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Introduction For patients with inflammatory bowel diseases, switching from infliximab originator to biosimilars is effective and safe. Few data on single switch have been published, and data on multiple switches of different infliximab are unavailable. Methods A retrospective analysis of patients who switched from CT-P13 to SB2, and of those with multiple switches among different infliximab compounds was conducted. Clinical activity, C reactive protein (CRP), adverse events (AE) and loss of response (LOR) were recorded. Results Thirty-six patients (26 males, 14 Crohn's disease and 22 ulcerative colitis) were enrolled and followed up for >6 months. All patients switched from CT-P13 to SB2; 12 of them (33.3%) had already switched from reference Infliximab to CT-P13, and for the remaining patients CT-P13 was the first infliximab. The clinical remission rate six months before and three months after SB2-switch was the same (58.3%) and the rate of mild activity varied from 27.8 to 33.3% (P = 0.68); the percentage of patients with normal CRP values passed from 94.4 to 91.7% (P = 1). Two patients (5.5%) had AE and 11 (30.5%) a LOR. At univariate analysis, patients with a single switch had a non-significant risk of LOR during SB2 [odds ratio (OR) = 7.86; 95% confidence interval (CI) 0.87-71, P = 0.06]. SB2-LOR was associated with previous AE under CT-P13 (OR = 9.1, 95% CI 0.82-100, P = 0.07). None of such factors was significant at multivariate analysis. Conclusion Switching from CT-P13 to SB2 seems to be safe and effective either in patients with a single than in those with multiple switches.

The pathogenesis of ulcerative colitis (UC) is unknown, although genetic loci and altered gut microbiota have been implicated. Up to a third of patients with moderate to severe UC require proctocolectomy with ileal pouch ano-anastomosis (IPAA). We aimed to explore the mucosal microbiota of UC patients who underwent IPAA. Methods: For microbiome analysis, mucosal specimens were collected from 34 IPAA individuals. Endoscopic and histological examinations of IPAA were normal in 21 cases, while pouchitis was in 13 patients. 19 specimens from the healthy control (10 from colonic and 9 from ileum) were also analyzed. Data were analyzed using an ensemble of software packages: QIIME2, coda-lasso, clr-lasso, PICRUSt2, and ALDEx2. Results: IPAA specimens had significantly lower bacterial diversity as compared to normal. The microbial composition of the normal pouch was also decreased also when compared to pouchitis. Faecalibacterium prausnitzii, Gemmiger formicilis, Blautia obeum, Ruminococcus torques, Dorea formicigenerans, and an unknown species from Roseburia were the most uncommon in pouch/pouchitis, while an unknown species from Enterobacteriaceae was over-represented. Propionibacterium acnes and Enterobacteriaceae were the species most abundant in the pouchitis and in the normal pouch, respectively. Predicted metabolic pathways among the IPAA bacterial communities revealed an important role of immunometabolites such as SCFA, butyrate, and amino acids. Conclusions: Our findings showed specific bacterial signature hallmarks of dysbiosis and could represent bacterial biomarkers in IPAA patients useful to develop novel treatments in the future by modulating the gut microbiota through the administration of probiotic immunometabolites-producing bacterial strains and the addition of specific prebiotics and the faecal microbiota transplantation.

