Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero.

BACKGROUND & AIMS: Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. METHODS: This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. RESULTS: A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. CONCLUSIONS: Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.

Magnetic resonance enterography for predicting the clinical course of Crohn's disease strictures.

BACKGROUND AND AIMS: Strictures are the most common Crohn's disease complication, but their natural history is unknown. This study aimed to characterize inflammation, predict prognosis, and understand the impact of drug therapy using magnetic resonance enterography (MRE). METHODS: Patients with a stricture diagnosed on MRE over a 5-year period were reviewed for MRE disease extent and inflammation, clinical course, C-reactive protein, response to anti-TNF therapy, endoscopic dilatation, hospitalization, and surgery. RESULTS: 136 patients had 235 strictures (77, one and 59, ≥ 2 strictures). TREATMENT: 46% of patients underwent surgery after a median 6 months; median follow-up for those not requiring surgery was 41 months. Predictors of surgery: Hospitalization because of obstruction predicted subsequent surgery (OR 2.50; 95% CI 1.06-5.90) while anti-TNF therapy commenced at stricture diagnosis was associated with a reduced risk (OR 0.23; 95% CI 0.05-0.99). MRE characteristics associated with surgery were proximal bowel dilatation ≥ 30-mm diameter (OR 2.98; 95% CI 1.36-6.55), stricture bowel wall thickness ≥ 10-mm (OR 2.42; 95% CI 1.11-5.27), and stricture length > 5-cm (OR 2.56; 95% CI 1.21-5.43). 81% of patients with these three adverse MRE features required surgery versus 17% if none were present (P < 0.001). Accuracy for these three MRE variables predicting surgery was high (AUC 0.76). CONCLUSION: Magnetic resonance enterography findings in Crohn's disease strictures are highly predictive of the disease course and the need for future surgery. MRE may also identify who would benefit from treatment intensification. Anti-TNF therapy is associated with reduced risk of surgery and appears to alter the natural history of this complication.

Updates in the management of inflammatory bowel disease during pregnancy.

The best pregnancy outcomes for women with inflammatory bowel disease (IBD) occur when their disease is in remission at conception and remains in remission throughout pregnancy. Active IBD can lead to adverse pregnancy outcomes, including spontaneous abortion, pre-term birth and low birthweight. The majority of women with IBD who are taking maintenance medication will require medication throughout the pregnancy to prevent disease relapse. Most IBD medications are considered safe in pregnancy and breastfeeding, except for methotrexate. Pre-conception counselling should be arranged with the patient's IBD specialist and should include discussions regarding the importance of optimising disease control before and during pregnancy as well as the medication management plan for pregnancy. Patients with IBD should be reassured that their fertility is normal when the disease is quiescent, with the exception of women who have had pelvic surgery. IBD activity should be carefully monitored during pregnancy using non-invasive techniques, and disease flares during pregnancy should be treated promptly with escalation of therapy in consultation with the patient's IBD specialist. Mode of delivery should be determined by obstetric need; however, caesarean delivery is preferred for women with a history of ileal pouch anal anastomosis surgery or active perianal Crohn's disease.

Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population-based study.

OBJECTIVES: To determine the factors associated with survival of patients with hepatocellular carcinoma (HCC) and the effect of HCC surveillance on survival. DESIGN, SETTING AND PARTICIPANTS: Prospective population-based cohort study of patients newly diagnosed with HCC in seven tertiary hospitals in Melbourne, 1 July 2012 - 30 June 2013. MAIN OUTCOME MEASURES: Overall survival (maximum follow-up, 24 months); factors associated with HCC surveillance participation and survival. RESULTS: 272 people were diagnosed with incident HCC during the study period; the most common risk factors were hepatitis C virus infection (41%), alcohol-related liver disease (39%), and hepatitis B virus infection (22%). Only 40% of patients participated in HCC surveillance at the time of diagnosis; participation was significantly higher among patients with smaller median tumour size (participants, 2.8 cm; non-participants, 6.0 cm; P < 0.001) and earlier Barcelona Clinic Liver Cancer (BCLC) stage disease (A/B, 59%; C/D, 25%; P < 0.001). Participation was higher among patients with compensated cirrhosis or hepatitis C infections; it was lower among those with alcohol-related liver disease or decompensated liver disease. Median overall survival time was 20.8 months; mean survival time was 18.1 months (95% CI, 16.6-19.6 months). Participation in HCC surveillance was associated with significantly lower mortality (adjusted hazard ratio [aHR], 0.60; 95% CI, 0.38-0.93; P = 0.021), as were curative therapies (aHR, 0.33; 95% CI, 0.19-0.58). Conversely, higher Child-Pugh class, alpha-fetoprotein levels over 400 kU/L, and later BCLC disease stages were each associated with higher mortality. CONCLUSIONS: Survival for patients with HCC is poor, but may be improved by surveillance, associated with the identification of earlier stage tumours, enabling curative therapies to be initiated.

Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection.

BACKGROUND & AIMS: Little is known about in utero exposure to and postnatal clearance of anti-tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life. METHODS: We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected. RESULTS: The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval [CI], 0.94-1.49) and 1.97 for infliximab (95% CI, 1.50-2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9-5.0) and 7.3 months for infliximab (95% CI, 6.2-8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09-6.78; P = .02). CONCLUSIONS: In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.

Serologic antibodies in relation to outcome in postoperative Crohn's disease.

BACKGROUND AND AIM: Disease recurs frequently after Crohn's disease resection. The role of serological antimicrobial antibodies in predicting recurrence or as a marker of recurrence has not been well defined. METHODS: A total of 169 patients (523 samples) were prospectively studied, with testing peri-operatively, and 6, 12 and 18 months postoperatively. Colonoscopy was performed at 18 months postoperatively. Serologic antibody presence (perinuclear anti-neutrophil cytoplasmic antibody [pANCA], anti-Saccharomyces cerevisiae antibodies [ASCA] IgA/IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2, anti-Fla-X) and titer were tested. Quartile sum score (range 6-24), logistic regression analysis, and correlation with phenotype, smoking status, and endoscopic outcome were assessed. RESULTS: Patients with ≥ 2 previous resections were more likely to be anti-OmpC positive (94% vs 55%, ≥ 2 vs < 2, P = 0.001). Recurrence at 18 months was associated with anti-Fla-X positivity at baseline (49% vs 29%; positive vs negative, P = 0.033) and 12 months (52% vs 31%, P = 0.04). Patients positive (n = 28) for all four antibacterial antibodies (anti-CBir1, anti-OmpC, anti-A4-Fla2, and anti-Fla-X) at baseline were more likely to experience recurrence at 18 months than patients negative (n = 32) for all four antibodies (82% vs 18%, P = 0.034; odds ratio 6.4, 95% confidence interval 1.16-34.9). The baseline quartile sum score for all six antimicrobial antibodies was higher in patients with severe recurrence (Rutgeert's i3-i4) at 18 months, adjusted for clinical risk factors (odds ratio 1.16, 95% confidence interval 1.01-1.34, P = 0.039). Smoking affected antibody status. CONCLUSIONS: Anti-Fla-X and presence of all anti-bacterial antibodies identifies patients at higher risk of early postoperative Crohn's disease recurrence. Serologic screening pre-operatively may help identify patients at increased risk of recurrence.

Crohn's disease management after intestinal resection: a randomised trial.

BACKGROUND: Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS: In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS: Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION: Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING: AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.

Measurement of fecal calprotectin improves monitoring and detection of recurrence of Crohn's disease after surgery.

