Publications

BACKGROUND: Sucrose malabsorption and small intestinal bacterial overgrowth (SIBO) present with symptoms that overlap with those of disorders of gut-brain interaction (DGBI). Recent studies suggest that sucrose malabsorption is more prevalent than previously thought. This study aims to determine the prevalence of sucrose malabsorption based on 13C-sucrose breath test (SBT) in patients undergoing SIBO breath testing and assess whether symptoms distinguish sucrose malabsorption from SIBO.

METHODS: Three hundred patients referred for SIBO breath testing between August 2020 and March 2022 were recruited and asked to complete the Rome IV Questionnaire for bowel disorders, Irritable Bowel Syndrome Severity Score (IBS-SSS), and the Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM). After in person SIBO breath testing, they were provided an at-home 13C-SBT.

RESULTS: One-hundred-and-forty patients returned the SBT. Of the SIBO negative patients, 22% (25/113) were SBT positive. No statistically significant differences were found in predominant symptoms or Rome IV diagnoses (IBS, functional constipation, or functional diarrhea), bloating frequency, IBS-SSS, or PAGI-SYM Scores between SBT positive and SBT negative patients. SBT positive only patients (n = 24) reported less abdominal pain (p = 0.04) than abnormal SIBO test only patients (n = 23).

CONCLUSION: Sucrose malabsorption was present in 22% of SIBO negative patients, indicating that it is a possible contributor to DGBI symptoms. Symptom profile alone did not predict sucrose malabsorption, nor distinguish between sucrose malabsorption and SIBO. This emphasizes the importance of considering carbohydrate malabsorption syndromes, such as sucrose malabsorption, when evaluating patients with symptoms consistent with functional gastrointestinal disorders (FGID).

BACKGROUND & AIMS: Safe and effective treatment for irritable bowel syndrome with diarrhea (IBS-D) is needed. ORP-101 is a novel partial μ receptor agonist and full κ receptor antagonist designed to act peripherally without central nervous system exposure. This study evaluated the efficacy and safety of ORP-101 in IBS-D.

METHODS: In this randomized, double-blind, adaptive design placebo-controlled trial, eligible participants were randomized to receive ORP-101 50 mg, 100 mg, or placebo once daily for 12 weeks. As part of the adaptive design, the 50 mg ORP-101 dose was discontinued after interim analysis. The primary endpoint was composite response status of improvement in abdominal pain (improvement of 30% from baseline) and stool consistency (average daily stool consistency <5 on the Bristol Stool Form Scale, or 30% improvement in abdominal pain if no bowel movement) for 50% of days over 12-week treatment period.

RESULTS: 320 participants with IBS-D were randomized to ORP-101 50 mg (n=65), 100 mg (n=127), or placebo (n=128). The proportion of primary endpoint responders for ORP-101 50 mg, 100 mg, and placebo participants was 16.9%, 28.3%, and 21.9%, respectively (p= 0.79 for the three groups and p= 0.12 for ORP-101 100 mg vs. placebo). Secondary and exploratory endpoints favored ORP-101 100 mg vs placebo across multiple endpoints. ORP-101 was well tolerated, including in those without gallbladders.

CONCLUSION: In this phase II trial, ORP-101 100 mg did not achieve a statistically significant difference vs. placebo for the primary endpoint; however, it showed higher response across multiple key endpoints. Future studies will study ORP-101 in other chronic pain conditions.

BACKGROUND: Intestinal tissue levels of infliximab (IFX) in patients with inflammatory bowel disease (IBD) treated with subcutaneous (SC) therapy have not been previously assessed.

OBJECTIVE: To compare serum and colonic tissue IFX concentrations in IBD patients receiving SC versus intravenous (IV) IFX.

METHODS: This observational cross-sectional study included IBD patients on stable SC or IV IFX maintenance therapy undergoing routine follow-up colonoscopy. Clinical activity required elevated CDAI or Mayo score plus ≥ 1 biomarker (fecal calprotectin > 250 μg/g or CRP > 5 mg/L). Blood samples and two colonic biopsies were collected for serum and tissue IFX measurements.