Background Patients with inflammatory bowel diseases (IBD), both ulcerative colitis (UC) and Crohn’s disease (CD), are at risk of developing a colorectal cancer (CRC). No information is available on the contribution of patients’ genetic background to CRC occurrence. This study investigates germline alterations in patients with IBD-associated CRC. Methods We profiled a panel of 39 genes potentially involved in cancer predisposition and searched for germline variants in IBD patients with CRC or high-grade dysplasia. Results After clinical exclusion of genetic cancer syndromes, 25 IBD patients (4 CD and 21 UC) with CRC or high-grade dysplasia were studied. After excluding variants with low likelihood of pathogenicity (classes 1 or 2 according the International Agency for Research on Cancer [IARC]), the panel identified pathogenic variants, likely pathogenic, or variants with unknown significance in 18 patients (72%). Six patients (24%) carried pathogenic or likely variants (IARC class 5 or 4). Of the identified variants, 4 encompassed the APC region, 3 the MLH1 gene, and the remaining ones the MSH2, MSH3, monoallelic MUTYH, EPCAM, BRCA1, CHEK2, POLD1, POLE, CDKN2A, and PDGFRA genes. Four patients carried at least 2 variants in different genes. Duration of IBD was significantly shorter in carriers of 4 or 5 IARC variants (7 years; range 0–21; P = .002) and in those with variants with unknown significance (12 years; range 0–22; P = .005) compared with patients without or with only benign variations (23.5 years; range 15–34). Conclusions In silico analysis and sequence-based testing of germline DNA from IBD patients with CRC or high-grade dysplasia detected 24% of variants positioned in pathogenic classes. In patients with type 3, 4, and 5 variants, the onset of high-grade dysplasia or CRC was significantly earlier than in patients with benign or unidentified variants. The screening for these genes could identify IBD patients requiring a more intensive endoscopic surveillance for earlier detection of dysplastic changes.

Background Patients receiving biologic therapies are at risk for viral infections. This study investigated the impact of the SARS-CoV-2 infection and the serum prevalence of SARS-CoV-2 antibodies in patients with inflammatory bowel disease (IBD) treated with biologic drugs. Methods Information on demography, co-morbidities, clinical data regarding IBD, symptoms suggestive of the SARS-CoV-2 infection, close contacts with SARS-CoV-2 positive patients, hospitalization, and therapies administered for COVID-19 was collected for all patients who were being treated with biologic drugs. All patients underwent SARS-CoV-2 antibody testing. Results Two hundred and fifty-nine patients (27 children) with a mean age of 42.2 ± 16.7 years (range 9 - 88) and a mean duration of disease of 13.4 ± 10 years (range 0.2 – 49) were enrolled. One hundred four patients (40.2%) had ulcerative colitis, and 155 (59.8%) had Crohn's disease. About the therapy: 62 patients were receiving infliximab, 89 adalimumab, 20 golimumab, 57 vedolizumab, 27 ustekinumab, 1 thalidomide, and 3 an experimental compound. The mean Charlson Comorbidity Index was 2. Thirty-two patients (12.3%) reported respiratory symptoms, and 2 of them were hospitalized (0.77%). Two patients resulted positive for IgG against SARS-CoV-2 (0.77%). Conclusions In patients with IBD, treatment with biologic drug does not represent a risk factor for the SARS-CoV-2 infection.

Background The SARS-CoV-2 pandemic has led to a remodeling of care activity, including the inflammatory bowel disease (IBD) centers. According to international recommendations, we did not discontinue immunosuppressive or biologic drugs and reorganized biologic drug infusions’ administration to minimize the risk of infection. The aim of this study is to describe the clinical outcome of SARS-CoV-2 infection and the adherence to the scheduled biologic therapies in a single tertiary center including both IBD adult and pediatric patients treated with biological agents during COVID-19 pandemic. Methods Demographic information, clinical data and the adherence to the therapy were collected in all consecutive IBD patients treated with biologic agents from March 2020 to February 2021. Moreover, we reported the clinical outcome of IBD patients infected with SARS-CoV-2. Results A total of 278 subjects (171 male) treated with a biologic agent (34 children) were included. The mean age was 41.6 ± 17.3 years (range 5 – 88), and the mean disease duration was 12.7 ± 10.1 years (range 0.2 – 49). One hundred eleven patients (39.9 %) had ulcerative colitis, and 167 (60.0 %) had Crohn’s disease. About the therapy: 73 patients were receiving infliximab, 93 adalimumab, 20 golimumab, 59 vedolizumab, 29 ustekinumab, and 4 an experimental compound. 31 patient, including 1 child, (11.1 %) were treated with combination therapy. The mean Charlson Comorbidity Index was 1.5 (range 0 – 8). Twenty one patients (2 pediatrics and nineteen adults) (7.5 %) had a confirmed diagnosis of SARS-COV-2 infection. Only one of them (an adult man) was hospitalized but did not require intensive care unit measures. Compared to cumulative SARS-CoV-2 infection in the general population in our Region, the cumulative incidence of SARS-CoV-2 infection in our cohort was significantly higher (7.5% vs 4.0%, p < 0.002). Twelve adult patients (4.3%) postponed biologic therapy for fear of SARS-CoV-2 infection during the first wave of the pandemic, and two of them (16.6%) experienced a clinical relapse. Conclusion In our cohort, the adherence to biologic therapy was high during the pandemic, but the rate of clinical relapse in patients who postponed the scheduled administration of therapy was relevant. Although the incidence of SARS-CoV-2 infection was significantly higher than in general population, the clinical impact was mild as no patients experienced a severe form of COVID-19.

