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OBJECTIVES: Ulcerative colitis (UC) is a chronic inflammatory disorder of unknown aetiology. Gut virome dysbiosis is fundamental in UC progression, although its role in the early phases of the disease is far from fully understood. Therefore, we sought to investigate the role of a virome-associated protein encoded by the Orthohepadnavirus genus, the hepatitis B virus X protein (HBx), in UC aetiopathogenesis. DESIGN: HBx positivity of UC patient-derived blood and gut mucosa was assessed by RT-PCR and Sanger sequencing and correlated with clinical characteristics by multivariate analysis. Transcriptomics was performed on HBx-overexpressing endoscopic biopsies from healthy donors.C57BL/6 mice underwent intramucosal injections of liposome-conjugated HBx-encoding plasmids or the control, with or without antibiotic treatment. Multidimensional flow cytometry analysis was performed on colonic samples from HBx-treated and control animals. Transepithelial electrical resistance measurement, proliferation assay, chromatin immunoprecipitation assay with sequencing and RNA-sequencing were performed on in vitro models of the gut barrier. HBx-silencing experiments were performed in vitro and in vivo. RESULTS: HBx was detected in about 45% of patients with UC and found to induce colonic inflammation in mice, while its silencing reverted the colitis phenotype in vivo. HBx acted as a transcriptional regulator in epithelial cells, provoking barrier leakage and altering both innate and adaptive mucosal immunity ex vivo and in vivo. CONCLUSION: This study described HBx as a contributor to the UC pathogenesis and provides a new perspective on the virome as a target for tailored treatments.
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Colitis Ulcerosa , Colitis , Animales , Ratones , Colitis Ulcerosa/patología , Viroma , Ratones Endogámicos C57BL , Colon/patología , Colitis/metabolismo , Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Modelos Animales de Enfermedad , Sulfato de DextranRESUMEN
Very early onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella classification composed of IBD-like diseases encompassing both classic IBD (Crohn's disease and ulcerative colitis) and monogenic disorder, both arising before 6 years of age. VEO-IBD patients present significant clinical differences from IBD occurring in older children and in adults, including more severe disease, often unresponsive to conventional IBD therapy and a greater proportion of cases featuring an underlying genetic alteration. Histologic findings of gastrointestinal biopsies can show an IBD-like pattern (both Crohn's disease-like and ulcerative colitis-like pattern), an apoptotic-like and enterocolitis-like pattern. Findings of specific morphologic alterations, such as villous blunting, apoptosis, dense eosinophilic infiltrates, lack of plasma cells and severe glandular atrophy, can suggest a monogenic disorder. Moreover, individuals with monogenic disorders may develop significant problems such as primary immunodeficiency, impacting treatment options. Finally, IBD histology in childhood can differ from that in older patients and adults. This complexity makes a differential diagnosis between IBD and other pediatric diseases involving the gastrointestinal tract difficult, especially considering that histologic features can be similar between different diseases. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery and more intensive medical therapies rather than specific therapy directed toward the underlying defect. For these reasons, a pattern-based histologic approach correlated with clinical and laboratory findings with a multidisciplinary approach is fundamental to reach a correct diagnosis in an adequate clinical context.
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Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Edad de Inicio , Anciano , Niño , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/terapia , Diagnóstico Diferencial , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , FenotipoRESUMEN
PURPOSE: For superficial colonic lesions, the NICE and Kudo classifications are used in the in vivo prediction of histology and as guide to therapy. The NICE system derives information from unmagnified NBI endoscopic images. The Kudo one necessitates a magnification, but, as this tool is not commonly available, it is applied also to characterize unmagnified pictures to compare their diagnostic performances. METHODS: We conducted a prospective comparison of the NICE versus the Kudo classification for the differential diagnosis of colonic polyps taking histology as the gold standard. The inter-observer agreement for both classifications among 11 colonoscopists was also evaluated. Short unmagnified NBI videoclips of 64 colonic polyps were sent twice to the participants. In the first round, they classified the lesions according to the NICE classification; 4 months later, the same videos were assessed with the Kudo system. The diagnosis provided by the participants was grouped in non-neoplastic, non-invasive neoplasia, invasive neoplasia. RESULTS: Overall, the diagnostic accuracy was 82% (95%CI: 79-85) with the NICE system and 81% (95%CI: 78-84) with the Kudo one (ρ = 0.78). The accuracy of the NICE classification for non-neoplastic lesions was greater compared with the Kudo's (ρ = 0.03). Sensitivity sub-analyses revealed a higher ability of the NICE in distinguishing between neoplastic vs. non-neoplastic lesions (ρ = 0.01). The overall inter-rater agreement did not differ when the classifications were compared. CONCLUSION: The NICE and the Kudo classifications might be considered comparable. Our data could allow the use of the NBI Kudo classification even in those centers where magnification is not available.
