Publications

INTRODUCTION: Cumulative evidence suggests that proactive therapeutic drug monitoring (TDM) of anti-tumor necrosis factor (anti-TNF) therapy is associated with favorable outcomes in inflammatory bowel disease (IBD). However, there is limited information regarding the role of proactive TDM for de-escalating anti-TNF therapy in IBD.

AREAS COVERED: This narrative review will provide an overview of the role of proactive TDM for anti-TNF therapy de-escalation in IBD. A literature search was performed using PubMed between 2005 and June 2025.

EXPERT OPINION: Cumulative evidence suggests that proactive TDM plays a key role in guiding anti-TNF therapy de-escalation, as in patients with supra-therapeutic drug concentrations and discontinuation of the IMM in case of combination therapy with infliximab, as in patients with high drug concentrations prior to IMM withdrawal. Moreover, preliminary data suggest that proactive TDM may also help guiding anti-TNF therapy withdrawal, as in patients with sustained remission and undetectable or low drug concentrations at the time of drug discontinuation. Finally, proactive TDM is also important for surveillance of patients after treatment de-escalation to prevent low drug concentrations and immunogenicity. However, there are still some knowledge gaps including the ideal drug concentration before treatment de-escalation and if drug clearance rather than concentration can better guide anti-TNF therapy de-escalation.

Background/Objectives: There is limited data regarding the association of anti-drug antibody (ADA) levels with the efficacy of anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). We aimed to investigate the association between antibody to adalimumab (ATA) and antibody to infliximab (ATI) levels and treatment failure in IBD. Methods: This single-center, retrospective cohort study included consecutive IBD patients with ADA evaluated with a drug-tolerant assay between September 2012 and February 2023. A time-to-event analysis was performed for treatment failure, defined as the need for drug discontinuation due to primary non-response, loss of response, a serious adverse event, or an IBD-related surgery. Patients were followed from first positive ADA until treatment failure or the end of the follow-up (May 2024). Results: The study population consisted of 134 patients with IBD [n = 58 (43%) on adalimumab; n = 86, (64%) with Crohn's disease]. Multiple COX regression analysis identified higher ADA levels to be associated with treatment failure (HR: 1.034, 95%CI: 1.024-1.045, p < 0.001). A ROC analysis identified an ATA and ATI level threshold of 5.2 U/mL (AUC: 0.705; 95%CI: 0.569-0.841; p = 0.003; sensitivity: 64%; specificity: 82%) and 8.8 U/mL (AUC: 0.809; 95%CI: 0.713-0.906; p < 0.001; sensitivity: 69%; specificity: 93%), respectively, to distinguish patients with or without treatment failure. Conclusions: In this large retrospective cohort study, higher levels of ADA were associated with treatment failure to anti-TNF therapy in IBD. Moreover, we identified ATA and ATI level thresholds of 5.2 U/mL and 8.8 U/mL, respectively, to be associated with treatment failure.

BACKGROUND: EUS and MRCP are considered equivalent for pancreatic cancer screening. ASGE guidelines suggest that the choice between these modalities should be based upon patient preferences, however, there is limited data to help guide clinicians.

METHODS: All consecutive patients undergoing pancreatic cancer screening who had undergone both EUS and MRCP between 2021 and 2024 were identified. We also selected a comparison cohort of patients undergoing pancreatic cyst surveillance. A survey to elicit patient preferences and experience regarding physical discomfort, anxiety, dread, convenience, reassurance and cancer worry was administered to both groups.

RESULTS: Of 150 pancreatic cancer screening patients approached, 74 % agreed to participate. We compared mean response scores between EUS and MRCP and found patients favored EUS: less claustrophobia(p = 0.001), less dread(p = 0.02), more reassurance(p = 0.01), and more likely to recommend to family(p = 0.059). While 41.4 % reported no overall preference, 33.3 % preferred EUS and 25.2 % MRCP. Of 70/150(47 %) pancreatic cyst surveillance patients who responded, no difference in anxiety, dread or reassurance was noted between EUS and MRCP, but patients reported more claustrophobia with MRCP(p = 0.001). However, patients were more likely to recommend MRCP to family(p = 0.055). While 36.8 % reported no overall preference, 44.1 % preferred MRCP and 19.1 % EUS. Higher levels of cancer worry were reported by screening than cyst surveillance patients, but both groups reported that this rarely interfered with daily activities.

CONCLUSIONS: Almost 60 % of patients prefer one screening modality over the other, with a trend towards screening patients favoring EUS and cyst surveillance patients MRCP. These findings support a patient-centered individualized approach to pancreatic cancer screening.