Background Roughly 50% of patients with IBD have symptoms of psychological distress (Mikocka-Walus et al. 2019) but only 15.2% receive attention for their mental health although the effect on disease severity can be profound. It is necessary to have an easy-to-administer psychological distress screening tool. The distress thermometer (DT) is a single-item distress screening scale with 11-likert response widely used in oncological patients. The aim of study was to determine whether the single-item DT compared favourably with IBD clinical indices and time consuming measures currently used to screen for distress. Methods Two hundered and twenty IBD patients (51.43% male) who were recruited in eight Italian hospitals completed the DT and identified the presence or absence of 34 problems using standardised problem list (PL). They completed the 14-item Hospital Anxiety and Depression Scale (HADS) and the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ). Disease clinical indices have been collected for each patient (Mayo score, Harvey–Bradshaw Index–HBI, years of illness, and exacerbation in the last year). Using receiver operating characteristic (ROC) analyses validated the use of the DT in Italian IBD population. Results 47.6% reported anxiety and depression symptoms (HADS ≥15) and needs emotional care. Anxiety is much more associated (43.8%) than depressive problems (26.2%). Data are confirmed by responses to DT and PL: 44.5% of patients reported moderate–severe emotional distress (TD ≥ 5), 43.1% of patients report nervousness and worry, 27.1% reported depression. We observed a strong positive correlation between IBDQ and HADS (r = 0.74, p < 0.001) and DT (r = 0.58, p < 0.001), while there was a slightly smaller association with Mayo score (r = 0.46, p < 0.001) and HBI (r = 0.39, p < 0.001). There was not a statistical significant correlation between disease indices and the emotional distress as measured by HADS or DT. ROC analyses showed that a DT cutoff score of 5 or higher had optimal sensitivity (83%) and specificity (68%) relative to the HADS score as ‘gold’ standard. DT scores yielded area under the curve estimates relative to the HADS cutoff score indicative of good overall accuracy (AUC = 0.81–95% CI: 0.77–0.85). Conclusion Our study confirms that anxiety and depression symptoms are associated with IBD. This is the first study that demonstrated that DT is an easy-to-administer screening tool of psychosocial distress in IBD population. We propose that gastroenterologists use DT to identify patients with psychological distress: an early psychological support and a multidisclinar equipe can determinate a patient’s better disease course (Mawdsley et al. 2005). Our analyses indicated that using a DT’s cutoff of 5 to indicate high levels of distress.

Background: Achalasia is a rare idiopathic disease with a complex etio-pathogenesis still unknown. This study aimed to identify microRNA (miRNA)-mRNA regulatory networks underlying achalasia. Methods: The investigation was performed in tissue specimens from 11 patients and five controls using the microarray technology followed by an integrated bioinformatics analysis. Key Results: One hundred and six miRNAs were significantly up-regulated and 64 were down-regulated in achalasia patients. The expression of the most 10 differential expressed miRNAs (miR-122-5p, miR-133a-3p, miR-504-5p, miR-187-3p, miR-133b, miR-200c-3p, miR-375, miR-200b-5p, miR-200b-3p, and miR203a) was confirmed by droplet digital PCR in an independent cohort. The interactions between the significant miRNAs and their targets uncovered 14 miRNA-mRNA interacting pairs with experimentally predicted genes (ie, FN1, ROCK2, DPYSL2), and 35 pairs with not experimentally target genes (ie, SULF1, MRVI1, PRKG1); all genes were involved in immune cell trafficking, skeletal and muscular system development, nervous system development macro-processes. Conclusion & Inferences: The mRNA–miRNA regulatory networks described in this study provide new insights in the genetic background of the disease, suggesting further investigations in novel pathogenic mechanisms.

