Adult Crohn's Disease Patients Research Articles

A Comparison of Clinical Outcomes of Colectomies for Pediatric and Adult Patients With Inflammatory Bowel Disease.

Background: Crohn's disease (CD) and ulcerative colitis (UC) are prevalent in adult and pediatric populations, but their differences are not well studied using national data. We compared the clinical outcomes of these patients using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) databases.Methods: Colectomy cases for CD and UC, the 2 major forms of inflammatory bowel disease (IBD), were compared between adult and pediatric patients using the 2017-2019 ACS NSQIP databases. Various clinical factors were analyzed, with postoperative complications being the primary outcome of interest.Results: We identified 542 pediatric and 5174 adult CD patients and 360 pediatric and 1292 adult UC patients. Adults with CD or UC were more likely to be on steroids preoperatively (CD: 60.15% vs 24.54%; UC: 65.63% vs 51.39%). Children with IBD were more likely to have preoperative transfusions (CD: 1.48% vs .33%; UC: 8.33% vs .62%), systemic inflammatory response syndrome (CD: 3.51% vs .93%; UC: 12.78% vs 3.10%), or sepsis (CD: 1.85% vs .66%; UC: 1.39% vs .31%). Unplanned reoperations were more common among pediatric patients in both disease states compared to adults (CD: 6.27% vs 4.10%; UC: 11.11% vs 4.26%), with P-values for all factors described as ≤.02. Multivariate logistic regression found pediatric age to be associated with higher odds of needing a reoperation among UC patients but not CD patients.Conclusion: Pediatric patients were sicker at the time of surgery, and those with either disease were more likely to require a reoperation within 30days.

Are Internet Information Sources Helpful for Adult Crohn's Disease Patients Regarding Nutritional Advice?

Background: Adult patients suffering from Crohn's disease (CD) are often dissatisfied with the information they receive from their physicians about nutrition and its impact on CD inflammation activity. Only a few publications are available about patients' internet research on nutrition in CD. The study aim is to elucidate the internet information sources of adult CD patients regarding nutritional advice via a questionnaire. Methods: A questionnaire with 28 (general and specific) questions for outpatients at our tertiary center with CD was created and used for an analysis of their information sources about nutrition in CD. Four CD and/or nutritional medicine experts examined the 21 most relevant websites referring to nutritional advice for CD patients. Results: One hundred and fifty CD patients reported their Internet research behavior for nutritional advice and their dietary habits. Many CD patients prefer to consult the Internet instead of asking their general practitioner (GP) for nutritional recommendations. Most of the websites providing nutritional advice for CD patients are of very poor quality and cannot be recommended. We found significant correlations between (a) nutritional habits of CD patients, (b) their information sources and several demographic or CD-related factors. There is a lack of websites which provide high-quality, good nutritional advice to CD patients. Conclusions: The majority of the examined websites did not provide sufficient information according to the CD guidelines and nutritional medicine guidelines. A higher quality level of website content (e.g., on social media or on university/center websites) provided by experienced physicians is required to secure trustworthy and reliable nutritional information in CD.

Real-world Effectiveness and Safety of Risankizumab in Patients with Moderate to Severe Multirefractory Crohn's Disease: A Belgian Multicentric Cohort Study.

As real-world data on risankizumab in patients with moderate to severe Crohn's disease (CD) are scarce, we evaluated its effectiveness and safety in multirefractory Belgian patients. Data from consecutive adult CD patients who started risankizumab before April 2023 were retrospectively collected at 6 Belgian centers. Clinical remission and response were defined using the 2-component patient-reported outcome. Endoscopic response was defined as a decrease in baseline Simple Endoscopic Score with ≥50%. Both effectiveness end points were evaluated at week 24 and/or 52, while surgery-free survival and safety were assessed throughout follow-up. A total of 69 patients (56.5% female, median age 37.2 years, 85.5% exposed to ≥4 different advanced therapies and 98.6% to ustekinumab, 14 with an ostomy) were included. At week 24, 61.8% (34 of 55) and 18.2% (10 of 55) of patients without an ostomy achieved steroid-free clinical response and remission, respectively. At week 52, these numbers were 58.2% (32 of 55) and 27.3% (15 of 55), respectively. Endoscopic data were available in 32 patients, of whom 50.0% (16 of 32) reached endoscopic response within the first 52 weeks. Results in patients with an ostomy were similar (steroid-free clinical response and remission, 42.9% and 14.3%, respectively). During a median follow-up of 68.3 weeks, 18.8% (13 of 69) of patients discontinued risankizumab, and 20.3% (14 of 69) of patients underwent CD-related intestinal resections. The estimated surgery-free survival at week 52 was 75.2%. No new safety issues were observed. In this real-world cohort of multirefractory CD patients, risankizumab was effective in inducing both clinical remission and endoscopic response. Risankizumab was well tolerated with no safety issues.

