Introduction

Crohn’s Disease (CD) is a chronic inflammatory disease of the gastrointestinal tract often requiring lifelong treatment. An important proportion of CD patients with ileitis or ileocolitis require bowel resection during the course of their disease. [1] Although ileocolonic resection (ICR) induces clinical and endoscopic remission, more than half of patients develop postoperative recurrence in the first years following surgery. [2] In the recent REPREVIO trial, we showed that vedolizumab treatment (VDZ) is effective to prevent the incidence and severity of recurrence. [3]
Currently, the gold standard to diagnose postoperative CD recurrence is through ileocolonoscopy using the Rutgeerts scoring system. A modified Rutgeerts score ≥i2b predicts early clinical recurrence. Given the invasive nature and high cost of endoscopy, we investigated the value of fecal calprotectin (FC) in a prospective cohort of patients enrolled in the REPREVIO trial.

Aims & Methods

CD patients were randomized to blinded treatment with 8-weekly IV VDZ 300 mg or placebo for 26 weeks within 1 month following ICR. Faecal calprotectin (FC) and serum CRP were measured at baseline, week 8, week 16 and week 24. At week 26-28 ileocolonoscopy was performed to evaluate CD recurrence and scored by blinded investigators. Statistical analysis was performed using SPSS (IBM). Predictors for endoscopic recurrence were examined by univariable and multivariable logistic regression analysis. Receiver operating characteristic (ROC) curves were used to assess accuracy of FC in predicting endoscopic recurrence.

Results

Eighty patients (median age 36 [IQR 27-52], median disease duration 8.5 years [IQR 1-16]) participated in REPREVIO, all having at least 1 risk factor for postoperative recurrence (smoking 16.3%, >1 prior resection 35%, perforating complications 36.3%, previous exposure to TNF inhibitors 48.8%).
Median FC at baseline (BL) was 157.2 µg/g [IQR 68.3-310.3] for all patients. In patients without week 26 endoscopic recurrence, FC decreased from BL to week 8 (from 139 to 80.5 µg/g, p<0.001). Conversely, FC remained stable or increased in patients who had week 26 recurrence independently from allocation (VDZ or PLC).
Week 8 FC levels were significantly higher in patients with week 26 endoscopic recurrence (Rutgeerts ≥i2b) (158 µg/g [IQR 53.9-397]) than in patients without recurrence (Rutgeerts ≤i2a) (80.5 µg/g [IQR 19.3-181.8], p= 0.011). After correction for treatment (PLC or VDZ), the predictive power of FC was only significant for patients in the PLC group (Rutgeerts ≤i2a 46 µg/g [IQR 18.8-139] versus Rutgeerts ≥i2b 200 µg/g [43.1-425.3])(p=0.018), respectively). ROC analysis revealed that FC had an area under the curve (AUC) of 0.703 for a cut-off FC value of 45 µg/g at week 8, with a sensitivity of 85% and a specificity of 40% to predict endoscopic recurrence. Further analysis of the predictive value of week 16 and 24 FC was hampered by the number of missing samples. Serum CRP was not predictive of recurrence.

Conclusion

In the REPREVIO study, week 8 FC levels were predictive of clinically relevant endoscopic recurrence at week 26. A FC >45 µg/g 8 weeks post-surgery has a sensitivity of 85% to predict significant endoscopic recurrence and treatment escalation should be considered in these patients.

References

[1] Tsai, L., et al., Contemporary Risk of Surgery in Patients With Ulcerative Colitis and Crohn's Disease: A Meta-Analysis of Population-Based Cohorts. Clin Gastroenterol Hepatol, 2021. 19(10): p. 2031-2045.e11.
[2] Lamb, C.A., et al., British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut, 2019. 68(Suppl 3): p. s1-s106.
[3] D’Haens, G.R.A.M., et al., Prevention of postoperative recurrence of Crohn's disease with vedolizumab: First results of the prospective placebo-controlled randomised trial REPREVIO. [Abstract] ECCO, 2023.