The authors would like to indicate that Dr. Orazio Palmieri and Dr. Teresa Maria Creanza contributed equally to the work published in the International Journal of Molecular Sciences [1] [...]

Introduction Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic, systemic Inflammatory Bowel Diseases (IBDs) that need a multidisciplinary approach involving not only different medical specialists but also qualified nurses. Aim We evaluated the concordance between IBD-nurse and physician in computing Clinical Activity Scores in IBD-patients treated with biologics. Methods We enrolled all consecutive IBD-patients treated with biologics in two referral centers for IBD-care. For each patient, a gastroenterologist and a nurse blindly filled-out a form to assess the Harvey–Bradshaw Index (HBI) in CD or the partial MAYO score in UC. All data were recorded to assess the beyond chance agreement (concordance) using the k statistic. Results 87 patients were enrolled. The agreement in all patients by k value was substantial (66%), ranging from moderate to substantial (95% CI from 51% to 80%). The main reason of disagreement was about the scoring of remission versus mild activity, and that of mild versus moderate activity, both in CD and UC. For the HBI, the best agreement was for well-being on the previous day (k 62%) and the least one for abdominal mass (k 35%). Conclusions Our study shows an acceptable strength of agreement among nurse and gastroenterologist in evaluating the disease activity of IBD-patients through the calculation of clinical scores.

Background Crohn’s disease (CD) is a pathologic condition with different clinical expressions that may reflect an interplay between genetics and environmental factors. Recently, it has been highlighted that three genetic markers, NOD2, MHC and MST1, were associated to distinct CD sites, supporting the concept that genetic variations may contribute to localize CD. Genetic markers, previously shown to be associated with inflammatory bowel disease (IBD), were tested in CD patients with the aim to better dissect the genetic relationship between ileal, ileocolonic and colonic CD and ascertain whether a different genetic background would support the three disease sites as independent entities. Methods A panel of 29 SNPs of 19 IBD loci were analyzed by TaqMan SNP allelic discrimination method both evaluating their distinct contribute and analyzing all markers jointly. Results Seven hundred and eight CD patients and 537 healthy controls were included in the study. Of the overall population of patients, 237 patients had an ileal involvement (L1), 171 a colonic localization (L2), and the 300 remaining an ileocolon location (L3). We confirmed the association for 23 of 29 variations (P < 0.05). Compared to healthy controls, 16 variations emerged as associated to an ileum disease, 7 with a colonic disease and 14 with an ileocolonic site (P < 0.05). Comparing ileum to colonic CD, 5 SNPs (17%) were differentially associated (P < 0.05). A genetic model score that aggregated the risks of 23 SNPs and their odds ratios (ORs), yielded an Area Under the Curve (AUC) of 0.70 for the overall CD patients. By analyzing each CD location, the AUC remained at the same level for the ileal and ileocolonic sites (0.73 and 0.72, respectively), but dropped to a 0,66 value in patients with colon localization. Conclusions Our findings reaffirm the existence of at least three different subgroups of CD patients, with a genetic signature distinctive for the three main CD sites.

