Infant Ustekinumab Clearance, Risk of Infection, and Development After Exposure During Pregnancy.

BACKGROUND: Evidence on ustekinumab safety in pregnancy is gradually expanding, but its clearance in the postnatal period is unknown. The aim of this study was to investigate ustekinumab concentrations in umbilical cord blood and rates of clearance after birth, as well as how these correlate with maternal drug concentrations, risk of infection, and developmental milestones during the first year of life. METHODS: Pregnant women with inflammatory bowel disease were prospectively recruited from 19 hospitals in Denmark and the Netherlands between 2018 and 2022. Infant infections leading to hospitalization/antibiotics and developmental milestones were assessed. Serum ustekinumab concentrations were measured at delivery and specific time points. Nonlinear regression analysis was applied to estimate clearance. RESULTS: In 78 live-born infants from 76 pregnancies, we observed a low risk of adverse pregnancy outcomes and normal developmental milestones. At birth, the median infant-mother ustekinumab ratio was 2.18 (95% confidence interval, 1.69-2.81). Mean time to infant clearance was 6.7 months (95% confidence interval, 6.1-7.3 months). One in 4 infants at 6 months had an extremely low median concentration of 0.015 µg/mL (range 0.005-0.12 µg/mL). No variation in median ustekinumab concentration was noted between infants with (2.8 [range 0.4-6.9] µg/mL) and without (3.1 [range 0.7-11.0] µg/mL) infections during the first year of life (P = .41). CONCLUSIONS: No adverse signals after intrauterine exposure to ustekinumab were observed with respect to pregnancy outcome, infections, or developmental milestones during the first year of life. Infant ustekinumab concentration was not associated with risk of infections. With the ustekinumab clearance profile, live attenuated vaccination from 6 months of age seems of low risk.

Vedolizumab as first-line biological therapy in elderly patients and those with contraindications for anti-TNF therapy: a real-world, nationwide cohort of patients with inflammatory bowel diseases.

BACKGROUND: Data from real-life populations about vedolizumab as first-line biological therapy for ulcerative colitis (UC) and Crohn's disease (CD) are emerging. OBJECTIVE: To investigate the efficacy and safety of vedolizumab in bio-naïve patients with UC and CD. METHODS: A Danish nationwide cohort study was conducted between November 2014 and November 2019. Primary outcomes were clinical remission, steroid-free clinical remission, and sustained clinical remission from weeks 14 through 52. RESULTS: The study included 56 patients (UC:31, CD:25) who initiated treatment with vedolizumab mainly because of contraindications to anti-TNFs, of whom 54.8 and 24.0%, respectively received systemic steroids at the initiation. Rates of clinical remission at weeks 6, 14, and 52 were 32.0, 48.0, and 40.0%, respectively, in UC, and 36.8, 36.8, and 47.4% in CD. Steroid-free clinical remission at week 52 was achieved among 36.0 and 47.4% of UC and CD patients, while sustained clinical remission was achieved in 32.0 and 36.8%. Lack of remission was associated with being female (68.8 vs. 11.1%, p = .01) in UC and non-structuring, non-penetrating behavior in CD (90.0 vs. 44.4%, p = .03); however, this was not confirmed in multivariate analysis. Discontinuation due to primary non-response occurred in 20.0 and 5.3% of UC and CD patients, respectively, while rates of secondary loss of response were 12.0 and 5.3% after 52 weeks of follow-up. Vedolizumab was well-tolerated as only one UC patient experienced a serious adverse event. CONCLUSION: Vedolizumab is effective in the achievement of short-term, long-term, and steroid-free clinical remission in bio-naïve UC and CD patients.

[Practical guide to the use of thiopurinesin patients with inflammatory bowel diseases].