BACKGROUND & AIMS: Regulatory T cell (Treg) dysfunction is a hallmark of autoimmune hepatitis (AIH), a serious hepatopathy often progressing to end-stage liver disease despite immunosuppression. Treg impairment in AIH has been linked to defective signaling through the aryl hydrocarbon receptor (AhR), a modulator of adaptive immunity. Herein, we investigated whether increased estrogen receptor alpha (ERα), an AhR non-canonical binding partner, impacts Treg immunity and contributes to the sex bias observed in AIH.

METHODS: Tregs were isolated from the peripheral blood of pre-menopausal, post-menopausal and male patients with AIH, as well as controls. Their function, stability, transcriptome and response to AhR were assessed in the absence or presence of methylpiperidinopyrazole (MPP), an ERα-selective antagonist. Therapeutic effects of MPP were tested in a model of Concanavalin-A-induced liver injury in humanized mice.

RESULTS: ERα was upregulated in Tregs from pre-menopausal females with AIH (1.1 ± 0.3) compared with healthy pre-menopausal females (0.4 ± 0.1; p = 0.038), and in pre-menopausal compared with post-menopausal females with AIH (0.3 ± 0.1; p = 0.04). In pre-menopausal females with AIH, MPP enhanced Treg suppressive capacity (2.5-fold increase; p = 0.001), restored response to AhR activation (2-fold increase; p = 0.03), and reduced functional plasticity, evidenced by decreased IL-17A and RORC expression under pro-inflammatory conditions. MPP also ameliorated Concanavalin-A-induced hepatitis in NOD/scid/gamma mice reconstituted with human CD4+ ERα+ cells, as shown by reduced ALT levels (101 ± 24 vs. 25 ± 8; p = 0.024), diminished hepatic inflammation on histology, and increased intrahepatic CD4+FOXP3+ and CD4+CD39+ T-cell frequencies. Bioinformatic and inhibition analyses identified hypoxia-inducible factor-1α as a key inducer of ERα in AIH Tregs.

CONCLUSIONS: ERα upregulation drives Treg dysfunction in pre-menopausal females with AIH and likely contributes to the sex bias in the disease. ERα blockade stabilizes Tregs and limits inflammation in vivo, representing a promising therapeutic strategy to enhance and sustain immune tolerance in AIH.

IMPACT AND IMPLICATIONS: Regulatory T cell (Treg) dysfunction plays a key role in the breakdown of immune tolerance in autoimmune hepatitis (AIH), a severe hepatopathy that often progresses to end-stage liver disease despite immunosuppression. Here we report that upregulation of estrogen receptor-alpha (ERα) alters Treg function and stability in pre-menopausal females with AIH, and that blockade of ERα using a specific antagonist stabilizes Tregs and curbs inflammation in humanized mice with liver injury. These findings implicate aberrant ERα signaling in the sex bias of AIH and support ERα inhibition as a potential therapeutic strategy to re-establish immune tolerance.

INTRODUCTION: Inflammatory bowel disease (IBD) commonly affects young women and frequently overlaps with peak reproductive years. Despite this overlap, there remains limited data on the safety and efficacy of IBD treatments during pregnancy and lactation, and many gastroenterology trainees report limited exposure to managing pregnant patients with IBD. Optimal management of IBD in pregnancy ideally starts before conception, with a goal of at least 3 months of steroid-free remission. The preconception period is critical for patient education and therapeutic optimization for patients with IBD. Optimized management during pregnancy and lactation is necessary to prevent adverse maternal and fetal outcomes.

AREAS COVERED: In this review, we discuss latest evidence on the safety and efficacy of available IBD therapies during conception, pregnancy, and lactation. Medications discussed include 5-aminosalicylates, biologic therapies, calcineurin inhibitors, Janus kinase inhibitors, corticosteroids, immunomodulators, and sphingosine 1-phosphate receptor modulators.

EXPERT OPINION: While most IBD therapies can be safely continued during pregnancy and lactation. Patient education during the preconception period is critical for maintenance of remission during pregnancy and postpartum. Evidence-based research and representation of pregnant patients with IBD in future studies are necessary to address existing knowledge gaps to optimize maternal and neonatal outcomes.

BACKGROUND: Rectal bleeding is a common concern among primary care patients and a risk marker for colorectal cancer. Yet, primary care patients who present with rectal bleeding frequently do not complete timely colonoscopies. We sought to determine if a phone-based, scheduling intervention for patients presenting with rectal bleeding in primary care would improve the rate of scheduling and completion of ordered colonoscopies.

METHODS: We conducted a nonrandomized pre-post intervention study at an urban, academic, hospital-based primary care clinic. We included patients with a colonoscopy order for rectal bleeding who had not scheduled a colonoscopy within 2 weeks of the order date. We created a baseline cohort from August to October 2022 and an intervention cohort from November 2022 to June 2023. The pilot intervention involved up-to-3 outreach phone calls by a primary care-based phone service representative to study participants.

RESULTS: Compared to the baseline cohort, patients in the intervention cohort had a significantly higher rate of colonoscopy completion at 365 days ( p = .04). Higher rates in loop closure were seen across demographic cohorts.

