Fecal Calprotectin Concentration Research Articles

Real-World Outcomes of Patients Starting Intravenous and Transitioning to Subcutaneous Vedolizumab in Inflammatory Bowel Disease.

Real-world data on starting intravenous (IV) vedolizumab (VDZ) and transitioning to subcutaneous (SC) treatment in inflammatory bowel disease (IBD) are scarce. To assess treatment outcomes of patients with IBD starting IV VDZ and switching to SC VDZ in routine clinical care. Adult patients with IBD switching from IV to SC VDZ treatment between 1 March 2020 and 31 December 2021 were identified from the Swedish IBD quality register. The primary outcome was SC VDZ persistence. Secondary outcomes included clinical remission, changes in quality of life (QoL) according to EuroQual 5-Dimensions 5-Levels (EQ-5D-5L) and the Short-Health Scale (SHS) and inflammatory markers, including faecal Calprotectin (FCP). Altogether, 406 patients with IBD (Crohn's disease, n = 181; ulcerative colitis, n = 225) were identified. After a median follow-up of 30months from starting IV VDZ treatment, the persistence rates were 98%(178/181) in Crohn's disease and 94% (211/225) in ulcerative colitis. Most patients (84%) transitioned during maintenance therapy, and the median follow-up from switch to SC VDZ was 10months. Compared to baseline, statistically significant improvements were observed in all domains of the SHS, EQ-5D index value and visual analogue scale. Median (interquartile range) FCP concentrations (μg/g) decreased from 459(185-1001) to 65(26-227) in Crohn's disease (n = 45; p < 0.001) and from 646(152-1450) to 49(20-275) in ulcerative colitis (n = 58; p < 0.001). Initiating IV VDZ and switching to SC treatment was associated with high persistence rates and improvements in measures of QoL and FCP. These findings are reassuring for patients who start IV VDZ and switch to SC VDZ.

Diagnostic Value of Faecal Calprotectin in Children with Chronic Gastrointestinal Disorders at Yaounde General Hospital

&amp;lt;i&amp;gt;Introduction&amp;lt;/i&amp;gt;: Chronic gastrointestinal disorders are common in children. Numerous faecal biomarkers, such as faecal calprotectin, are used in the aetiological diagnosis of these digestive disorders. The study aimed to investigate the diagnostic value of faecal calprotectin in paediatric chronic gastrointestinal disease compared with that obtained in healthy children. &amp;lt;i&amp;gt;Methodology&amp;lt;/i&amp;gt;: This was a comparative, analytical cross-sectional study from October 2022 through June 2023 at Yaoundé General Hospital. Participants were children aged between four and eighteen with chronic digestive disorders. Using a pre-established questionnaire, we collected the socio-demographic and clinical characteristics of each participant. The participants&amp;apos; faecal calprotectin was tested at the laboratory of the Yaoundé University Hospital Center by Enzyme-Linked Immunosorbent Assay (ELISA). Associations between variables were investigated by linear regression and calculation of the odds ratio (OR). The significance threshold was 5%. &amp;lt;i&amp;gt;Results&amp;lt;/i&amp;gt;: Sixty stool samples were analysed for faecal calprotectin from 30 patients and 30 healthy participants. The mean age of the population was 9.47 (± 3.35) years for patients and 10.67 (± 3.70) years for healthy participants, with a sex ratio of 1.14 for patients and 0.87 for healthy participants. The threshold value for faecal calprotectin was 2.75 µg/g, with a sensitivity of 60%, a specificity of 63%, a positive predictive value of 61.20% and a negative predictive value of 62.06%. There were no significant differences in faecal calprotectin concentrations between children with chronic gastrointestinal disorders (peptic ulcer disease: p=0.10; functional gastrointestinal disorder associated with peptic ulcer disease: p= 0.710; functional gastrointestinal disorder: p= 0.143) and healthy children. &amp;lt;i&amp;gt;Conclusion&amp;lt;/i&amp;gt;: The diagnostic value of faecal calprotectin as a biomarker in the diagnosis of chronic gastrointestinal disease was not observed in this study. However, the biological parameters assessed were measured only once, and given that their concentrations may vary over time, we recommend a subsequent longitudinal study.

Treatment success in cats with chronic enteropathy is associated with a decrease in fecal calprotectin concentrations.

