Objectives and Study

Background:

Perianal Crohn’s Disease (PCD) including perianal fistulas, abscesses, fissures, or inflammatory skin tags are common manifestations of Crohn’s disease (CD) at diagnosis. Perianal fistulizing Crohn’s disease (PFCD), fistulas/abscesses, usually dictate a poor prognosis in children. The primary aim of this study was to investigate factors associated with PFCD at diagnosis. The secondary aim was to assess factors associated with PFCD severity according to the Van Assche score (VAS), a scoring system developed in 2003.

Methods

Methods:

We retrospectively collected data from patients (4-18 years) diagnosed with CD (2009-2021) in our center. PCD were assessed clinically and on magnetic resonance imaging (MRI) performed within 3 months of the diagnosis. Two radiologists independently evaluated the MRI, recorded the occurrence of PFCD and graded the severity with the VAS. Multivariate analyses were performed to compare characteristics at diagnosis and PFCD with multivariate binary logistic regression and linear regression considering the VAS.

Results

Results:

In total, 489 patients were included (57,9% males; median age 13,8 years [interquartile range (IQR)=11,4-15,5]), of which 216 (44,2%) had PCD. PFCD was identified with MRI in 115 (23,5%) patients. The rate of PFCD was higher in patients with clinical PCD (76/177;42,9%), as compared to those without clinical PCD (39/312;12,5%)(p<0,0001).

The median (IQR) VAS for patients with PFCD was 13,0 (9,0-15,0) as compared to 2,0 (0,0-2,0) for patients without PFCD (p<0,0001). Male sex (OR=3,00[1,37-6,74]), granulomas on intestinal biopsies (OR=3,30[1,54-7,08]) and anal fissures (OR=5,69[2,13-15,17]) were associated with PFCD. Granulomas on intestinal biopsies (adjusted beta coefficient [aβ]=3,16;p=0,0188) and anal fissures ([aβ]=3,30;p=0,0310) were associated with higher VAS. The female sex ([aβ]=-2,87;p=0,037) was associated with lower VAS.

Conclusions

Conclusion:

This study stresses the importance to perform perianal MRI early at diagnosis of CD, as occult PFCD may be discovered. Male sex, granulomas on intestinal biopsies and anal fissures were associated with higher PFCD prevalence and severity.

Objectives and Study

The involvement of oxidative stress in the pathogenesis of Inflammatory Bowel Diseases (IBD) has already been shown and the ongoing multicentre OXIBDiet trial (NCT04513015) has demonstrated a major impairment of oxidative stress repair mechanisms in children with IBD compared to adults. As further step, we aim to evaluate the efficacy of an antioxidant diet (OD) in children with IBD. Preliminary results of the dietetic study are presented.

Methods

Children with IBD with mild symptoms were assigned to consume the OD (intake of polyphenols > 650 mg/die) or the MD for 12 weeks. A control group (on free diet, FD) was also enrolled. In the three groups the total antioxidant capacity (measured through ferric reducing ability of plasma, FRAP), the degree of protein oxidation (AOPP), inflammatory biomarkers, clinical variables and quality of life were evaluated at the beginning and at the end of the study period.

Results

Twenty of the 25 enrolled children and adolescents (10 OD, 10 MD, 5 FD) have completed the dietetic study. Preliminary results show a significant increase in FRAP (Figure 1) and a significant reduction in AOPP (5.7 vs. 4.7 µmol/g protein, p=0.0435) only in OD group.

Serum levels of zinc, vitamin E and A show an improvement in OD and MD, and a decrease in FD. A decrease in faecal calprotectin (FC) was observed only in the OD and MD groups, while no significant changes in the other parameters were observed between groups.

Conclusions

Preliminary results show an improvement of oxidative parameters in IBD children with an OD. The MD seems to be comparable to OD in terms of anti-inflammatory, clinical, quality of life effects, and both diets show an equivalent reduction of FC levels. The comprehensive results of the OXIBDiet trial and subgroup analysis will clarify the role of an antioxidant dietetic approach.

