The Effect of Pregnancy and Inflammatory Bowel Disease on the Pharmacokinetics of Drugs Related to Inflammatory Bowel Disease:A Systematic Literature Review

Due to ethical and practical reasons, a knowledge gap exists on the pharmacokinetics (PK) of inflammatory bowel disease (IBD)-related drugs in pregnant women with IBD. Before evidence-based dosing can be proposed, insight into the PK has to be gained to optimize drug therapy for both mother and fetus. This systematic review aimed to describe the effect of pregnancy and IBD on the PK of drugs used for IBD. One aminosalicylate study, two thiopurine studies and twelve studies with biologicals were included. Most drugs within these groups presented data over multiple moments before, during and after pregnancy, except for mesalazine, ustekinumab and golimumab. The studies for mesalazine, ustekinumab and golimumab did not provide enough data to demonstrate an effect of pregnancy on concentration and PK parameters. Therefore, no evidence-based dosing advice was given. The 6-thioguanine nucleotide levels decreased during pregnancy to 61% compared to pre-pregnancy levels. The potentially toxic metabolite 6-methylmercaptopurine (6-MMP) increased to maximal 209% of the pre-pregnancy levels. Although the PK of the thiopurines changed throughout pregnancy, no evidence-based dosing advice was provided. One study suggested that caution should be exercised when the thiopurine dose is adjusted, due to shunting 6-MMP levels. For the biologicals, infliximab levels increased, adalimumab stayed relatively stable and vedolizumab levels tended to decrease during pregnancy. Although the PK of the biologicals changed throughout pregnancy, no evidence-based dosing advice for biologicals was provided. Other drugs retrieved from the literature search were mesalazine, ustekinumab and golimumab. We conclude that limited studies have been performed on PK parameters during pregnancy for drugs used in IBD. Therefore, more extensive research to determine the values of PK parameters is warranted. After gathering the PK data, evidence-based dosing regimens can be developed

Optimized sampling conditions for fecal volatile organic compounds analysis by means of field asymmetric ion mobility spectrometry

Background Fecal volatile organic compounds (VOCs) are increasingly considered as potential non-invasive, diagnostic biomarkers for various gastrointestinal diseases. Knowledge of influence of sampling conditions on VOC outcomes is limited. We aimed to evaluate effects of sampling conditions on fecal VOC profiles and to assess under which conditions an optimal diagnostic accuracy in the discrimination between pediatric inflammatory bowel disease (IBD) and controls could be obtained. Methods Fecal samples from de novo treatment-naïve pediatric IBD patients and healthy controls (HC) were used to assess effects of sampling conditions compared to the standard operating procedure (reference standard), defined as 500mg of sample mass, diluted with 10mL tap water, using field asymmetric ion mobility spectrometry (FAIMS). Results A total of 17 IBD (15CD and 2 UC) and 25 HC were included. IBD and HC could be discriminated with high accuracy (accuracy=0.93, AUC=0.99, p<0.0001). Smaller fecal sample mass resulted in a decreased diagnostic accuracy (300mg accuracy=0.77; AUC=0.69, p=0.02; 100mg accuracy=0.70, AUC=0.74, p=0.003). A loss of diagnostic accuracy was seen towards increased numbers of thaw-freeze cycles (one cycle: accuracy=0.61, AUC=0.80, p=0.0004, two cycles: accuracy=0.64, AUC=0.56, p=0.753, three cycles: accuracy=0.57, AUC=0.50, p=0.5101) and when samples were kept at room temperature for 180 minutes prior to analysis (accuracy=0.60, AUC=0.51, p=0.46). Diagnostic accuracy of VOC profiles was not significantly influenced by storage duration differences of 20 months. Conclusion Application of 500mg sample mass analyzed after one thaw-freeze cycle, showed best discriminative accuracy for differentiation of IBD and HC. VOC profiles and diagnostic accuracy were significantly affected by sampling conditions, underlining the need for implementation of standardized protocols in fecal VOC analysis

