Background and Aims Crohn’s disease (CD) recurrence following ileocolic resection (ICR) is common. We sought to identify blood-based biomarkers associated with CD recurrence. Methods CD patients undergoing ICR were recruited across six centres. Serum samples were obtained at post-operative colonoscopy. A multiplex immunoassay was used to analyse 92 inflammation-related proteins (Olink Proteomics). Bayesian analysis was used to identify proteins associated with increasing Rutgeerts score. Identified proteins were employed in receiver operating characteristic (ROC) analysis to examine ability to identify CD recurrence (Rutgeerts score ≥ i2). Existing single cell data was interrogated to further elucidate the role of identified proteins. Results Data from 276 colonoscopies in 213 patients were available. Median time from surgery to 1st and 2nd colonoscopy was 7 (IQR 6-9) and 19 (IQR 16-23) months, respectively. Disease recurrence was evident at 60 (30%) first and 36 (49%) second colonoscopies. Of 14 proteins significantly associated with Rutgeerts score, the strongest signal was seen for CXCL9 and MMP1. Among patients on anti-TNF, CXCL9 and CXCL11 were most strongly associated with Rutgeerts score. Both are CXCR3 ligands. Incorporation of identified proteins into ROC analysis improved the ability to identify disease recurrence as compared to C-reactive protein alone; area under the curve (AUC) 0.75 (95% CI: 0.66-0.82) vs. 0.64 (95% CI 0.56-0.72), p=0.012. Single cell transcriptomic data provide evidence that innate immune cells are the primary source of identified proteins. Conclusions CXCR3 ligands are associated with CD recurrence following ICR. Incorporation of novel blood-based candidate biomarkers may aid identification of CD recurrence.
Background Up to 60% of patients with ulcerative colitis (UC) ultimately fail anti-tumor necrosis factor (TNF) treatment. We aimed to investigate early predictive markers of clinical and endoscopic outcomes in patients with UC who were anti-TNF-naïve commencing anti-TNF treatment, with particular focus on changes in albumin and C-reactive protein levels in the first 2 weeks of treatment. Methods We retrospectively investigated 210 patients with UC who started infliximab or adalimumab between 2009 and 2016 (male, 62.4%; median age at diagnosis, 37.9 years [interquartile range, 25.5–48.9 years]; median follow-up duration, 3.3 years [1.9–5.0 years]). Logistic and Cox proportional-hazards regressions were performed to identify variables associated with primary nonresponse (PNR), endoscopic outcomes, time-to-colectomy, and anti-TNF failure. Results Forty-one patients (19.5%) experienced PNR; week 0/week 2 ratio serum albumin was associated with PNR (adjusted odds ratio [aOR], 1.8; 95% confidence interval [CI], 1.1–2.9, per interquartile range increase). Week 0/week 2 ratio albumin was also associated with endoscopic response (aOR, 0.28; 95% CI, 0.31–0.82) and endoscopic remission (aOR, 0.61; 95% CI, 0.39–0.96) at weeks 8 to 14, time-to-colectomy (adjusted hazard ratio, 2.12; 95% CI, 1.29–3.49) and time-to-anti-TNF failure (adjusted hazard ratio, 1.54; 95% CI, 1.22–1.96), regardless of age, disease severity, or in-patient status. Association with time-to-colectomy and anti-TNF failure was externally validated in an independent cohort of inpatients with UC starting infliximab. Conclusions Change in serum albumin within the first 2 weeks of anti-TNF treatment is predictive of PNR, endoscopic outcomes, time-to-colectomy, and anti-TNF failure in patients with UC. Timely access to this biomarker enables early identification of patients with UC at risk of anti-TNF failure and may guide early optimization of anti-TNF treatment to improve disease outcomes.
Spread of the novel coronavirus SARS-CoV-2 has resulted in a global pandemic that is affecting the health and economy of all WHO regions. Clinical and translational research activities have been impacted drastically by this global catastrophe. In this document we provide a suggested roadmap for resuming gastrointestinal translational research activities, emphasizing physical distancing and use of personal protective equipment. We discuss modes of virus transmission in enclosed environments (including clinical workplaces and laboratories) and potential risks of exposure in the endoscopy environment for research staff. The proposed guidelines should be considered in conjunction with local institutional and government guidelines so that translational research can be resumed as safely as possible.
