Category Archives: Gastroenterology

Comparing Vedolizumab in “Early” and “Late” Crohn’s Disease

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Lancet Gastroenterol Hepatol 2026; 11: 12-21. Vedolizumab in early and late Crohn’s disease (LOVE-CD): a phase 4 open-label cohort study

Methods: Eligible patients were adults aged 18–80 years with moderate to severe Crohn’s disease (Crohn’s Disease Activity Index [CDAI] 220–450, with ulcers at endoscopy). Patients were divided into two groups: those with early Crohn’s disease, n=86 (defined as a diagnosis less than 2 years ago and naive to advanced treatment [naive or only treated with corticosteroids or immunomodulators, or both]); and those with late Crohn’s disease, n=174 (defined as a diagnosis more than 2 years ago and previously treated with corticosteroids, immunomodulators, and anti-TNF agents). The primary endpoint was the proportion of patients with clinical and endoscopic remission (defined as CDAI ≤150 and SES-CD <4) at both week 26 and 52.

Key findings:

  • Clinical and endoscopic remission at both week 26 and 52 was achieved in 27 (31·4%) of 86 patients with early Crohn’s disease versus 15 (8·6%) of 174 patients with late Crohn’s disease (difference 22·8%, 95% CI 12·6–33·7)
  • Serious adverse events occurred in three (3·5%) of 86 patients with early Crohn’s disease versus 46 (26·4%) of 174 patients with late Crohn’s disease and included infections (one [1·2%] vs 13 [7·5%]), surgery (none vs eight [4·6%]), intestinal obstruction (none vs four [2·3%]), exacerbation of Crohn’s disease (one [1·2%] vs six [3·4%]), and malignancy (none vs three [1·7%])
Corticosteroidfree clinical remission at all timepoints

Discussion:

  • “After 52 weeks of open-label treatment, almost 60% of patients with early disease achieved clinical remission and more than 50% were in endoscopic remission. By contrast, deep remission rates at both weeks 26 and 52 were observed in less than 10% of patients with late Crohn’s disease (ie, those with longstanding disease and previous exposure to anti-TNF
    agents).”
  • “Despite the earlier stage at which vedolizumab was initiated, disease severity was comparable betweenthe early and late Crohn’s disease groups, from a clinical (median CDAI 255 vs 259), endoscopic (median SES-CD 9 vs 12), and biochemical perspective (median serum C-reactive protein 9 mg/L vs 8 mg/L).”
  • “A pivotal observation in LOVE-CD was that dose intensification after week 26 (ie, doubling the dose) in patients without an endoscopic response did not lead to higher endoscopic remission rates, despite significantly higher serum vedolizumab concentrations. This
    finding suggests that the dosing schedule that was originally designed and approved is optimal for most patients and saturates the target. Patients who do not respond most likely have other dominant immune pathways that are activated and remain unaffected by
    vedolizumab.”
  • “All three classes of biologics approved for the treatment of Crohn’s disease perform better when initiated early in the disease course.”

My take: For Crohn’s disease (CD), vedolizumab should be mainly used in those without prior biologic therapy. In addition, changes in vedolizumab dosing based on concentrations is much less helpful than it is with anti-TNF agents.

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How to Score the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Properly

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J Blackwell et al. Gastroenterol 2026; 170: 452-455: Open Access! A Normal UCEIS Is Zero: A Score Divided by a Common Language

“The index uses a Likert scale of vascular pattern, bleeding, erosions and ulcers, with a total score intended to reflect severity of disease. When the index was first published, the baseline score for each descriptor was 1, meaning that a normal vascular pattern, no bleeding, and no erosions or ulcers scored 3. However, when the index was subsequently validated, the values attributed to each descriptor were rebased to 0, to improve clinical utility…This means that a completely normal flexible sigmoidosopy scored 0 rather than 3, and the worst activity of UC ever seen by the investigators (compared with a visual analogue scale 0 to 100) was 8 rather than 11…

The UCEIS has since been shown to predict the need for escalation of medical treatment and has recently been incorporated into a validated prognostic clinical index to predict response to intravenous steroids among patients with acute severe UC.10,11 Accurate scoring is therefore essential, with direct implications for clinical decision making.”

