.55 – 0.88, optimal concentration 8.4 μg/mL). With ustekinumab ≥ 8.4 μg/mL, higher proportions had radiologic remission (63.2% vs. 21.1%, P=.01) and absence of severe inflammation (78.9% vs. 36.8%, P=.01) compared to patients with lower concentrations. Ustekinumab concentrations had good diagnostic accuracy (AUROC 0.73, 95% CI 0.52 – 0.94) for FCP biomarker remission (optimal concentration: 6.1 μg/mL). Patients with ustekinumab concentrations ≥ 6.1 μg/mL had higher proportions with biomarker remission (72.2% vs. 12.5% P < .01) compared to those with lower concentrations. (Figure) Conclusion: Ustekinumab concentrations are associated with radiologic and biomarker outcomes in CD. These data validate the need for higher ustekinumab concentrations.Figure 1.: (A) Receiver-operating characteristic curve analysis for sMaRIA score of < 2, absence of any inflammation, based on ustekinumab trough concentrations. The optimal concentration is 8.4 μg/mL as indicated by the best receiver-operating characteristic curve (area under curve, 0.76; sensitivity, 75%; specificity 68%). (B) Receiver-operating characteristic curve analysis for sMaRIA score of < 3, absence of severe inflammation, based on ustekinumab concentrations. The optimal serum concentration is 8.4 μg/mL as indicated by the best receiver-operating characteristic curve (area under curve, 0.71).
(1) Many patients with inflammatory bowel disease (IBD) in endoscopic remission have persistent histologic activity, which is associated with worse outcomes. There are limited data on the association between adalimumab drug concentrations and histologic outcomes using validated histologic indices. We aimed to assess the relationship between adalimumab concentrations and the Robarts Histopathology Index (RHI). (2) Patients from a tertiary IBD center from 2013 to 2020 with serum adalimumab (ADA) trough concentrations measured during maintenance therapy (≥14 weeks) and a colonoscopy or flexible sigmoidoscopy with biopsies performed within 90 days of drug level were included. Blinded histologic scoring using the RHI was performed. Primary analysis assessed the relationship between adalimumab drug concentrations and histologic remission using receiver operating characteristic curve analysis. (3) In 36 patients (26 Crohn’s Disease, 9 ulcerative colitis, 1 indeterminate), median adalimumab concentrations were higher (17.3 ug/mL, 12.2–24.0) in patients with histologic remission compared to those without (10.3 ug/mL, 6.8–13.9, p = 0.008). The optimal ADA concentration identified using the Youden threshold was ≥16.3 ug/mL (sensitivity 70%, specificity 90%). Patients with ADA ≥ 16.3 ug/mL had higher histologic remission rates (78%) compared to lower ADA concentrations (14%, p= 0.002), as well as higher mucosal healing rates (86%) compared to lower levels (12%, p = 0.001). Symptoms correlated weakly and non-significantly with both histologic (RHI) scores (r = 0.25, p = 0.2) and adalimumab concentrations (r = 0.05, p = 0.8). (4) The current study demonstrated that higher serum adalimumab concentrations (≥16.3 ug/mL) are needed for histologic remission and mucosal healing assessed using the RHI.