Clinical Case Summary

Introduction: Demodicosis is a disease of the pilosebaceous unit, involving mainly face and head areas, caused by Demodex mites.
It can be seen in primary or secondary forms (Chen and Plewig). Secondary demodicosis is defined as skin lesions associated with an abnormal increase of Demodex mites due to skin or systemic diseases. It occurs significantly in immunosuppressed patients with leukaemia, human immunodeficiency virus infection or those being treated with topical or systemic immunosuppressants.
We report the case of a patient treated for Crohn's disease with Infliximab who developed Demodicosis.
Case report: A 26-year-old man, with 4 years history of stricturing ileo-caecal Crohn’s for which he had an ileo-caecal resection with an ileo-colic anastomosis, and perianal fistula treated by seton placement and antibiotics.
Subsequently, Infliximab treatment was initiated at a dose of 5mg/kg every 8 weeks.1 year into the treatment, the patient experienced pruritus, redness and dryness of the cheeks leading to a referral for a dermatology consultation.
Physical examination revealed skin xerosis, scaly erythematous plaques around the periphery, circinate on the forearm and facial erythema.
At polarized-light dermoscopy of the facial lesions, Demodex tails with Demodex follicular openings and telangiectasias were observed.
The diagnosis of demodicosis was made and the patient was treated with oral doxycycline (100mg/day), and a topical cream based on sertaconazole with noticeable improvement .
Conclusion: Demodicosis should be taken into account in patients treated with biological medications and presenting atypical inflammatory skin lesions.

References

1. Chen W, Plewig G. Human demodicosis: revisit and a proposed classification. Br J Dermatol 2014; 170: 1219-25.
2. CORDAN YAZICI A, Güliz İKİZOĞLU G. Demodicosis. Turkiye Klinikleri J Med Sci. 2019;39(2):231-6

Introduction

Pancreatic cancer has remained one of the most serious malignancies and is still a leading cause of cancer-related deaths worldwide. Great attention has been paid to the relationship between diabetes mellitus and pancreatic cancer. At the time of diagnosis of pancreatic cancer, impaired glucose metabolism has been reported to be present in variable rates according to particular studies (ref.).

Aims & Methods

Aims: The aim of our study was to analyse mutual association of pancreatic cancer and diabetes mellitus in the whole population of the Czech Republic within a 5-year period.
Methods: Based on the individual population data from the Czech National Cancer Registry, the incidence of pancreatic cancer in 2017-2021 was estimated. Another data source, the National Registry of Reimbursed Health Services that collects data from health insurance companies, was used to estimate people recently diagnosed with diabetes mellitus. For the purpose of this study, diagnosis of new-onset of diabetes mellitus was defined as the time of the first prescription of any antidiabetic drug (subgroup of patients with prediabetes treated with metformin was included). Patients with diabetes treated with diet only were not included. Subsequently, people diagnosed with pancreatic cancer in 2021 were retrospectively followed up to see if they had been diagnosed with diabetes mellitus in the last 5 years (or earlier) before diagnosis of pancreatic cancer.

Results

There were 310,427 new cases of diabetes mellitus identified within the period 2017 - 2021. Over this period, an average of 2,448 people were diagnosed with pancreatic cancer per year (23.1 / 100,000 population). In 2021, 2,064 patients > 60 years were diagnosed with pancreatic cancer. New onset of diabetes mellitus was recorded in 12.2% three years before the diagnosis of pancreatic cancer and four or five years before this diagnosis in another 5.2%. If we focus only on the 60-74 age group, the proportion was 13.8% and 5.8 %, respectively. Mutual association of diabetes mellitus and pancreatic cancer is displayed in the Table 1.

Table 1
Mutual association of diabetes mellitus and pancreatic cancer within the period 2017-2021

Conclusion

Incidence of pancreatic cancer in the Czech Republic belongs to the highest ones in Europe. New-onset of diabetes mellitus precedes the diagnosis of pancreatic cancer in nearly 20 % of cases within a 5-year period. These findings lead to considerations of the introduction of an early detection programme for pancreatic cancer in the Czech Republic based on new-onset of diabetes mellitus and possible other risk factors.