Exclusive Enteral Nutrition Orchestrates Immunological Balances as Early as Week 4 in Adult Patients of Crohn's Disease: A Pilot, Open-Lable Study.

The efficacy and underlying mechanisms of exclusive enteral nutrition (EEN) in adult patients with Crohn's disease (CD) remain controversial. This study aimed to evaluate the role of EEN in adult patients with CD and to explore the mechanisms from the perspective of immunoregulation. This is a prospective, open-label pilot study. Active patients with CD were enrolled and prescribed an amino-acid-rich elemental diet for 12 weeks. Dynamic changes in immune cells, including neutrophils, monocytes, T cells and B cells, were detected by flow cytometry. Plasma cytokines were evaluated by ELISA. Twenty adult patients with CD were enrolled. Among them, 1 discontinued treatment due to poor compliance, and 19 patients were included for final analysis. Clinical remission was achieved in 47.37% (9/19), 63.16% (12/19), and 73.68% (14/19) patients at weeks 4, 8, and 12, respectively. Endoscopic remission and transmural healing were achieved in 52.63% (10/19) and 15.79% (3/19) patients at week 12. Notably, there was no significant difference in clinical remission between week 4 and week 8 (p = 0.33) or week 12 (p = 0.09). Furthermore, we observed a rapid reconstitution of immunologic homeostasis as early as week 4. At week 4, both the frequency and activation of neutrophils and monocytes were decreased after EEN therapy. Significant decreases in Th17 cells and naïve B cells, increases in memory B cells, and regulatory B cells were also detected. These changes remained stable at weeks 8 and 12. EEN with an amino-acid-rich elemental diet orchestrated immunological balances and induces clinical remission in adult CD patients as early as week 4, suggesting a 4-week EEN therapy may be feasible and practicable in clinical practice.

Real-World Surgical and Endoscopic Recurrence Based on Risk Profiles and Prophylaxis Utilization in Postoperative Crohn’s Disease

Background & AimsPreoperative risk stratification may help guide prophylactic biologic utilization for the prevention of postoperative Crohn's disease (CD) recurrence; however, there is limited data exploring and validating proposed clinical risk factors. We aimed to explore preoperative clinical risk profiles, quantify individual risk factors, and assess the impact of biologic prophylaxis on postoperative recurrence (POR) risk in a real-world cohort. MethodsIn this multicenter retrospective analysis, patients with CD who underwent ileocecal resection (ICR) from 2009-2020 were identified. High-risk (active smoking, ≥2 prior surgeries, penetrating and/or perianal disease) and low-risk (nonsmokers and age>50 years) features were used to stratify patients. We assessed the risk of endoscopic (Rutgeerts’ score ≥i2b) and surgical recurrence by risk strata and biologic prophylaxis (≤90 days postoperatively) with logistic and time-to-event analyses. ResultsA total of 1404 adult CD patients who underwent ICR were included. Of the high-risk factors, ≥2 ICR (OR 1.71; 95% CI [1.13-2.57]), active smoking (OR 1.73, 95% CI [1.17-2.53]), penetrating disease (OR 1.41, 95% CI [1.02-1.94]), and history of perianal disease alone (OR 1.99, 95% CI [1.42-2.79]) were associated with surgical but not endoscopic recurrence. Surgical recurrence was lower in high-risk patients receiving prophylaxis versus not (10.2% vs 16.7%; p=0.02), and endoscopic recurrence was lower in those receiving prophylaxis irrespective of risk strata (High-risk: 28.1% vs 37.4%; p=0.03 and Low-risk: 21.1% vs 38.3%; p=0.002). ConclusionsClinical risk factors accurately illustrate patients at risk for surgical recurrence, but have limited utility in predicting endoscopic recurrence. Biologic prophylaxis may be of benefit irrespective of risk stratification and future studies should assess this.

