Joana Roseira

Background: Iron deficiency is a common complication in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). However, standard iron markers are influenced by inflammation, complicating the diagnosis of true iron deficiency. Soluble transferrin receptor (sTfR) has been proposed as a more reliable, inflammation-independent marker of iron demand. This study aimed to assess the utility of sTfR in identifying iron deficiency without anemia (IDWA). Methods: The ID_IBD study was a multicenter, cross-sectional study. Iron status was classified using two approaches: the ECCO consensus definition, focusing on ferritin thresholds adjusted for inflammatory markers (C-reactive protein [CRP] and fecal calprotectin [FCAL]), and a stricter definition that adds transferrin saturation to the ECCO criteria. sTfR levels were compared across groups, and ROC curve analysis was used to identify optimal diagnostic cut-offs. Results: This analysis included 411 IBD patients (130 UC, 281 CD) and 178 controls. sTfR showed no correlation with CRP or FCAL. In UC, patients with IDWA had significantly higher sTfR levels (median 1.20 mg/L, IQR 1.02-1.42) compared to non-IDWA patients (median 1.05 mg/L, IQR 0.92-1.22; P = .013). Anemic UC patients also showed elevated sTfR levels (median 1.27 mg/L, IQR 1.14-1.59) compared to non-IDWA individuals (P < .001). In CD, sTfR did not significantly differ between IDWA and non-IDWA patients but was significantly higher in anemic patients (P = .003). Conclusions: sTfR appears to be an inflammation-independent marker of iron status in IBD. It showed greater potential for identifying IDWA in UC, while in CD it mainly reflected increased iron demand in anemia. Overall, sTfR may be useful as a complementary parameter to conventional iron markers. Further longitudinal studies are warranted to validate these findings and assess their clinical utility in IBD.

Oral gut-restricted therapies are being explored as a drug delivery strategy for inflammatory bowel disease (IBD), with the aim of achieving therapeutic effects within the intestinal mucosa while minimizing systemic exposure. Advances in molecular engineering and formulation technologies have enabled the development of orally administered agents intentionally designed to act locally within the gastrointestinal tract. This narrative review examines the biological, pharmacokinetic, and formulation principles underlying oral gut-restricted drug delivery in IBD, including an analysis of discontinued clinical development programs in ulcerative colitis and Crohn’s disease. Across locally acting antibodies, peptides, and small molecules, the analysis of these programs reveals recurring factors contributing to discontinuation. These include limited or absent clinical efficacy despite evidence of mucosal target engagement, challenges in achieving consistent and adequate intestinal exposure, constraints related to formulation or delivery technologies, and trial-related factors such as high placebo response rates. In several cases, manufacturing variability or strategic considerations also influenced development outcomes. The review of the current clinical trial pipeline suggests an evolution in development strategies relative to earlier programs, with increasing emphasis on the confirmation of local tissue drug levels, incorporation of mucosal pharmacodynamic readouts, and selection of endpoints aligned with localized mechanisms of action, including endoscopic and histologic outcomes. These elements appear critical for interpreting early phase efficacy signals for agents designed to have minimal systemic activity. Effective translation requires alignment between mechanism of action, intestinal drug delivery, tissue-level pharmacodynamics, and clinical trial design. Incorporating these lessons may improve the likelihood of success for future oral gut-restricted therapies in IBD.

Background and Aims: Hepcidin, the master regulator of systemic iron metabolism, is influenced by iron availability and inflammation. In inflammatory bowel disease (IBD), the interplay between iron deficiency and inflammatory activity remains incompletely understood. This study aimed to characterize hepcidin regulation in ulcerative colitis (UC) and Crohn’s disease (CD) in relation to iron status and inflammatory markers. Methods: In this cross-sectional multicenter study, 589 individuals were enrolled: 178 controls, and 130 UC and 281 CD patients. Patients were stratified by iron status and disease activity. Serum hepcidin, iron parameters, and inflammatory and clinical data were collected. Iron deficiency was defined using the ECCO criteria and a combined ferritin and transferrin saturation definition. Group comparisons, correlations, and multivariable linear regressions were performed. Results: Hepcidin correlated positively with C-reactive protein in CD (r = .125; P = .038) and negatively with fecal calprotectin in UC (r = −.311; P < .001). Using the ECCO definition, hepcidin levels in CD were higher than in controls within comparable iron-status categories (iron deficiency: 4.359 [IQR 2.094-8.906] ng/mL vs 2.300 [IQR 1.375-4.950] ng/mL, P = .019; normal iron stores: 10.402 [IQR 6.398-17.683] ng/mLvs 8.500 [IQR 5.300-12.150] ng/mL, P = .023). In UC, no significant differences from controls were observed, under the same criteria. In correlation analyses, ferritin showed the strongest association with hepcidin across groups (P < .001). Conclusions: Ferritin showed the strongest association with hepcidin across IBD, but regulation differed by disease. In UC, lower hepcidin levels were associated with intestinal inflammatory activity measured by fecal calprotectin, whereas in CD, higher hepcidin levels were associated with systemic inflammation despite iron deficiency. These findings highlight hepcidin’s potential as a biomarker linking iron status and inflammatory type in IBD.