Background The satisfaction perceived by patients with chronic diseases affects clinical outcomes and healthcare costs. Some patients with inflammatory bowel disease (IBD) develop a more severe form requiring biologic therapy. We assessed the quality of care perceived by IBD patients in dedicated centers. Methods This prospective, cross-sectional, multicenter study enrolled consecutive IBD patients who underwent biologic therapy in the participating centers. The nurses directly involved in the management of these patients explained the rationale of the survey, provided a specific questionnaire (CACHE), and collected data. The CACHE included 31 items structured in 6 domains: staff care, clinician care, center facilities, patient information, accessibility, and patient support. Patients’ satisfaction score for each domain ranged from 0 to 100%. Results Sixteen different Italian centers participated and a total of 450 patients were enrolled (283 with Crohn’s disease and 167 with ulcerative colitis). The overall score was 82.2±19.6, satisfaction with the clinicians care scoring the highest (87.6±3.2) and the information provided to the patient scoring the lowest (70.7±7.9). More specifically, it emerged that 5.2-19.5% of patients were unsatisfied with: 1) the communication between the IBD medical team and primary care physicians; 2) information received about the disease or patients’ associations; and 3) the accessibility of the center. Conclusion Although our data revealed an acceptably high rate of global satisfaction among IBD patients receiving biologic therapy, more effort should be made to improve patient information and communication between IBD teams, other specialists and primary care physicians. Keywords Inflammatory bowel disease, Crohn’s disease, ulcerative colitis, biologic therapy, patient satisfaction Ann Gastroenterol 2017; 30 (1): 96-100

Idiopathic achalasia is characterized by the absence of peristalsis secondary to loss of neurons in the myenteric plexus that hampers proper relaxation of the lower esophageal sphincter. Achalasia can be considered a multifactorial disorder as it occurs in related individuals and is associated with HLA class II genes, thereby suggesting genetic influence. We used microarray technology and advanced in-silico functional analyses to perform the first genome-wide expression profiling of mRNA in tissue samples from 12 achalasia and 5 control patients. It revealed 1,728 differentially expressed genes, of these, 837 (48.4%) were up-regulated in cases. In particular, genes participating to the smooth muscle contraction biological function were mostly up-regulated. Functional analysis revealed a significant enrichment of neuronal/muscular and neuronal/immunity processes. Upstream regulatory analysis of 180 genes involved in these processes suggested TLR4 and IL18 as critical key-players. Two functional gene networks were significantly over-represented: one involved in organ morphology, skeletal muscle system development and function and neurological diseases and the other participating in cell morphology, humoral immune response and cellular movement. These results highlight on pivotal genes that may play critical roles in neuronal/muscular and neuronal/immunity processes and that may contribute to the onset and development of achalasia.

Simultaneous analysis of the transcripts of thousands of genes by cDNA microarrays allows the identification of genetic regulatory mechanisms involved in disease pathophysiology. The circadian clock circuitry controls essential cell processes and the functioning of organ systems, which are characterized by rhythmic variations with 24-hour periodicity. The derangement of these processes is involved in the basic mechanisms of inflammatory, metabolic, degenerative and neoplastic diseases. We evaluated by genome-wide cDNA microarray analysis the transcriptome of endoscopic mucosal biopsies of patients with inflammatory bowel diseases (IBD) focusing on the expression of circadian genes in Crohn’s disease (CD) and ulcerative colitis (UC). Twenty-nine IBD patients (15 with CD and 14 with UC) were enrolled and mucosal biopsies were sampled at either inflamed or adjacent non-inflamed areas of the colon. A total of 150 circadian genes involved in pathways controlling crucial cell processes and tissue functions were investigated. In CD specimens 50 genes were differentially expressed, and 21 genes resulted up-regulated when compared to healthy colonic mucosa. In UC specimens 50 genes were differentially expressed, and 27 genes resulted up-regulated when compared to healthy colonic mucosa. Among the core clock genes ARNTL2 and RORA were up-regulated, while CSNK2B, NPAS2, PER1 and PER3 were down-regulated in CD specimens. Conversely, ARNTL2, CRY1, CSNK1E, RORA and TIPIN were up-regulated, while NR1D2 and PER3 were down-regulated in UC. In conclusion, in CD and UC patients there are differences in the expression of circadian genes between normal and diseased intestinal mucosa. The deregulated genes evidenced by transcriptome analysis in the major IBDs may play a crucial role in the pathophysiological mechanisms and may suggest novel therapeutic approaches.