Safety and efficacy of the immunosuppressive agent 6-tioguanine in murine model of acute and chronic colitis

<p>Abstract</p> <p>Background</p> <p>Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD.</p> <p>Methods</p> <p>We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry.</p> <p>Results</p> <p>6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice.</p> <p>Conclusions</p> <p>Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.</p

Differentiation between pediatric irritable bowel syndrome and inflammatory bowel disease based on fecal scent : proof of principle study

The diagnostic work-up of pediatric irritable bowel syndrome (IBS) and functional abdominal pain-not otherwise specified (FAP-NOS) commonly includes invasive tests for discrimination from inflammatory bowel disease (IBD). As this carries a high burden on patients, an ongoing need exists for development of noninvasive diagnostic biomarkers for IBS and FAP-NOS. Several studies have shown microbiota alterations in IBS/FAP, which are considered to be reflected by fecal volatile organic compounds (VOCs). The object of the study was to evaluate whether pediatric IBS/FAP-NOS could be discriminated from IBD and healthy controls by fecal VOC analysis. IBS/FAP-NOS was diagnosed according to the ROME IV criteria, and de novo IBD patients and healthy controls (HCs) aged 4 to 17 years were matched on age and sex. Fecal VOCs were analyzed by means of field asymmetric ion mobility spectrometry. Fecal VOCs of 15 IBS/FAP-NOS, 30 IBD (15 ulcerative colitis, 15 Crohn's disease) patients and 30 HCs were analyzed and compared. Differentiation between IBS/FAP-NOS and IBD was feasible with high accuracy (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.88-1; P < 0.00001). IBS/FAP-NOS profiles could not be differentiated from HCs (AUC, 0.59; 95% CI, 0.41-0.77; P = 0.167), whereas IBD profiles could with high accuracy (AUC, 0.96; 95% CI, 0.93-1; P < 0.00001). Pediatric IBS/FAP-NOS could be differentiated from IBD by fecal VOC analysis with high accuracy, but not from healthy controls. The latter finding limits the potential of fecal VOCs to serve as a diagnostic biomarker for IBS/FAP-NOS. However, VOC could possibly serve as additional noninvasive biomarker to differentiate IBS/FAP-NOS from IBD

Prediction of inflammatory bowel disease course based on fecal scent

The early prediction of changes in disease state allows timely treatment of patients with inflammatory bowel disease (IBD) to be performed, which improves disease outcome. The aim of this pilot study is to explore the potential of fecal volatile organic compound (VOC) profiles to predict disease course. In this prospective cohort, IBD patients were asked to collect two fecal samples and fill in a questionnaire at set intervals. Biochemically, active disease was defined by FCP ≥ 250 mg/g and remission was defined by FCP 100 mg/g. Clinically, active disease was defined by a Harvey Bradshaw Index (HBI) ≥ 5 for Crohn’s disease or by a Simple Clinical Colitis Activity Index (SCCAI) ≥ 3 for ulcerative colitis. Clinical remission was defined by an HBI 4 or SCCAI ≤ 2. Fecal VOC profiles were measured using gas chromatography-ion mobility spectrometry (GC-IMS). The fecal samples collected first were included for VOC analysis to predict disease state at the following collection. A total of 182 subsequently collected samples met the disease-state criteria. The fecal VOC profiles of samples displaying low FCP levels at the first measurements differed between patients preceding exacerbation versus those who remained in remission (AUC 0.75; p 0.01). Samples with FCP levels at the first time point displayed different VOC profiles in patients preceding remission compared with those whose disease remained active (AUC 0.86; p 0.01). Based on disease activity scores, there were no significant differences in any of the comparisons. Alterations in fecal VOC profiles preceding changes in FCP levels may be useful to detect disease-course alterations at an early stage. This could lead to earlier treatment, decreased numbers of complications, surgery and hospital admission