DISCUSSION: Proactive, primary care-based, outreach phone calls increased rates of completion of colonoscopies ordered for rectal bleeding.

GIM/FP/GP: [Formula: see text] Endocrinology: [Formula: see text] Gastroenterology: [Formula: see text].

Sterile inflammation, resulting from hepatocyte death and subsequent release of damage-associated molecular patterns (DAMPs), significantly contributes to liver disease pathogenesis. Neutrophils, as primary responders to liver injury, undergo NETosis-an immune response generating neutrophil extracellular traps (NETs), further amplifying inflammatory damage. Extracellular DNA (ecDNA), a major constituent of NETs and released cell fragments, potentiates inflammation through pattern recognition receptor activation. Mitochondrial DNA, released during hepatocyte damage, especially provokes robust immune responses due to its bacterial DNA-like structure and unmethylated CpG motifs. Concurrently, purinergic signaling-particularly via ATP release and its conversion into adenosine by ectonucleotidases CD39 and CD73-critically modulates immune homeostasis and inflammatory responses. Dysregulated expression of CD39/CD73, driven by altered aryl hydrocarbon receptor (AhR) signaling, exacerbates inflammatory states through disturbed regulatory T (Treg) and T helper (Th) 17 cell balance. Recent insights highlight that neutrophils and NETs not only drive innate inflammatory responses but significantly influence adaptive immunity by modulating T cell differentiation. NET components, such as cathelicidin and histones, actively promote Th17 differentiation while simultaneously impairing Treg functions, thereby sustaining inflammatory conditions. In addition, T cells reciprocally influence neutrophil activation and recruitment, predominantly through interleukin-17A (IL-17A) production. Detailed mechanisms underlying neutrophil-T cell cross talk in autoimmune hepatitis, acute liver failure, ischemia/reperfusion injury, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease underscore potential therapeutic targets. Future strategies targeting NET formation, ecDNA clearance via DNase therapy, purinergic receptor modulation, and restoring AhR signaling hold promise for effectively attenuating sterile inflammation and immune dysregulation in liver diseases.

PURPOSE: There are limited data regarding the role of proactive therapeutic drug monitoring (TDM) in patients with inflammatory bowel disease (IBD) treated with adalimumab (ADM). The aim of the study was to investigate the long-term outcome of patients with IBD undergoing proactive versus reactive TDM in terms of treatment failure.

METHODS: This single-center, retrospective, cohort study included consecutive patients with IBD who received maintenance ADM therapy and underwent TDM from January 2018 to March 2023. The proactive TDM group consisted of patients who had at least one proactive TDM during the follow-up time, while the reactive TDM group consisted of patients who underwent only reactive TDM. Patients were followed from first TDM until treatment failure or the end of the follow-up period (May 2024). Treatment failure was defined as either drug discontinuation due to loss of response/serious adverse event or an IBD-related surgery.

RESULTS: The study population consisted of 277 patients with IBD (n = 206, 74% with Crohn's disease), who underwent either proactive (n = 217) or reactive (n = 60) TDM. Patients were followed for a median of 39.5 (interquartile range 25.1-55.2) months. Multiple Cox regression analysis identified proactive TDM to be associated with less treatment failure [hazard ratio (HR 0.26, 95% confidence interval (CI) 0.16 to 0.42, p < 0.001], while stricturing CD (HR 2.1, 95% CI 1.3 to 3.5, p = 0.003) and antibodies to ADM at first TDM (HR 2.5, 95% CI 1.4 to 4.4, p = 0.002) were associated with treatment failure.

CONCLUSIONS: In this large cohort study, proactive when compared to reactive TDM was associated with less treatment failure in patients with IBD receiving ADM maintenance therapy.

Inflammatory bowel disease, encompassing ulcerative colitis and Crohn's disease, is characterised by chronic immune-mediated inflammation and variable treatment response. Loss of drug efficacy due to underexposure, pharmacokinetic variability, and immunogenicity remains a key challenge. Therapeutic drug monitoring, using drug levels and anti-drug antibody measurements, is an important strategy for optimising the treatment of inflammatory bowel disease. It helps ensure adequate dosing and can distinguish between pharmacokinetic and mechanistic drug failure. Most evidence pertains to infliximab and adalimumab. Multiple factors influence drug pharmacokinetics, affecting both target drug levels and the doses required to achieve them. These include inflammatory burden, bodyweight, age, disease phenotype, and route of administration, all of which are important considerations for individualising treatment in inflammatory bowel disease. This narrative review explores how special clinical situations-acute severe ulcerative colitis, perianal fistulising Crohn's disease, hypoalbuminaemia, extremes of body composition, pregnancy, paediatrics, and advanced age-alter drug pharmacokinetics and influence the utility and interpretation of therapeutic drug monitoring in inflammatory bowel disease.