Background We investigated relationships between induction ustekinumab levels and clinical and biochemical outcomes in Crohn’s disease. Methods Following standard IV induction, ustekinumab levels were measured at week 2 (wk2) and week 6 (wk6). Ustekinumab levels were compared in patients receiving 260, 390 and 520 mg at induction. Crohn’s disease activity index (CDAI), serum albumin, C-reactive protein (CRP) and fecal calprotectin (FCP) were measured at baseline and week 12 (wk12). Associations between ustekinumab levels and these parameters were assessed. Ustekinumab levels were compared between patients requiring dose intensification within one year of induction and those remaining on standard dosing. Results Of 23 wk2 ustekinumab levels, 22(95.7%) were above the upper limit of quantification of the assay (25 µg/mL). Median wk6 ustekinumab level (n = 25) was 14.2 μg/mL [interquartile range (IQR), 9.6–20.1]. Median wk6 ustekinumab levels in patients receiving 260, 390 and 520 mg were 8.6, 16.3 and 25.0 µg/mL, respectively, P = 0.01. There were significant correlations between baseline albumin and wk6 ustekinumab levels; r = 0.644 [95% confidence interval (CI), 0.304–0.839], P < 0.001, and between baseline FCP and wk6 ustekinumab levels; r = −0.678 (95% CI, −0.873 to −0.296), P < 00.01. Median wk12 CDAI (n = 18), CRP (n = 22) and FCP (n = 13) were 78 (IQR, 52.5–152), 1.75 mg/L (IQR, 0.93–7.03) and 746 μg/g (IQR, 259–2100), respectively. There were significant correlations between wk6 ustekinumab levels and wk12 CDAI; r = −0.513 (95% CI, −0.796 to −0.046), P = 0.03; and between wk6 ustekinumab levels and wk12 CRP; r = −0.578 (95% CI, −0.808 to −0.194), P < 0.01. Wk6 ustekinumab levels were lower in patients undergoing subsequent dose intensification; 12.5 vs. 19.6 µg/mL, P = 0.04. Conclusion Wk6 ustekinumab levels are significantly associated with baseline Crohn’s disease biomarkers and subsequent clinical and biochemical outcomes.
Background Optimal ustekinumab levels (UST) in Crohn’s disease (CD) treatment have not been defined. We set out to define the optimal UST to differentiate between remission and active CD, as defined using the serum-based endoscopic healing index (EHI). Methods Paired serum UST and EHI tests were analyzed. Remission was defined as EHI <20. Active disease was defined as EHI ≥50. The proportion of patients in remission was compared across UST quartiles. UST in subjects with EHI <20 and EHI ≥50 were compared. An area under receiver operating characteristic (AUROC) curve was generated to identify an optimal UST to differentiate between active disease and remission. Results A total of 337 unique patients were identified; median UST and EHI were 5.0µg/mL (IQR 2.7-9.1) and 37 (IQR 26-53), respectively. EHI <20 (remission) was found in 57(16.9%) patients. EHI ≥50 (active disease) was found in 97(28.8%) patients. Higher proportions of subjects were in remission for increasing UST quartiles, p= 0.01. Median UST in patients with EHI <20 and EHI ≥50 were 7.5µg/mL (IQR4.6-10.9) and 3.1µg/mL (IQR1.8-6.6) respectively, p<0.001. An UST threshold of 3.75µg/mL optimally differentiated between active disease and remission (AUC 0.725). UST levels >3.75µg/mL were associated with a lower proportion of subjects with active disease (EHI ≥50; 18.9%) compared with UST levels ≤3.75µg/mL (45.6%, p<0.001). Conclusion Using the EHI, we identified a threshold UST level of 3.75µg/mL to optimally differentiate between active and quiescent CD. These data suggest that UST serum concentrations of >3.75µg/mL are optimally associated with endoscopic remission in CD.
431 Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. Previous studies have provided limited evidence for and against both POE effect and anticipation in Lynch syndrome. We sought evidence for a specific POE effect and anticipation in Irish Lynch syndrome families. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from kindreds (N = 20) from two hospital-based registries of MMR mutation carriers. POE were investigated by studying the ages at diagnosis in the offspring of affected parent-child pairs. Anticipation was assessed using the bivariate Huang and Vieland model. Results: Paired t-test revealed anticipation with children developing cancer mean 11.8 years earlier than parents, and 12.7 years using the Veiland and Huang bivariate model (p < 0.001). Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. Affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring; however, this finding failed to reach statistical significance. Genetic anticipation was present in this cohort of LS families, emphasizing the importance of early-onset screening. An additional 60 LS kindreds are under review and updated data will be presented at the meeting. [Table: see text]
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