A retrospective analysis of treatment patterns, drug discontinuation and healthcare costs in Crohn's disease patients treated with biologics.

This real-world analysis evaluated the persistence and direct healthcare costs of Crohn's Disease (CD) patients treated with biologics in Italy. A retrospective analysis on administrative databases of Italian healthcare entities, covering 10.4 million residents, was performed. Adult CD patients under biologics between 2015 and 2020 were included and attributed to first/second treatment line based on absence/presence of biologic prescriptions 5-years before index-date (first biologic prescription). Of 16,374 CD patients identified, 1,398 (8.5%) were biologic-treated: 1,256 (89.8%) in first line and 135 (9.7%) in second line. Kaplan-Meier curves estimated a higher persistence for ustekinumab-treated patients followed by vedolizumab, infliximab and adalimumab, in both lines. Considering baseline variables and adalimumab as reference, infliximab in first line (HR: 0.537) and ustekinumab in first (HR: 0.057) and second line (HR: 0.213) were associated with significantly reduced risk of drug-discontinuation. First line total/average healthcare direct-costs were €13,636, €11,201, €17,104 and €18,339 in patients persistent on adalimumab, infliximab, ustekinumab and vedolizumab, respectively. This real-world analysis showed differences in persistence over 12-months between biologic treatments, being higher in ustekinumab-treated group, followed by vedolizumab, infliximab and adalimumab. Patients' management was associated with comparable direct healthcare costs among treatment lines, mainly driven by drug-related expenses.

The effects and predictive value of calcium and magnesium concentrations on nutritional improvement, inflammatory response and diagnosis in patients with Crohn's disease.

Crohn's disease (CD) is a progressive inflammatory disease of the gastrointestinal tract associated with malnutrition, high levels of inflammation and calcium and magnesium deficiencies. However, the relationships between these symptoms are poorly defined. Seventy-six adult CD patients who had not yet started treatment and 83 healthy volunteers were recruited. The dietary intakes, serum calcium and magnesium levels, nutritional indicators and biochemical markers of disease activity were measured. Most participants had inadequate magnesium and calcium intake. The serum magnesium and calcium levels, as well as nutritional and inflammatory indicators, differed significantly between CD patients and controls, especially in the active phase. Serum levels of magnesium and calcium correlated with both nutritional status and inflammation. The cut-off values for CD development were 0.835 mmol/L (magnesium) and 2.315 mmol/L (calcium), whereas those for the active phase were 0.785 and 2.28 mmol/L, respectively. Adequate intake of magnesium and calcium may both improve the nutritional status of CD patients and reduce inflammation, benefiting disease relief. As both magnesium and calcium reflect CD status, they may be useful markers for CD diagnosis and disease activity.

Characteristics, Clinical Outcomes, and Prognosis of Anal and Pouch-related Carcinoma in Patients With Crohn's Disease.

This study described the clinical characteristics, outcomes, and prognosis of Crohn's disease (CD) patients with anal cancer in a tertiary referral center. The electronic medical records of 35 adult CD patients, including CD of the pouch, with anal carcinoma evaluated at Mayo Clinic Rochester, Florida, or Arizona between January 1989 and August 2022 were retrospectively reviewed. Before cancer diagnosis, patients with pouch-related carcinoma had a shorter median duration of inflammatory bowel disease than those with anal carcinoma (10 vs 26 years). Twenty-six patients (74%) had perianal diseases or rectovaginal fistula, and 35% had a history of human papillomavirus infection. Twenty-one patients (60%) were diagnosed with cancer by anal examination under anesthesia (EUA). More than half of adenocarcinomas were mucinous. Sixteen patients (47%) were American Joint Committee on Cancer (AJCC) Tumor Nodes Metastasis (TNM) stage 3, and 83% were treated by surgery. At last follow-up, 57% of patients were alive without cancer. The 1-, 3- and 5-year overall survival rates were 93.8% (95% confidence interval [CI], 85.7%-100%), 71.5% (95% CI, 56.4%-90.7%), and 67.7% (95% CI, 51.2%-87.7%), respectively. Advanced AJCC TNM stage (hazard ratio, 3.20 per stage; 95% CI, 1.05-9.72; P = .040) was significantly associated with increased risk of death, whereas the period of cancer diagnosis in 2011-2022 (HR, relative to 1989-2000, 0.16; 95% CI, 0.04-0.72; P = .017) was significantly related to decreased risk of death. Anal and pouch-related carcinomas were rare complications of CD, and long-standing perianal diseases were an important risk factor. Anal EUA improved the diagnostic yield. Newer cancer treatment strategies and surgery were associated with excellent survival outcome.

