AIM:To review pediatric cases of orofacial granulomatosis(OFG),report disease characteristics,and explore the association between OFG and Crohn’s disease.METHODS:We conducted a systematic review ...according to the PRISMA guidelines.We searched Medline,LILACS,Virtual Health Library,and Web of Knowledge in September 2013 for cases of OFG in the pediatric age range(<18 years),with no language limitations.All relevant articles were accessed in full text.The manual search included references of retrieved articles.We extracted data on patients’characteristics,disease characteristics,association with other diseases,and treatment.We analyzed the data and reported the results in tables and text.RESULTS:We retrieved 173 reports of OFG in children.Mean age at onset was 11.1±3.8 years(range:2.0-18years).Prevalence in males was significant higher than in females(P<0.001),with a male:female ratio of 2:1.Gastrointestinal signs or symptoms were present in 26.0%of children at the time of OFG diagnosis.Overall,70/173(40.4%)children received a concomitant diagnosis of Crohn’s disease.In about half(51.4%)of the cases the onset of OFG anticipated the diagnosis of Crohn’s disease,with a mean time between the two diagnoses of 13.1±11.6 mo(range:3-36 mo).Overall,21/173(12.1%)of the children with OFG had perianal disease,while 11/173(6.4%)had a family history of Crohn’s disease.Both perianal disease and a family history of Crohn’s disease were significantly associated with a higher risk of Crohn’s disease diagnosis in children with OFGrelative risk(RR)=3.10,95%confidence interval(CI):2.46-3.90;RR=2.74,95%CI:2.24-3.36,P<0.0001 for both).Treatment of OFG included steroids(70.8%of children)and other immunosuppressive drugs(42.7%),such as azathioprine,thalidomide and infliximab.CONCLUSION:High prevalence of Crohn’s disease in children with OFG suggests that OFG may be a subtype of Crohn’s disease.
Improving the quality of life (QoL) is crucial in the management of pediatric inflammatory bowel disease (IBD). We aimed to (1) Validate the IMPACT-III questionnaire in Italian IBD children; (2) ...explore factors associated to QoL in pediatric IBD. Internal consistency, concurrent validity, discriminant validity and reproducibility of the Italian version of the IMPACT-III questionnaire was measured in IBD children/adolescents in 8 centers. Associations between patient and disease characteristics and the IMPACT-III domains were analyzed through quantile regression analysis. The IMPACT-III questionnaire, collected in 282 children with IBD (median age: 14.8 years; IQR 12.4-16.4) showed a median total score of 76 (IQR 67-83). Female gender, active disease and age were negatively associated with the total IMPACT-III score. Specifically, female gender was negatively associated with the Bowel/Systemic Symptoms, Emotional and Treatment domain scores, while disease activity was significantly associated with Bowel Symptoms and Treatment/Interventions reported QoL. The IMPACT- III showed good internal consistency (Cronbach's alpha coefficient = 0.87, 95% CI 0.85-0.89) and reproducibility (Concordance Correlation Coefficient = 0.66, 95% CI 0.57-0.74). In Italian children with IBD active disease, female gender and adolescence are associated to a worse QoL, indicating the need of more attention in this subgroup of young patients. IMPACT-III questionnaire is a reliable instrument to measure QoL in Italian children.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The aim of the study was to investigate the burden of mental health problems in children and adolescents admitted to a pediatric ward with physical complaints. We conducted a retrospective study, ...considering all patients admitted to the pediatric ward of the IRCCS Burlo Garofolo, Trieste, Italy, between January 2015 and September 2016. We selected all patients, from 5 to 17 years old, who were admitted with physical complaints and were discharged with a diagnosis suggestive of a mental health problem: somatic symptom disorder, anxiety disorder, depressive disorder, factious disorders. For every patient, we collected demographic features, medical characteristics, health care services utilization, length of hospital stay, and after discharge referral. We selected 1456 patients; of these, 101 (6.9%) revealed a mental health problem. The median duration of symptoms was 5 months (IQR 1.5–12), and pain was the main reported symptom (69%). Of the 101 patients, 23 (23%) were affected by a previously documented chronic organic disease. Somatic symptom disorder was the most common diagnosis. In 69/78 patients (88%), a loss of social contacts emerged; 49/95 patients frequenting school (51%) had chronic school absenteeism in the previous school year.
Conclusion
: A considerable proportion of patients admitted to a pediatric ward with physical complaints have mental health problems.
What is Known:
• It has been suggested that mental health problems in children and adolescents are increasing and frequently burden on pediatric healthcare services, but how they impact on a general pediatric ward is not clear.
What is New:
• Among 1456 patients admitted to a general pediatric ward with physical symptoms, 101 patients (6.9%) had a mental health problem. Among them, pain was the most commonly reported symptom and somatic symptom disorder was the commonly reported diagnosis.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
The long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (
) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), ...implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of
in regulating
and
expression in pediatric patients with IBD and in vitro.
In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and
,
, and
were quantified by TaqMan assay. The expression of
and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of
was assessed by overexpressing the lncRNA and evaluating the MMPs levels.
Real-time PCR results demonstrated a downregulation of
and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of
while an increase of MMPs was observed. Overexpression experiments showed that higher levels of
lead to a decrease of both enzymes.