Objectives and Study

Ustekinumab is used off-label in paediatric Crohn’s disease (CD) refractory to anti-tumour necrosis factor (TNF). Data on optimal dosing and attainment of adequate trough levels in children is limited.

Methods

We describe a series of four adolescents with CD who were refractory to anti-TNF and to ustekinumab standard dosing. We escalated by giving a second intravenous dose and shortening the interval to 4 weeks. Ustekinumab levels were measured before every administration.

Results

Patient 1 failed on anti-TNFs despite azathioprine co-medication. After 1.5 years of standard ustekinumab therapy, ileocecal resection was performed. Ustekinumab was continued. Recurrence of inflammation caused an ileus, for which ustekinumab was escalated. Trough levels increased and the patient is now in sustained remission.
Patient 2 failed on infliximab and vedolizumab. Biochemical remission was not reached on standard ustekinumab therapy and escalation was deployed. As this did not lead to a higher trough level, ustekinumab therapy was discontinued. Current treatment consists of adalimumab, but remission has not been achieved.
Patient 3 failed on corticosteroids and infliximab. Ustekinumab was escalated because of non-response, without any improvement. Ileocecal resection was performed and adalimumab was initiated post-surgery, but remission has not been achieved.
Patient 4 failed on exclusive enteral nutrition, corticosteroids and anti-TNFs and had disease recurrence in the neoterminal ileum after ileocecal resection. PCDAI scores and faecal calprotectin were persistently high on standard ustekinumab treatment and escalation was deployed. Trough levels increased considerably and the patient has now reached clinical remission, although faecal calprotectin remains high.

Figure 1: Ustekinumab levels, faecal calprotectin and C-reactive protein over time.
The vertical dashed line represents intravenous re-induction of ustekinumab. The reported age was at the start of ustekinumab therapy.

Conclusions

Intravenous reinduction and interval shortening to attain higher ustekinumab levels should be considered before the drug is abandoned as ineffective.

Objectives and Study

IMPACT-III and IMPACT-III-P are Health-Related Quality of Life (HRQoL) questionnaires for pediatric Inflammatory Bowel Disease (p-IBD) patients and their parents/caregivers. They evaluate 6 domains through 35 items, answered with a 1-5 points Likert scale. Higher scores indicate better HRQoL. We aimed to perform a transcultural adaptation and validation of the Spanish versions.

Methods

After obtaining permission of the questionnaires’ authors, we followed the internationally agreed methodology of translation, back-translation, and evaluation by a committee of experts to reach a consensus version. A small group of p-IBD families (n=12) completed the questionnaires to identify confusing items. Members of the SEGHNP were invited to recruit p-IBD patients aged 10-18 and their parents/caregivers (February’21-November’22) who completed the questionnaire. The validation study was performed calculating the Cronbach's alpha coefficient, globally and by domains (considering 0.8-0.9 a good internal consistency, and >=0.9 excellent). A confirmatory factorial analysis with Varimax rotation was made (desirable values ​​>0.5). Both the Kaiser Meyer Olkin (KMO) measure (>0.5 good correlation) and the Barlett’s sphericity test (p<0.05) were calculated to confirm the adequacy of the factor analysis. The utility (method and completion time) was considered. Data were collected and analyzed with REDCap and SPSS v.24.

Results

We included 273 patients and 258 parents/guardians from 31 hospitals. The KMO measure (0.8929 and 0.9088, respectively) and the Barttlet's sphericity test (p-value <0.001 for both) confirmed the factor analysis’ adequacy. The factorial model with 4 factors, complying with the Kaiser’s rule, explained 86.73% and 85.41% of the variance of the model. Cronbach's alphas (0.9148 and 0.9388, respectively) indicated an excellent internal consistency. The use of a Likert scoring system and the completion median time of 10 minutes for both questionnaires was considered optimal.

Conclusions

The SEGHNP’s versions of the IMPACT-III and IMPACT-III-P are valid and reliable instruments for their use with p-IBD families in our clinical setting.