Feline chronic enteropathies (FCE) are challenging to diagnose and monitor for progression and response to treatment. Fecal calprotectin might be a useful non-invasive marker to evaluate clinical endpoints of therapeutic monitoring in FCE. We evaluated fecal calprotectin concentrations in cats with FCE before and after initiation of treatment comprised of immunomodulation and/or dietary intervention. Included were 17 cats with FCE and 18 healthy controls. Clinical investigation of FCE cases included clinical severity grading (feline chronic enteropathy activity index, FCEAI) in all cats, abdominal ultrasonography in 15 cats, and gastrointestinal biopsies in 6 cats. Fecal calprotectin was measured in samples from 12 cats with FCE before treatment, all 17 FCE cats ≥6 weeks after treatment initiation, and all healthy controls. Fecal calprotectin concentrations in FCE cases before treatment (median: 61 μg/g) were significantly higher than after treatment initiation (median: 15 μg/g; p = 0.0098) and compared to controls (median: 6 μg/g; p = 0.0235) and correlated with the FCEAI scores (ρ = 0.54, p = 0.0316). Fecal calprotectin concentrations after treatment initiation were higher with more severe duodenal/proximal jejunal pathology (ρ = 0.83, p = 0.0427) and shorter intervals between sampling time points (ρ = -0.54, p = 0.0250). Relevant decreases in initially increased fecal calprotectin concentrations are seen in cats with FCE on varying treatment strategies that significantly improve or have remission of clinical signs. This supports the utility of fecal calprotectin as a surrogate biomarker to assess disease severity in FCE cases. Further studies need to evaluate fecal calprotectin concentrations longitudinally in relation to mucosal healing vs. clinical response.

Lower Diet Quality Associated with Subclinical Gastrointestinal Inflammation in Healthy United States Adults

BackgroundHigher diet quality has been associated with lower risk of developing inflammatory bowel disease, but associations between diet and gastrointestinal (GI) inflammation in healthy adults prior to disease onset are understudied. ObjectivesThe purpose of this project was to examine associations between reported dietary intake and markers of GI inflammation in a healthy adult human cohort. MethodsIn a cross-sectional observational trial of 358 healthy adults, participants completed ≤3 unannounced 24-h dietary recalls using the Automated Self-Administered Dietary Assessment Tool and a Block 2014 Food Frequency Questionnaire to assess recent and habitual intake, respectively. Those who provided a stool sample were included in this analysis. Inflammation markers from stool, including calprotectin, neopterin, and myeloperoxidase, were measured by ELISA along with LPS-binding protein from plasma. ResultsRecent and habitual fiber intake was negatively correlated with fecal calprotectin concentrations (n = 295, P = 0.011, 0.009). Habitual soluble fiber intake was also negatively correlated with calprotectin (P = 0.01). Recent and habitual legume and vegetable intake was negatively correlated with calprotectin (P = 0.013, 0.026, 0.01, 0.009). We observed an inverse correlation between recent Healthy Eating Index (HEI) scores and calprotectin concentrations (n = 295, P = 0.026). Dietary Inflammatory Index scores were calculated and positively correlated with neopterin for recent intake (n = 289, P = 0.015). When participants with clinically elevated calprotectin were excluded, recent and habitual fiber, legume, vegetable, and fruit intake were negatively correlated with calprotectin (n = 253, P = 0.00001, 0.0002, 0.045, 0.001, 0.009, 0.001, 0.004, 0.014). Recent total HEI score was inversely correlated with subclinical calprotectin (P = 0.003). ConclusionsHigher diet quality may be protective against GI inflammation even in healthy adults.This trial was registered at clinicaltrials.gov as NCT02367287.

A234 DOES FECAL CALPROTECTIN CORRELATE WITH INFLAMMATION ON ULTRASOUND IN CROHN’S DISEASE STRICTURES?