My take: The UCEIS is more detailed than the Mayo score. However, I expect that before long artificial intelligence will be able to review images and give a more consistent interpretation of the severity of endoscopic findings than either of these scoring systems.

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Extent of Eosinophilic Esophagitis and Response to PPI Therapy

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DA Hartnett et al. Clin Gastroenterol Hepatol 2026; 24: 375-384. Open Access! Distribution of Esophageal Eosinophilia as a Predictor of Proton Pump Inhibitor Response in Eosinophilic Esophagitis

Methods: This was a retrospective cohort study of newly diagnosed adult patients with EoE — All patients received ≥8-week PPI trial and underwent repeat biopsies to assess response. There were including 66 with isolated distal and 200 with proximal/diffuse disease. 86% of patients received twice daily PPI therapy (73% in those with isolated distal disease and 87% in the diffuse/isolated proximal disease.

Key findings:

PPI response was higher among patients with isolated distal disease:

  • histologic remission [<15 eosinophils/hpf post-PPI]: 63.6% vs 44.5%; P = .01
  • deep remission [<6 eosinophils/hpf]: 54.5% vs 31.0%; P = .001
  • symptom improvement: 92.4% vs 81.0%; P = .03).

The discussion noted that there has been limited studies of EoE distribution and response to treatment. “Godat et al observed that the distribution of esophageal eosinophilia had no impact on clinicohistologic remission rates (defined as ≤2 on a scale of 0–10 for dysphagia/odynophagia in the last 7 days and a peak eosinophil count <5 eos/hpf) in patients treated with budesonide orodispersible tablets.19“

“The generally higher PPI response with isolated/predominant distal disease suggests that acid suppression and improved mucosal barrier function likely play a key role in how PPI may lead to EoE remission…prior studies have demonstrated no correlation between findings on ambulatory pH monitoring and PPI response in EoE.25 Therefore, the differential response to PPI based on eosinophil distribution phenotypes may be due to more than comorbid GERD alone.”

My take: While the pathophysiology of how PPIs work for EoE is unclear, it appears that the response to PPIs is better with in those with isolated distal EoE. The difference in response may have been even more pronounced if both groups had a similar percentage of receiving twice daily PPI treatment.

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How Long Should a pH Probe Last to Accurately Diagnose Gastroesophageal Reflux

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RI Rusu et al. Clin Gastroenterol Hepatol 2026; 24: 365-374. Open Access! The Optimal Duration of pH Monitoring: Testing the Validity of Lyon 2.0 Recommendations for Wireless pH Measurement

Background: “The Lyon 2.0 consensus recommends 96-hour wireless pH studies for gastroesophageal reflux disease (GERD) diagnosis…Ninety-six-hour monitoring is not always possible, either for technical reasons (eg, early detachment of the pH sensor) or for practical and financial reasons (48-hour studies are routine and cost-efficient in many centers).”

Methods: Data from 944 patients (16-85 years) with 4-day recordings (Bravo capsule) was reviewed. Patients were classified at 24, 48, and 72 hours against the 96-hour reference standard. Acid exposure time (AET) <4% was conclusively negative, and AET >6% was conclusively positive for GERD.

Key findings:

  • With longer duration, more patients were able to be diagnosed with GERD and fewer patients were in the indeterminate group. The proportion of patients with inconclusive results (AET 4%–6%) reduced from 113 of 944 at 24 hours to 40 of 113 at 96 hours (35% of subgroup; P = .02)
  • Only 3 of 60 patients with LA grade B esophagitis demonstrated physiologic reflux burden across all 96 hours of recording (which indicates that for significant reflux esophagitis, pH monitoring is not needed in most cases)
  • In the associated editorial (pg 306-308), the authors note that “the minimum duration for an effective study seems to be 3 days, because ~90% of conclusively positive studies identified over 4 days would be detected with 72 hours of recording. However, to achieve this, a 4-day study would need to be planned because of potential data loss, reported in almost a third of the cases in this and prior cohorts.”
  • “96-hour wireless monitoring is optimal for ruling out GERD when the pretest likelihood of reflux is low, especially when empiric PPI therapy is ineffective.”

