Introduction

Exocrine pancreatic insufficiency (EPI) following acute pancreatitis (AP) has been reported heterogeneously with unclear recovery timeline.

Aims & Methods

Aim: To determine the prevalence of EPI after AP and the prevalence and predictors of persistent EPI after AP for at least 6 months.
Methods: Prospective longitudinal study of consecutive adult patients diagnosed with first episode of AP. Excluded patients with previous EPI, follow-up after AP <12months and after EPI <6months. EPI was assessed by elastase fecal-1 and endocrine pancreatic insufficiency (EnPI) by fasting serum glucose, HbA1c and oral glucose tolerance test. Patients with AP who developed EPI were randomized to receive pancreatic enzyme replacement therapy (PERT, 4000IU with each meal and 20000IU with snacks; clinicaltrials.gov NCT05480241) vs. placebo. Clinical, inflammatory, nutritional and immunological factors were evaluated. Evaluated predictors for persistent EPI (≥6months) and compared with transient EPI (<6months) and AP with no EPI groups.

Results

A total of 105 patients (65.7%(n=69) males; mean age:63.8±17.1yo) were enrolled and followed-up, 65.7% with alcoholic/biliary etiology. AP was moderately-severe in 32.4% and severe in 16.2%. EPI (mean elastase fecal-1 176.9±175.8 (vs. 425.1±105.0; p<0.001) was observed in 50 (47.6%) patients, being severe in 60% and 38% of patients with mild AP: 64% at the time, 14% at 1 month, 16% at 3 months and 6% at 6 months of AP diagnosis. EnPI was diagnosed in 17.1%(n=18) and 19.0%(n=20) has previous diabetes mellitus. EPI was persistent (≥6 months after EPI diagnosis) in 58%(n=29; mean elastase fecal-1 83.8±58.5 (vs. 373.6±118.4; p<0.001)), being 31%(n=9) with mild AP. 6-month post-randomization, 44%(n=11/25) under PERT and 40%(n=10/25) under placebo resolved EPI (p=0.598), with statically significance for severe EPI (resolved EPI: PERT-20%; placebo-12%; p=0.04).
After univariate/multivariate analysis, factors significantly associated with persistent EPI were previous diabetes (OR 15.382; p=0.001), EnPI (OR 9.906; p=0.042), recurrent AP (OR 7.182; p=0.028), non-biliary etiology (OR 5.744; p=0.037), increasing AP severity (OR 21.386; p<0.001), mMarshal score ≥2 (OR 23.026; p=0.001), intermediate/intensive care unit admission (OR 19.583; p=0.003), pancreatic necrosis (OR 21.05; p=0.007) and low magnesium (OR 45.690; p=0.045).

Conclusion

EPI following AP is a non-negligible condition, present in almost half of patients during first 6months after AP diagnosis, being severe in about 2/3 of patients and persists for at least 6 months in more than half of patients, Previous diabetes, EnPI, recurrent AP, non-biliary etiology, severe AP and low magnesium were strongly and independent associated with persistent PEI. Since can occur and be persistent even in mild AP, is crucial understand injury mechanisms, stratify patient’s risk, tailoring screening and start PERT early.

References

1. Phillips AE, Beijani J, Culp S, Chennat J, Lee PJ, Machicado JD, et al. Prevalence of exocrine pancreatic insufficiency at 12 months after acute pancreatitis: a prospective, multicentre, longitudinal cohort study. E Clinical Medicine 2024;75:102774.
2. Huang W, de la Iglesia-García D, Baston-Rey I, Calviño-Suarez C, Lariño-Noia J, Iglesias-Garcia J, et al. Exocrine pancreatic insufficiency following acute pancreatitis: Systematic review and meta-analysis. Dig Dis Sci 2019;64(7):1985-2005.
3. Jawaid S, Forsmark CE. Exocrine pancreatic insufficiency following acute pancreatitis: true association or EPIphenomenon?. Dig Dis Sci 2019;67(7):1731-1733.

Introduction

Acute pancreatitis (AP) is a common clinical emergency, with 20%–30% of cases progressing to severe acute pancreatitis (SAP), which has a mortality rate of up to 40%. Gut microbiota dysbiosis is closely associated with AP severity, yet its underlying mechanisms remain unclear.

Aims & Methods

This study aimed to elucidate how microbiota dysbiosis exacerbates AP.AP was induced in Specific Pathogen-Free (SPF) and Germ-Free (GF) C57BL/6 male mice to investigate the effects of microbiota dysbiosis on neutrophil recruitment, neutrophil extracellular trap (NET) formation, pancreatic injury, and systemic inflammation. Single-cell sequencing of neutrophils from SPF and GF AP mice was conducted to assess microbiota-driven changes in neutrophil distribution, gene expression, and signaling pathways. Serum cfDNA levels were measured in 50 AP patients and 30 healthy controls. Key findings were validated in vivo and in vitro.