Abstract Background Fibrostenotic Crohn’s Disease (CD) is a challenging phenotype particularly due to the absence of intestinal anti-fibrotic therapies. Differentiating between strictures that are predominantly fibrotic as opposed to inflammatory remains a diagnostic dilemma. The ability to make this differentiation is critical to inform decisions for therapeutic approach. Fecal calprotectin (FC) is a stool marker reflective of intestinal inflammation. Very few studies have evaluated the relationship of FC concentration in ileal CD strictures and parameters of inflammation on intestinal ultrasound (IUS). Strictures on imaging are defined as 1) increased bowel wall thickness (BWT), 2) narrowed luminal apposition, and 3) pre-stenotic dilation (PSD). BWT and hyperemia (color Doppler signal (CDS)) are the most sensitive markers for CD inflammation on IUS. It is predicted that FC will match CDS in ileal strictures, similar to non-stricture phenotypes. Aims We aim to correlate FC levels with IUS inflammation of ileal CD strictures. Methods We performed a retrospective cohort pilot study exploring the relationship between FC levels and IUS inflammatory parameters in ileal strictures. FC levels were obtained ≤ 60 days of index IUS in fibrostenotic ileal CD patients. Individuals who underwent medication changes or experienced a clinical flare during this period were excluded. Inflammation was measured as BWT and CDS using a modified Limberg (ML) score. Pearson correlation for continuous variables, Spearman rank correlation and a Kruskal-Wallis test for FC and Limberg scale were completed. Results A total of 25 fecal samples were obtained from 17 patients with ileal strictures (47% male, median age 59 years (range 18-76)) were assessed. Median FC concentrations was 204.9 ug/g, IQR: 250.4. Median ileal stricture BWT was 7.0 mm (range 3.0–10.0). 40% (10/25) had ML1 (short chains in bowel), 32% (8/25) ML2 (long chains in bowel), and 28% (7/25) ML3 (long chains and perienteric fat). There was no correlation between FC and BWT (r= .02, p = 0.92), nor FC with ML scores (r=0.20, p= 0.25). In those with ML1, median FC was 232.4, while those with ML2 or 3, had a FC of 155.6 and 469.7, respectively. FC values were significantly different between the ML scores, pampersand:003C0.0001. Conclusions FC levels were not correlated with inflammatory parameters as seen on IUS in ileal CD. This unexpected finding may be due to ML2 scores having lower FC than anticipated, and small sample size. Other imaging factors such as loss of wall stratification need to be taken into account, and are perhaps more reflective of inflammation than BWT and CDS. This study provides the initial data to assess accuracy of FC and hyperemia of ileal CD strictures on IUS compared to histologic measures of inflammation on resected specimens. Funding Agencies None

A green tea extract confection decreases circulating endotoxin and fasting glucose by improving gut barrier function but without affecting systemic inflammation: A double-blind, placebo-controlled randomized trial in healthy adults and adults with metabolic syndrome

Anti-inflammatory activities of catechin-rich green tea extract (GTE) in obese rodents protect against metabolic endotoxemia by decreasing intestinal permeability and absorption of gut-derived endotoxin. However, translation to human health has not been established. We hypothesized that GTE would reduce endotoxemia by decreasing gut permeability and intestinal and systemic inflammation in persons with metabolic syndrome (MetS) compared with healthy persons. A randomized, double-blind, placebo-controlled, crossover trial in healthy adults (n = 19, 34 ± 2 years) and adults with MetS (n = 21, 40 ± 3 years) examined 4-week administration of a decaffeinated GTE confection (890 mg/d total catechins) on serum endotoxin, intestinal permeability, gut and systemic inflammation, and cardiometabolic parameters. Compared with the placebo, the GTE confection decreased serum endotoxin (P = .023) in both healthy persons and those with MetS, while increasing concentrations of circulating catechins (P < .0001) and γ-valerolactones (P = .0001). Fecal calprotectin (P = .029) and myeloperoxidase (P = .048) concentrations were decreased by GTE regardless of health status. Following the ingestion of gut permeability probes, urinary lactose/mannitol (P = .043) but not sucralose/erythritol (P > .05) was decreased by GTE regardless of health status. No between-treatment differences (P > .05) were observed for plasma aminotransferases, blood pressure, plasma lipids, or body mass nor were plasma tumor necrosis factor-α, interleukin-6, or the ratio of lipopolysaccharide-binding protein/soluble cluster of differentiation-14 affected. However, fasting glucose in both study groups was decreased (P = .029) by the GTE confection compared with within-treatment arm baseline concentrations. These findings demonstrate that catechin-rich GTE is effective to decrease circulating endotoxin and improve glycemic control in healthy adults and those with MetS, likely by reducing gut inflammation and small intestinal permeability but without affecting systemic inflammation.

FROM RESISTANCE TO RESPONSE: 52 WEEKS OF SUBCUTANEOUS INFLIXIMAB IN REFRACTORY CROHN'S DISEASE PATIENTS AFTER THE MULTIPLE TREATMENT FAILURES