My take: pH probe tests have many limitations. This study reinforces the need for longer studies in many patients when the findings would be equivocal with shorter duration studies.

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Oral Integrin Inhibitor for Moderate to Severe Ulcerative Colitis

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BE Sands et al. Clin Gastroenterol Hepatol 2026; 23: 525-534. Open Access! A Phase 2 Study of MORF-057, an Oral α4β7 Integrin Inhibitor in Moderately to Severely Active Ulcerative Colitis

Background: MORF-057 is an orally administered small-molecule drug that inhibits α4β7 integrin-mediated recruitment of α4β7-expressing lymphocytes to the gut. It has a similar target as vedolizumab, a monoclonal anti-integrin antibody used to treat ulcerative colitis (approved in 2014), but it requires parenteral administration.

Methods: This open-label, phase 2a, single-arm, multicenter trial (EMERALD-1) comprised a 6-week screening period, a 52-week active treatment period (including a 12-week induction period and 40-week maintenance period), and a 4-week safety follow-up period. Of the 35 participants enrolled in the main cohort, 18 participants received 100 mg of oral MORF-057 twice daily for the entire treatment period.

The primary efficacy endpoint was a change in the Robarts Histopathology
Index (RHI) score from baseline to week 12. “RHI was chosen as the primary efficacy assessment because it is an objective measure that can be assessed in a blinded fashion, which was critical given the open label study design. RHI also allows for a deeper, more quantitative probe than endoscopy.”

Key findings:

  • MORF-057 was well tolerated, and no treatment-emergent serious adverse events were
    observed
  • At week 12, participants (n= 35) exhibited a mean change from baseline in RHI
    score of ‒6.4 (standard deviation, 11.2). Additionally, 22.9% of participants (8/35) achieved
    RHI remission (RHI score ≤3)
  • In participants with evaluable data (n=18), the effects of MORF-057 on pharmacokinetics, pharmacodynamics, and clinical efficacy were achieved at week 12 and remained consistent to week 52
Symptomatic remission based on whether patient was advanced therapy (AT)-naive or AT-experienced

My take: This small open label study shows that an oral medication targeting α4β7 integrin has potential as an effective therapy for ulcerative colitis. If effective, then it would be important to understand how it compares to vedolizumab.

Related blog post: In Trials: An Oral IL-23 Antagonist Peptide

Afimkibart for Ulcerative Colitis (TUSCANY-2)

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S Danese et al. The Lancet Gastroenterology & Hepatology 2025; 10: 882 – 895. Anti-TL1A antibody, afimkibart, in moderately-to-severely active ulcerative colitis (TUSCANY-2): a multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b trial

Briefly noted:

Methods: “The multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b, TUSCANY-2 trial” enrolled 228 people who completed induction. All patients had moderate to severe ulcerative colitis who were treated with either subcutaneous afimkibart (a TNF-like ligand 1A (TL1A)) or placebo. There was a 12-week induction phase followed by a 40-week maintenance phase.

Key findings:

  • At week 14, the primary endpoint of clinical remission by total Mayo score was reported in 12 (26%) of 47 patients in the afimkibart 50 mg group, 14 (23%) of 60 patients in the afimkibart 150 mg group, and 21 (24%) of 88 patients in the in the afimkibart 450 mg group versus five (12%) of 43 patients in the placebo group
  • Incidences of treatment-emergent adverse events during induction were similar with placebo and afimkibart
  • The percentages of remission were higher for every afimkibart dose but this did not reach statistical significance compared to placebo

My take: Further testing is needed to determine whether afimkibart will have a significant place for treatment of inflammatory bowel disease.

Iguazu Falls

Case Report: Car-T for Refractory Ulcerative Colitis

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 F Muller et al. NEJM 2025;393:1239-1241. CD19 CAR T-Cell Therapy in Multidrug-Resistant Ulcerative Colitis

This case study involved the use of “autologous chimeric antigen receptor (CAR) T cells targeting CD19 in a 21-year-old woman with severe multidrug-resistant ulcerative colitis, who had declined colectomy. Previous treatments with prednisolone, mesalamine, infliximab, ustekinumab, ozanimod, filgotinib, vedolizumab, upadacitinib, and cyclosporine combined with mirikizumab had not induced clinical remission.”