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Pólipos del Colon , Neoplasias Colorrectales , Colon , Pólipos del Colon/diagnóstico por imagen , Colonoscopía , Humanos , Variaciones Dependientes del Observador , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: COVID-19 has rapidly become a major health emergency worldwide. Patients with IBD are at increased risk of infection, especially when they have active disease and are taking immunosuppressive therapy. The characteristics and outcomes of COVID-19 in patients with IBD remain unclear. DESIGN: This Italian prospective observational cohort study enrolled consecutive patients with an established IBD diagnosis and confirmed COVID-19. Data regarding age, sex, IBD (type, treatments and clinical activity), other comorbidities (Charlson Comorbidity Index (CCI)), signs and symptoms of COVID-19 and therapies were compared with COVID-19 outcomes (pneumonia, hospitalisation, respiratory therapy and death). RESULTS: Between 11 and 29 March 2020, 79 patients with IBD with COVID-19 were enrolled at 24 IBD referral units. Thirty-six patients had COVID-19-related pneumonia (46%), 22 (28%) were hospitalised, 7 (9%) required non-mechanical ventilation, 9 (11%) required continuous positive airway pressure therapy, 2 (3%) had endotracheal intubation and 6 (8%) died. Four patients (6%) were diagnosed with COVID-19 while they were being hospitalised for a severe flare of IBD. Age over 65 years (p=0.03), UC diagnosis (p=0.03), IBD activity (p=0.003) and a CCI score >1 (p=0.04) were significantly associated with COVID-19 pneumonia, whereas concomitant IBD treatments were not. Age over 65 years (p=0.002), active IBD (p=0.02) and higher CCI score were significantly associated with COVID-19-related death. CONCLUSIONS: Active IBD, old age and comorbidities were associated with a negative COVID-19 outcome, whereas IBD treatments were not. Preventing acute IBD flares may avoid fatal COVID-19 in patients with IBD. Further research is needed.
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Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus , Enfermedades Inflamatorias del Intestino , Pandemias , Manejo de Atención al Paciente , Neumonía Viral , Factores de Edad , COVID-19 , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/terapia , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/terapia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Evaluación de Procesos y Resultados en Atención de Salud , Gravedad del Paciente , Manejo de Atención al Paciente/métodos , Manejo de Atención al Paciente/estadística & datos numéricos , Neumonía Viral/diagnóstico , Neumonía Viral/etiología , Neumonía Viral/mortalidad , Neumonía Viral/fisiopatología , Neumonía Viral/terapia , Estudios Prospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: Takotsubo syndrome (TTS) is an acute cardiac dysfunction in the absence of viral causes or obstructive coronary disease completely reversible within 4-8 weeks. Inflammatory bowel diseases (IBD) are a group of diseases caused by the interaction between immune system, genetic, and environmental factors against intestinal mucosa. Both these syndromes are characterized by complex mechanisms involving endothelial dysfunction and affective disorders. AIM: To assess the possibility of an association between IBD and TTS. METHODS: First, we present a case of TTS in a patient affected by active stenosing Crohn's disease. Articles in English language were collected from PubMed and Google Scholar databases with the search terms "takotsubo," "IBD," "crohn disease," "ulcerative colitis". RESULTS: Both TTS and IBD show multiple common features: preference for female patients, recurrent course of disease, association with endothelial dysfunction, and affective disorders. Patients affected by IBD could show specific triggers for TTS, such as malabsorption, electrolytes disturbances, and affective disorders. CONCLUSIONS: Despite pathophysiological similarities between TTS and IBD in active phase, future studies are needed to confirm this apparently possible association and to assess the presence of a pathophysiological link between these diseases.