Article first published online 21 April 2015. Supplemental Digital Content is Available in the Text., Background: Ulcerative colitis (UC) and Crohn's disease (CD) share some pathogenetic features. To provide new steps on the role of altered gene expression, and the involvement of gene networks, in the pathogenesis of these diseases, we performed a genome-wide analysis in 15 patients with CD and 14 patients with UC by comparing the RNA from inflamed and noninflamed colonic mucosa. Methods: Two hundred ninety-eight differentially expressed genes in CD and 520 genes in UC were identified. By bioinformatic analyses, 34 pathways for CD, 6 of them enriched in noninflamed and 28 in inflamed tissues, and 19 pathways for UC, 17 in noninflamed and 2 in inflamed tissues, were also highlighted. Results: In CD, the pathways included genes associated with cytokines and cytokine receptors connection, response to external stimuli, activation of cell proliferation or differentiation, cell migration, apoptosis, and immune regulation. In UC, the pathways were associated with genes related to metabolic and catabolic processes, biosynthesis and interconversion processes, leukocyte migration, regulation of cell proliferation, and epithelial-to-mesenchymal transition. Conclusions: In UC, the pattern of inflammation of colonic mucosa is due to a complex interaction network between host, gut microbiome, and diet, suggesting that bacterial products or endogenous synthetic/catabolic molecules contribute to impairment of the immune response, to breakdown of epithelial barrier, and to enhance the inflammatory process. In patients with CD, genes encoding a large variety of proteins, growth factors, cytokines, chemokines, and adhesion molecules may lead to uncontrolled inflammation with ensuing destruction of epithelial cells, inappropriate stimulation of antimicrobial and T cells differentiation, and inflammasome events.

Crohn’s disease (CD) is a debilitating inflammatory bowel disease (IBD) that emerges due to the influence of genetic and environmental factors. microRNAs (miRNAs) have been identified in the tissue and sera of IBD patients and may play an important role in the induction of IBD. Our study aimed to identify differentially expressed miRNAs and miRNAs with the ability to alter transcriptome activity by comparing inflamed tissue samples with their non-inflamed counterparts. We studied changes in miRNA–mRNA interactions associated with CD by examining their differential co-expression relative to normal mucosa from the same patients. Correlation changes between the two conditions were incorporated into scores of predefined gene sets to identify biological processes with altered miRNA-mediated control. Our study identified 28 miRNAs differentially expressed (p-values < 0.01), of which 14 are up-regulated. Notably, our differential co-expression analysis highlights microRNAs (i.e., miR-4284, miR-3194 and miR-21) that have known functional interactions with key mechanisms implicated in IBD. Most of these miRNAs cannot be detected by differential expression analysis that do not take into account miRNA–mRNA interactions. The identification of differential miRNA–mRNA co-expression patterns will facilitate the investigation of the miRNA-mediated molecular mechanisms underlying CD pathogenesis and could suggest novel drug targets for validation.

Aim To investigate the association of single nucleotide polymorphisms (SNPs) of genes involved in the regulation of immune responses, IL33 , IL1RL1 , IL23R , and IL10 , with idiopathic achalasia in an Italian cohort of patients. Materials and methods A panel of eleven polymorphisms were genotyped in 116 unrelated idiopathic achalasic patients and 371 healthy subjects, by using TaqMan genotyping assays. Results Significant differences of allele ( P = 0.0065, OR = 1.59, CI = 1.14–2.22) and genotype ( P = 0.0097, OR = 1.74, CI = 1.14–2.65) frequencies of the IL33 rs3939286 variant were found between achalasic patients and controls. No association of the other investigated SNPs was detected. No differences in genotype and allele distribution were found with respect to clinical characteristics of patients. Conclusion We provide for the first time an association between the risk of developing idiopathic achalasia and IL-33 variant, underling the role of cytokines and inflammatory mediators on the pathogenesis of the disease.

