Introduction

Mesenchymal stem cells (MSCs) exhibit immunomodulatory properties through Treg induction^[1], yet their clinical efficacy varies across gastrointestinal immune disorders^[2]. This study integrates systematic evidence from 79 MSC-GVHD trials with preclinical IBD models to identify critical determinants of MSC therapeutic success.

Aims & Methods

• Clinical Analysis: Meta-analysis of 79 trials (4,710 patients) evaluating MSC efficacy in GVHD, stratified by MSC source (bone marrow vs. umbilical cord), dosing, and disease severity.
• Preclinical Validation: DSS-induced murine colitis treated with human umbilical cord-derived MSCs (hUCB-MSCs; 2×10^6 cells/IP, n=8/group). Outcomes included histopathology, Treg quantification (flow cytometry), and IDO/PGE2 mechanisms (qPCR/ELISA).

Results

1. GVHD Clinical Data:
   • Umbilical cord MSCs showed superior 1-year survival vs. bone marrow sources (76% vs. 47%, p=0.016) in steroid-refractory GVHD.
   • Pediatric patients exhibited 71.2% response rate with early MSC intervention (<48h post-diagnosis).
2. IBD Preclinical Findings:
   • hUCB-MSCs reduced colitis activity index by 67% (p=0.003) and increased colonic Foxp3+ Tregs 3.2-fold vs. controls (p=0.017).
   • IFN-γ priming enhanced hUCB-MSC immunosuppression via IDO↑ (4.8-fold, p=0.008) and PGE2↑ (2.1-fold, p=0.03).

Conclusion

MSCs demonstrate disease-specific therapeutic hierarchies: Umbilical cord-derived cells optimized for acute GVHD and IBD through Treg/IDO/PGE2 axis activation. Timing (early intervention) and inflammatory priming (IFN-γ) are critical modulators. These insights warrant phase II trials of IFN-γ-primed UCMSCs for immune-mediated gastroenterological diseases.

References

[1]Zhang M, Johnson-Stephenson TK, Wang W, Wang Y, Li J, Li L, Zen K, Chen X, Zhu D. Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17⁺ regulatory T cell. Stem Cell Res Ther. 2022 Sep 24;13(1):484.
[2]Wang Y, Huang B, Jin T, Ocansey DKW, Jiang J, Mao F. Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy. Front Immunol. 2022 Mar 18;13:835005.

Introduction

While inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), affects people of all sexes, potential disparities in the diagnostic process—such as differences in symptom onset, symptom reporting, and time to diagnosis—have not been systematically investigated in depth to date.

Aims & Methods

This analysis aims to explore potential sex differences in the pre-diagnostic symptom presentation and the diagnostic pathway of IBD, spanning from the onset of first symptoms to the eventual clinical diagnosis. In this interim analysis of a multicenter cross-sectional study, data of 1180 participants with IBD (women: n=770, men: n=410) from 42 recruiting units all over Germany were included. A comprehensive set of demographic data was collected via an online survey, encompassing the following variables: the IBD entity, sex and gender identity, age, the initial symptoms of IBD, the time from symptom onset to first consultation, the time from first consultation to referral, and the time to diagnosis. In addition, the respective physician's sex was documented. Moreover, the distinct disease-related and therapeutic histories have been collected. Inclusion criteria were a minimum age of 18 years and a confirmed diagnosis of UC or CD for a minimum of three months.

Results

No significant sex differences were observed in the median time to initial physician consultation for either CD or UC (CD: women 3 months [IQR: 1–12], men 3 months [IQR: 0.5–10], p=0.567, g=0.1; UC: women 2 months [IQR: 0.8–5], men 1.3 months [IQR: 0.5–4], p=0.091, g=0.1). Similarly, the median time from first consultation to referral did not differ significantly between sexes (CD: women 1.5 months [IQR: 0.5–5], men 1 month [IQR: 0.5–6], p=0.154, g=0.1; UC: women 0.8 months [IQR: 0.3–3], men 0.5 months [IQR: 0.2–1], p=0.113, g=0.2).
However, women experienced significantly longer median time from symptom onset to final IBD diagnosis compared to men (CD: women 12 months [IQR: 5–48], men 6.5 months [IQR: 2.5–24], p=0.002, g=0.3; UC: women 5 months [IQR: 2–14.5], men 3 months [IQR: 1.3–8], p=0.006, g=0.2). The misdiagnosis rate was found to be significantly higher in women with IBD than in men (IBD women: n=311 (40.4%); IBD men: n=141 (34.4%); p=0.044). Furthermore, sex-specific differences in the initial presentation of symptoms were observed. Women with CD were more likely to present with diarrhea (p=0.005, ϕ =0), nausea (p=0.013, ϕ=0), or arthralgia (p=0.012, ϕ =0) compared to CD men. In UC, women were more likely to initially experience fever (p < 0.001, ϕ = 0) or abdominal pain (p = 0.004, ϕ = 0) compared to men.

