Introduction

Abdominal pain is the most common symptom among children, but its pathophysiology is heterogeneous and its mechanisms are incompletely understood. To date, various risk factors for abdominal pain have been reported ^1–3 but reports of genetic associations for abdominal pain in children are scarce. To understand the determinants of abdominal pain in children, phenotypic-genotypic associations using robust stratification in a large sample are necessary.

Aims & Methods

To stratify children with abdominal pain according to common characteristics by machine learning (ML) algorithms and to identify phenotype-genotype associations.
The Born in Bradford birth cohort has 13,858 children registered between 2007 and 2011 whose primary care medical records are available. In 1,274 children who developed abdominal pain from the whole cohort　(average age: 8.4 ± 1.1 years old, male/female: 615/659), we investigated the frequencies of comorbidities associated with abdominal pain and then clustered them using the unsupervised ML algorithm. Genome-wide association studies (GWAS) were used to seek significant variants of single nucleotide polymorphisms (SNPs) responsible for the differences among clusters, using 6,488 (male/female = 3,375/3,113) children without abdominal pain as the control. Gene annotations for each SNP were obtained to identify gene sets for each cluster, and these were used in enrichment analysis.

Results

Children with abdominal pain were classified into 3 unique clusters: 137 children in cluster 1 (10.8 %), 677 children in cluster 2 (53.1 %), and 340 children in cluster 3 (26.7 %). Significant results of comparison of clinical characteristics among 3 clusters are shown in the table. Children in cluster 1 were characterized by allergic diseases (99.3 %), and all mothers had allergic diseases (100 %). In cluster 2, mothers' comorbidities, e.g., abdominal pain (70.0 %), allergic diseases (40.0 %), and migraine (34.0 %), were the highest compared to the other 2 clusters. In cluster 3, the frequencies of comorbidities, including allergic diseases and mother's comorbidities, were very low. GWAS showed that there were 2, 1, and 4 SNPs with genome-wide significance (p < 5.0×10^-8) in clusters 1, 2, and 3, respectively. Enrichment analysis revealed that ARPC5 and CLDN genes associated with Tight junction might account for abdominal pain in cluster 1. Genes associated with bile acid biosynthesis might also be associated with abdominal pain in clusters 1 and 2; there no significant findings in cluster 3.

Conclusion

We detected 3 distinct phenotypes of abdominal pain in children. Each phenotype may need a tailor-made therapeutic approach according to its etiology and pathophysiology. Furthermore, genetic findings can be a target for future studies to investigate the mechanisms of abdominal pain. In particular, the link between allergy and intestinal barrier may be of mechanistic and therapeutic importance.

References

1. Korterink, J., Devanarayana, N. M., Rajindrajith, S., Vlieger, A. & Benninga, M. A. Childhood functional abdominal pain: Mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 12, 159–171 (2015).
2. Sjölund, J. et al. Allergy-related diseases in childhood and risk for abdominal pain-related functional gastrointestinal disorders at 16 years—a birth cohort study. BMC Med. 19, 1–11 (2021).
3. Levy, R. L. et al. Increased somatic complaints and health-care utilization in children: Effects of parent IBS status and parent response to gastrointestinal symptoms. Am. J. Gastroenterol. 99, 2442–2451 (2004).

Introduction

One in four patients experiencing a first episode of non-gallstone-related acute pancreatitis (AP) will develop recurrent disease. Recurrent episodes of AP or acute-on-chronic pancreatitis (CP) lead to decreased quality of life and disease progression. Aside from addressing the underlying cause of pancreatitis (which is sometimes impossible), effective measures to prevent recurrence are lacking. Meta-analyses of randomized controlled trials and epidemiological and cohort studies indicate that statins may provide protection against the development of initial AP.

Aims & Methods

The SIMBA study is a triple-blind, randomized, placebo-controlled, parallel-group multicenter trial. Patients with non-biliary recurrent acute pancreatitis (AP) or acute flares of chronic pancreatitis (CP) (at least two episodes in the last 12 months) were randomized to receive either simvastatin 40 mg daily or a placebo and followed up for 1 year. The sample size was calculated to be 144 patients, but slow recruitment prompted an interim analysis. The primary aim was to compare the recurrence of AP or acute flares in CP (RAP/AF).