BACKGROUND & AIMS: Crohn's disease (CD) usually recurs after intestinal resection; postoperative endoscopic monitoring and tailored treatment can reduce the chance of recurrence. We investigated whether monitoring levels of fecal calprotectin (FC) can substitute for endoscopic analysis of the mucosa. METHODS: We analyzed data collected from 135 participants in a prospective, randomized, controlled trial, performed at 17 hospitals in Australia and 1 hospital in New Zealand, that assessed the ability of endoscopic evaluations and step-up treatment to prevent CD recurrence after surgery. Levels of FC, serum levels of C-reactive protein (CRP), and Crohn's disease activity index (CDAI) scores were measured before surgery and then at 6, 12, and 18 months after resection of all macroscopic Crohn's disease. Ileocolonoscopies were performed at 6 months after surgery in 90 patients and at 18 months after surgery in all patients. RESULTS: Levels of FC were measured in 319 samples from 135 patients. The median FC level decreased from 1347 µg/g before surgery to 166 µg/g at 6 months after surgery, but was higher in patients with disease recurrence (based on endoscopic analysis; Rutgeerts score, ≥i2) than in patients in remission (275 vs 72 µg/g, respectively; P < .001). Combined 6- and 18-month levels of FC correlated with the presence (r = 0.42; P < .001) and severity (r = 0.44; P < .001) of CD recurrence, but the CRP level and CDAI score did not. Levels of FC greater than 100 µg/g indicated endoscopic recurrence with 89% sensitivity and 58% specificity, and a negative predictive value (NPV) of 91%; this means that colonoscopy could have been avoided in 47% of patients. Six months after surgery, FC levels less than 51 µg/g in patients in endoscopic remission predicted maintenance of remission (NPV, 79%). In patients with endoscopic recurrence at 6 months who stepped-up treatment, FC levels decreased from 324 µg/g at 6 months to 180 µg/g at 12 months and 109 µg/g at 18 months. CONCLUSIONS: In this analysis of data from a prospective clinical trial, FC measurement has sufficient sensitivity and NPV values to monitor for CD recurrence after intestinal resection. Its predictive value might be used to identify patients most likely to relapse. After treatment for recurrence, the FC level can be used to monitor response to treatment. It predicts which patients will have disease recurrence with greater accuracy than CRP level or CDAI score.

Liver stiffness plus platelet count can be used to exclude high-risk oesophageal varices.

BACKGROUND/AIMS: Endoscopic screening for high-risk gastro-oesophageal varices (GOV) is recommended for compensated cirrhotic patients with transient elastography identifying increasing numbers of patients with cirrhosis without portal hypertension. Using liver stiffness measurement (LSM) ± platelet count, the aim was to develop a simple clinical rule to exclude the presence of high-risk GOV in patients with Child-Pugh A cirrhosis. METHODS: A retrospective analysis of 71 patients with Child-Pugh A cirrhosis diagnosed by transient elastography (LSM >13.6 kPa) who underwent screening gastroscopy was conducted. A predictive model using LSM ± platelet count was assessed to exclude the presence of high-risk GOV (diameter >5 mm and/or the presence of high-risk stigmata) and validated using a second cohort of 200 patients from two independent centres. RESULTS: High-risk GOV were present in 10 (15%) and 16 (8%) of the training and validation cohorts, respectively, which was associated with LSM and Pl count (P < 0.05). A combined model based on LSM and Pl count was more accurate for excluding the presence of high-risk GOV than either alone (training cohort AUROC: 0.87 [0.77-0.96] vs. 0.78 [0.65-0.92] for LSM and 0.71 [0.52-0.90] for platelets) with the combination of LSM ≤25 kPa and Pl ≥100 having a NPV of 100% in both the training and validation cohorts. A total of 107 (39%) patients meet this criterion. CONCLUSION: The combination of LSM ≤25 kPa and Pl ≥100 can be used in clinical practice to exclude the presence of high-risk GOV in patients with Child-Pugh A cirrhosis.

Evaluation and management of ileal pouch-anal anastamosis (IPAA) complications in pregnancy, and the impacts of an IPAA on fertility.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) remains the preferred surgical option for medically refractory ulcerative colitis. Management of individuals with an IPAA prior to and during pregnancy presents challenges that can have serious consequences. Infertility, mechanical obstructive and inflammatory pouch complications are frequently encountered in pregnant women with an IPAA. Mechanical obstructions occur due to a variety of underlying aetiologies, including stricturing disease, adhesions and pouch twists. Conservative management of such obstructions often results in resolution of symptoms without a need for endoscopic or surgical intervention, although endoscopic decompression may be attempted in isolation or as a bridge to definitive surgical intervention. Parenteral nutrition, and early delivery, may also be necessary. Faecal calprotectin and intestinal ultrasound, both of which are accurate in pregnancy, are useful in the setting of suspected inflammatory pouch complications, in some circumstances allowing for avoidance of pouchoscopy. Penicillin-based antimicrobials can be considered first line in pregnancy for the management of pouchitis and pre-pouch ileitis, and biologics can be safely instituted in the setting of refractory disease or suspected Crohn's disease-like inflammation of the pouch or pre-pouch ileum. Pragmatism, clear patient communication and multidisciplinary discussion are essential in approaching pregnant women with complications of an IPAA, particularly given the lack of definitive evidence to guide therapeutic decisions.