References

Cancers (Basel) 2023; 15(14): 3669

Introduction

Transcriptomics is a fast-evolving field with translational applications and is broadly used in research. However, gene expression (GE) can be affected by many environmental and biological factors. The effect of commonly prescribed medications on GE is still understudied, especially in the context of a large cohort of chronic inflammatory disease (CIDs) patients. The unravelling of transcriptomic changes induced by therapies used by CIDs patients can further aid in the minimization of disease-unspecific signals and contribute to insights into medications’ mechanisms of action and repurposing.

Aims & Methods

The study aimed at the identification of prednisolone (PRED), azathioprine (AZA), and anti-TNF biologics signatures on the transcriptome of patients with inflammatory bowel disease (IBD) and other CIDs. RNA-seq was performed in peripheral blood samples of 625 CIDs patients included in a cross-sectional cohort. CIDs comprised IBD, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, and arthrosis. Patients using the systemic therapies PRED and AZA, and anti-TNF biologics were compared against patients using no systemic therapies or no biologics, respectively. Linear mixed models were used with sex, age, body mass index (BMI), diagnosis, and C-reactive protein (CRP) as covariates. Differentially expressed genes (DEGs) (q-value < 0.05) were compared to the overall top 2000 varying genes (TVGs) to investigate how much the medication DEGs contribute to the general variation in gene expression.

Results

PRED investigation with low clinical disease activity patients revealed 224 down and 602 upregulated genes that were among the TVGs. Significantly enriched gene ontology (GO) terms of downregulated genes included adaptive immune response, immunoglobulin production, and B cell proliferation, whereas upregulated genes were related to acute inflammation, innate immune response, and positive NF-κB regulation. The AZA investigation comprised 24 IBD patients using AZA and 103 IBD patients using no systemic therapies, all with low clinical disease activity. Significant GO terms from the 144 downregulated genes part of the TVGs were related to cytokine production, cell proliferation, and T, B, and NK cell activity, whereas GO terms from the 301 upregulated genes included platelet aggregation and erythrocyte development. IBD, T-helper cell differentiation and NK cell-mediated toxicity were among suppressed enriched pathways. Variance partition analysis revealed that 151 genes have AZA as the driver of at least 25% of variation and 70 of those were part of the TVGs. GO terms of the upregulated DEGs in common with TVGs from the anti-TNF analysis were related to B cell and innate immune response activities, whereas the downregulated DEGs terms showed no direct relation to immune processes.

Conclusion

Transcriptomics analysis revealed that AZA and PRED, two commonly prescribed therapies to treat CID, modulate the expression of genes that contribute to the overall variation in gene expression and are potentially involved in other gene expression analyses. We suggest that the use of these medications should be considered when performing other transcriptomic analysis on blood samples from CID patients.

Introduction

Lymphocytic colitis (LC) is a debilitating, non-destructive inflammatory bowel disease (IBD) that causes intense watery, non-bloody diarrhoea. LC is diagnosed by an increased lymphocyte infiltration in the mucosa that has been correlated with increased Th1/Th17 cytokine secretion and subsequent sodium malabsorption. Still, LC pathomechanisms have not been fully characterized and its relation to other forms of IBD is unclear.

Aims & Methods

Our aim was to define a LC-specific transcriptome to gain insight into LC pathology, identify genetic signatures uniquely linked to LC, and uncover potentially druggable disease pathways. For that, we performed whole mucosa bulk RNA-sequencing of LC and collagenous colitis (CC) samples from patients with active disease, and healthy controls (n=4-10 per cohort). Differential gene expression was analyzed by gene-set enrichment and deconvolution analyses to identify pathologically relevant pathways and cells, respectively, altered in LC. Key findings were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared our sequencing data to a previous cohort of ulcerative colitis and Crohn’s disease patients (n=4 per group) to distinguish non-destructive from classic IBD.

Results

The LC-specific transcriptome was defined by a limited mucosal immune response against microbiota compared to CC and classic IBD samples. In contrast, we noted a distinct induction of regulatory non-coding RNA species in LC samples. Moreover, compared to CC, we observed decreased water channel and cell adhesion molecule gene expression, which was associated with reduced intestinal epithelial cell proliferation.