Introduction: Melanoma is a malignant tumour arising from melanocytes, with cutaneous melanoma accounting for the vast majority of cases. Less frequently, melanomas originate from extracutaneous melanocytes, including those of the uveal tract. Although primary gastrointestinal melanomas exist, gastrointestinal involvement by melanoma more commonly represents metastatic disease. Recognition of gastrointestinal metastatic lesions and their variable endoscopic appearance has become increasingly relevant with the advances in systemic therapies. Case Presentation: We report a case of a 74-year-old man referred for investigation of iron-deficiency anaemia. Esophagogastroduodenoscopy revealed multiple flat, dark millimetric lesions in the distal oesophagus, stomach, and duodenum. Histopathological examination with immunohistochemistry revealed melanoma. Cross-sectional imaging and positron emission tomography demonstrated widespread metastatic disease involving the liver, lungs, brain, bone, and gallbladder, as well as a hypermetabolic intraocular lesion. Ophthalmological and dermatological evaluation was consistent with primary uveal melanoma, with no evidence of a cutaneous primary. The patient experienced rapid neurological deterioration due to brain metastases and died shortly after diagnosis. Conclusion: Gastrointestinal metastases of melanoma are rare, particularly in uveal melanoma, and are often clinically silent. Endoscopic findings are heterogeneous and may be detected during the investigation of nonspecific symptoms such as anaemia. This case highlights the importance of recognising and sampling atypical pigmented gastrointestinal lesions, as endoscopy may play a key role in the diagnosis of advanced melanoma and prompt multidisciplinary management.

Lay Summary: This editorial discusses the post-hoc analysis by Dubinsky et al. evaluating upadacitinib’s efficacy and safety by baseline corticosteroid use in Crohn’s disease, highlighting its corticosteroid-sparing potential, the need for standardized tapering in trials, and the implications for achieving durable corticosteroid-free remission.

Background: Endoscopy‐related musculoskeletal injuries (ERIs) are a major occupational hazard, impacting career longevity and personal well‐being.Objective: This systematic review and meta‐analysis aimed to update and expand on previous findings by assessing prevalence, risk factors and management of ERIs among endoscopists.Methods: Following PRISMA guidelines, we systematically searched MEDLINE, Web of Science and Scopus for relevant studies published since the last comprehensive review. A manual search of the references of relevant manuscripts was also performed. Outcomes of interest included the prevalence of ERIs, common pain syndromes, risk factors, and preventive or treatment strategies. Studies' quality was assessed using the National Institutes of Health (NIH) Quality Assessment Tool.Results: Thirty studies were included, incorporating data from 7646 gastrointestinal endoscopists. The pooled career‐long prevalence of overall ERI was 62.5% (CI 52.6–71.8, I² = 98%), including pain (67.5%; CI 46.4%–85.6%; I² = 98%) and numbness (12.4%; 95% CI 6.6%–19.7%; I² = 98%) syndromes. Among pain syndromes, the most affected areas were the hand (28.2%; CI 19.2%–38.2%; I² = 99%), lower back (27.3%; CI 20.1%–35.2%; I² = 97%), thumb (27.1%; CI 18.9%–37.7%; I² = 99%) and neck (25.7%; CI 19.3%–32.7%; I² = 98%). Higher procedural volume, years in practice and female gender were consistently reported as risk factors for ERIs.Concerning therapy, 41.8% of endoscopists used medications (CI 31.2%–52.8%; I² = 94%), while 28.2% engaged in physical therapy (CI 18.2%–39.5%; I² = 96%). Sick leave was reported by 13.8% of endoscopists (CI 7.9%–20.9%; I² = 94%). Practice modifications to manage ERIs included adjusting monitor (45.5%, CI 22.2%–69.9%; I² = 96%) and table (32.4%, CI 14.5%–53.5%; I² = 97%) height, but also reducing the number of cases per endoscopy session (14.6%; CI 10.4%–19.4%; I² = 72%).Conclusion: ERIs are highly prevalent among international gastrointestinal endoscopists, and are linked to procedural volume, years in practice, and gender. Ergonomic training and workplace adaptations are essential to mitigate risks and support career sustainability.Trial Registration: PROSPERO Registration: CRD42024534349

Background and aims: Predicting the treatment outcomes of biological therapies is an unmet need in Crohn's Disease. In this study, we explored the potential of serum neutrophil‐related biomarkers to predict infliximab therapeutic results and disease progression in Crohn's Disease patients, over a 2‐year period, in a real‐world setting.Methods: The study included 100 asymptomatic Crohn's Disease patients in the IFX maintenance phase from the prospective, observational, multicenter DIRECT study. Patients were categorized according to a composite outcome reflecting progression that included surgery, hospitalizations, new fistulae, abscess or stricture, and drug treatment escalation. Serum neutrophil elastase, lipocalin‐2, lactoferrin, and resistin (non‐neutrophil control) were analyzed via multiplex magnetic bead assays at multiple touchpoints. Fecal calprotectin was assessed by ELISA.Results: Over up to 2 years of follow‐up, serum biomarkers did not differentiate between the composite outcome groups, whereas fecal calprotectin was significantly higher in patients with worse outcomes. During the infliximab maintenance phase, there was a significant, sustained reduction of neutrophil elastase (p < 0.001), lipocalin‐2 (p < 0.001), and lactoferrin (p < 0.001), but not of resistin, despite stable neutrophil levels. Correlations between NE and NGAL levels were strong (Pearson correlations 0.75–0.85); all other correlations were of small magnitude.Conclusion: Our real‐world data do not support using serum neutrophil elastase, lipocalin‐2, or lactoferrin concentrations as predictors of treatment outcomes or disease evolution in infliximab ‐treated Crohn's Disease patients. On the other hand, the sustained decrease in biomarkers over time suggests that neutrophil stabilization might be an additional infliximab mechanism of action.