Objectives and Study

Paediatric inflammatory bowel disease (PIBD; which encompasses Crohn’s disease (CD), ulcerative colitis (UC) and IBD-unclassified (IBD-U)) has an increased overall risk of mortality and malignancy compared to the general population however this is not fully characterized in children. Scotland has a population of 5.5 million people and one of the highest PIBD prevalences worldwide; we aim to present long-term nationwide PIBD cancer and mortality data.

Methods

Scottish PIBD care is provided through 3 regional network centres. We identified all PIBD patients within paediatric care who developed cancer or died between 01.01.2003 - 30.11.22. Accurate case accrual was ensured through review of the yearly national PIBD in Scotland Audit (PISA) data and a follow-up questionnaire to each regional centre. Electronic medical records were reviewed retrospectively.

Results

10 patients were included in the analysis. 6 patients (100% male, all CD) were diagnosed with malignancy with a median age at cancer diagnosis of 16.7 yrs (IQR 13.2 – 17.5) and a median disease duration prior to diagnosis of 3.0 yrs (IQR: 1.5 – 3.1). No patients had a family history of cancer or primary sclerosing cholangitis. 5/6 (83%) received an immunomodulator or anti-TNF within the past 3 months and all patients had been exposed during their disease course.

5 patients died, including 1 cancer patient, (80% female, 2 UC, 2 CD, 1 IBDU) with a median age at death of 12.2 years (IQR: 11.7 – 18.0). 2/6 (33.3%) likely died as a direct consequence of their disease (1 late surgical complication and 1 thiopurine associated malignancy).

Table 1 summarises the characteristics of each case.

Conclusions

Death and malignancy are a rare but significant consequence of PIBD. While causation cannot be proved, six cases of malignancies associated with thiopurine/anti-TNF use were observed over a 20 year period.

Objectives and Study

The human circadian clock is present in all cells. It includes the CLOCK and BMAL1 genes which heterodimerize to mediate transcription of many genes, including their negative regulators: PERIODs (PERs) and CRYPTOCHROMEs (CRYs). We have shown that patients with active ulcerative colitis (UC) display misalignment of the molecular clock that reverts to normal following effective treatment. Several circadian clock genes also function as anti-inflammatory regulators. For example, RORα, PPARα and PPARγ positively regulate the expression of both the clock mechanism and that of IkB, the NFkB suppressor. Similarly, PCG1α​​​​​​​ induces transcription of IL10. Our aim was to characterize the expression of these clock genes and regulators and determine their correlations in UC patients.

Methods

Using whole transcriptome RNA sequencing from the IBD Transcriptome and Metatranscriptome Meta-Analysis platform(TaMMA IBD), we compared rectal biopsy gene expression levels and correlations of AMPK, BMAL1, CLOCK, CRY1, CRY2, PER1, PER2, PCG1α, PPARα, PPARγ, REV-ERBα, RORα, RORγ and SIRT1 in 206 treatment naïve pediatric UC patients (age 12.9±3.2; 54% male) and 20 healthy controls (age 13.9±3.3; 45% male).

Results

Core clock genes, BMAL (p<0.0001), CLOCK (p<0.01) and CRY1 (p<0.0001), and the anti-inflammatory regulatory gene RORα (p<0.0001) were upregulated in patients compared to controls. In contrast, expression of other anti-inflammatory regulatory genes, PCG1α (p<0.0001), PPARα (p<0.01), PPARγ (p<0.0001) and RORγ (p<0.0001) were decreased in patients. Clock gene expression of healthy controls showed discordant correlations compared to UC patients, e.g., BMAL/REV-ERBα and PPARγ/REV-ERBα correlations were inverted between controls and patients (r=-0.44 vs. r=0.13 and r =-0.4 vs. r=0.3, respectively).

Conclusions

Core clock gene expression was disrupted, and anti-inflammatory regulatory gene expression was decreased in patients with active UC. The discordant correlations in UC patients highlight clock disruption in active inflammation. Since these clock regulators also ameliorate inflammation, their reduced expression may explain not only clock dysregulation but also increased tissue inflammation.