Abstract BACKGROUND Infliximab (IFX), an anti-TNFα monoclonal antibody, has been utilized since the late 1990s as an effective therapeutic agent for the treatment of Crohn's disease (CD). Since 2020, subcutaneous IFX (IFX-SC) has been available for treating CD. This study aimed to conduct a 52-week observation of IFX-SC treatment in refractory CD patients who had failed on at least two previous lines of biologic therapy patients. MATERIALS AND METHODS The study included 32 patients diagnosed with CD who had failed on 2 to 7 previous lines of biological therapy. Observed cohort was monitored at weeks W0, W4, W14, W30, and W52, recording Harvey-Bradshaw Index (HBI) , C-reactive protein (CRP) and fecal calprotectin (FC) concentrations, trough infliximab (TL-IFX) and anti-infliximab (anti-IFX) serum levels. Endoscopic, ultrasonographic and magnetic resonance disease scores (SES-CD, IUS and MaRIA) were determined at baseline and W52. RESULTS 52-week persistence on IFX-SC treatment was recorded in 18 out of 32 patients (56.3%). A significant decrease of HBI (P &amp;lt;0 .0001), CRP (P =0 .0035), FC (P =0.0012), SES-CD (P =0.013), IUS (P =0.0034) and MaRIA (P =0.0261) was observed. TL IFX increased significantly (.0073), and median TL-IFX levels reached 19.75 μg/mL at W52. During the therapy, 8 out of 16 initially anti-IFX positive individuals seroconverted to negative anti-IFX (50 %); no new sensitization to IFX was recorded in the cohort. None of the patients treated with IFX-SC in W52 needed concomitant immune-modifying treatment. Baseline clinical, laboratory, and imaging markers did not demonstrate any predictive value for IFX-SC treatment failure, except for baseline high levels of anti-IFX (P = &amp;lt;0.0001). CONCLUSION In the cohort of refractory CD patients, over half achieved one-year treatment persistence on IFX-SC, displaying a highly favorable trend in all disease activity markers. The IFX-SC treatment appears to be effective and safe; however, further research is needed to identify potential predictors of therapeutic responsiveness. Acknowledgement: This work was supported by the IBD-COMFORT Foundation

P348 Increased pre-treatment faecal calprotectin concentration predicts resistance to ustekinumab induction in ulcerative colitis

Abstract Background Rates of resistance to advanced therapy remain high in ulcerative colitis (UC). Pre-treatment predictors of poor outcomes would provide valuable information for treating clinicians so other therapies could be given or early treatment switches could be considered if response is inadequate. We investigated whether baseline, pre-treatment faecal calprotectin (FCP) can predict resistance to ustekinumab. Methods Clinical outcomes at week 8, including clinical remission, endoscopic healing and mucosal healing were determined in patients enrolled in the UNIFI phase 3 placebo-controlled trial program, investigating the efficacy of ustekinumab for moderate-to-severe UC (GSE206285), in whom FCP concentrations were available at baseline, prior to initiation of treatment. Clinical outcomes were defined in patients with FCP &amp;lt; 250mcg/g, 250 – 999mcg/g, 1000 – 1999mcg/g and &amp;gt;= 2000mcg/g. Chi-squared test was used to assess statistical significance. Area under the receiver operating characteristics curve (AUROC) analyses were used to determine the ability of faecal calprotectin level to predict treatment resistance. Analyses were performed using R 4.2.3 (Vienna, Austria) and GraphPad Prism 10.0.3 (Massachusetts, United States). Results Outcome data and linked faecal calprotectin levels were available for 340 patients. FCP values ranged from 15 – 25249mcg/g. The median FCP value was 1402mcg/g (interquartile range: 600.8 – 2772.0mcg/g). In general, all clinical outcome measures were progressively worse with increasing FCP concentrations. For the respective FCP cut-offs, 22.0%, 19.3%, 11.3% and 6.7% achieved clinical remission; 39.0%, 24.1%, 20.6% and 16.0% achieved endoscopic healing; and 29.3%, 16.9%, 15.5% and 7.6% achieved mucosal healing (Figure 1). ROC analyses revealed that pre-treatment FCP predicts resistance to ustekinumab therapy for all stated outcomes, including clinical remission (AUROC: 0.66, P=0.001), endoscopic healing (AUROC: 0.63, P=0.0013) and mucosal healing (AUROC: 0.65, P=0.0005). Conclusion Increasing concentrations of pre-treatment FCP predicts resistance to ustekinumab therapy in moderate-to-severe UC. Patients with FCP &amp;gt;= 2000mcg/g were significantly less likely than those with FCP &amp;lt;1000 mcg/g to achieve clinical remission or mucosal healing. Since neutrophils are the main producers of FCP, these data build on other emerging data indicating that excessive accumulation of mucosal neutrophils is associated with treatment resistance in IBD.

P476 Correlation between fecal calprotectin and inflammation on ultrasound in fibrostenotic Crohn’s Disease

