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Background and Aims The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine 'shunting', with a 6-methylmercaptopurine [MMP] to 6-thioguanine [TGN] ratio of >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesised impact of thiopurine shunting, and identify risk minimisation strategies. Methods This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician. Results Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. MMP/TGN ratio increased from preconception to third trimester [ p  <0.01], with approximately 25% of participants shunting in pregnancy. Second trimester split dosing led to a decrease in the median MMP/TGN ratio from 18 (interquartile range [IQR] 6-57) to 3 [IQR 2-3.5] at delivery [ p  = 0.04]. The risk of ICP was increased in thiopurine-exposed pregnancies (6.7% [7/105] vs 0% [0/112], p  <0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (risk ratio [RR] 8.10, 95% confidence interval [CI] 1.88-34.85, p  = 0.005) and shunting in third trimester [6.20, 1.21-30.73, p  = 0.028] and at delivery [14.18, 1.62-123.9, p  = 0.016] were associated with an increased risk of ICP. Conclusions Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted. [ABSTRACT FROM AUTHOR]

A 72-year-old man with a history of diabetes was initially diagnosed with autoimmune hepatitis due to symptoms of fevers, night sweats, and weight loss. However, further investigation revealed that he was suffering from visceral leishmaniasis, a rare disease in Australia transmitted by infected sandflies. The patient responded well to treatment with intravenous liposomal amphotericin, highlighting the importance of considering visceral leishmaniasis as a differential diagnosis in individuals with travel history to endemic regions. The case underscores the need for thorough diagnostic evaluation and awareness of atypical presentations of diseases in diverse patient populations. [Extracted from the article]

Background and Aim: Cytomegalovirus (CMV) colitis is associated with negative outcomes in inflammatory bowel disease (IBD) and immunosuppressed cohorts and therefore requires timely recognition for appropriate management. We aimed to evaluate the diagnostic tools for CMV colitis and their associations with clinical outcomes. Methods: A retrospective cohort study of patients in a metropolitan health service with colonic samples analysed for CMV between 2012 and 2022, stratified into IBD and non‐IBD groups, was performed. The main outcome measures were the prevalence of positive and negative results for each CMV test, as well as need for colectomy, use of antiviral and hospital length of stay. Results: Five hundred eighty‐two biopsies from 418 patients were included; the median age was 36 years (interquartile range, 24–52 years) and 223 (53.3%) were men. Four hundred sixty‐one (79.2%) biopsies were from patients with IBD and 121 (20.8%) were from those without IBD. There were similar proportions of positive CMV histology (IBD 5.9% and non‐IBD 7.4%) and tissue CMV polymerase chain reaction (PCR) in the two groups (IBD 5.6% and non‐IBD 5.0%), but within each group, results were discordant. Positive CMV histology was significantly associated with need for colectomy in the IBD group, while positive tissue CMV PCR was not. Positive CMV histology, and tissue and serum CMV PCR were all significantly associated with antiviral use. Positive serum CMV PCR was significantly associated with colectomy. Conclusions: Histopathology remains the most predictive tool in assessing CMV colitis, while qualitative tissue CMV PCR was found to have limited utility. Quantitative serum CMV PCR may be useful but requires further evaluation. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is becoming more common in the Western world due to changes in diet-related microbial dysbiosis, genetics and lifestyle. Incidences of gut permeability can predate IBD and continued gut barrier disruptions increase the exposure of bacterial antigens to the immune system thereby perpetuating chronic inflammation. Currently, most of the approved IBD therapies target individual pro-inflammatory cytokines and pathways. However, they fail in approximately 50% of patients due to their inability to overcome the redundant pro inflammatory immune responses. There is increasing interest in the therapeutic potential of T regulatory cells (Tregs) in inflammatory conditions due to their widespread capability to dampen inflammation, promote tolerance of intestinal bacteria, facilitate healing of the mucosal barrier and ability to be engineered for more targeted therapy. Intestinal Treg populations are inherently shaped by dietary molecules and gut microbiota-derived metabolites. Thus, understanding how these molecules influence Treg-mediated preservation of the intestinal barrier will provide insights into immune tolerance-mediated mucosal homeostasis. This review comprehensively explores the interplay between diet, gut microbiota, and immune system in influencing the intestinal barrier function to attenuate the progression of colitis. [ABSTRACT FROM AUTHOR]