These results provide new information about the role of
in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Although the use of glucocorticoids (GC) is well established, the therapeutic response to these agents often shows important interindividual differences, in particular among young patients with ...inflammatory bowel diseases (IBD). Currently, GC resistance or dependence cannot be predicted by clinical or laboratory findings. The aim of this study was to investigate the association of gender and age with GC efficacy and with the expression of Glucocorticoid-Induced Leucine Zipper (GILZ). One hundred thirty patients (mean age at enrolment 12.6 years, 53 Crohn’s disease, 70 males) were enrolled in this retrospective study. IBD patients with active disease despite prednisone at a daily dose of up to 2 mg/kg over a period of 4 weeks were defined as steroid resistant. Patients who initially responded but relapsed upon dose reduction were considered steroid-dependent. Total RNA was extracted from biopsies of 14 patients (9 males) and the levels of GILZ mRNA were evaluated by real-time PCR. Association between clinical response to prednisone and the considered demographic variables was evaluated using logistic regression models. After 4 weeks of treatment, 112 patients were responders to prednisone and 18 were resistant; at this time-point, resistant patients were older than responders (p=0.032). After 12 weeks, 42, 71 and 12 patients were sensitive, dependent and resistant respectively; at this time-point, females were more prone than males to develop prednisone dependence vs a good response (p=0.028) while age had no effect. Age was associated with response both at 4 and 12 weeks in the subgroups of females: resistant patients were older than sensitive ones at 4 weeks (p=0.02). Likewise, at 12 weeks of therapy, dependent patients resulted older than sensitive ones (p=0.05). No association of age with prednisone response was found in males. In a subgroup of 14 patients (5 females), GILZ mRNA expression in intestinal biopsies was higher in males (p=0.0031). Patients with unfavorable response (7) presented lower GILZ expression at disease onset in comparison to the responder group (p=0.017). Older females with IBD have a higher incidence of prednisone unfavorable response and reduced intestinal expression of the GC pharmacodynamic marker GILZ.
Infliximab is commonly used in inflammatory bowel disease (IBD), however, differences in clinical response among patients are common. Several studies have considered the possibility that these ...differences are caused by genetic variability even if no unique marker has been yet identified in pediatric patients. We evaluated the impact of two candidate single‐nucleotide polymorphisms (SNPs) rs396991 in FCGR3A and rs1800629 in TNFα genes on infliximab response in an Italian cohort of 76 pediatric patients with IBD. Results showed that patients with the variant FCGR3A allele had a reduced clinical response at the end of induction (p value = 0.004), at 22 weeks (p value = 0.001), and at 52 weeks of treatment (p value = 0.01). A significant association between the FCGR3A variant and median infliximab levels measured during maintenance therapy was also observed: patients with wild type genotype had higher infliximab levels compared to patient with variant allele. Furthermore, patients with the variant allele had a higher probability to produce antidrug antibodies (ADAs). No association was found among the TNFα SNP, clinical response, and infliximab levels. This study addressed for the first time in pediatric patients with IBD, the association of FCGR3A SNP, infliximab response, and ADA production.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon (CRBN), a component of ...E3 protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, has been identified as the primary target of thalidomide. CRBN plays a crucial role in thalidomide teratogenicity, however it is unclear whether it is also involved in the therapeutic effects in IBD patients. This study aimed at identifying the molecular mechanisms underpinning thalidomide action in pediatric IBD. In this study, ten IBD pediatric patients responsive to thalidomide were prospectively enrolled. RNA-sequencing (RNA-seq) analysis and functional enrichment analysis were carried out on peripheral blood mononuclear cells (PBMC) obtained before and after twelve weeks of treatment with thalidomide. RNA-seq analysis revealed 378 differentially expressed genes before and after treatment with thalidomide. The most deregulated pathways were cytosolic calcium ion concentration, cAMP-mediated signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling also emerged. Connectivity Map analysis revealed that thalidomide gene expression changes were similar to those exposed to MLN4924, an inhibitor of NEDD8 activating enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on the ubiquitin-proteasome pathway. In vitro experiments on cell lines confirmed the effect of thalidomide on candidate altered pathways observed in patients. These results represent a unique resource for enhanced understanding of thalidomide mechanism in pediatric patients with IBD, providing novel potential targets associated with drug response.
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•Thalidomide induces specific gene expression alterations in children with IBD.•Calcium signalling, immune response and neuronal pathways are significant enriched.•Overrepresented pathway emerged can be recapitulated in vitro.•CMap analyses identify drugs that could be repurposed for the treatment of IBD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Crohn's disease (CD) is a chronic inflammatory disease of the digestive tract. The incidence of pediatric CD is increasing and is currently 2.5-11.4 per 100000 world-wide. Notably, approximately 25% ...of children with CD develop stricturing CD (SCD) that requires intervention. Symptomatic stricturing diseases refractory to pharmacological management frequently require non-pharmacological interventions. Non-pharmacological therapeutic strategies include endoscopic balloon dilatation, stricturoplasty, and surgical resection of the strictured segment. However, strictures tend to recur postoperatively regardless of treatment modality. The lifetime risk of surgery in patients with childhood SCD remains at 50%-90%. Thus, new and emerging strategies, advanced diagnostic tools, and minimally invasive approaches are under investigation to improve the outcomes and overall quality of life of pediatric patients with SCD.
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