The Effect of In Utero Exposure to Maternal Inflammatory Bowel Disease and Immunomodulators on Infant Immune System Development and Function.

Autoimmune and inflammatory disorders, including inflammatory bowel disease (IBD), commonly affect women of childbearing age, warranting the use of immunomodulatory agents at a time where pregnancy may be desired. In utero exposure to pro-inflammatory mediators from maternal IBD, IBD-associated intestinal dysbiosis, and immunomodulatory drug use may impact neonatal immune system development during what is considered to be a critical period, with potential long-lasting impacts on susceptibility to disease. Both the innate and adaptative immune systems of the neonatal differ to that of the adult in terms of both cellular composition and sensitivity to antigenic and innate stimulation. The infant immune system gradually develops to more closely resemble that of the adult. Exposure to maternal inflammation in utero may aberrantly impact this period of infant immune system development, with maternal autoimmune and inflammatory disorders shown to affect the physiologic changes in serum cytokine abundance observed during pregnancy. The maternal and neonatal intestinal microbiome greatly influence infant mucosal and peripheral immune system development, and thereby impact the susceptibility to short-term inflammatory diseases, the adequacy of vaccine response, and later life risk of atopic and inflammatory disorders. Maternal disease, mode of delivery, method of feeding, time of weaning to include solid foods in the diet, and neonatal antibiotic exposure all influence the composition of the infant microbiome, and thereby infant immune system maturation. How exposure to specific immunosuppressive medications in utero alters infant immune cell phenotype and response to stimulation has been explored, but with existing studies limited by the time at which samples are performed, heterogenicity in methods, and small sample size. Furthermore, the impact of more recently introduced biologic agents have not been explored. Evolving knowledge in this field may influence therapeutic preferences for individuals with IBD planning to conceive, particularly if substantive differences in the risk of infant infection and childhood immune disease are identified.

Comparison of clinical characteristics and management of inflammatory bowel disease in Hong Kong versus Melbourne.

BACKGROUND AND AIM: Inflammatory bowel disease (IBD), common in Melbourne, was rare but is now increasing in incidence in Hong Kong (HK). To investigate whether these are the same diseases in the West and East, potential causes of changing incidence, and to plan resource needs, an appreciation of clinical characteristics in contrasting populations is essential. METHODS: Disease characteristics were collected from prospectively populated IBD databases in two specialist centers in Melbourne, Australia and HK. RESULTS: Of 795 patients (Crohn's disease [CD] : ulcerative colitis [UC] Melbourne 272:159 and HK 161:203), the age of diagnosis was higher, there were proportionally more male patients with CD but no UC sex difference, fewer patients were current or ex-smokers (CD 8% vs 50%; UC 17% vs 35%) and a family history of IBD was less common (2% vs 11%; P < 0.001) in HK compared to Melbourne. Stricturing and perianal CD were more common in HK (12% vs 6%; P < 0.001; and 29% vs 16%; P = 0.001, respectively). In HK for UC, more patients had extensive disease at diagnosis (42% vs 22%) but colectomy was less common (7% vs 20%; P < 0.001). In Melbourne there was greater steroid use at diagnosis and patients were more likely to receive an immunomodulator or anti-tumor necrosis factor agent. CONCLUSIONS: IBD in HK was diagnosed at an older age, and had more complicated disease behavior than in Melbourne. Medical therapy, however, was less intense in HK. These differences may relate to real differences in disease or delayed diagnosis due to late presentation and less disease recognition in HK.

Preconception, antenatal and postpartum management of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, commonly affects individuals of childbearing age. Pregnancy in women with IBD presents an anxiety-provoking prospect for practitioners and patients alike, with disease flares occurring in between 20% and 55% of patients antenatally. OBJECTIVE: The aim of this review is to provide an overview of antenatal IBD management principles and therapeutic goals, with a specific focus on the role of general practitioners. DISCUSSION: A collaborative approach is favoured in managing pregnancy and IBD. Preconception counselling should be prioritised, with emphasis on the importance of achieving three months of preconception corticosteroid-free remission. Close monitoring of disease activity in pregnancy is crucial, warranting the careful interpretation of both clinical and biochemical parameters. Reassurance regarding the safety of IBD medications in pregnancy and vaginal delivery can be provided in the majority of cases. Specialist support should be sought expeditiously in the setting of disease flare, particularly where symptoms and biochemical parameters are refractory to escalation of 5-aminosalicylates or topical therapies, corticosteroids or biologic agents are required, or an emergent IBD complication is suspected.