Simultaneous assessment of urinary and fecal volatile organic compound analysis in De Novo Pediatric IBD

Endoscopic evaluation is mandatory in establishing the diagnosis of pediatric inflammatory bowel disease (IBD), but unfortunately carries a high burden on patients. Volatile organic compounds (VOC) have been proposed as alternative, noninvasive diagnostic biomarkers for IBD. The current study aimed to assess and compare the potential of fecal and urinary VOC as diagnostic biomarkers for pediatric IBD in an intention-to-diagnose cohort. In this cohort study, patients aged 4–17 years, referred to the outpatient clinic of a tertiary referral center under suspicion of IBD, were eligible to participate. The diagnosis was established by endoscopic and histopathologic assessment, participants who did not meet the criteria of IBD were allocated to the control group. Participants were instructed to concurrently collect a fecal and urinary sample prior to bowel lavage. Samples were analyzed by means of gas chromatography–ion mobility spectrometry. In total, five ulcerative colitis patients, five Crohn’s disease patients, and ten age and gender matched controls were included. A significant difference was demonstrated for both fecal (p-value, area under the curve; 0.038, 0.73) and urinary (0.028, 0.78) VOC profiles between IBD and controls. Analysis of both fecal and urinary VOC behold equal potential as noninvasive biomarkers for pediatric IBD diagnosis

Decreasing Trends in Intestinal Resection and Re-Resection in Crohn's Disease A Nationwide Cohort Study:A Nationwide Cohort Study

OBJECTIVE: To assess time trends in intestinal resection and re-resection in Crohn's disease (CD) patients.SUMMARY OF BACKGROUND DATA: CD treatment has changed considerably over the past decades. The effect of these advances on the necessity of intestinal resections and the risk of re-resection is unclear.METHODS: In this nationwide cohort study, adult CD patients with ileocolonic, small bowel, colon, or rectum resections between 1991 and 2015 were included. Data were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). Time trends were analyzed with a broken stick model and Cox proportional hazard model with smoothing splines.RESULTS: The identified cohort comprised 8172 CD patients (3293/4879 male/female) in whom 10,315 intestinal resections were performed. The annual intestinal resection rate decreased nonlinearly from 22.7/100,000 CD patients (1991) to 2.5/100,000 (2015). A significantly steeper decrease was observed before 1999 (slope -1.56) as compared to subsequent years (slope -0.41) (P &lt; 0.001). Analogous trends were observed for ileocolonic, small bowel, and colon resections. Overall cumulative risk of re-resection was 10.9% at 5 years, 18.6% at 10 years, and 28.3% at 20 years after intestinal resection. The hazard for intestinal re-resection showed a nonlinear decreasing trend, with hazard ratio 0.39 (95% confidence interval 0.36-0.44) in 2000 and hazard ratio 0.25 (95% confidence interval 0.18-0.34) in 2015 as compared to 1991.CONCLUSION: Over the past 25 years, intestinal resection rate has decreased significantly for ileocolonic, small bowel, and colonic CD. In addition, current postoperative CD patients are at 75% lower risk of intestinal re-resection.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.</p

Vedolizumab for Inflammatory Bowel Disease:Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, A Nationwide Prospective Observational Cohort Study: ICC Registry - Vedolizumab

Contains fulltext : 220028.pdf (Publisher’s version ) (Open Access)Prospective data of vedolizumab treatment for patients with inflammatory bowel disease (IBD) beyond 1 year of treatment is scarce but needed for clinical decision making. We prospectively enrolled 310 patients with IBD (191 with Crohn's disease (CD) and 119 patients with ulcerative colitis (UC)) with a follow-up period of 104 weeks (interquartile range: 103-104) in a nationwide registry. The corticosteroid-free clinical remission rate (Harvey Bradshaw Index ≤ 4, Short Clinical Colitis Activity index ≤ 2) at weeks 52 and 104 were 28% and 19% for CD and 27% and 28% for UC, respectively. Fifty-nine percent maintained corticosteroid-free clinical remission between weeks 52 and 104. Vedolizumab with concomitant immunosuppression showed comparable effectiveness outcomes compared with vedolizumab monotherapy (week 104: 21% vs. 23%; P = 0.77), whereas 8 of 13 severe infections occurred in patients treated with concomitant immunosuppression. To conclude, the clinical effect was 19% for CD and 28% for UC after 2 years of follow-up regardless of concomitant immunosuppression