Conclusion

Despite similar timelines for initial physician contact and referral, women with IBD experienced significantly longer diagnostic delays and higher rates of misdiagnoses than men. Sex-specific differences in initial symptom presentation were observed, suggesting that diagnostic disparities may be partly driven by variations in symptom profiles and their interpretation. These challenges call for a broader, global perspective and increased awareness to improve the overall care of individuals with IBD on an international scale.

Introduction

The correlation between fecal calprotectin (FC) levels and small bowel (SB) inflammation in patients with Crohn's Disease (CD) remains a subject of debate.

Aims & Methods

This study aims to investigate the relationship between FC levels and SB inflammatory activity in patients diagnosed with SB CD.
We conducted a retrospective cohort study involving patients with SB CD who underwent small bowel capsule endoscopy (SBCE) and FC testing. Patients with colon inflammation were excluded. Participants were categorized into four groups based on their SB inflammatory status: no inflammation (all three SB tertiles showed Lewis Score (LS) <135); proximal SB inflammation (first and/or second SB tertiles had LS ≥ 135, with no inflammation in the third SB tertile); distal SB inflammation (third SB tertile had LS ≥ 135, with no inflammation in the proximal SB); pan-SB inflammation (both proximal and distal SB with inflammation).

Results

A total of 87 patients were included in the study, with a median age of 35 years, 75.9% being female. The distribution of inflammation among the patients was as follows: no inflammation in 21.8%; proximal inflammation in 4.6%; distal inflammation in 33.3%; pan-SB inflammation in 40.4%.
FC median values exhibited an ascending trend along the SB axis: no inflammation 58 µg/g (33-180); proximal SB inflammation 65 µg/g (30-128); distal SB inflammation 122 µg/g (42-507); pan-SB inflammation 400 µg/g (205-852).
Statistically significant differences in FC levels were observed between pan-SB inflammation vs. isolated proximal inflammation (p = 0.014), and isolated distal inflammation (p = 0.012).
Additionally, FC showed a positive correlation with LS in the second (r = 0.464, p<0.001) and third tertiles (r = 0.435, p<0.001), but no correlation was noted in the first tertile.
FC demonstrated good predictive capacity for identifying inflammation in the distal SB and pan-SB vs. no inflammation and proximal inflammation, with an area under the curve of 0.790 (p < 0.001) and an optimal cutoff value of 228 µg/g.

Conclusion

FC levels correlate positively with the presence of SB lesions in the second and third tertiles of the small bowel. However, it is not a reliable marker for detecting inflammation in the first tertile, highlighting the importance of conducting a SBCE in these patients.

Introduction

The Pisa EoE Adaptation Questionnaire (PiEAQ) on adaptive behaviors at mealtime significantly improves the correlation between dysphagia scores and histological disease activity (HDA) in eosinophilic esophagitis (EoE) [Reference 1].

Aims & Methods

Whether longitudinal variations of PiEAQ scores (∆PiEAQ) can capture HDA trends following pharmacological treatment of EoE has not been investigated. Consecutive adults (>18 years) with histologically active EoE (i.e., ≥15 eos/high-power field) were prospectively enrolled. Clinical characteristics, HDA, a recall-modified dysphagia symptom questionnaire (mDSQ), esophageal hypervigilance and anxiety scale (EHAS), and PiEAQ (drinking water to push the bolus, lubricating food, chewing for long, and blending food) were recorded longitudinally at baseline (T0) and 12 weeks post-treatment using a 30-day recall period (T1). ROC curve analysis with DeLong test was used to calculate the diagnostic accuracy (AUC) of clinical scores for predicting HDA following treatment. Significance threshold was p<0.05.