BACKGROUND Efficacy of erythrocyte-mediated delivery of dexamethasone 21-phosphate in patients with steroid-dependent ulcerative colitis. METHODS Thirty-seven patients with steroid-dependent ulcerative colitis were randomized to infusions of dexamethasone 21-phosphate encapsulated into autologous erythrocytes (n = 19) or to sham infusions (n = 18). Each infusion was given monthly for 6 months. The primary endpoint was the proportion of patients able to discontinue oral corticosteroids during treatment while maintaining clinical remission or stable disease. Secondary endpoint was the proportion of patients with disappearance of steroid-related adverse events. RESULTS At each infusion, a mean of 9.8 ± 4.6 mg dexamethasone 21-phosphate was administered at each infusion, which allowed steady-state plasma levels of 8 ng/mL for the following 28 days. Thirteen patients in the dexamethasone 21-phosphate group and 4 sham-treated patients attained the primary outcome of the study, i.e., maintaining a stable condition despite oral steroids withdrawal (P = 0.008). In the remaining patients (6 and 15 in the 2 experimental groups, respectively), the treatment was prematurely withdrawn because of clinical deterioration while tapering oral steroids. At endoscopy, mucosal healing was ascertained in 4 patients and 1 patient of the 2 experimental groups, respectively (P = 0.339). At inclusion, 14 and 13 patients in the 2 experimental groups complained of steroid-related adverse events; at end of the treatment, events were still present in 5 and 13 patients, respectively (P = 0.008). CONCLUSIONS In patients with steroid-dependent ulcerative colitis, 6-month therapy with low dose of dexamethasone 21-phosphate allowed the withdrawal of oral steroids and the reversal of steroid-related adverse events in most patients while maintaining clinical remission (ClinicalTrials.gov number, NCT01171807).

BACKGROUND: Recent GWAs and meta-analyses have outlined about 100 susceptibility genes/loci for inflammatory bowel diseases (IBD). In this study we aimed to investigate the influence of SNPs tagging the genes/loci PTGER4, TNFSF15, NKX2-3, ZNF365, IFNG, PTPN2, PSMG1, and HLA in a large pediatric- and adult-onset IBD Italian cohort. METHODS: Eight SNPs were assessed in 1,070 Crohn's disease (CD), 1,213 ulcerative colitis (UC), 557 of whom being diagnosed at the age of ≤16 years, and 789 healthy controls. Correlations with sub-phenotypes and major variants of NOD2 gene were investigated. RESULTS: The SNPs tagging the TNFSF15, NKX2-3, ZNF365, and PTPN2 genes were associated with CD (P values ranging from 0.037 to 7×10(-6)). The SNPs tagging the PTGER4, NKX2-3, ZNF365, IFNG, PSMG1, and HLA area were associated with UC (P values 0.047 to 4×10(-5)). In the pediatric cohort the associations of TNFSF15, NKX2-3 with CD, and PTGER4, NKX2-3, ZNF365, IFNG, PSMG1 with UC, were confirmed. Association with TNFSF15 and pediatric UC was also reported. A correlation with NKX2-3 and need for surgery (P = 0.038), and with HLA and steroid-responsiveness (P = 0.024) in UC patients was observed. Moreover, significant association in our CD cohort with TNFSF15 SNP and colonic involvement (P = 0.021), and with ZNF365 and ileal location (P = 0.024) was demonstrated. CONCLUSIONS: We confirmed in a large Italian cohort the associations with CD and UC of newly identified genes, both in adult and pediatric cohort of patients, with some influence on sub-phenotypes.

In both main forms of Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), intestinal commensal microbiota are thought to trigger the disease in genetically susceptible individuals. Approximately one third of patients with CD have a mutation in the NOD2 gene that encodes an intracellular bacterial pattern-recognition receptor located within Paneth-cells. The maturation of Paneth cells is regulated via the canonical Wnt cascade. The Nkd1 (naked cuticle homologue 1), gene, a Wnt antagonist, is located near NOD2 at 16q12, and it has been found weakly associated with CD in WTCCC dataset (rs8047222 P