Abstract Background Fibrostenotic Crohn’s Disease (CD) is a challenging phenotype particularly due to the absence of intestinal anti-fibrotic therapies. Differentiating between strictures that are predominantly fibrotic versus inflammatory remains a diagnostic dilemma. The ability to make this differentiation is critical to inform therapeutic decisions. Fecal calprotectin (FC) is a stool marker reflective of intestinal inflammation. Very few studies have evaluated the relationship of FC concentration in ileal CD strictures and parameters of inflammation on intestinal ultrasound (IUS). Strictures on imaging are defined as 1) increased bowel wall thickness (BWT), 2) narrowed luminal apposition, and 3) pre-stenotic dilation (PSD). BWT and hyperemia (color Doppler signal (CDS)) are the most sensitive markers for CD inflammation on IUS. It is predicted that FC will match CDS in ileal strictures, similar to non-stricture phenotypes. We aim to correlate FC levels with IUS inflammation of ileal CD strictures. Methods We performed a retrospective cohort pilot study exploring the relationship between FC levels and IUS inflammatory parameters in ileal strictures. FC levels were obtained ≤ 60 days of index IUS in fibrostenotic ileal CD patients. Individuals who underwent medication changes or experienced a clinical flare during this period were excluded. Inflammation was measured as BWT and CDS using a modified Limberg (ML) score. Pearson correlation for continuous variables, Spearman rank correlation and a Kruskal-Wallis test for FC and Limberg scale were completed. Results A total of 25 fecal samples were obtained from 17 patients with ileal strictures (47% male, median age 59 years (range 18-76)) were assessed. Median FC concentrations was 204.9 ug/g, IQR: 250.4. Median ileal stricture BWT was 7.0 mm (range 3.0–10.0). 40% (10/25) had ML1 (short chains in bowel), 32% (8/25) ML2 (long chains in bowel), and 28% (7/25) ML3 (long chains and perienteric fat). There was no correlation between FC and BWT (r=0.02, p=0.92), nor FC with ML scores (r=0.20, p=0.25). In those with ML1, median FC was 232.4, while those with ML2 or 3, had a FC of 155.6 and 469.7, respectively. FC values were significantly different between the ML scores, p&amp;lt;0.0001. Conclusion FC levels were not correlated with inflammatory parameters as seen on IUS in ileal CD. This unexpected finding may be due to ML2 scores having lower FC than anticipated, and small sample size. Other imaging factors such as loss of wall stratification need to be taken into account, and are perhaps more reflective of inflammation than BWT and CDS. This study provides the initial data to assess accuracy of FC and hyperemia of ileal CD strictures on IUS compared to histologic measures of inflammation on resected specimens.

P430 The influence of persistent organ damage on IFX pharmacokinetic modeling and disease progression assessment: findings from a prospective real-world study in inflammatory bowel disease patients

Abstract Background Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. Methods The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. Results The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in all its different definitions, when adjusted for several confounding factors (Fig. 1). Additionally, alongside FC, both IFX and C-reactive protein demonstrated a significant impact on the temporal aspect of disease progression. Conclusion In this 2-year prospective real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that persistent gut damage, as mirrored by FC, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of the progression of the underlying disease. These findings underscore the imperative need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

P1080 Real-world Study on Early Predictors of Infliximab Treatment Efficacy in Crohn's disease

Abstract Background Infliximab (IFX) can effectively induce and maintain the clinical remission of Crohn's disease (CD). However, a substantial number of CD patients experience primary or secondary nonresponse to IFX during treatment. Therefore, it is essential to identify early predictors of IFX treatment efficacy. Methods This study included 147 CD patients. Based on clinical outcomes, patients were categorized into IFX nonresponse and response group. We collected and compared laboratory data on blood routine examination, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fecal calprotectin and post-induction IFX drug concentration and antibody levels in both groups. Logistic regression models were employed to identify potential factors associated with the risk of IFX nonresponse. Machine learning using random forest analysis was utilized to quantitatively assess the predictive features for IFX treatment efficacy and ROC curves was used to evaluate the model’s accuracy. Additionally, we performed HE staining and double immunofluorescence staining for CD64 and CD206 on intestinal biopsy tissues obtained before IFX treatment to compare the difference of macrophage subtypes between the nonresponse and response groups. Results Data from both cohorts revealed that patients in the IFX nonresponse group had lower drug concentration (P &amp;lt; 0.001), higher antibody levels (P &amp;lt; 0.001), and increasing ESR during the induction therapy (P &amp;lt; 0.001). Univariate and multivariate Logistic regression models demonstrated that IFX drug concentration and the ratio of ESR before and after induction therapy were associated with the risk of nonresponse. After the induction period, for each unit increase in drug concentration (1 μg/ml), the risk of IFX nonresponse decreased by 23% (RR= 0.77, 95% CI = 0.68-0.89), while each doubling of the ESR ratio after induction was associated with a 1.43-fold increase in the risk of nonresponse (RR= 2.43, 95% CI = 1.48-4.00). After combining data from the two cohorts, random forest machine learning analysis revealed that drug concentration below 1.5 μg/ml and an increase in ESR during induction could predict IFX nonresponse, with ROC curve areas of 0.740 and 0.651, respectively. Furthermore, immunofluorescence staining of intestinal mucosal biopsy tissues before IFX treatment showed a higher proportion of M1-type macrophages in the nonresponse group compared to the response group (P &amp;lt; 0.05). Conclusion Our study suggests that lower post-induction IFX drug concentrations and an increase in ESR during the induction phase are predictive of IFX nonresponse. Additionally, a higher proportion of M1-type macrophages in the intestinal mucosa before IFX treatment is associated with IFX nonresponse.