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Enfermedades Inflamatorias del Intestino/complicaciones , Cardiomiopatía de Takotsubo/complicaciones , Anciano , Anciano de 80 o más Años , Enfermedad de Crohn/complicaciones , Femenino , HumanosRESUMEN
BACKGROUND: Golimumab is a new anti-TNF-alpha monoclonal antibody for patients with ulcerative colitis. AIMS: To assess the short- and long-term effectiveness and safety of golimumab in daily clinical practice and to identify predictors of response. METHODS: Consecutive patients treated with golimumab in 22 Italian centers were enrolled. Clinical, laboratory, and endoscopic data were prospectively collected before and during treatment. A subgroup of patients completed a questionnaire to assess personal satisfaction with a golimumab autoinjector system. RESULTS: A total of 196 patients were included. After 3 months, 130 patients were responders (66.3%) and showed significant reductions in mean partial, total, and endoscopic Mayo scores and in mean ESR, C-reactive protein, and fecal calprotectin levels (p < 0.001). Multivariate analysis revealed that a higher total Mayo score (p < 0.001, OR 1.5, 95% CI 1.2-1.8) and naïve status to anti-TNF-alpha (p = 0.015, OR 3.0, 95% CI 1.2-7.5) were predictive of a favorable response. Seventy-seven (39.3%) of the 130 responders maintained a response at month 12 of therapy. There were 17 adverse events, 28 patients needed hospitalization, and 15 patients underwent surgery. Self-administration of the drug was appreciated by most patients. CONCLUSIONS: The efficacy and safety of golimumab in daily clinical practice were confirmed for the short- and long-term treatment of patients with active ulcerative colitis. Patients naïve to the anti-TNF-alpha monoclonal antibody and those with a higher total Mayo score were more likely to respond to golimumab.
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Anticuerpos Monoclonales/uso terapéutico , Colitis Ulcerosa/terapia , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor ß1 (TGF-ß1) due to high levels of SMAD7, an inhibitor of TGF-ß1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. METHODS: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. RESULTS: The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease. CONCLUSIONS: We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).
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Enfermedad de Crohn/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Oligonucleótidos/administración & dosificación , Proteína smad7/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Proteína C-Reactiva/análisis , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Glucocorticoides/administración & dosificación , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Oligonucleótidos/efectos adversos , Oligonucleótidos Antisentido/uso terapéutico , Inducción de Remisión , Adulto JovenRESUMEN
BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.
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Corticoesteroides/uso terapéutico , Antiinflamatorios/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Colon/efectos de los fármacos , Fármacos Gastrointestinales/uso terapéutico , Metotrexato/uso terapéutico , Corticoesteroides/efectos adversos , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Colitis Ulcerosa/diagnóstico , Colon/patología , Método Doble Ciego , Quimioterapia Combinada , Europa (Continente) , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Humanos , Inyecciones Intramusculares , Inyecciones Subcutáneas , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Inducción de Remisión , Factores de Tiempo , Resultado del Tratamiento , Cicatrización de Heridas/efectos de los fármacosRESUMEN
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.
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Enfermedad de Crohn/genética , Regulación de la Expresión Génica , MicroARNs/genética , Interferencia de ARN , ARN Mensajero/genética , Biología Computacional/métodos , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Enfermedades Inflamatorias del Intestino/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , TranscriptomaRESUMEN
OBJECTIVE: Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. DESIGN: We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800â mg, or placebo, three times daily for 12â weeks, and were followed for additional 12â weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. RESULTS: A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. CONCLUSIONS: Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. TRIAL REGISTRATION NUMBER: ClincialTrials.gov number, NCT00626288.