Comparison of infliximab with adalimumab in biologic-naïve patients with Crohn's disease: a single-center 13-year experience.

Long-term comparison studies between infliximab (IFX) and adalimumab (ADA) with or without immunomodulator therapy are still needed in Crohn's disease (CD). In this study, we evaluated IFX and ADA for long-term clinical effectiveness and safety in CD patients who had not previously received a biologic treatment. The data of adult CD patients were collected retrospectively between December 2007 and February 2021. We compared CD-related hospitalization, CD-related abdominal surgery, steroid use, and serious infections. Out of 224 CD patients, 101 started IFX first (median age: 38.12 years, 61.4% male), while 123 started ADA first (median age: 30.2 years, 64.2% male). The disease durations were 7.01 years and 6.91 years for IFX and ADA, respectively. There were no significant differences between the two groups with respect to age, gender, smoking, immunomodulator usage, and disease activity score at the onset of anti-TNF therapy (p>0.05). Overall, the median follow-up time was 2.36 and 1.86 years after starting anti-tumor necrosis factor-alpha (anti-TNF) therapy in the IFX and ADA groups, respectively. Steroid use (4.0% vs. 10.6%, p=0.109), hospitalization for CD (13.9% vs. 22.8%, p=0.127), abdominal surgery for CD (9.9% vs. 13.0%, p=0.608), and major infections (1.0% vs. 0.8%, p>0.999) did not differ significantly from one another. There were also no significant differences in the rates of these outcomes between concomitant immunomodulator therapy and monotherapy (p>0.05). In this study, we observed no significant differences in the long-term effectiveness and safety of IFX and ADA in biologic-naïve patients with CD.

Relationships Between Intestinal Ultrasound Parameters and Histopathologic Findings in a Prospective Cohort of Patients With Crohn's Disease Undergoing Surgery.

Recognition of intestinal lesions with substantial fibrosis is strategic for optimal management of patients with Crohn's disease (CD). We aimed to assess the relationships between intestinal ultrasound parameters and histopathologic findings in a prospective cohort of patients with CD undergoing surgery. Seventeen consecutive adult CD patients with involvement of the terminal ileum or the sigmoid colon who underwent bowel resective surgeries were enrolled and performed intestinal ultrasound (IUS) within 30 days prior to surgery. Uni- and multivariable analyses were used to assess the relationships between IUS parameters and histopathological elements of lesions. Sensitivity, specificity, accuracy, PPV and NPV (95% CI) of IUS in detecting stricturing and penetrating complications (surgical specimen as reference standard) were 93% (68-100), 86% (42-100), 91% (71-99), 93% (68-100) and 86% (42-100), and 78% (40-97), 92% (64-100), 86% (65-97), 88% (47-100) and 86% (57-98), respectively. Only the presence of hyperechogenic spiculates was statistically significantly associated with collagen content (b=7.29, 95% CI=1.88/12.69, P= .012), while only the presence of vascular signals at color Doppler (Limberg score 3 or 4) was significantly associated with active inflammation (OR=10.0, 95% CI=0.9/108.6, P= .037). There was a strong correlation between IUS and histological measurements of the wall thickness (r= 0.67, P= .01). The presence of hyperechogenic spiculates was associated with the presence of fibrosis, while the presence of marked vascular signals was associated with the presence of inflammation. Wall thickness measured by IUS was reliable and reproducible in comparison with histological measurement.

Validating the Simplified Endoscopic Mucosal Assessment for Crohn's Disease: A Novel Method for Assessing Disease Activity.