Ustekinumab levels in pregnant women with inflammatory bowel disease and infants exposed in utero.

BACKGROUND: Ustekinumab is increasingly used in pregnant women with inflammatory bowel disease (IBD). Existing safety data are reassuring, but the stability of ustekinumab levels in pregnancy, degree of transfer to the infant and time to infant clearance are unknown. METHODS: In this prospective observational study, ustekinumab-exposed women with IBD had trough levels measured in each trimester of pregnancy and at delivery. Infant ustekinumab levels were measured at delivery and ongoing until clearance was achieved. Trough ustekinumab level stability in individuals across pregnancy was compared by Skillings-Mack test. Spearman coefficients were used to correlate maternal and infant delivery levels, and median time to infant ustekinumab clearance was defined. RESULTS: 19 pregnant women receiving ustekinumab were included. There was no difference in ustekinumab levels across pregnancy in those with two or more representative trough levels (P = 0.83, n = 11). Infant delivery ustekinumab levels were higher than maternal levels, with a median infant:maternal ratio of 1.79 (IQR 1.26-3.1). There was a positive correlation between maternal and infant delivery ustekinumab levels (r = 0.75, P = 0.001) and an inverse correlation between the number of days from final antenatal dose and delivery infant ustekinumab level (r = -0.65, P = 0.006). Median time of infant ustekinumab clearance was 9 (range 6-19) weeks (n = 9). CONCLUSION: Ustekinumab drug levels appear stable in pregnancy, with a delivery infant:maternal ratio similar to that of anti-TNFs. Infant ustekinumab clearance was complete by 20 weeks post-partum, however, infants exposed in utero should avoid live vaccination before 12 months of age until further clearance data are obtained.

Timing of Live Attenuated Vaccination in Infants Exposed to Infliximab or Adalimumab in Utero: A Prospective Cohort Study in 107 Children.

BACKGROUND AND AIMS: For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy. METHODS: We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included. RESULTS: Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/. CONCLUSIONS: Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children.

Intensive drug therapy versus standard drug therapy for symptomatic intestinal Crohn's disease strictures (STRIDENT): an open-label, single-centre, randomised controlled trial.

BACKGROUND: Strictures are the most common structural complication of Crohn's disease. Surgery and endoscopic balloon dilation are the main treatments; drug therapy has been considered contraindicated. Given that most strictures have an inflammatory component, we aimed to find out whether strictures are responsive to drug treatment and whether intensive drug therapy is more effective than standard drug therapy. METHODS: This open-label, single-centre, randomised controlled trial was performed in one specialist inflammatory bowel disease centre in Australia. Patients aged 18 years or older with Crohn's disease were included. Eligible patients had a de novo or postoperative anastomotic intestinal stricture on MRI or ileocolonoscopy, symptoms consistent with chronic or subacute intestinal obstruction (postprandial abdominal pain in the presence of a confirmed stricture), and evidence of active intestinal inflammation. Patients were randomly assigned (2:1) to receive intensive high-dose adalimumab (160 mg adalimumab once per week for 4 weeks followed by 40 mg every 2 weeks, with escalation of dose at 4 months and 8 months if assessment of disease activity indicated active inflammation) plus thiopurine (initial dose of azathioprine 2·5 mg/kg or mercaptopurine 1·5 mg/kg, with dose adjustment based on thiopurine metabolite testing) or standard adalimumab monotherapy (160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks) using stratified fixed block randomisation. Stratification factors were stricture dilation at study baseline colonoscopy and current biologic drug use. The primary endpoint was improvement (decrease) in the 14-day obstructive symptom score at 12 months by one or more points compared with baseline. This trial is registered with ClinicalTrials.gov, NCT03220841, and is completed. FINDINGS: Between Sept 10, 2017, and Sept 6, 2019, 123 patients were screened and 77 randomly assigned to intensive adalimumab plus thiopurine treatment (n=52) or standard adalimumab treatment (n=25). At 12 months, improvement in obstructive symptom score was noted in 41 (79%) of 52 patients in the intensive treatment group and 16 (64%) of 25 in the standard treatment group (odds ratio [OR] 2·10 [95% CI 0·73-6·01]; p=0·17). Treatment failure occurred in five (10%) patients in the intensive treatment group versus seven (28%) in the standard treatment group (OR 0·27 [95% CI 0·08-0·97]; p=0·045); four patients in each group required stricture surgery (0·44 [0·10-1·92]; p=0·27). Crohn's Disease Activity Index was less than 150 in 36 (69%) patients in the intensive treatment group versus 15 (60%) in the standard treatment group (1·50 [0·56-4·05]; p=0·42). MRI at 12 months showed improvement using the stricture MaRIA score (≥25%) in 31 (61%) of 51 versus seven (28%) of 25 patients (3·99 [1·41-11·26]; p=0·0091). MRI complete stricture resolution was seen in ten (20%) versus four (16%) patients (1·28 [0·36 to 4·57]; p=0·70). Intestinal ultrasound at 12 months showed improvement (>25%) in bowel wall thickness in 22 (51%) of 43 versus seven (33%) of 21 patients (2·10 [0·71 to 6·21]; p=0·18). Faecal calprotectin normalised in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Normalisation of CRP was seen in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Eight (15%) patients in the intensive treatment group and four (16%) in the standard treatment group reported serious adverse events. No deaths occurred during the study. INTERPRETATION: Crohn's disease strictures are responsive to drug treatment. Most patients had improved symptoms and stricture morphology. Treat-to-target therapy intensification resulted in less treatment failure, a reduction in stricture-associated inflammation, and greater improvement in stricture morphology, although these differences were not significantly different from standard therapy. FUNDING: Australian National Health and Medical Research Council, Gastroenterological Society of Australia Ferring IBD Clinician Establishment Award, Australasian Gastro Intestinal Research Foundation, AbbVie, and the Spotlight Foundation.