“Clinical and biochemical remission occurred and were maintained over the 14-week follow-up period… without the use of concomitant therapy. Endoscopic, histologic, and ultrasonographic assessments showed signs of mucosal healing over time….These data suggest the possibility that CD19 CAR T-cell therapy can induce rapid drug-free remission in refractory ulcerative colitis, a disease that was previously thought to be largely B-cell–independent, given that rituximab treatment showed no efficacy..”

My take: This is only a single case report. However, it shows that modulation of the immune system could potentially cure ulcerative colitis. At the same time, long term adverse effects of CAR-T therapy will need to be monitored.

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PREdiCCt Trial: Lower Calprotectin Targets in Crohn’s Disease and Ulcerative Colitis

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Constantine-Cooke N, Gros B, Plevris N, et al Gut 2026. doi: 10.1136/gutjnl-2025-337846. (Open Access!) Associations between demographic, clinical and dietary factors and flares in inflammatory bowel disease: the PRognostic effect of Environmental factors in Crohn’s and Colitis (PREdiCCt) prospective cohort study

Methods: Multicentre, prospective cohort study conducted across 47 UK centres. Patients with Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBDU) in self-reported remission were prospectively followed up. 2629 participants (1370 CD; 1259 UC/IBDU) – followed up for a median of 4.1 years.

Key findings:

  • Baseline FC was strongly associated with patient-reported flares (FC ≥250 µg/g: adjusted HR (aHR) 2.22; FC 50–250 µg/g: aHR 1.52 (reference <50 µg/g)).
  • Baseline FC was also strongly associated with objective flares (FC ≥250 µg/g: aHR 3.25; FC 50–250 µg/g: aHR 1.98). Objective flares were “clinical flare plus C-reactive protein >5 mg/L and/or faecal calprotectin (FC) >250 µg/g with treatment escalation.” In ulcerative colitis, the probability of an objective flare within two years rose from 11% in those with baseline calprotectin below 50 µg/g to 34% in those above 250.
  • At 24 months, cumulative patient-reported and objective flare rates were 28% and 12% in CD, and 33% and 15% in UC/IBDU, respectively. Overall, patient-reported flares were more common (31%), while objective flares were less frequent (14%).
  • In UC, higher total meat intake was associated with increased risk of objective flares (highest versus lowest quartile: aHR 1.95, 95% CI 1.07 to 3.56). The absolute two-year risk rose from 12% in the lowest quartile of meat intake to 26% in the highest.
  • No consistent associations were observed for ultraprocessed foods, fiber or polyunsaturated fatty acids and flare.
Flares by faecal calprotectin (FC) stratified into FC < 50, 50 ≤ FC ≤ 250, and FC >250 μg/g. (A) Patient-reported flare in Crohn’s disease; (B) objective flare in Crohn’s disease; (C) patient-reported flare in ulcerative colitis/inflammatory bowel disease unclassified; (D) objective flare in ulcerative colitis/inflammatory bowel disease unclassified. aHR, adjusted hazard ratio.

My take: Lower calprotectin values, even in remission, are associated with better outcomes. Risk was meaningfully increased even in the 50–250 µg/g range, compared with levels below 50. Higher meat intake may increase the risk of flares for UC.

Summary of study information from Charlie Lees: The PREdiCCt Study: Can We Predict IBD Flares?

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Preliminary Work: A Vaccine to Prevent Colon Cancer and A Blood Test to Detect Colon Cancer

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D’Alise, A.M., Willis, J., Duzagac, F. et al. Nat Med (2026). https://doi.org/10.1038/s41591-025-04182-9. Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial. (Open Access!)

Background: “Lynch syndrome (LS) is a prevalent hereditary cancer syndrome affecting ~1 in 300 individuals, with an overall lifetime cancer risk as high as 80%. LS is caused by germline mutations in the DNA mismatch repair genes, leading to microsatellite instability (MSI) and accumulation of shared mutations. When these occur in coding regions, they generate frameshift peptides (FSPs). Nous-209 is a neoantigen-directed immunotherapy” against these FSPS. These are “the results from cohort 1 of a phase 1b/2 single-arm trial of Nous-209 for cancer interception in LS carriers (n = 45).”