To demonstrate treatment efficacy in Crohn's disease (CD), regulatory authorities require that trials include an endoscopic remission/response end point; however, standardized endoscopic assessment of disease activity, such as the Simple Endoscopic Score for Crohn's Disease (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. The novel Simplified Endoscopic Mucosal Assessment for Crohn's Disease (SEMA-CD) was developed to be easy to use in routine clinical practice and as a trial end point. We conducted a study to assess and validate the reliability and feasibility of SEMA-CD as a measure of endoscopic disease activity. Pre- and post-treatment ileocolonoscopy videos of pediatric (n = 36) and adult (n = 74) CD patients from 2 ustekinumab clinical trials were each scored with SEMA-CD by 2 to 3 professional central readers, blinded to clinical history and other video scorings; the correlation between SEMA-CD and SES-CD previously completed during the trials was assessed. Sensitivity to change, inter- and intrarater reliability, and comparative ease of scoring were also assessed. The SEMA-CD strongly correlated with SES-CD (Spearman ρ = 0.89; 95% confidence interval, 0.86-0.92). Pre- to post-treatment changes in SEMA-CD vs in SES-CD were strongly correlated, and the correlation remained strong between the scores when compared by study population (pediatric, adult), disease severity, and video quality. Intra- and inter-rater reliability were good, and SEMA-CD was rated easier than SES-CD to score 63.0% of the time, although slightly more difficult than SES-CD to score <1.0% of the time. The SEMA-CD is reliable, reproducible, sensitive to change, and easy to use in both pediatric and adult patients with CD.

Early Initiation of Antitumor Necrosis Factor Therapy Reduces Postoperative Recurrence of Crohn's Disease Following Ileocecal Resection.

Postoperative recurrence (POR) of Crohn's disease (CD) is common after surgical resection. We aimed to compare biologic type and timing for preventing POR in adult CD patients after ileocecal resection (ICR). We performed a retrospective cohort study of CD patients who underwent an ICR at 2 medical centers. Recurrence was defined by endoscopy (≥ i2b Rutgeerts score) or radiography (active inflammation in neoterminal ileum) and stratified by type and timing of postoperative prophylactic biologic within 12 weeks following an ICR (none, tumor necrosis factor antagonists [anti-TNF], vedolizumab, and ustekinumab). We identified 1037 patients with CD who underwent an ICR. Of 278 (26%) who received postoperative prophylaxis, 80% were placed on an anti-TNF agent (n = 223) followed by ustekinumab (n = 28, 10%) and vedolizumab (n = 27, 10%). Prophylaxis was initiated in 35% within 4 weeks following an ICR and in 65% within 4 to 12 weeks. After adjusting for factors associated with POR, compared with no biologic prophylaxis, the initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR (adjusted hazard ratio, 0.61; 95% CI, 0.40-0.93). Prophylaxis after 4 weeks following an ICR or with vedolizumab or ustekinumab was not associated with a reduction in POR compared with those who did not receive prophylaxis. Early initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR. Vedolizumab or ustekinumab, at any time following surgery, was not associated with a reduction in POR, although sample size was limited.

Intra-abdominal septic complications after ileocolic resection increases risk for endoscopic and surgical postoperative Crohn's disease recurrence.

Postoperative recurrence [POR] of Crohn's disease following ileocolonic resection is common. The impact of immediate postoperative intra-abdominal septic complications [IASC] on endoscopic and surgical recurrence has not been elucidated. To evaluate if IASC is associated with an increased risk for endoscopic and surgical POR. This was a retrospective study of adult Crohn's disease patients undergoing ileocolonic resection with primary anastomosis between 2009 and 2020. IASC was defined as anastomotic leak or intra-abdominal abscess within 90 days of the date of surgery. Multivariable logistic and Cox proportional hazard modelling were performed to assess the impact of IASC on endoscopic POR [modified Rutgeerts' score ≥ i2b] at index postoperative ileocolonoscopy and long-term surgical recurrence. In 535 Crohn's disease patients [median age 35 years, 22.1% active smokers, 35.7% one or more prior resection] had an ileocolonic resection with primary anastomosis. A minority of patients [N = 47; 8.8%] developed postoperative IASC. In total, 422 [78.9%] patients had one or more postoperative ileocolonoscopies, of whom 163 [38.6%] developed endoscopic POR. After adjusting for other risk factors for postoperative recurrence, postoperative IASC was associated with significantly greater odds (adjusted odds ratio [aOR]: 2.45 [1.23-4.97]; p = 0.01) and decreased time (adjusted hazards ratio [aHR]: 1.60 [1.04-2.45]; p = 0.03] to endoscopic POR. Furthermore, IASC was associated with increased risk (aOR: 2.3 [1.04-4.87] p = 0.03) and decreased survival-free time [aHR: 2.53 [1.31-4.87]; p = 0.006] for surgical recurrence. IASC is associated with an increased risk for endoscopic and surgical POR of Crohn's disease. Preoperative optimization to prevent IASC, in addition to postoperative biological prophylaxis, may help reduce the risk for endoscopic and surgical POR.

Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn's Disease Patients.

Background & AimsThe intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients.MethodsColonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types.ResultsOur analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes.ConclusionsSingle-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD.

Real-world outcomes associated with switching to anti-TNFsversusother biologics in Crohn’s Disease patients: A retrospective analysis using German claims data

The positioning of new biologic agents for the treatment of Crohn's disease (CD) following failure of initial anti-tumor necrosis factor (anti-TNF) therapy remains a challenge in the real world. This study aims to investigate the real-world outcomes associated with the sequential use of biologics in CD patients that newly initiate anti-TNFs, specifically comparing those that switch to another anti-TNF versus biologics with other modes of action. Retrospective cohort study. We identified CD patients who newly began anti-TNF therapy between 1 October 2014 and 31 December 2018 using two German claims databases. Patients were classified as within-class switchers (WCS) if they switched to another anti-TNF or outside-class switchers (OCS) if they switched to vedolizumab (VDZ) or ustekinumab (UST). To compare WCS and OCS, baseline covariates were adjusted through inverse probability of treatment weighting (IPTW), and time-to-event analyses were performed using Cox Proportional Hazard regressions. Results from both databases were meta-analyzed using an inverse variance model. Overall, 376 prevalent adult CD patients who initiated anti-TNFs and switched to another biologic were identified. After IPTW, there were 152 and 177 patients in the WCS and OCS group, respectively. WCS were more likely to receive prolonged corticosteroid therapy [hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.17-2.27, p = 0.004], switch a second time to a different biologic (HR: 2.44, 95% CI: 1.63-3.66, p < 0.001), and discontinue treatment (HR: 1.71, 95% CI: 1.25-2.34, p = 0.001) than OCS. This study suggests that CD patients exhibit more favorable outcomes when switching outside the anti-TNF class to VDZ or UST after initial anti-TNF failure than switching to a second anti-TNF. With loss of response to anti-TNFs as a concern in the real world, comparative evidence from claims data assessing sequential use of biologics can help optimize treatment algorithms of patients after anti-TNF failure.

P016 Impact of Non-Remission on Health-Related Quality of Life and Patient Reported Outcomes in Patients With Crohn's Disease: Targeted Literature Review.

