Introduction

Lipocalin-2 (LCN2) is a pleiotropic mediator of various inflammatory processes. Upon gastrointestinal damage, bacterial infection, or intestinal inflammation, LCN-2 is strongly upregulated, resulting in high concentrations of this molecule.

Aims & Methods

We determined the serum levels of LCN-2 in a cohort of newly diagnosed UC children, and we compared them with healthy controls.
We conducted a prospective cross-sectional observational study conducted at the Pediatric Gastroenterology Unit of the Umberto I Hospital and at the IBBC – Institute of Biochemistry and Cell Biology – CNR in Rome. All children aged 6-18 years of age, newly diagnosed with UC were consecutively enrolled. Blood withdrawal was conducted upon diagnosis. Human serum LCN-2 (Cat. No. DY1757) was measured using a sandwich enzyme-linked-immunosorbent assay (ELISA) kits (R&D Systems, Minneapolis, MN, USA), according to the protocols provided by the manufacturer. Clinical, demographic, biochemical and endoscopic data were recorded.

Results

Thirty-two children with a new diagnosis of UC [11 (34%) female, mean age 12,7 ± 4] and 38 age- and sex-matched healthy control [21 (55%) females, mean age 11.71 ± 4] were consecutively enrolled. Serum LCN-2 levels were significantly higher in cases compared to controls (280 ± 152 ng/mL vs 66 ± 55 ng/mL), p < 0,001]. Among UC children, significantly higher LCN2 levels were measured in pancolitis (363.7± 155.2 ng/mL) compared to proctitis, left-sided and extensive colitis (184.9 ± 74.65 ng/mL; P = 0.0003). A significant inverse correlation was observed between LCN-2 and albumin levels at the diagnosis by the Spearman coefficient correlation (r = −0.455; P = 0.03) and a significant direct correlation was observed between LCN-2 and CRP values at the diagnosis (r = 0.44; P <0.05).

Conclusion

Serum LCN-2 levels are significantly higher in children with UC compared to the healthy control group, with the highest levels observed in children with the most extensive disease. Such results as well as and its correlation with the actual disease monitoring tool, make this protein an interesting candidate biomarker.

Introduction

Ulcerative colitis (UC) disease course is unpredictable at the diagnosis and its management is still based on a "one-size-fits-all" approach.

Aims & Methods

We aimed to investigate the predictive factors of a rapidly progressive disease course in pediatric UC.
This was a retrospective case-control study conducted at the Pediatric Gastroenterology Unit of Umberto I Hospital in Rome. We included newly diagnosed UC patients aged < 18 years, with a minimum follow-up of 24 months. Demographic data, clinical features, laboratory, endoscopic and histologic findings at the diagnosis were collected and compared between patients with indolent UC and those with a rapidly progressive (RP) course. Children were classified as having a RP course if they experienced at least one of the following within the first 24 months after diagnosis: acute severe colitis, need for colectomy, necessity to transition to anti-TNFα therapy, or initiation of second-line biologic therapy.

Results

One hundred-sixteen patients were included, 67 (58 %) with a RP course and 49 (42 %) with an indolent disease. RP Children had higher age (11.5 vs 9, p=0.0008), PUCAI (50 vs 40, p=0.0005) and UCEIS (4 vs 3, p=0.002) at the diagnosis than those with indolent course. Hemoglobin was lower in the RP group (11.5 vs 12.3 g/dL, p=0.05). RP children had higher rate of cecal patch at endoscopy (18 % vs 2 % p=0.007) and a lower rate of sclerosing cholangitis (0 vs 8.2%, p=0.02). No differences were observed for all other clinical, laboratory, and histologic findings. Multivariate analysis confirmed that age and the presence of a cecal patch were associated with the risk of RP course (p=0.02, and p=0.04, respectively).

Conclusion

Among the clinical and easily obtainable information at the diagnosis in children with UC, an older age at the diagnosis, along with an endoscopic finding of a cecal patch seem associated with the risk of a more aggressive disease. Such results warrant confirmation in larger prospective cohorts for a future personalized approach to UC.

Introduction

Mirikizumab is a p19-directed anti-interleukin-23 antibody approved for treatment of adults with moderately to severely active ulcerative colitis (UC). Here, we report mirikizumab pharmacokinetics and exposure-response in pediatric patients with moderately to severely active UC from the phase-2, multicenter, open-label study SHINE-1 (NCT04004611).