Results

Thirty-seven histologically active EoE patients were included (Table 1). The mDSQ, PiEAQ, and EHAS score at baseline were 2.97 (IQR, 2-5), 2.00 (IQR, 1-3), and 21 (IQR, 14– 25), respectively. Following treatment with budesonide orodispersible tablets (72.2%), PPIs (19.6%), dupilumab (5.5%), or milk-free diet (2.7%), histological remission was achieved in 78.4% of patients, while 21.6% remained histologically active. Post-treatment (T1), mDSQ, PiEAQ, and EHAS scores decreased significantly only in patients who achieved histological remission (Table 2 and Figure1). ROC curve analysis showed that a post-treatment reduction of at least 2 adaptive behaviors compared to baseline (∆PiEAQ=-2) had AUC of 85.0%, with 100% specificity and 64% sensitivity for the identification of patients achieving histological remission following treatment. Similarly, a post-treatment reduction of at least 3 points in mDSQ scores compared to baseline (∆mDSQ=-3) had AUC of 81.1% with 100% specificity and 57.7% sensitivity. The non-inferiority analysis showed that the ∆PiEAQ had similar performance to ∆DSQ (DeLong p-value= 0.46). A combined score integrating both ∆PiEAQ and ∆DSQ scores increased the AUC of clinical scores for capturing variations of HDA post-treatment to 90%, with 100% specificity and 73.1% sensitivity for detecting patients achieving histological remission post-treatment (Figure 2).

Conclusion

The PiEAQ is the first questionnaire investigating adaptive behaviors as a standalone domain in EoE. We demonstrated that longitudinal variations in PiEAQ scores are sensitive to HDA variations over time and can monitor histological disease activity trends after treatment. This study confirms that, similar to dysphagia, adaptive behaviors contribute to disease burden in EoE and improve with treatment.

References

1. Visaggi P, Del Corso G, Solinas I, Ovidi F, Adamo G, Dulmin I, Baiano Svizzero F, Bellini M, Savarino EV, de Bortoli N. Adaptive Behaviors, Esophageal Anxiety, and Hypervigilance Modify the Association Between Dysphagia Perception and Histological Disease Activity in Eosinophilic Esophagitis. Am J Gastroenterol. 2024 Dec 30. doi: 10.14309/ajg.0000000000003272. Epub ahead of print. PMID: 39787341.

Disclosure

Speaker or Consultancy for Apogee Therapeutics, Dr Falk Pharma, Malesci, JB Pharmaceuticals, Sanofi, Alfasigma

Introduction

Sarcoidosis is a multisystem disorder marked by non-caseating granulomas, primarily affecting the lungs but capable of involving almost any organ system. Hepatic involvement is reported in 10-65%, ranging from asymptomatic presentations to severe complications such as chronic cholestasis, portal hypertension, or cirrhosis. Its broad spectrum of clinical presentations makes diagnosis challenging; therefore our hypothesis was that hepatic sarcoidosis is underdiagnosed.

Aims & Methods

This study aims to evaluate the prevalence and clinical characteristics of hepatic sarcoidosis by analyzing two distinct cohorts – a hepatology cohort and a pneumology cohort.
The hepatology cohort included 37 patients from a university hepatology center with clinically and/or histologically confirmed hepatic involvement in sarcoidosis. Clinical characteristics were recorded at initial diagnosis, and at 3- and 12-month follow-up.
In parallel, a pneumology cohort of 346 patients with biopsy-proven sarcoidosis from a pneumology center was examined for abnormal liver values or imaging findings. Regarding this cohort, statistical comparisons between sarcoidosis patients with and without hepatic abnormalities were conducted.

Results

In the hepatology cohort, 43.2% of patients (n = 16) were male and 56.8% (n = 21) female. At initial presentation, the mean BMI was 27.7 ± 7.3 kg/m² (median 25.8; range 19.0–50.5). The number of organ manifestations per patient ranged from 1 to 6, with a median of 3 and a mean of 2.97 ± 1.5; notably, 18.9% of patients (n = 7) presented with isolated hepatic involvement. Liver involvement was biopsy-confirmed in 62.9% of patients (n = 22), whereas only 40% (n = 15) showed corresponding morphological findings on imaging. Laboratory results predominantly showed a cholestatic pattern with elevated ALP and gamma-GT. Mean levels of elevated liver enzymes decreased over the follow-up period. The most common symptoms were fever (27.0%) and weight loss (24.3%), while 16.2% of patients (n = 6) were asymptomatic. 51.3% of patients (n = 19) were treated with glucocorticoids, 43.2% (n = 16) received no therapy.
In the pneumology cohort, 172 (49.7%) sarcoidosis patients showed abnormal liver values or imaging. In the cohort, 139 (40.2%) patients were female, and 207 patients (59.8%) were male. Hepatic abnormalities were observed significantly more frequent in males than females (54% vs. 43%, p = 0.046). Patients with hepatic involvement had a mean age of 52.9 ± 12.0 years (range 20–83) at the time of inpatient stay (n = 172). BMI was significantly higher in patients with hepatic involvement (median 29.8 vs. 27.1 kg/m², p < 0.001), while no significant age difference was observed. Splenic abnormalities were more common in those with hepatic involvement (23.4% vs. 7.7%, p < 0.001).