P951 Efficacy and safety of tofacitinib for the treatment of moderate- severe ulcerative colitis in biologic naïve patients

Abstract Background To assess the rates of clinical response at week 8, biochemical response, steroid-free clinical remission, endoscopic healing and safety data at week 26 of tofacitinib in biologic naive patients with moderate-severe ulcerative colitis (UC). Methods This was a retrospective analysis of prospectively collected data extracted from the notes of biologic naïve patients with moderate-severe UC who were treated with tofacitinib in the last 3 years in 5 Greek IBD centers and who had a follow up of at least 26 weeks after initiation of treatment. Tofacitinib was administered at a dose of 10 mg bid for 8 or 16 weeks followed by a maintenance dose of 5mg bid thereafter. Week-8 or -16 clinical response was defined as the reduction in the partial Mayo score of at least 2 points, without concomitant use of any steroid preparation [budesonide, prednis(ol)one, or methylprednisolone]. Steroid free clinical remission at week 26 was defined as a partial Mayo score of ≤1 points without concomitant use of any steroid preparation. Biochemical response at week 26 was defined as any reduction in fecal calprotectin or plasma C-reactive protein concentrations as compared to their baseline levels.Mucosal healing at week 26 was defined as Mayo endoscopic sub-score of ≤1. A safety list of all reported adverse events was completed. Treatment discontinuation due to adverse events was considered as treatment failure, whereas patients needing escalation of the maintenance dose were also considered as non-responders. Results Overall, 41 patients (26 males), aged (mean, SD) 35.2 (12.7) years and disease duration of mean (SD) 6.5 (4.8) years were included. UC was extensive in 22, left-sided in 17, and proctitis in 2 patients. Clinical response was seen in 31 (75.6%) and 34 (82.9%) patients at week 8 and 12 respectively.Biochemical response and steroid free clinical remission at week 26 were seen in 35 (85.4%) patients. Endoscopic healing was seen in 29 (70.7%) patients. Adverse events,which did not lead to treatment discontinuation, occurred in 5 patients (hyperlipidemia n=3, elevated liver enzymesn=1, herpes zoster n=1). Conclusion In this retrospective real-world ongoing cohort study, tofacitinib demonstrated clinical response at week 8 or 16 and steroid free clinical remission at week 26 in more than 75% of biologic naïve patients with moderate-severe UC with a good safety profile.

The influence of subclinical active inflammation on IFX pharmacokinetic modeling and disease progression assessment: findings from a prospective real-world study in inflammatory bowel disease patients.

Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in all its different definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression. In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

Serum Amyloid A as a Potential Biomarker in Inflammatory Bowel Diseases, Especially in Patients with Low C-Reactive Protein.

The acute phase protein Serum Amyloid A (SAA) is synthesised by the liver in response to inflammatory stimuli. Previous studies have revealed that SAA may be a better biomarker of disease activity in inflammatory bowel disease (IBD) compared to C-reactive protein (CRP). This retrospective monocentric study evaluated whether SAA correlates with biomarkers like faecal calprotectin (FC), CRP, the Neutrophil to Lymphocyte ratio (NLR), the platelet count and clinical disease activity of IBD patients. Serum samples from the IBD outpatient clinic of the University Hospital Heidelberg were analysed for SAA concentrations if an FC concentration measurement was available from ±14 days to collection of the serum sample. Three hundred and six serum samples from 265 patients (166 with Crohn's disease, 91 with ulcerative colitis and 8 with IBD unclassified) met the inclusion criteria. There was a significant positive correlation between SAA and FC, CRP, NLR, platelet count and the Simple Clinical Colitis Activity Index (SCCAI). The cut-off for SAA serum concentration at 4.55 mg/L achieved a sensitivity of 57.5% and a specificity of 69.7% for the detection of active inflammation in IBD. SAA may be used as an additional biomarker in the disease monitoring strategy of IBD patients, especially in patients with low CRP concentrations.

Methanogenic Archaea in the Pediatric Inflammatory Bowel Disease in Relation to Disease Type and Activity.