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Antiinflamatorios no Esteroideos/uso terapéutico , Síndrome del Colon Irritable/tratamiento farmacológico , Mesalamina/uso terapéutico , Adulto , Anciano , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Infliximab is a safe and effective therapy for ulcerative colitis (UC). We conducted a multicenter retrospective cohort study that included 7 European countries and Israel to examine whether infliximab discontinuation can be considered for patients who achieve sustained remission. METHODS: We performed a retrospective cohort study, collecting medical records from 13 tertiary care referral inflammatory bowel disease centers of all patients with UC treated with infliximab (n = 193). We compared the disease course of patients with at least 12 months of clinical remission who discontinued infliximab (n = 111) with that of patients who continued scheduled treatment (controls, n = 82). We examined the incidence rates of relapse, hospitalization and colectomy, the comparative effectiveness of different therapeutic strategies after discontinuation, and assessed the rates of response, remission, and adverse effects after infliximab re-initiation. Statistical analyses used time-to-event methods. RESULTS: In the entire cohort, 67 patients (34.7%) relapsed during the follow-up period. The incidence rate of relapse was significantly higher after discontinuation (23.3 per 100 person-years) compared with the control group (7.2 per 100 person-years) in univariable analysis (log-rank P < .001; hazard ratio, 3.41; 95% confidence interval, 1.88-6.20) and multivariable analysis (hazard ratio, 3.70; 95% confidence interval, 2.02-6.77). Rates of hospitalization and colectomy did not differ between groups. Thiopurines appeared to be the best treatment option after infliximab discontinuation (incidence of relapse: 15.0 per 100 person-years for thiopurines, 27.4 per 100 person-years for thiopurines plus aminosalicylates, and 31.2 per 100 person-years for aminosalicylates alone; log-rank P = .032). Response was regained in 77.1% of patients and remission in 51.4% of patients who re-initiated infliximab. However, 17.1% had infusion reactions and 17.1% reported other adverse events. CONCLUSIONS: In a multinational retrospective cohort study of patients with UC in sustained clinical remission, we associated discontinuation of infliximab with an increased risk of relapse. Treatment re-initiation is effective and safe.
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Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Infliximab/administración & dosificación , Privación de Tratamiento , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Europa (Continente) , Femenino , Humanos , Israel , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Adulto JovenRESUMEN
To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
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Cromosomas Humanos Par 13 , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 7 , Epistasis Genética , Sitios Genéticos , Cirrosis Hepática Biliar/genética , Polimorfismo de Nucleótido Simple , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Cirrosis Hepática Biliar/inmunología , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Various extrinsic and intrinsic factors such as drug exposures, antibiotic treatments, smoking, lifestyle, genetics, immune responses, and the gut microbiome characterize ulcerative colitis and Crohn's disease, collectively called inflammatory bowel disease (IBD). All these factors contribute to the complexity and heterogeneity of the disease etiology and pathogenesis leading to major challenges for the scientific community in improving management, medical treatments, genetic risk, and exposome impact. Understanding the interaction(s) among these factors and their effects on the immune system in IBD patients has prompted advances in multi-omics research, the development of new tools as part of system biology, and more recently, artificial intelligence (AI) approaches. These innovative approaches, supported by the availability of big data and large volumes of digital medical datasets, hold promise in better understanding the natural histories, predictors of disease development, severity, complications and treatment outcomes in complex diseases, providing decision support to doctors, and promising to bring us closer to the realization of the "precision medicine" paradigm. This review aims to provide an overview of current IBD omics based on both individual (genomics, transcriptomics, proteomics, metagenomics) and multi-omics levels, highlighting how AI can facilitate the integration of heterogeneous data to summarize our current understanding of the disease and to identify current gaps in knowledge to inform upcoming research in this field.