Background: Thiopurines are effective therapies for inflammatory bowel disease (IBD); however, treatment comes with safety concerns and adverse effects. Knowledge of the impact of pharmacists performing thiopurine monitoring is limited. Aims: To determine the impact of a pharmacist‐led monitoring service in patients with IBD commencing thiopurine therapy managed in the ambulatory care setting. Methods: Patients commencing thiopurine therapy for IBD pre‐ and post‐introduction of a pharmacist‐led monitoring intervention were assessed. Pre‐intervention patients received standard of care, while the post‐intervention cohort was managed by the pharmacist. Data were acquired via retrospective audit of hospital medical records. The primary end‐point was the proportion of patients with documented review for thiopurine adverse effects within the initial 3 weeks. Secondary end‐points included achievement of therapeutic drug levels, persistence with thiopurine therapy, IBD‐related episodes of care and number of outpatient medical reviews. Results: Pre‐ and post‐intervention cohorts comprised of 37 and 33 patients respectively. Pharmacist intervention increased the proportion of patients with documented monitoring within 3 weeks from 8.1% to 84.8% (P < 0.01). No difference in thiopurine dose optimisation was seen (27% vs 27.3%). Persistence with thiopurine therapy increased from 65.7% to 87.9% (P < 0.03) at 6 months. IBD‐related emergency department presentations were not significantly decreased (8.1% vs 3%; P = 0.62). No significant change was observed in hospital admissions (16.2% vs 12.1%; P = 0.74) or outpatient medical reviews. Conclusions: Pharmacist monitoring of thiopurine therapy initiation in IBD outpatients improves adverse effect monitoring and increases medication persistence. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Background and Aims Differential responsiveness to interleukin [IL]-2 between effector CD4+ T cells [Teff] and regulatory T cells [Treg] is a fundamental mechanism of immunoregulation. The single nucleotide polymorphism [SNP] rs61839660, located within IL2RA [CD25], has been associated with the development of Crohn's disease [CD]. We sought to identify the T cell immune phenotype of IBD patients who carry this SNP. Methods Teff and Treg were isolated from individuals homozygous [TT], heterozygous [CT], or wild-type [CC] for the minor allele at rs61839660, and used for phenotyping [flow cytometry, Cytometry Time Of Flight] functional assays or T cell receptor [TCR] sequencing. Phosphorylation of signal transducer and activator of transcription 5 [STAT5] was assessed in response to IL-2, IL-7, and in the presence of basiliximab, a monoclonal antibody directed against CD25. Teff pro-inflammatory cytokine expression levels were assessed by reverse transcription quantitative polymerase chain reaction after IL-2 and/or TCR stimulation. Results Presence of the minor T allele enhances CD25 expression, leading to increased STAT5 phosphorylation and pro-inflammatory cytokine transcript expression by Teff in response to IL-2 stimulation in vitro. Teff from TT individuals demonstrate a more activated gut homing phenotype. TCR sequencing analysis suggests that TT patients may have a reduced clonal capacity to mount an optimal regulatory T cell response. Conclusions rs61839660 regulates the responsiveness of T cells to IL-2 signalling by modulating CD25 expression. As low-dose IL-2 is being trialled as a selective Treg modulator in CD, these findings highlight the potential for adverse effects in patients with this genotype. [ABSTRACT FROM AUTHOR]

Background and aim Thymus-derived regulatory T cells (Tregs) mediate dominant peripheral tolerance and treat experimental colitis. Tregs can be expanded from patient blood and were safely used in recent phase 1 studies in graft versus host disease and type 1 diabetes. Treg cell therapy is also conceptually attractive for Crohn's disease (CD). However, barriers exist to this approach. The stability of Tregs expanded from Crohn's blood is unknown. The potential for adoptively transferred Tregs to express interleukin-17 and exacerbate Crohn's lesions is of concern. Mucosal T cells are resistant to Treg-mediated suppression in active CD. The capacity for expanded Tregs to home to gut and lymphoid tissue is unknown. Methods To define the optimum population for Treg cell therapy in CD, CD4+CD25+CD127loCD45RA+ and CD4+CD25+CD127loCD45RA- Treg subsets were isolated from patients' blood and expanded in vitro using a workflow that can be readily transferred to a good manufacturing practice background. Results Tregs can be expanded from the blood of patients with CD to potential target dose within 22-24 days. Expanded CD45RA+ Tregs have an epigenetically stable FOXP3 locus and do not convert to a Th17 phenotype in vitro, in contrast to CD45RA- Tregs. CD45RA+ Tregs highly express α4β7 integrin, CD62L and CC motif receptor 7 (CCR7). CD45RA+ Tregs also home to human small bowel in a C.B-17 severe combined immune deficiency (SCID) xenotransplant model. Importantly, in vitro expansion enhances the suppressive ability of CD45RA+ Tregs. These cells also suppress activation of lamina propria and mesenteric lymph node lymphocytes isolated from inflamed Crohn's mucosa. Conclusions CD4+CD25+CD127loCD45RA+ Tregs may be the most appropriate population from which to expand Tregs for autologous Treg therapy for CD, paving the way for future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Despite reassuring clinical safety data, thrombocytosis, anemia, lymphopenia, and liver function derangements have been observed in infants born to women with inflammatory bowel disease (IBD) treated with thiopurines and biologics. We aimed to define the prevalence, course, associations, and clinical impact of hematological and biochemical abnormalities in such infants., Methods: This multicenter prospective cohort study assessed clinical, hematologic, and biochemical outcomes of infants exposed to thiopurines or biologics in utero for management of maternal IBD. Liver transaminases, full blood examination, and infant thiopurine metabolites (where exposed) were taken at delivery and 6 weeks of age. Abnormal results were repeated until normalization. Infants were followed clinically by a pediatric gastroenterologist up to 2 years of age., Results: A total of 130 infants were included. Thrombocytosis and elevated alanine transaminase (ALT) were seen in over half of infants up to 6 months of age with no significant clinical impact. Elevated ALT was associated with increasing maternal C-reactive protein in second trimester, while thrombocytosis was associated with increasing maternal C-reactive protein and fecal calprotectin in third trimester. Preceding infection and vaccination were associated with an increased risk of elevated alkaline phosphatase at 3 months. In those exposed to thiopurines, increasing maternal 6-methylmercaptopurine at delivery was associated with increased ALT to 6 months., Conclusions: Infants born to women with IBD commonly developed thrombocytosis, elevated alkaline phosphatase, and elevated ALT. These findings were associated with exposure to maternal inflammation, elevated 6-methylmercaptopurine at delivery, and infant vaccinations and infections, and had minimal clinical consequence., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)