Results

Serum cfDNA (NETs) levels were significantly elevated in AP patients compared to healthy controls and decreased during recovery. GF-treated mice exhibited reduced pancreatic edema, inflammatory infiltration, and acinar cell necrosis, with lower pathology scores. Immunohistochemistry confirmed decreased MPO and F4/80-positive cells in pancreatic tissues, while ELISA showed reduced levels of amylase, lipase, IL-6, and TNF-α in GF-treated mice. Single-cell sequencing revealed a lower proportion of pancreatic neutrophils and an increase in acinar cells in GF-treated mice, whereas the NET formation pathway was activated in SPF-treated mice. The TLR2/MYD88/NLRP3/Caspase-1 signaling cascade, which promotes NET formation, was also activated in SPF mice. Consistent with pathway analysis, CXCL1, CCL9, and CXCR2 expression was upregulated, while Reg3β expression was downregulated in SPF_AP mice. Dual immunofluorescence demonstrated reduced MPO/CitH3 (NETs) formation in GF-treated mice. Neutrophils from GF-treated mice released significantly less cfDNA upon PMA stimulation. Serum cfDNA levels were elevated in both AP-induced mice and AP patients.

Conclusion

Gut microbiota dysbiosis exacerbates AP severity by promoting neutrophil recruitment, activating the TLR2/NLRP3/MYD88/Caspase-1 signaling cascade, and enhancing NET formation, leading to aggravated pancreatic injury and systemic inflammation. These findings highlight microbiota modulation as a potential therapeutic strategy to prevent AP progression.

Disclosure

The authors declare that they have no conflict of interests.

Introduction

Management of perianal fistulas in Crohn’s disease (CD) is challenging and requires a multidisciplinary approach, combining surgical drainage and biologic therapies, such as infliximab (IFX). Higher IFX trough concentrations have been associated with improved fistula healing rates. The subcutaneous (SC) formulation of IFX achieves 2–3 times higher and more stable trough levels compared to intravenous (IV) formulation. This study hypothesizes that SC IFX could enhance perianal fistula healing rates in CD patients.

Aims & Methods

REMSILAP study is part of the 3TLAP cohort, a French prospective multicenter observational study evaluating optimal therapeutic strategies for achieving clinical and radiological remission of perianal fistulas in CD at 12 months post-surgical drainage. The REMSILAP substudy focuses specifically on patients receiving SC IFX. Patients who received SC IFX after or within six months prior to surgical drainage were included. Baseline was defined as the day of surgical drainage. The primary outcome was the proportion of patients achieving complete clinical remission defined as Perianal Disease Activity Index (PDAI) fistula drainage subscore = 0 associated with PDAI activity restriction subscore <3 and absence of seton, and radiological remission at 12 months. Here, we present preliminary findings from REMSILAP.

Results

Among the 353 patients enrolled in the 3TLAP cohort, 54 were included in REMSILAP. The cohort consisted of 61.1% male patients, with a median age of 36 years and a median disease duration of 4.5 years. Penetrating disease (B3 phenotype) was present in 40.7%, and 33.3% had a history of surgical resection. At baseline, 40.7% of patients had quiescent disease regarding Harvey-Bradshaw index, while 5.6% had severe disease activity. Biologic exposure prior to inclusion was noted in 42.6%. Surgical drainage, with seton placement, was performed in 74.1% of patients. Forty-eight patients (88%) initiated SC IFX treatment after surgical drainage. Of the patients receiving SC IFX, 50% transitioned to SC IFX after less than three IV infusions. Among those on IV IFX at baseline, 20.4% were receiving a 10 mg/kg dose. Forty-three patients (79.6%) received SC IFX in combination with immunomodulators (azathioprine, methotrexate, or 6-mercaptopurine). The median duration of SC IFX treatment was 13.1 months, with treatment maintained for 67.5% of the follow-up period (mean: 19.3 ± 11.3 months). Forty-three patients (79.6%) were treated with a stable dose of 120 mg/14 days and 6 patients (11.1%) had an intensification of SC IFX dosage to 120mg / 7 days. At 12 months, 42 patients were evaluable for clinical outcomes. Complete clinical healing at 12 months was achieved in 11 patients (27.5%) and association of PDAI restriction subscore <3 and drainage subscore = 0 was found in 18 patients (42.9%). Thirteen patients (34.2%) from the 25 patients who had received at least 6 months of SC IFX treatment showed clinical healing at 6 months. Out of the 26 patients treated with at least 12 months of SC IFX treatment, clinical healing was achieved in 16 patients (61.5%) at 12 months. Among the 11 patients with clinical healing at 12 months, 8 (72.2%) were treated with SC IFX treatment following more than three IFX IV infusions. None of the 11 patients with available MRI date showed radiological healing at 12 months.

Conclusion

Subcutaneous infliximab following surgical drainage of Crohn’s disease perianal fistula demonstrates high treatment persistence and promising rates of fistula healing.

Disclosure

This study was funded by Celltrion Healthcare France