Abstract Background A majority of Crohn’s disease (CD) patients require surgery. Ileitis recurs after most ileocolectomies and is a critical determinant for outcomes. The impact of ileocolectomy-induced bile acid (BA) perturbations on intestinal microbiota and inflammation are unknown. We characterized relationships between ileocolectomy, stool BA, microbiota, and intestinal inflammation in inflammatory bowel disease (IBD). Methods Validated IBD clinical and endoscopic assessments were prospectively collected. Matched primary and secondary BA concentrations measured in stool using Agilent Quadrupole Time of Flight Liquid chromatography-mass spectrometry were compared based on ileocolectomy and ileitis status. Primary BA thresholds for ileitis were evaluated using area under the receiver operating characteristic curve analyses. In CD, endoscopic remission was defined as SES-CD <3 or Rutgeerts <i2b. Ileal ER was defined as ileal SES-CD ≤ 1 and colonic ER was defined as colonic SES-CD≤2 without any segment >1. In UC, ER was defined as UC-ESS ≤ 1. Metagenomic sequencing profiled microbial composition and function. Relationships between ileocolectomy, BA and microbiota were assessed. Results In 166 patients, elevated primary and secondary BA existed with ileocolectomy. With ileitis, only primary BA (795 nMol/g vs 398 nMol/g, p=0.009) were higher compared to without ileitis. The optimal primary BA threshold (≥228nMol/g) identified ileitis on multivariable analysis (OR=2.3, p=0.04). Similar primary (471 nMol/g vs. 606 nMol/g, p=0.8) and secondary (382 nMol/g vs. 242 nMol/g, p=0.2) BA concentrations existed with and without colonic inflammation. Microbial diversity (Shannon index, p=0.0006), Faecalibacterium prausnitzii and O-acetylhomoserine aminocarboxypropyltransferase (MetY, p=0.0002) were decreased with elevated primary BA. Amongst ileocolectomy patients, only those with elevated primary BA had diversity (p=0.01), F.prausnitzii and MetY (p=0.04) reductions. Those with both ileocolectomy and intermediate (p=0.002) or high (≥228nMol/g, p=9.1e-11) ) primary BA had reduced F.prausnitzii compared to without ileocolectomy (Figure 1). Those with ileocolectomy and low (<29.2nMol/g) primary BA had similar F.prausnitzii as those without ileocolectomy (P=0.13). MetY was reduced with ileitis (p=0.02). Conclusion Elevated primary bile acids were associated with ileitis, and reduced microbial diversity, F.prausnitzii abundance, and enzymatic expression of MetY (acetate and L-methionine producing enzyme expressed by F.prausnitzii) and were the only factor associated with these findings after ileocolectomy.
Introduction: The endoscopic healing index (EHI) is a validated, serum-based biomarker panel that identifies endoscopic Crohn’s Disease (CD) activity. Both endoscopy and biomarkers are limited in assessing small bowel disease compared to magnetic resonance enterography (MRE). The Simplified Magnetic Resonance Index of Activity (MaRIAs) is validated to detect CD activity. No data exists on the relationship between EHI and MRE. We assessed the performance of the EHI to diagnose CD-related intestinal inflammation identified on MRE. Methods: Data were retrospectively extracted on CD patients with EHI within 90 days of an MRE. We assessed the diagnostic accuracy of the EHI for any (MaRIAs≥1) or severe (MaRIAs >3) inflammation identified on MRE using area under the receiver operator characteristic (AUROC) curve analyses. Proportions with inflammation on MRE were compared between groups above and below the identified EHI threshold and to the established remission cutoff of 20. Analyses were repeated between EHI and active endoscopy (SES-CD≥5) and active clinical symptoms (CD PRO-2≥8). Results: 43 CD patients with EHI level within 90 days of an MRE were included. Mean age was 43±16, 51% were female, and 84% had ileal involvement. The median EHI was 26 (IQR 15-41). Optimal EHI threshold to detect any inflammation on MRE was 40 (AUROC:0.6, 34% sensitivity, 100% specificity). Patients with an EHI >40 (n=11) were significantly more likely to have both any (100% vs 66%, p=0.02) and severe (55% 6/11 vs 22% 7/32, p=0.04) inflammation on MRE compared to those with EHI≤40 (Figure 1). Conclusions were similar when compared to EHI< 20. In a subgroup with endoscopy within 90 days of EHI, those with EHI >40 had numerically higher rates of endoscopic activity compared to EHI≤40 (60% 3/5 vs 29% 6/21, p=0.2). Patients with MRE activity had a higher proportion of endoscopic activity compared to patients without MRE activity (42% 8/19 vs 0% 0/6, p=0.1). In patients with CD PRO-2 scores, patients in clinical remission had similar proportions with active inflammation on endoscopy (38% 6/16 vs 33% 3/9, p=0.8), MRE (71% 15/21 vs 72% 13/18, p=0.95), and EHI >40 (23% 5/22 vs 33% 6/18, p=0.5) compared to those without clinical remission (Table 1). Conclusion: In patients with predominantly ileal CD, EHI >40 is specific to confirm inflammation on MRE and endoscopy. Lower EHI values were associated with low rates of severe radiologic inflammation. These data uniquely validate the EHI using radiographic disease activity indices.Figure 1.: Endoscopic healing index compared to disease activity on magnetic resonance enterography and endoscopy.Table 1.: Patient Reported Clinical Scores Compared to Serum, Endoscopic, and MRE Disease Activity.