Conclusion

Analysis of the hepatology cohort highlights that biopsy-confirmed hepatic sarcoidosis can occur even in the absence of corresponding imaging findings. The clinical course of hepatic sarcoidosis is often self-limiting. In selected cases, treatment with glucocorticoids, other immunosuppressants, or ursodeoxycholic acid (UDCA) in patients with cholestatic symptoms is required.
The high number of liver abnormalities in the pneumology cohort suggests that hepatic sarcoidosis is underdiagnosed. Sarcoidosis patients should be assessed for potential hepatic involvement. Screening via ALP levels is recommended. The need to screen for hepatic involvement applies regardless of patient age.

Disclosure

There are no conflict of interest.

Introduction

EoE is a debilitating disease with physical, behavioral, and psychosocial impacts, resulting in substantial impairment in quality of life for patients and caregivers. Children with EoE can present with nonspecific symptoms such as food refusal or feeding difficulties, gastroesophageal reflux disease (GERD), nausea, and vomiting. Dupilumab is approved in the USA and EU for patients with EoE aged ≥1 year, weighing ≥15 kg. In the phase 3 randomized placebo-controlled EoE KIDS study (NCT04394351), in children aged 1 to 11 years, dupilumab significantly improved symptoms of EoE vs placebo, as measured by the Pediatric Eosinophilic Esophagitis Symptom Score version 2.0 (caregiver version; PEESSv2.0) after 16 weeks of treatment.

Aims & Methods

In this post-hoc analysis of the EoE KIDS study, we evaluated the effects of long-term dupilumab treatment on PEESSv2.0 scores during the Part C open-label extension. PEESSv2.0 is a validated observer-reported outcome measure that assesses the frequency and severity of EoE symptoms and adaptive behaviors, divided into four domains: GERD, dysphagia, pain, and nausea; each is scored 0–100, with higher scores indicating a greater symptom domain severity. Patients who completed Week 52 in Part B of EoE KIDS were eligible for Part C, where all patients received open-label dupilumab, using the weight-tiered regimen later approved by the FDA (similar to the Part A and B higher-exposure regimen). In patients who received placebo or dupilumab higher exposure during Parts A and B, changes from baseline of the EoE KIDS study (Part A baseline) in the PEESSv2.0 total, frequency, severity, and domain scores were assessed at Week 52 (Part C baseline), Week 76, and Week 100.

Results

At Week 52, the mean change from baseline (95% confidence interval) in PEESSv2.0 total score was –23.8 (–32.1, –15.6; Table), with further reductions observed at Week 100 (–31.5 [–41.5, –21.4]). Mean changes from baseline in PEESSv2.0 frequency and severity scores were further reduced from Week 52 (–25.1 [–34.2, –16.1] and –22.2 [–30.3, –14.1], respectively), to Week 100 (–33.8 [–44.9, –22.7] and –28.6 [–38.3, –19.0]). Similar patterns of reduction were observed for individual primary domain scores, namely, GERD, dysphagia, pain, and nausea. During the Part C open-label extension, dupilumab safety was consistent with the known dupilumab safety profile.

Conclusion

Children with EoE, treated with long-term dupilumab, experienced sustained improvements in the frequency and severity of symptoms of EoE up to Week 100, assessed by the PEESSv2.0. Reductions in GERD, dysphagia, pain, and nausea domain scores were also maintained or in some cases further improved, although interpretation of Part C symptom data is limited due to the open-label study design. Future studies should consider the correlation of symptoms with trends in both endoscopic and histologic outcomes.

Disclosure

Oliva S: Celgene/Receptos/Bristol Myers Squibb, Medtronic, Ocean Pharma, Sanofi/Regeneron Pharmaceuticals Inc – advisory board/consulting fees. Medtronic, Sanofi/Regeneron Pharmaceuticals Inc. – speaker fees.
Gold B: Diasorin Molecular, IQVIA/AstraZeneca, Ironwood Pharmaceuticals, Johnson&Johnson, Mead Johnson/Reckitt, Nutricia, Pfizer Inc, Sanofi/Regeneron Pharmaceuticals – advisory board/consultancy fees.
Ashok D: Alexion Pharma, LaunchitDTx, Mirum Pharma – advisory board/consulting fees. Sanofi – speaker fees.
Parrish C: Sanofi/Regeneron, Takeda – advisory board/consulting. Regeneron Pharmaceuticals Inc., Sanofi – speaker fees. DBV technologies, NIH/NIAID – research support.
Xia C, Raphael BP, Radwan A, Thomas RB: Regeneron Pharmaceuticals Inc. – employees and may hold stock or shares.
Cazeau C, Almansa C, Tilton ST: Sanofi – employees and may hold stock or shares.