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Growing evidence suggests that alterations in the gut microbiome impact the development of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). Although IBD often requires the use of immunosuppressant drugs and biologic therapies to facilitate clinical remission and mucosal healing, some patients do not benefit from these drugs, and the reasons for this remain poorly understood. Despite advancements, there is still a need to develop biomarkers to help predict prognosis and guide treatment decisions. The aim of this study was to investigate the gut microbiome of IBD patients using biologics to identify microbial signatures associated with responses, following standard accepted criteria. Microbiomes in 66 stool samples from 39 IBD patients, comprising 20 CD and 19 UC patients starting biologic therapies, and 29 samples from healthy controls (HCs) were prospectively analyzed via NGS and an ensemble of metagenomics analysis tools. At baseline, differences were observed in alpha and beta metrics among patients with CD, UC and HC, as well as between the CD and UC groups. The degree of dysbiosis was more pronounced in CD patients, and those with dysbiosis exhibited a limited response to biological drugs. Pairwise differential abundance analyses revealed an increasing trend in the abundance of an unannotated genus from the Clostridiales order, Gemmiger genus and an unannotated genus from the Rikenellaceae family, which were consistently identified in greater abundance in HC. The Clostridium genus was more abundant in CD patients. At baseline, a greater abundance of the Odoribacter and Ruminococcus genera was found in IBD patients who responded to biologics at 14 weeks, whereas a genus identified as SMB53 was more enriched at 52 weeks. The Collinsella genus showed a higher prevalence among non-responder IBD patients. Additionally, a greater abundance of an unclassified genus from the Barnesiellaceae family and one from Lachnospiraceae was observed in IBD patients responding to Vedolizumab at 14 weeks. Our analyses showed global microbial diversity, mainly in CD. This indicated the absence or depletion of key taxa responsible for producing short-chain fatty acids (SCFAs). We also identified an abundance of pathobiont microbes in IBD patients at baseline, particularly in non-responders to biologic therapies. Furthermore, specific bacteria-producing SCFAs were abundant in patients responding to biologics and in those responding to Vedolizumab.
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BACKGROUND: The administration of biological drugs in inflammatory bowel diseases (IBD) is increasingly moving from intravenous to subcutaneous formulations. AIMS: To evaluate the efficacy and safety of vedolizumab subcutaneous administration after switching from intravenous administration in ulcerative colitis (UC) patients in corticosteroid-free clinical remission. METHODS: An observational, multicentre, prospective study was conducted by the Italian Group for the study of IBD (IG-IBD). UC patients in clinical remission (pMAYO < 2) not receiving steroids for > 8 months before the switch, and with at least 6 months of follow-up were included. Switch from intravenous to subcutaneous vedolizumab was defined as successful in patients not experiencing a disease flare (pMAYO ≥ 2) or needing oral steroids or stopping subcutaneous vedolizumab during the 6 months of follow-up after the switch. RESULTS: Overall, 168 patients were included. The switch was a success in 134 patients (79.8%). Vedolizumab retention rate was 88.7% at month six. C-reactive protein and faecal calprotectin values did not change after the switch (p = 0.07 and p = 0.28, respectively). Ten of the 19 patients who stopped subcutaneous formulation switched back to intravenous formulation recapturing clinical remission in 80%. Side effects were observed in 22 patients (13.1%). CONCLUSION: Effectiveness of switching from intravenous to subcutaneous vedolizumab formulation in UC patients in steroid-free clinical remission is confirmed in a real-world setting.
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Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Humanos , Administración Intravenosa , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Estudios Prospectivos , Esteroides/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: The RIDART I study found a 13.6% prevalence of anemia in Italian patients with inflammatory bowel disease (IBD); most cases were due to iron-deficiency anemia (IDA). AIMS: To evaluate changes in hemoglobin concentration during a 24-week follow-up of anemic patients with IBD. METHODS: Follow-up laboratory and clinical data were obtained from RIDART I study patients with anemia. Factors affecting hemoglobin concentration, the impact of anemia on fatigue and quality of life (QoL), and its relationship with treatment, disease activity and disease complications were investigated. RESULTS: Hemoglobin was 108 g/L at baseline, increased to 121 g/L at follow-up week 12 (p < 0.001) and then stabilized until week 24, but most patients remained anemic, with IDA, throughout the study. Hemoglobin improvement was greater in patients receiving either oral or parenteral iron supplementation. Following hemoglobin normalization, anemia relapse rate during follow-up was 30%. Oral iron did not cause disease reactivation. Lower follow-up hemoglobin was associated with a higher probability of having active disease, clinical complications, increased fatigue and reduced QoL. CONCLUSIONS: In anemic patients with IBD, anemia represents a long-lasting problem, in most cases persisting for up to 24 weeks, with high relapse rate and a negative impact on fatigue and QoL.