Aims & Methods

Patients aged 2 to <18 years weighing >10kg with a modified Mayo score (MMS) of 4-9 and endoscopic subscore ≥2 received intravenous mirikizumab induction doses (300mg for weight >40kg; 5 or 10mg/kg for weight ≤40kg) every 4 weeks (Q4W) through Week 12. At Week 12, patients achieving MMS clinical response received subcutaneous maintenance doses of mirikizumab 200mg (>40kg), 100mg (>20-≤40kg), or 50mg (≤20kg) Q4W for 36 weeks. Pharmacokinetic parameters were analyzed by nonlinear mixed-effects modeling with fixed allometry for size. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations. Exposure-response for patients achieving clinical response, remission, and endoscopic response at Weeks 12 and 52 were explored using graphical approaches.

Results

The analysis included 232 samples from 26 patients. Estimated systemic clearance, volume of distribution, and subcutaneous bioavailability were 0.000296 L/hr/kg, 0.069 L/kg, and 49.8%, respectively. Pharmacokinetic model-estimated exposures in all weight groups were similar to those in adult phase-3 studies LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) except for the 10‑mg/kg induction dose, which was 2-fold higher (Figure). In the exposure range studied in SHINE-1, exposure-response analysis using post-hoc grouping by average concentration quartile revealed no improvement trend in clinical response, remission, or endoscopic response and showed similar efficacy to that in adults.

Conclusion

Mirikizumab pharmacokinetic exposures and efficacy results at intended phase-3 doses across all pediatric weight groups were similar to those reported in adults. No patient factors other than weight justify dose adjustment. Exposure-matching to the adult exposure data and exposure-response analysis support a phase-3, weight group-divided dosing strategy in pediatric patients.

Disclosure

Y. Otani, L. Chua, W. Komocsar, A. Larkin and X. C. Zhang are employees and shareholders of: Eli Lilly and Company.

Introduction

The pathogenesis of ulcerative colitis (UC) involves complex immune responses, including Th1, Th2, and Th17 pathways, and is characterized by substantial heterogeneity. Cytokine profiling may contribute to understanding individual disease mechanisms and guiding personalized therapeutic strategies; however, its clinical application remains limited due to technical complexity. This study aimed to investigate whether endocytoscopic and histopathological findings correlate with mucosal cytokine expression levels and could serve as surrogate markers.

Aims & Methods

Thirty-five patients with UC receiving treatment at our institution were enrolled. Endocytoscopy (ultra-magnifying endoscopy) was performed in all patients, and the findings were classified according to the Endocytoscopic Classification system (EC classification: EC-A, EC-B, EC-C, EC-D). Mucosal biopsies were obtained from the most inflamed areas identified during endocytoscopy. Histological evaluation included the Matts histological grade and assessments of neutrophil, eosinophil, and lymphocyte infiltration; goblet cell depletion; crypt distortion; and epithelial damage, each graded on a four-point scale (absent, mild, moderate, severe). mRNA expression levels of cytokines (IFN-γ, TGF-β1, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, and IL-23) were quantified using RT-PCR. Statistical analyses were performed to assess correlations between endocytoscopic/histopathological findings and cytokine expression levels.

Results

The median age of participants was 44 years (IQR: 35–57), with 24 males and 11 females. Disease types included pancolitis (n = 16), left-sided colitis (n = 14), and proctitis (n = 5). The median Mayo score was 1 (IQR: 0–5). EC classification scores showed significant positive correlations with the expression levels of IL-1β, IL-6, IL-8, IL-13, IL-17, and IL-23 (Spearman’s rank correlation, p < 0.05; r = 0.555, 0.526, 0.584, 0.441, 0.422, and 0.449, respectively). Similarly, Matts histological grades were significantly correlated with the expression of IFN-γ, IL-1β, IL-6, IL-8, IL-13, IL-17, and IL-23 (p < 0.05; r = 0.493, 0.756, 0.692, 0.730, 0.656, 0.623, and 0.448, respectively). Histopathological features—including neutrophil and lymphocyte infiltration, goblet cell depletion, epithelial damage, and crypt distortion—were significantly associated with the expression of IFN-γ, IL-1β, IL-6, IL-8, IL-13, IL-17, and IL-23. Additionally, eosinophil infiltration was positively correlated with the expression levels of IL-1β, IL-5, and IL-13.

Conclusion

This study demonstrates that endocytoscopic and histopathological indicators of inflammation are associated with mucosal expression levels of several cytokines—particularly inflammatory and Th17-related cytokines—in patients with ulcerative colitis (UC). These findings suggest that such evaluations may serve as surrogate markers, potentially improving disease assessment and informing therapeutic decision-making.