Crohn's disease (CD) leads to chronic inflammation of the gastrointestinal tract that significantly impacts patients over an entire lifetime. The decrease in health-related quality of life (HRQoL) may have an impact on patient's level of functioning, work productivity, and other activities. The goal of treatment for CD is clinical remission based on clinical, endoscopic, and biological parameters. There has been introduction of new treatments in recent years. A review was conducted to assess the impact of non-remission on HRQoL and patient reported outcomes (PROs) in patients with CD. Literature search of English language publications from 2015-2021 was conducted in Embase® and MEDLINE®. Real world studies meeting predefined criteria (adult CD patients in non-remission presenting data for HRQoL or PROs) were included in the review. Data on study characteristics, disease characteristics, HRQoL and PROs were extracted from the included studies. The review retrieved 1384 records from which only 10 studies presented data for HRQoL and/or PROs. The definition of remission varied across the included studies. In most studies (90%), remission was defined using Harvey-Bradshaw Index and/or Crohn's disease activity index. Different tools were used to assess HRQoL and sleep quality. In a study, no normalization of long-term HRQoL was observed in patients who did not achieve clinical remission. A negative correlation was found between utility indexes & disease activity in a study (ρ = -0.586, p < 0.001). A significant correlation was also observed in a study between HRQoL and disease activity where HRQoL in patients with active disease was poor compared to patients in remission. The HRQoL domains of anxiety, depression and pain were impacted in non-remitters. The mean IBDQ score was 189 ± 16.1 in remitters and 145 ± 15.9 in non-remitters (p < 0.001). A strong negative correlation between IBDQ and disease activity was reported by a study. In a study, work productivity was moderately but significantly correlated with disease activity indicating reduction in work productivity of patients with active disease (mild, moderate, and severe) compared to remitters. In another study, severe disease activity was significantly associated with an increased amount of fragmented sleep. Patients with moderate to severe disease had a significantly longer time awake after falling asleep compared to patients in remission or with mild disease activity (65.8 minutes, 44.3 minutes, 49.1 minutes, respectively). Patients with active disease also reported poor sleep quality and suffered from excessive daytime sleepiness. There was a significant difference in the median sleep efficiency for patients with moderate to severe disease compared to patients with remission. This targeted review found in general that not being able to achieve/maintain remission had an impact on the HRQoL of patients with CD. Patients not achieving remission were associated with decreased work productivity, poor sleep quality, lower sleep efficiency, daytime sleepiness and poor HRQoL. However, studies assessing HRQoL and PROs in the real-world are scarce, with discrepancies based on remission status. Further research is warranted, and health care providers and payers should consider the impact of therapies on the improvement in HRQoL of patients with CD.

Relationship between IGF-1 and body weight in inflammatory bowel diseases: Cellular and molecular mechanisms involved

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and β-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology.

Increased colonic expression of ACE2 associates with poor prognosis in Crohn\u2019s disease

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. We examined the expression of colonic ACE2 in 67 adult CD and 14 NIBD control patients using RNA-seq and quantitative (q) RT-PCR. We validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan–Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. Colonic ACE2 expression was significantly higher in a subset of adult CD patients which was defined as the ACE2-high CD subset. IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of CD diagnosis, and a Cox regression analysis found that high ACE2 levels is an independent risk factor for surgery (OR 2.17; 95% CI, 1.10–4.26; p = 0.025). Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that can impact CD disease-related outcomes.

Systematic review: efficacy of escalated maintenance anti-tumour necrosis factor therapy in Crohn's disease.

Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD. EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes. Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.

Ultrasonography Tight Control and Monitoring in Crohn’s Disease During Different Biological Therapies: A Multicenter Study

Bowel ultrasonography (BUS) is a noninvasive tool for evaluating bowel activity in Crohn's disease (CD) patients. Aim of our multicenter study was to assess whether BUS helps to monitor intestinal activity improvement/resolution following different biological therapies. Adult CD patients were prospectively enrolled at 16 sites in Italy. Changes in BUS parameters [i.e. bowel wall thickening (BWT), lesion length, echo pattern, blood flow changes and transmural healing (TH: normalization of all BUS parameters)] were analyzed at baseline and after 3, 6 and 12 months of different biological therapies. One hundred eighty-eight out of 201 CD patients were enrolled and analyzed (116 males [62%]; median age 36 years). Fifty-five percent of patients were treated with adalimumab, 16% with infliximab, 13% with vedolizumab and 16% with ustekinumab. TH rates at 12 months were 27.5% with an NNT of 3.6. TH at 12 months after adalimumab was 26.8%, 37% after infliximab, 27.2% after vedolizumab and 20% after ustekinumab. Mean BWT improvement from baseline was statistically significant at 3 and 12 months (P < .0001). Median Harvey-Bradshaw index, C-reactive protein and fecal calprotectin decreased after 12 months from baseline (P < .0001). Logistic regression analysis showed colonic lesion was associated with a higher risk of TH at 3 months and a greater BWT at baseline was associated with a lower risk of TH at 3 months [P= .03 (OR 0.70, 95% CI 0.50-0.97)] and 12 months [P= .01 (OR 0.58, 95% CI 0.38-0.89)]. At 3 months therapy optimization during the study was the only independent factor associated with a higher risk of no ultrasonographic response [P= .02 (OR 3.34, 95% CI 1.18-9.47)] and at 12 months disease duration [P= .02 (OR 3.03, 95% CI 1.15-7.94)]. Data indicate that BUS is useful to monitor biologics-induced bowel activity improvement/resolution in CD.