Asunto(s)
Anemia Ferropénica , Hemoglobinas , Enfermedades Inflamatorias del Intestino , Calidad de Vida , Humanos , Masculino , Femenino , Italia/epidemiología , Hemoglobinas/análisis , Adulto , Estudios de Seguimiento , Enfermedades Inflamatorias del Intestino/complicaciones , Persona de Mediana Edad , Anemia Ferropénica/etiología , Anemia Ferropénica/tratamiento farmacológico , Hierro/administración & dosificación , Hierro/uso terapéutico , Fatiga/etiología , Anemia/etiología , Recurrencia , Adulto JovenRESUMEN
BACKGROUND: Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), with a 6% to 74% prevalence and a negative impact on patient survival and quality of life, although the prevalence is apparently declining due to improved disease treatment. We aimed to investigate the prevalence, pathogenesis, and clinical correlates of anemia in Italian patients with IBD. METHODS: A multicenter, prospective, observational study, involving 28 Italian gastroenterology centers, was conducted to investigate the epidemiology and consequences of IBD-associated anemia. Clinical and laboratory data of anemic patients were obtained at study enrolment. RESULTS: Anemia was diagnosed in 737 of 5416 adult IBD outpatients (prevalence 13.6%); females were more commonly affected than males (odds ratio, 1.5; 95% confidence interval [CI], 1.2-1.7) and had more severe anemia. In the majority of cases, anemia was due to iron deficiency (62.5% of cases; 95% CI, 58.3%-66.6%), either isolated or in association with inflammation and/or vitamin deficiencies; anemia of inflammation accounted for only 8.3% of cases. More severe anemia was associated with increasing fatigue and worse quality of life. Only 68.9% of anemic patients with iron deficiency (95% CI, 63.4%-73.8%) and 34.6% of those with vitamin deficiencies (95% CI, 26.2%-44.2%) were properly treated with supplementation therapy. CONCLUSIONS: In Italy, the prevalence of IBD-associated anemia is lower than previously reported. Anemia of IBD is most commonly due to iron deficiency and contributes to fatigue and poor quality of life, but remains untreated in a large proportion of patients with iron and/or vitamin deficiencies. This study is registered at clinicaltrials.gov as NCT02872376.
The prevalence of inflammatory bowel diseaseassociated anemia is 13.6%. The prevalence is higher among females younger than 50. Anemia is usually due to iron deficiency and adversely affects fatigue and quality of life. Many patients with iron or vitamin deficiency (31% and 65%, respectively) remain untreated.
Asunto(s)
Anemia Ferropénica , Anemia , Avitaminosis , Enfermedades Inflamatorias del Intestino , Deficiencias de Hierro , Masculino , Adulto , Femenino , Humanos , Prevalencia , Calidad de Vida , Estudios Prospectivos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/epidemiología , Anemia/epidemiología , Anemia/etiología , Anemia/terapia , Avitaminosis/complicaciones , Inflamación/complicaciones , Fatiga/etiología , Anemia Ferropénica/epidemiología , Anemia Ferropénica/etiología , Anemia Ferropénica/terapiaRESUMEN
Background: Immune checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different solid tumors over the last ten years. Gastrointestinal (GI) adverse events (AEs), such as diarrhea and colitis, occur in up to 50% of patients treated with ICIs. Materials and methods: We conducted a single-center retrospective analysis in patients with solid tumors treated with ICIs in a 6-year period, from 2015 to 2021, developing GI AEs, for which an endoscopic analysis was performed, with available histological specimens or surgery. Results: Twenty-one patients developed GI AEs under ICIs. The median time from the start of ICIs to the onset of GI AEs was 5 months. Diarrhea was the most frequent symptom (57.2%), upper GI symptoms presented in four patients (19%), while three patients (14.3%) had no symptoms and were diagnosed occasionally. Two patients underwent surgical resection for acute abdomen. Histological findings observed in endoscopic sampling were eosinophilic-pattern gastro-enterocolitis, apoptotic damage, IBD-like features, and ischemic-like changes. Histological damage was also documented in patients with unremarkable endoscopy. Conclusions: Under ICI therapy, GI toxicity is an expected event. Since GIAEs can mimic a broad range of primary GI diseases, a multidisciplinary approach is advocated with upper and lower GI mucosal sampling to remodel therapy and avoid complications.
RESUMEN
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.