Despite the increasing availability of biological treatment in recent years, thiopurines remain an important treatment option in patients with inflammatory bowel diseases (IBD) both as monotherapy and in combination therapy with biologicals. Pre-treatment screening of thiopurine-methyltransferase activity and monitoring of thiopurine metabolites during treatment are essential to optimize the effectiveness and safety of thiopurines. This review provides an evidence-based practical guide to prescribing and monitoring thiopurines in patients with IBD.

Outcomes and Long-Term Effects of COVID-19 in Patients with Inflammatory Bowel Diseases - A Danish Prospective Population-Based Cohort Study with Individual-Level Data.

BACKGROUND AND AIMS: The health consequences of coronavirus disease 2019 [COVID-19] among patients with ulcerative colitis [UC] and Crohn's disease [CD] remain largely unknown. We aimed to investigate the outcomes and long-term effects of COVID-19 in patients with UC or CD. METHODS: We conducted a prospective, population-based study covering all Danish patients with CD or UC and confirmed COVID-19 between January 28, 2020 and April 1, 2021, through medical records and questionnaires. RESULTS: All 319 patients with UC and 197 patients with CD who developed COVID-19 in Denmark were included in this study and compared with the Danish background population with COVID-19 [N = 230 087]. A significantly higher risk of COVID-19-related hospitalization was observed among patients with UC (N = 46 [14.4%], relative risk [RR] = 2.49 [95% confidence interval, CI, 1.91-3.26]) and CD (N = 24 [12.2%], RR = 2.11 [95% CI 1.45-3.07]) as compared with the background population (N = 13 306 [5.8%]). A similar pattern was observed for admission to intensive care (UC: N = 8 [2.51%], RR = 27.88 [95% CI 13.88-56.00]; CD: N = 3 [1.52%], RR = 16.92 [95% CI 5.46-52.46]). After a median of 5.1 months (interquartile range [IQR] 4.5-7.9), 58 [42.3%] and 39 [45.9%] patients with UC and CD, respectively, reported persisting symptoms which were independently associated with discontinuation of immunosuppressive therapies during COVID-19 (odds ratio [OR] = 1.50 [95% CI 1.07-10.22], p = 0.01) and severe COVID-19 (OR = 2.76 [95% CI 1.05-3.90], p = 0.04), but not with age or presence of comorbidities. CONCLUSION: In this population-based study of 516 patients with IBD and COVID-19, 13.6% needed hospitalization and 2.1% required intensive care. Furthermore, sequelae were frequent, affecting 43.7% of COVID-19-infected patients. These findings might have implications for planning the healthcare of patients in the post-COVID-19 era.

Prevalence and Outcomes of COVID-19 Among Patients With Inflammatory Bowel Disease-A Danish Prospective Population-based Cohort Study.

BACKGROUND AND AIMS: As no population-based study has investigated the susceptibility and disease course of COVID-19 among patients with inflammatory bowel diseases [IBD], we aimed to investigate this topic in a population-based setting. METHODS: Two cohorts were investigated. First, a nationwide cohort of all IBD patients diagnosed with COVID-19 was prospectively followed to investigate the disease courses of both diseases. Second, within a population-based cohort of 2.6 million Danish citizens, we identified all individuals tested for SARS-CoV-2 to determine the occurrence of COVID-19 among patients with and without IBD and other immune-mediated inflammatory diseases [IMIDs]. RESULTS: Between January 28, 2020 and June 2, 2020, a total of 76 IBD patients with COVID-19 were identified in the national cohort and prospectively followed for 35 days (interquartile range [IQR]: 25-51). A large proportion [n = 19: 25%] required a COVID-19-related hospitalisation for 7 days [IQR: 2-8.5] which was associated with being 65 years or older (odds ratio [OR] = 23].80, 95% confidence interval [CI] 6.32-89.63, p <0.01) and presence of any non-IMID comorbidity [OR = 8.12, 95% CI 2.55-25.87, p <0.01], but not use of immunomodulators [p = 0.52] or biologic therapies [p = 0.14]. In the population-based study, 8476 of 231 601 [3.7%] residents tested positive for SARS-CoV-2; however, the occurrence was significantly lower among patients with IBD [62 of the 2486 patients = 2.5%, p <0.01] and other IMIDs [531 of 16 492 patients = 3.2%, p <0.01] as compared with patients without IMIDs. CONCLUSIONS: Patients with IMIDs, including IBD, had a significantly lower susceptibility to COVID-19 than patients without IMIDs, and neither immunosuppressive therapies nor IBD activity were associated with the disease course of COVID-19.

Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study.

BACKGROUND: Little is known about the consequences of intrauterine exposure to, and the post-natal clearance of, vedolizumab. AIMS: To investigate the levels of vedolizumab in umbilical cord blood of newborns and rates of clearance after birth, as well as how these correlated with maternal drug levels, risk of infection and developmental milestones during the first year of life METHODS: Vedolizumab-treated pregnant women with inflammatory bowel disease were prospectively recruited from 12 hospitals in Denmark and Canada in 2016-2020. Demographics were collected from medical records. Infant developmental milestones were evaluated by the Ages and Stages Questionnaire (ASQ-3). Vedolizumab levels were measured at delivery and, in infants, every third month until clearance. Non-linear regression analysis was applied to estimate clearance. RESULTS: In 50 vedolizumab-exposed pregnancies, we observed 43 (86%) live births, seven (14%) miscarriages, no congenital malformations and low risk of adverse pregnancy outcomes. Median infant:mother vedolizumab ratio at birth was 0.44 (95% confidence interval [CI], 0.32-0.56). The mean time to vedolizumab clearance in infants was 3.8 months (95% CI, 3.1-4.4). No infant had detectable levels of vedolizumab at 6 months of age. Developmental milestones at 12 months were normal or above average. Neither vedolizumab exposure in the third trimester (RR 0.54, 95% CI, 0.28-1.03) nor combination therapy with thiopurines (RR 1.29, 95% CI, 0.60-2.77) seemed to increase the risk of infections in the offspring. CONCLUSIONS: Neonatal vedolizumab clearance following intrauterine exposure is rapid. Infant vedolizumab levels did not correlate with the risk of infections during the first year of life. Continuation of vedolizumab throughout pregnancy is safe.

Management of intestinal failure in Europe. A questionnaire based study on the incidence and management.

BACKGROUND: Intestinal failure is the outcome of a number of gastrointestinal diseases and characterized by significant reduction in functional gut mass. If not resolved patients often face long-term nutritional support. This study gathered information about how patients referred with intestinal failure are managed in specialised European centres. METHODS: A questionnaire was circulated in 7 European countries via representatives of the ESPEN-HAN working group to seek information about experience in treating patients with intestinal failure. We asked about clinical outcome, information about structure and organisation of the department, referral criteria, treatment procedures and guidelines. RESULTS: 17 centres in 6 European countries completed the questionnaire: UK, n = 6, France, n = 4, Spain, n = 3, Denmark, n = 2, Italy, n = 1, Poland, n = 1. The experience of the centres in treating patients was in the range 12-30 years. The total number of patients on HPN in all centres was 590. The number of patients referred to centres with intestinal failure during the period January to December 2000 was n = 882: UK, n = 375 (range 2-175), France, n = 308 (range 24-182), Italy and Spain, n = 43 (range 9-52), Denmark n = 51 (range 14-37), the centre in Poland included 53 patients. Comparing all centres the following distribution among patients (median % (range%)) with regard to the endpoints were reported: Oral nutrition 32% (23-50%), enteral/tube feeding 11% (4-23%), HPN 36% (15-57%), lost to follow up 10% (0-35%), dead 9% (5-18%). No patients had an intestinal transplant. CONCLUSION: The study provides information about how patients with intestinal failure are managed across Europe and the data indicates that treatment practice varies between countries.