Risk Factors for Necrotizing Enterocolitis:A Prospective Multicenter Case-Control Study

BACKGROUND: The identification of independent clinical risk factors for necrotizing enterocolitis (NEC) may contribute to early selection of infants at risk, allowing for the development of targeted strategies aimed at the prevention of NEC. OBJECTIVE: The objective of this study was to identify independent risk factors contributing to the development of NEC in a large multicenter cohort. METHODS: This prospective cohort study was performed in 9 neonatal intensive care units. Infants born at a gestational age &lt;/=30 weeks were included. Demographic and clinical data were collected daily until day 28 postnatally. Factors predictive of the development of NEC were identified using univariate and multivariable analyses in a 1: 5 matched case-control cohort. RESULTS: In total, 843 infants (56 NEC cases) were included in this study. In the case-control cohort, univariate analysis identified sepsis prior to the onset of NEC and formula feeding to be associated with an increased risk of developing NEC, whereas the administration of antibiotics directly postpartum was inversely associated with NEC. In a multivariable logistic regression model, enteral feeding type and the number of days parenterally fed remained statistically significantly associated with NEC, whereas the administration of antibiotics directly after birth was associated with a lower risk of developing NEC. CONCLUSIONS: Formula feeding and prolonged (duration of) parenteral feeding were associated with an increased risk of NEC. Contrary to expectations, the initiation of treatment with antibiotics within 24 h after birth was inversely associated with NEC

Comorbidity, not patient age, is associated with impaired safety outcomes in vedolizumab- and ustekinumab-treated patients with inflammatory bowel disease-a prospective multicentre cohort study

Background: Few data are available on the effects of age and comorbidity on treatment outcomes of vedolizumab and ustekinumab in inflammatory bowel disease (IBD). Aims: To evaluate the association between age and comorbidity with safety and effectiveness outcomes of vedolizumab and ustekinumab in IBD. Methods: IBD patients initiating vedolizumab or ustekinumab in regular care were enrolled prospectively. Comorbidity prevalence was assessed using the Charlson Comorbidity Index (CCI). Association between age and CCI, both continuously assessed, with safety outcomes (any infection, hospitalisation, adverse events) during treatment, and effectiveness outcomes (clinical response and remission, corticosteroid-free remission, clinical remission combined with biochemical remission) after 52 weeks of treatment were evaluated. Multivariable logistic regression was used to adjust for confounders. Results: We included 203 vedolizumab- and 207 ustekinumab-treated IBD patients, mean age 42.2 (SD 16.0) and 41.6 (SD 14.4). Median treatment duration 54.0 (IQR 19.9-104.0) and 48.4 (IQR 24.4-55.1) weeks, median follow-up time 104.0 (IQR 103.1-104.0) and 52.0 weeks (IQR 49.3-100.4). On vedolizumab, CCI associated independently with any infection (OR 1.387, 95% CI 1.022-1.883, P = 0.036) and hospitalisation (OR 1.586, 95% CI 1.127-2.231, P = 0.008). On ustekinumab, CCI associated independently with hospitalisation (OR 1.621, 95% CI 1.034-2.541, P = 0.035). CCI was not associated with effectiveness, and age was not associated with any outcomes. Conclusions: Comorbidity - but not age - is associated with an increased risk of hospitalisations on either treatment, and with any infection on vedolizumab. This underlines the importance of comorbidity assessment and safety monitoring of IBD patients