The inflammatory bowel disease (IBD) is associated with gut microbiota dysbiosis; however, studies on methanogens-especially those focused on children-are extremely limited. The aim of this study was to determine the abundance of total methanogenic archaea and their three subgroups: Methanobrevibacter (Mb.) smithii, Methanosphaera (Ms.) stadtmanae, and Methanomassiliicoccales, in the feces of children with both active and inactive Crohn's disease (CD) and ulcerative colitis (UC). The results of a quantitative real-time PCR were cross-referenced with the disease type (CD vs. UC) and activity assessed with the use of Pediatric Crohn's Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI) indices, and fecal calprotectin (FCP) concentration, and compared with controls. There was a significant decrease in the number of total methanogens in CD and UC compared to controls. The prevalence of total methanogens was also lower in UC compared to controls. Furthermore, patients from the inactive UC group were colonized by a lower number of Mb. smithii, and demonstrated the most pronounced positive correlation between the number of Ms. stadtmanae and the FCP concentration. Our results demonstrate that gut methanogens are related to the type and activity of pediatric IBD.

Limosilactobacillus reuteri DSM 17938 and ATCC PTA 6475 for the treatment of moderate to severe irritable bowel syndrome in adults: a randomized controlled trial

BackgroundIrritable bowel syndrome (IBS) is a common functional gastrointestinal disorder in adults. Systematic reviews with meta-analyses have demonstrated the efficacy and safety of probiotics in improving symptoms of IBS.AimThe aim of the study was to demonstrate the efficacy and safety of Limosilactobacillus reuteri (L. reuteri) DSM 17938 combined with L. reuteri ATCC PTA 6475 regarding improving the symptoms associated with IBS in adults.MethodsA randomized, double-blind, placebo-controlled clinical trial was conducted in 140 adults aged 18 years to 65 years with a diagnosis of IBS (based on the Rome IV criteria). After 2 weeks of washout, subjects were randomized to receive either 2 × 108 colony-forming units (CFUs) of L. reuteri DSM 17938 combined with L. reuteri ATCC PTA 6475 plus standard of care or placebo plus standard of care for 14 weeks, followed by a post-intervention period of 2 additional weeks. Changes in gastrointestinal symptoms (as measured with the GSRS-IBS), stool pattern (as measured with the Bristol scale), quality of life, depression and anxiety, frequency of adverse events, and fecal calprotectin concentrations were evaluated.ResultsIn total, 70 subjects were allocated to receive L. reuteri and 70 were allocated to receive placebo. During the pre-randomization phase, no differences were observed between the groups in terms of IBS-associated symptoms and stool consistency. Starting at week 6 of the intervention, subjects in group L. reuteri showed a significant improvement in IBS-associated symptoms (p &amp;lt; 0.01). A significant improvement was also observed in fecal calprotectin concentration in the L. reuteri group at the end of interventions (30.2 ± 11.8 mg/g of stool in the L. reuteri group and 41.6 mg/g ± 10.7 mg/g in the placebo group; p = 0.019). The frequency of adverse events was similar between groups.ConclusionsA twice-a-day intervention for 14 weeks is safe and effective, reduces the symptoms associated with IBS in adults aged 18 years to 65 years, improves stool consistency, and reduces symptoms associated with anxiety after 6 weeks.

The probiotic Lacticaseibacillus rhamnosus HN001 influences the architecture and gene expression of small intestine tissue in a piglet model.

This study investigated the effects of Lacticaseibacillus rhamnosus HN001 supplementation on the architecture and gene expression in small intestinal tissues of piglets used as an animal model for infant humans. Twenty-four 10-d-old entire male piglets (4·3 (sd 0·59) kg body weight) were fed an infant formula (IF) (control) or IF supplemented with 1·3 × 105 (low dose) or 7·9 × 106 (high dose) colony-forming units HN001 per ml of reconstituted formula (n 8 piglets/treatment). After 24 d, piglets were euthanised. Samples were collected to analyse the histology and gene expression (RNAseq and qPCR) in the jejunal and ileal tissues, blood cytokine concentrations, and blood and faecal calprotectin concentrations. HN001 consumption altered (false discovery rate < 0·05) gene expression (RNAseq) in jejunal tissues but not in ileal tissues. The number of ileal goblet cells and crypt surface area increased quadratically (P < 0·05) as dietary HN001 levels increased, but no increase was observed in the jejunal tissues. Similarly, blood plasma concentrations of IL-10 and calprotectin increased linearly (P < 0·05) as dietary HN001 levels increased. In conclusion, supplementation of IF with HN001 affected the architecture and gene expression of small intestine tissue, blood cytokine concentration and frequencies, and blood calprotectin concentrations, indicating that HN001 modulated small intestinal tissue maturation and immunity in the piglet model.