Association Between the Clinical, Biochemical, and Endoscopic Activity of Inflammatory Bowel Diseases and Severity and Long-term Outcomes of Coronavirus Disease 2019-A Population-based Study.

This brief report investigated the impact of clinical, biochemical, and endoscopic activity of IBD on the severity and long-term outcomes of COVID-19 in a prospective population-based cohort. The study did not identify any association between IBD activity and COVID-19 outcomes.

Accuracy of body composition measurements by dual energy x-ray absorptiometry in underweight patients with chronic intestinal disease and in lean subjects.

BACKGROUND: To assess the accuracy of Dual-energy X-ray absorptiometry (DXA) in underweight patients with chronic gastrointestinal disease, we investigated the ability of DXA to detect variations in body composition induced by infusion of parenteral nutrition (PN). Furthermore, the influence of a low body weight per se on the accuracy of DXA was studied by placing packets of lard on lean healthy subjects. METHODS: The hydration study included 11 patients with short bowel syndrome on long-term home parenteral nutrition (9 women and 2 men), and (mean +/- SD) 49.5 +/- 17.1 yr., 19.3 +/- 3.1 kg/m2. The lard study, where packets of lard were placed either over the thighs or the trunk region, was performed in 8 healthy lean male volunteers, 26.4 +/- 7.4 yr., and 21.0 + 0.9 kg/m2. Body composition, including measures of the total mass (TM), soft tissue mass (STM), lean tissue mass (LTM), fat mass (FM), and total body mineral content (TBBMC), was assessed by DXA. The fat fraction of the lard packets (3.49 kg), measured in triplicate by chemical fat extraction, was 52.2%. RESULTS: Hydration study; The increase in scale weight (BW) of approximately 0.90 kg due to infusion of PN correlated significantly to the increase in TM (R-square = 0.72, SEE 0.36 kg, p < 0.01), and the increase in STM (R-square = 0.69, SEE 0.38 kg, p < 0.01), however not with the increase LTM (R-square = 0.30, SEE 1.06 kg, p = 0.08). Mean changes in TM (0.88 kg), STM (0.88 kg), and LTM (0.81 kg) were not significantly different from changes in BW (p > 0.05). Lard study; Regardless of position, measurements of FM and LTM of the added lard were not significantly different from expected values. However, the composition of the lard packets into FM and LTM was more accurately detected when the packets were placed over the thighs than over the trunk region. The accuracy of DXA in individual subjects, expressed as the SD of the difference between expected and measured values, was 1.03 kg and 1.06 kg for the detection of changes in LTM and FM, respectively, and 0.18 kg for the detection of changes in STM and TM. CONCLUSIONS: On a group level, DXA provided sufficient accuracy to detect small changes in body composition in underweight patients with chronic gastrointestinal disease. However, the accuracy errors were higher than reported in normal weight subjects. The accuracy was not influenced by a low body weight per se.

Effect of cyclical intravenous clodronate therapy on bone mineral density and markers of bone turnover in patients receiving home parenteral nutrition.

BACKGROUND: Patients receiving home parenteral nutrition (HPN) because of intestinal failure are at high risk of developing osteoporosis. OBJECTIVE: We studied the effect of the bisphosphonate clodronate on bone mineral density (BMD) and markers of bone turnover in HPN patients. DESIGN: A 12-mo, double-blind, randomized, placebo-controlled trial was conducted to study the effect of 1500 mg clodronate, given intravenously every 3 mo for 1 y, in 20 HPN patients with a bone mass T score of the hip or lumbar spine of less than -1. The main outcome measure was the difference in the mean percentage change in the BMD of the lumbar spine measured by dual-energy X-ray absorptiometry. Secondary outcome measures included changes in the BMD of the hip, forearm, and total body and biochemical markers of bone turnover, ie, serum osteocalcin, urinary pyridinoline, and urinary deoxypyridinoline. RESULTS: The mean (+/-SEM) BMD of the lumbar spine increased by 0.8 +/- 2.0% in the clodronate group and decreased by 1.6 +/- 2.0% in the placebo group (P = 0.43). At all secondary skeletal sites (ie, hip, total body, and distal forearm), we observed no changes or small increases in the BMD of the clodronate group and decreases in the BMD of the placebo group. In the clodronate group, biochemical markers of bone resorption decreased significantly (P < 0.05). CONCLUSIONS: Clodronate significantly inhibits bone resorption as assessed by changes in biochemical markers of bone turnover. Although the mean BMD increased in the clodronate group, cyclic clodronate therapy failed to increase spinal BMD significantly at 12 mo.