G80S-linked ferroportin disease: classical ferroportin disease in an Asian family and reclassification of the mutant as iron transport defective.

BACKGROUND & AIMS: Hereditary iron overload associated with mutations in the ferroportin gene produces a dichotomy of phenotypes resulting from either increase or decrease in iron efflux capacity. In this study, we examined the molecular basis of iron overload in a family of Vietnamese origin, characterized the molecular and cellular defect, and correlated it with the clinical and pathological phenotype. METHODS: We analyzed the ferroportin gene by DNA sequencing. The molecular characterization was performed by immunofluorescence microscopy analysis of transfected cells. We analyzed ferritin levels, in cells expressing wild-type and mutant ferroportin, to define the nature of the molecular defect in iron transport. RESULTS: We identified a G to A nucleotide change at position 238 in the ferroportin gene leading to the G80S substitution. Cellular analysis of the mutant protein indicates that this amino acid change does not affect the localization of the protein but does affect its ability to transport iron. CONCLUSIONS: The G80S mutation results in a mutated ferroportin associated with iron overload and is predicted to be defective in iron export.

Addressing pregnancy-related concerns in women with inflammatory bowel disease: Insights from the patient's perspective.

BACKGROUND AND AIM: Therapeutic options for inflammatory bowel disease (IBD) have expanded, as has the use of IBD medications in women during the reproductive period. However, no qualitative data exist that examine the pregnancy-related concerns of women with IBD in the current era of widespread immunomodulator and biologic use. Hence, we aimed to explore in detail the impact of IBD on pregnancy from the patient's perspective. METHODS: This qualitative study used semistructured interviews to explore participants' experiences regarding IBD and pregnancy until no new themes emerged. Key themes were identified using thematic analysis. RESULTS: Fifteen women with IBD were interviewed. The majority of participants reported lingering concerns regarding their IBD medications, despite advice from their gastroenterologist that the drugs were considered safe in pregnancy. Participants more often reported medication-related fears, such as potential negative effects on their child's immune system, than concerns regarding the effect of the disease itself on their pregnancy outcomes. A common theme was a perceived lack of knowledge among non-IBD clinicians regarding IBD medications during pregnancy, which augmented pre-existing anxiety. CONCLUSIONS: This study is the first of its kind to provide an in-depth assessment of female patients' perspectives of IBD in relation to conception, pregnancy, and caring for offspring. In particular, this research characterizes the unique fears and persisting anxieties regarding IBD medications in pregnancy. The study has unearthed important insights into the specific concerns and support needs of women with IBD in order to facilitate nonjudgmental counseling designed around patient concerns and beliefs.