Conclusion

We conclude that LC is a pathomechanistically distinct disease that is characterized by a dampened immune response despite massive mucosal immune cell infiltration. Our results point to regulatory micro-RNAs as a potential disease-specific feature that may be amenable to therapeutic intervention.

References

1. Carrasco A. et al. Immunological Differences between Lymphocytic and Collagenous Colitis. J Crohns Colitis. 2016 Sep;10(9):1055-66.
2. Kumawat AK. et al. Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile. Mol Immunol. 2013 Oct;55(3-4):355-64.
3. Barmeyer C. et al. ENaC Dysregulation Through Activation of MEK1/2 Contributes to Impaired Na+ Absorption in Lymphocytic Colitis. Inflamm Bowel Dis. 2016 Mar;22(3):539-47.

Disclosure

CEH, SK and AM received financial support from Ferring Pharmaceuticals (Switzerland). AM has received salary for consultancies from Tillots Pharma AG, Ferring, Vifor, and Dr Falk Pharma, speaker's honoraria from Tillots Pharma AG and Vifor. The remaining authors declare no conflicts of interest.

Introduction

Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA) with the production of superoxide anion. The accumulation of UA has been shown to initiate the inflammatory process through NLRP3 inflammasome and the production of reactive oxygen species (ROS), which contributes to inflammation-related tissue damage observed in inflammatory bowel disease (IBD). In murine models of colitis, XO inhibitors, allopurinol or febuxostat, reduced the expression of proinflammatory cytokines supporting the involvement of XO in the intestinal inflammatory process.

Aims & Methods

The aim of this study was to evaluate the expression level and enzymatic activity of XO in the intestinal mucosa of IBD patients (pts), both ulcerative colitis (UC) and Crohn’s disease (CD), compared to healthy controls (HC).
Sigmoid-colon biopsies from consecutive UC and CD pts, with a confirmed diagnosis (by ECCO guidelines) in regular follow-up at University Hospital of Cagliari with an indication to endoscopy according to standard clinical practice, were collected. Site-matched biopsies from individuals undergoing screening colonoscopy for colorectal cancer were used as controls.
Demographic data and endoscopic grade for disease activity scored by endoscopic Mayo and SES-CD score were collected. Real-Time PCR was used to evaluate XO relative expression levels (RQ) and data was confirmed by analyzing GEO database (study code GSE11223). XO activity was measured in whole protein extracts from biopsies by spectrophotometric quantification of UA production and expressed as nmol of UA/min/mg of total protein. The relative abundance of XO was further investigated by Western Blot. Finally, XO expression was assessed in sections of paraffin-embedded intestinal biopsies by immunohistochemistry.

Results

Biopsies of 15 HC, 20 UC, and 15 CD pts were collected. Mean age was 50 for UC, 49 for CD and 54 for HC. Mayo endoscopic subscore was 0 in 25% of UC pts, 1 in 18,75%, 2 in 21,2% and 3 in 25%. SES-CD was between 0-2 in 28,6% of CD pts, 3-6 in 21,4%, 7-14 in 42,8% and >14 in 7,1%. Real-time PCR showed that XO expression values were increased in the sigmoid mucosa of pts with UC compared with HC individuals (RQ 1,93 vs 0,99. p=0,004). This data was confirmed by analysis of XO expression in the GEO database study code GSE11223. The difference in XO expression between HC and CD was not statistically significant (p=0,13). Western blot analysis of XO protein expression in CD and UC pts compared with HC showed a significant increase in IBD pts (p<0,001).
XO activity was significantly higher in UC and CD pts as compared to HC. XO activity mean was 3,75 in UC pts and 5,10 in CD pts vs 1,11 nmol of UA/min/mg of protein in HC individuals (p<0.001). Moreover, in UC pts XO activity was correlated with Mayo endoscopic sub-score (r= 0.346; p=0.05). Immunohistochemistry confirmed higher expression of XO in IBD pts than HC with a prevalent expression observed in epithelial cells.

Conclusion

XO expression was higher in UC pts than in HC individuals. XO activity was higher in both CD and UC pts than HC and in UC pts XO activity correlated with endoscopic disease suggesting its potential role as therapeutic target.