Fecal calprotectin as a marker of inflammatory bowel diseases

Calprotectin is a calcium- and zinc-binding protein belonging to the S100 protein family. This protein is found mainly in the cytoplasm of neutrophils, and, to a lesser extent, in monocytes and macrophages, which can be found in any human organs, but mainly in blood, cerebrospinal fluid, feces, saliva, and synovial fluid. Calprotectin is an effective tool forthe differential diagnosis of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). There is a connection of fecal calprotectin (FC) with the endoscopic activity of IBD, however, the available literature shows significant differences in the sensitivity and specificity of FC for predicting the endoscopic activity of the disease. In addition, FC can be considered as a predictor of histological mucosal healing and as a marker for assessing the response to treatment, including surgical, but there is still no consensus on the threshold value of a biomarker for these purposes. Conflicting data are presented in reports on FC as a predictor of IBD recurrence. FC seems to be effective for detecting relapse, however, there is no specific threshold value, therefore, the marker cannot completely replace endoscopic examination methods. In addition, there is intraindividual variability in the concentration of FC in patients, depending on age, type of feeding in the first year of life, taking medications, which significantly complicates the interpretation of the results.

Subkutánní infliximab v léčbě refrakterních pacientů s Crohnovou nemocí – pilotní studie imunogenicity léčiva

Introduction: Despite infliximab (IFX) still being the “gold standard” of biological therapy for Crohn’s disease (CD), its effectiveness may vary depending on many factors. One of these factors is the individual patient’s reaction to the drug. A significant clinical problem is the immunogenicity of IFX, where up to 60% of treated patients may develop antibodies against the drug, leading to a loss of response to treatment and/or adverse reactions to therapy. Since 2020, subcutaneous infliximab (IFX-SC) has been available for treating CD patients, characterized by its stable and high trough level (TL) concentration in blood. It is possible that one consequence of this property of IFX-SC is its lower rate of immunogenicity. We present a prospective study of patients diagnosed with CD with severe to refractory courses, treated with IFX-SC. The aim of the study was to monitor the immunogenicity of IFX-SC, including the dynamics of TL and anti-drug antibodies (anti-IFX). The dynamics of clinical, imaging, and laboratory markers of CD over one year of monitoring and treatment are described. Materials and methods: The study included 23 patients diagnosed with CD who had failed 2 to 6 previous lines of biological therapy, one of which was intravenous infliximab (IFX-IV). Patients were divided into two arms of induction therapy based on the presence of anti-IFX. Maintenance therapy consisted of 120 mg s.c. every 14 days, and intensification was 240 mg s.c. every 14 days if necessary. Patients were monitored at weeks W0, W4, W14, W30, and W52, recording Harvey-Bradshaw Index (HBI), serum C-reactive protein (CRP), fecal calprotectin (FC) concentrations, drug trough levels (TL IFX) and serum anti-drug antibodies (anti-IFX). Endoscopic and ultrasonographic disease scores (SES-CD and IUS) were determined, and HLA DQA1*05 haplotype was examined in all patients. Data were analyzed using MedCalc® Statistical Software with non-parametric statistical methods and binary logistic regression. Results: 52-week persistence on IFX-SC treatment was recorded in 13 out of 23 patients (56.5%), with a significant decrease in all monitored clinical, imaging, and laboratory markers of CD activity. During the therapy, 8 out of 16 initially anti-IFX positive individuals seroconverted to negative anti-IFX (50%). None of the patients treated with IFX-SC in W52 needed concomitant immunomodulator treatment. No new sensitization to infliximab was recorded in the cohort during the 52-week therapy. Conclusion: The subcutaneous route of infliximab administration may be a suitable and successful solution in situations where reinduction of infliximab therapy is desired, including patients with the presence of neutralizing antibodies against the drug.

Validation of the fCAL turbo immunoturbidimetric assay for measurement of calprotectin in porcine and bovine fecal samples

The concentration of calprotectin in feces is a well-studied marker of gastrointestinal inflammation in humans. However, little is known about fecal calprotectin in farm animals. In this work, we have validated an immunoturbidimetric method for fecal calprotectin (Bühlmann fCAL® turbo assay, Schönenbuch, Switzerland) in porcine and bovine fecal samples. Linearity was evaluated by serial dilution (R2 > 0.97 was obtained for both species). Accuracy was assessed by a recovery study, with results between 80 and 120% for low, medium, and high samples in both species. Intra- and inter-assay variability was <20%. Limit of detection was 6.4 μg/g in pig and 5.3 μg/g in cow. Limit of quantification was 13.4 μg/g (pig) and 11.1 μg/g (cow). Additionally, clinical validation has been included to evaluate the ability of the assay to detect inflammatory status in the intestine under different management conditions. In experiments with porcine, it was found that piglets treated with ZnO had lower concentrations of fecal calprotectin. In a second experiment in bovine, calves with diarrhea had higher concentration of fecal calprotectin.The Bühlmann fCAL® turbo assay is suitable for measurement of calprotectin in porcine and bovine fecal samples. Moreover, fecal calprotectin could be a good biomarker of intestinal inflammation in both species.