RESULTS: Thirty-five patients were included. Serum and tissue IFX concentrations were significantly higher in the SC versus IV group (22 μg/mL vs. 9 μg/mL, p < 0.001; 25 μg/g vs. 10 μg/g, p = 0.002). Serum and colonic tissue IFX levels were positively correlated in both cohorts (IV: r = 0.42; p = 0.014; SC: r = 0.43; p = 0.001). Colonic tissue IFX concentrations were higher in patients with mild-moderate endoscopic activity than in those without active disease (p < 0.001). Serum and colonic tissue IFX levels both predicted sustained clinical remission, with optimal thresholds of 14.5 μg/mL (p = 0.015) and 17 μg/g (p < 0.005), respectively. Colonic tissue IFX showed higher predictive accuracy (AUROC 0.82, p = 0.01) than serum (AUROC 0.76, p = 0.045).

CONCLUSIONS: SC IFX achieved significantly higher serum and colonic tissue concentrations than IV IFX. Colonic tissue IFX levels demonstrated superior clinical relevance and may support future tissue-based therapeutic drug monitoring strategies in IBD.

BACKGROUND & AIMS: Infliximab is an established rescue therapy for patients with steroid-refractory acute severe ulcerative colitis (ASUC), yet optimal dosing strategies minimizing colectomy risk remain unclear. We aimed to develop a model-informed risk stratification algorithm to identify patients at high risk of colectomy within 90 days of initiating infliximab to support personalized dosing.

METHODS: We conducted a multicenter, retrospective population pharmacokinetics (popPK) and exposure-response study using data from patients with ASUC. A parametric time-to-event model was developed to characterize the 90-day colectomy risk. Patient characteristics and pharmacokinetic projections were evaluated as predictors. These modelling results informed the development of an algorithm for risk stratification and personalized infliximab rescue dosing.

RESULTS: Seven medical centers contributed data from 72 patients with ASUC, yielding a total of 152 infliximab serum concentrations. Eleven patients underwent colectomy within 90 days. The strongest predictor of colectomy was the clearance-normalized exposure between weeks 2 and 4 (area under the concentration-time curve, AUCw2-4 to Bayesian-forecasted infliximab clearance, CL), with an area under the receiver operating characteristic curve of 0.79 (95% confidence interval [CI], 0.52-1.00). The AUCw2-4/CL ratio was calculated by individualizing the popPK model using the patient's body weight, baseline C-reactive protein, and infliximab concentrations. Patients with a log-transformed AUCw2-4/CL ratio < 5.79 were classified as high risk for colectomy (sensitivity 83%, specificity 85%). Overall classification accuracy was 85% (95% CI, 74-92).

CONCLUSIONS: We developed a model-based dose-exposure-response framework to predict colectomy risk in ASUC. We integrated the algorithm into an interactive tool to enable individualized infliximab rescue therapy.

OBJECTIVES: There are limited data regarding adalimumab (ADM) clearance in inflammatory bowel disease (IBD). The aim of this study was to identify factors associated with ADM clearance and to assess its association with mucosal healing.

METHODS: This single-center, retrospective study included consecutive patients with IBD who received maintenance ADM therapy and underwent therapeutic drug monitoring (TDM) between January 2018 and May 2023. Drug clearance was determined using a nonlinear mixed-effect model with Bayesian priors. Mucosal healing was defined as an endoscopic Mayo score 1 or less; for ulcerative colitis, no ulcerations for patients with Crohn's disease, or a Rutgeerts score of i1 or less for patients with an ileocolonic resection for Crohn's disease and was evaluated within 3 months from TDM.

RESULTS: The study population consisted of 263 patients with IBD (74% Crohn's disease) who underwent a total of 515 TDM tests (388 proactive). Multivariable linear regression analysis identified that proactive TDM was associated with lower ADM clearance [beta coefficients (β): -0.173, 95% confidence interval (CI): -0.180 to -0.088, P < 0.001], while BMI (β: 0.125, 95% CI: 0.005-0.013, P < 0.001), prior biologic exposure (β: 0.087, 95% CI: 0.022-0.112, P = 0.004), and antibodies to ADM (β: 0.676, 95% CI: 0.628-0.750, P < 0.001) were associated with higher ADM clearance. Receiver operating characteristic analysis identified an ADM clearance threshold of 0.301 L/day (area under the receiver operating characteristic curve: 0.731; 95% CI: 0.654-0.808; P < 0.001; sensitivity: 61%; specificity: 78%) distinguishing patients with or without mucosal healing.

CONCLUSION: This study demonstrated that lower ADM clearance is associated with proactive TDM and mucosal healing in patients with IBD.

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.