Key findings:

  • Neoantigen-specific immune responses were observed after vaccination in 100% of evaluable participants (n = 37), with induction of potent T cell immunity
  • The immune response was durable and detectable at 1 year in 85% of participants
  • Both CD8+ and CD4+ T cells were induced, recognizing multiple FSPs
  • Peptide–human leukocyte antigen predictions allowed the identification of >100 immunogenic FSPs with demonstration of cytotoxic activity in vitro
Colorectal neoplasia burden observed at end-of-study colonoscopy inversely correlates with breadth of immune response. a, Number of participants who underwent screening colonoscopy at baseline and end of study (EoS; n = 43) who had no adenomas (adenomas absent), at least one adenoma (adenomas present) and advanced adenomas (advanced adenomas present) detected.
b, Number of adenomas per trial participant at baseline and end of study; comparison of baseline versus EoS was performed using a two-tailed Mann–Whitney U-test; NS, not significant. c, Number of reactive pools measured at 6 months (n = 34 evaluable subjects) between the participants with and without adenomas. Data are shown as the mean ± s.e.m.

My take (borrowed in part from authors): “Overall, this clinical trial provides important proof-of-concept data of the safety and the robustness of induced immunogenicity of
Nous-209 in LS carriers…and supporting its clinical development as a valuable intervention for cancer immune interception.” Vaccines have a long history in reducing cancer (for Hepatitis B, Cervical Cancer (due to HPV), Anal Cancer, Leukemia (by boosting immunity) and Others). Until recently, this has been by preventing viral infections that increase the risk of cancer. This is a new approach.

Related article: Blood test for colorectal cancer: A Mannucci et al. Gastroenterol 2026; 170: 330-343. An Exosome-Based Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer: The ENCODER Multicenter Study Methods: A panel of 6 cell-free and exosome-based circulating biomarkers were identified through small RNA sequencing from a biomarker discovery cohort (blood test). Key finding: “This study developed and independently tested a blood-based test with 97.3% sensitivity for screening-relevant CRC stages I–III and 61.5% for the noninvasive detection of high-grade dysplasia.”

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#5000: Simple Rule for Deciding When pH Impedance Testing Should Be Done While on Therapy

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Editor’s note: This is the 5000th post on this blog! The first post was on December 7th, 2011.

Iguazu Falls

CP Gyawali et al. Clin Gastroenterol Hepatol 2025; 23: 2459-2467. Open Access! pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but Not in Unproven GERD

Methods: Prospective 2-center study enrolled adult patients (n=79) with typical reflux symptoms with incomplete PPI response; they were studied both off PPI (wireless pH monitoring) and on PPI (pH-impedance monitoring)

Key findings:

  •  In 60 patients with proven GERD off-PPI, 56.7% had no ongoing GERD on PPI (despite reflux symptoms)
  • In unproven GERD, pH-impedance monitoring on acid suppressive therapy is unable to differentiate non-GERD symptoms from controlled GERD in the majority of patients, or identify patients who could benefit from discontinuation of acid suppression

Discussion points:

  • “Only a small proportion of PPI nonresponders have true GERD, and most have either no GERD or overlap between inconclusive GERD and a non-GERD process such as an esophageal disorder of gut-brain interaction (E-DGBI).10,11“
  • “On-therapy pH-impedance monitoring can identify refractory GERD in patients with previously proven GERD.”
  • “Definitive GERD evidence and persisting symptoms despite optimized PPI therapy is an indication for escalation of management.20… potassium competitive acid blockers provide better healing of advanced grade esophagitis21 as well as faster symptom response in nonerosive reflux disease,22,23 and could be an option”

My take:

  1. Simple rule: Only perform on-therapy pH-impedance monitoring in patients with proven GERD
  2. Many patients with GERD symptoms do not have GERD (see posts below)
  3. In patients with documented GERD, on therapy pH monitoring can be helpful in proving refractory GERD which may benefit from alternative treatments

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Nahuel Huapi Lake (near Bariloche, Argentina)