Introduction: The serum-based endoscopic healing index (EHI) test identifies endoscopic Crohn’s disease (CD) activity. Data are lacking on the relationship between EHI with other endpoints. We assessed the relationship between EHI and the simplified Magnetic Resonance Index of Activity. Materials and Methods: Data were prospectively collected on patients with CD with either an EHI or fecal calprotectin (FCAL) within 90 days of magnetic resonance enterography (MRE). Diagnostic accuracy was assessed using area under the receiver operator characteristics. Proportions with any, severe, and terminal ileum MR inflammation were compared above/below identified thresholds for both EHI and FCAL. Results: A total of 241 MREs paired to either EHI or FCAL from 155 patients were included. Both EHI and FCAL had similar accuracy to diagnose inflammation (area under the receiver operator characteristics: EHI: 0.635 to 0.651, FCAL: 0.680 to 0.708). Optimal EHI values were 42 and 26 for inflammation on MRE and endoscopy, respectively. Patients with EHI ≥42 (100% vs. 63%, P =0.002), FCAL >50 µg/g (87% vs. 64%, P <0.001) and FCAL >250 µg/g (90% vs. 75%, P =0.02) had higher rates of simplified Magnetic Resonance Index of Activity ≥1 compared with lower values. EHI differentiated ileitis numerically more than FCAL (delta: 24% to 25% vs. 11% to 21%). Patients with FCAL ≥50 µg/g had higher rates of severe inflammation compared with FCAL <50 µg/g (75% vs. 47%, P <0.001), whereas smaller differentiation existed for EHI threshold of 42 (63% vs. 49%, P =0.35). Conclusion: Both EHI and FCAL were specific in their confirmation of inflammation and disease activity on MRE in patients with CD. However, MRE-detected inflammation was frequently present in the presence of low EHI and FCAL in similar proportions.
Abstract Background Most Crohn’s disease [CD] patients require surgery. Ileitis recurs after most ileocolectomies and is a critical determinant for outcomes. The impacts of ileocolectomy-induced bile acid [BA] perturbations on intestinal microbiota and inflammation are unknown. We characterized the relationships between ileocolectomy, stool BAs, microbiota and intestinal inflammation in inflammatory bowel disease [IBD]. Methods Validated IBD clinical and endoscopic assessments were prospectively collected. Stool primary and secondary BA concentrations were compared based on ileocolectomy and ileitis status. Primary BA thresholds for ileitis were evaluated. Metagenomic sequencing was use to profile microbial composition and function. Relationships between ileocolectomy, BAs and microbiota were assessed. Results In 166 patients, elevated primary and secondary BAs existed with ileocolectomy. With ileitis, only primary BAs [795 vs 398 nmol/g, p = 0.009] were higher compared to without ileitis. The optimal primary BA threshold [≥228 nmol/g] identified ileitis on multivariable analysis [odds ratio = 2.3, p = 0.04]. Microbial diversity, Faecalibacterium prausnitzii and O-acetylhomoserine aminocarboxypropyltransferase [MetY] were decreased with elevated primary BAs. Amongst ileocolectomy patients, only those with elevated primary BAs had diversity, F. prausnitzii and MetY reductions. Those with both ileocolectomy and intermediate [p = 0.002] or high [≥228 nmol/g, p = 9.1e-11]] primary BA concentrations had reduced F. prausnitzii compared to without ileocolectomy. Those with ileocolectomy and low [<29.2 nmol/g] primary BA concentrations had similar F. prausnitzii to those without ileocolectomy [p = 0.13]. MetY was reduced with ileitis [p = 0.02]. Conclusions Elevated primary BAs were associated with ileitis, and reduced microbial diversity, F. prausnitzii abundance and enzymatic abundance of MetY [acetate and l-methionine-producing enzyme expressed by F. prausnitzii], and were the only factors associated with these findings after ileocolectomy.
Introduction: Limited data exist on ustekinumab (UST) and vedolizumab (VDZ) in post-operative Crohn’s disease (POCD). No data exist on their efficacy in Tumor Necrosis Factor antagonist (anti-TNF)-exposed POCD patients. Comparative POCD efficacy data are also lacking, hindering guidance on POCD medication selection. We compared the therapeutic efficacies of biologics in POCD patients. Methods: POCD patients receiving their first post-operative biologic were included (Weill Cornell Medicine biobanks). Demographics, biomarkers, and clinical and endoscopic scores were prospectively collected. For missing data, chart review was performed. The primary outcome compared rates of deep remission (DR, defined as both clinical (HBI< 5, CD-PRO2< 8, or remission stated) and objective (endoscopic (SES-CD< 3, Rutgeert’s