Body composition measured by dual-energy X-ray absorptiometry in patients who have undergone small-intestinal resection.

BACKGROUND: Patients who have undergone resection of the small intestine have lower body weight than do healthy persons. It remains unclear whether it is the body fat mass or the lean tissue mass that is reduced. OBJECTIVE: We compared body-composition values in patients who had undergone small-intestinal resection with reference values obtained in healthy volunteers, and we studied the relation between body-composition estimates and the net intestinal absorption of energy. DESIGN: In a cross-sectional study, we included 20 men and 24 women who had undergone small-intestinal resection and had malabsorption of energy > 2000 kJ/d. Diagnoses were Crohn disease (n = 37) and other conditions (n = 7). Body composition was estimated by dual-energy X-ray absorptiometry, and data were compared with those from a reference group of 173 healthy volunteers. Energy absorption was measured during 48-h balance studies by using bomb calorimetry, and individual values were expressed relative to the basal metabolic rate. RESULTS: Body weight and body mass index in patients were significantly (P < 0.05) lower than the reference values. Fat mass was 6.4 kg (30%) lower (95% CI: -8.8, -3.9 kg), but lean tissue mass was only slightly and insignificantly lower (1.5 kg, or 3.3%; 95% CI: -3.7, 0.60 kg). Weight, body mass index, and body-composition estimates by dual-energy X-ray absorptiometry did not correlate significantly with the net energy absorption relative to the basal metabolic rate, expressed as a percentage. CONCLUSIONS: Patients who had undergone small-intestinal resection had significantly lower body weights and body mass indexes than did healthy persons, and they had significant changes in body composition, mainly decreased body fat mass.

Assessment of the longitudinal changes in bone mineral density in patients receiving home parenteral nutrition.

BACKGROUND: Low bone mineral density (BMD) is commonly reported in patients receiving home parenteral nutrition (HPN), but it remains unclear whether or not an accelerated bone loss occurs during HPN therapy. We evaluated the spinal, hip, and forearm bone mass density longitudinally in a cohort of 75 patients receiving HPN. METHODS: A total of 943 regional dual-energy x-ray absorptiometry scans, 335 spinal, 318 hip, and 290 forearm, obtained between 1995 and 2003 in 75 patients receiving HPN, were used for the analysis of the annual changes in BMD. The average (SD) number of scans per patients was 4.4 (2.9), and follow-up time was 4.1 (1.9) years. Diagnoses were Crohn's disease (n = 35) and other conditions (non-Crohn's diseases; n = 40). Data were analyzed using a linear random coefficient model. RESULTS: There was a statistically significant overall decline over time in spinal, hip, and forearm BMD, corresponding roughly to a 1% annual loss (p < .005); however, the loss was not significantly larger than that of age and sex-matched healthy subjects. In Crohn's disease patients, model estimates of spinal and hip BMD on the initiation of HPN therapy were significantly reduced compared with normal, whereas values were not significantly reduced in non-Crohn's disease patients. CONCLUSIONS: With the current protocols for HPN treatment, the annual decline in BMD is moderate and not significantly larger than in age- and sex-matched healthy subjects. A considerable part of the metabolic bone disease in these patients is related to the underlying disease for which the HPN was indicated.