Results

Eighty-three patients were included from 22 centers from Spain and 1 from India. The median age was 54 years, and 49 (59%) were men. Sixty-one (73.5%) patients had AP and 22 (26.5%) CP. Thirty-nine (47%) patients received placebo and 44 (53%) simvastatin. The median follow-up was 262 months. During follow-up, there were 12 (30.8%) RAP/AF in the placebo group and 15 (34.1%) in the simvastatin group (p 0.747, intention-to-treat analysis). Nor were there significant differences in the Kaplan-Meier curve (p=0.543). These results did not change when analyzing the patients who had finished treatment (per-protocol analysis) or when analyzing AP and CP separately.

Conclusion

Simvastatin does not appear to protect against recurrent episodes of acute pancreatitis or acute-on-chronic pancreatitis.

Introduction

Type 1 autoimmune pancreatitis (AIP) represents the most common manifestation of IgG4-related disease. Type 1 AIP responds well to glucocorticoids, but relapses are common requiring multiple treatment courses and ultimately leading to end-organ damage and treatment-related morbidity. To date, scant reports exist on the long-term outcomes of these patients. Moreover, the role of maintenance treatment in preventing disease relapse is still debated.

Aims & Methods

We aimed to evaluate the long-term outcomes of a large European cohort of patients with type 1 AIP and to assess the role of maintenance treatment in preventing disease relapse. Patients with type 1 AIP fulfilling ICDC criteria were included in this multicentric retrospective study within the PrescrAIP framework involving 40 European university Hospital. Relapses were defined as new onset of either AIP related symptoms or radiological abnormalities after a successful induction of remission. Patients without either complete or partial remission were excluded. The primary endpoint was time to relapse. Predictors of relapse were identified by multivariable logistic regression. A bootstrapping technique was performed to internally validate the model. Regression coefficients from the multivariable model were employed to develop a score for computing the risk of relapse for each patient. Patients were divided into four categories according to the score, from the lowest to highest risk of relapse.

Results

477 patients were included in this analysis (325 male, 68%). Mean age at baseline was 59 (IQR 40-68). 60% of the patients presented with jaundice while 7% of the patient with acute pancreatitis. Other organs involvement was present in 238 patients (48%), being biliary involvement the most frequent one (40%). At baseline, diabetes mellitus and pancreatic exocrine insufficiency were present in 30% and 27% of patients, respectively. After a mean follow up of 32 months (IQR 13-68), 150 (31%) AIP relapses occurred. After accounting for confounders, biliary tree involvement (OR 1.62 95%CI 1.1-2.2), acute pancreatitis at baseline (OR 2.1 95%CI 1.1-4.2), narrowing of the main pancreatic duct (OR 1.6, 95%CI 1.1-2.1) were independently associated with relapse, while AIP presenting as a focal mass resulted in a protective factor (OR 0.65 95%CI 0.46-0.92). Increased serum IgG4 level (OR 1.2 95%CI 0.9-1.7) pointed to higher relapse rate without reaching statistical significance. Notably, any maintenance treatment reduced the relapse rate after correcting for the above-mentioned risk factors (OR 0.51, 95%CI 0.37-0.72). There was no difference in term of relapse free survival between maintenance treatment with any anti-rheumatic drugs (azathioprine, methotrexate, mycophenolate) and low-dose GCs. Maintenance treatment reduced relapse rate only in patients with higher relapse risk. At the longest follow up, DM and PEI were recorded in 33% and 29% of the patients, respectively. Only one pancreatic cancer was detected.

Conclusion

Several disease features increase the risk of relapse in type 1 AIP. Any of the maintenance treatment reduce relapse rate in type 1 AIP. Patients showing multiple risk factors for relapse benefit the most from maintenance treatment. The development of a score predicting disease relapse enhances a personalized approach toward AIP treatment. In European AIP patients the development of pancreatic cancer during follow up appears rare.