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Background & Aims: Wilson disease (WD) is caused by accumulation of copper primarily in the liver and brain. During maintenance therapy of WD with D-penicillamine, current guidelines recommend on-treatment ranges of urinary copper excretion (UCE) of 200-500 µg/24 h and serum non-ceruloplasmin-bound copper (NCC) of 50-150 µg/L. We compared NCC (measured by two novel assays) and UCE from patients with clinically stable WD on D-penicillamine therapy with these recommendations. Methods: This is a secondary analysis of data from the Chelate trial (NCT03539952) that enrolled physician-selected patients with clinically stable WD on D-penicillamine maintenance therapy (at an unaltered dose for at least 4 months). We analyzed laboratory samples from the first screening visit, prior to interventions. NCC was measured by either protein speciation (NCC-Sp) using anion exchange high-performance liquid chromatography protein speciation followed by copper determination with inductively coupled plasma mass spectroscopy or as exchangeable copper (NCC-Ex). NCC-Sp was also analyzed in healthy controls (n = 75). Results: In 76 patients with WD with 21.3±14.3 average treatment-years, NCC-Sp (mean±SD: 56.6±26.2 µg/L) and NCC-Ex (mean±SD: 57.9±24.7 µg/L) were within the 50-150 µg/L target in 61% and 54% of patients, respectively. In addition, 36% and 31%, respectively, were even below the normal ranges (NCC-Sp: 46-213 µg/L, NCC-Ex: 41-71 µg/L). NCC-Ex positively correlated with NCC-Sp (r2 = 0.66, p <0.001) but with systematic deviation. UCE was outside the 200-500 µg/24 h target range in 58%. Only 14/69 (20%) fulfilled both the NCC-Sp and UCE targets. Clinical or biochemical signs of copper deficiency were not detected. Conclusion: Clinically stable patients with WD on maintenance D-penicillamine therapy frequently have lower NCC-Sp or higher UCE than current recommendations without signs of overtreatment. Further studies are warranted to identify appropriate target ranges of NCC-Sp, NCC-Ex and UCE in treated WD. Impact and implications: Chelator treatment of patients with Wilson disease (WD) is currently guided by measurements of non-ceruloplasmin-bound copper (NCC) and 24 h urinary copper excretion (UCE) but validation is limited. In 76 adults with ≈21 years history of treated WD and clinically stable disease on D-penicillamine therapy, NCC was commonly found to be below normal values and recommended target ranges whether measured by protein speciation (NCC-Sp) or as exchangeable copper (NCC-Ex), while UCE values were above the recommended target range in 49%. Common wisdom would suggest overtreatment in these cases, but no clinical or biochemical signs of copper deficiency were observed. Exploratory analysis of liver enzymes suggested that NCC below levels seen in controls may be beneficial, while the relation to UCE was less clear. The data calls for critical re-evaluation of target ranges for treatment of WD, specific for drug and laboratory methodology. Clinical trial number: (NCT03539952).
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Inflammatory bowels diseases (IBD) are high risk conditions for colorectal cancer (CRC). The discovery of IBD and CRC noninvasive protein/peptide biomarkers using saliva and feces was the aim of this study involving 20 controls, 25 IBD (12 Crohn's Disease-CD), 37 CRC. By untargeted proteomic (LTQ-Orbitrap/MS), a total of 152 proteins were identified in saliva. Absent in controls, 73 proteins were present in both IBD and CRC, being mainly related to cell-adhesion, cadherin-binding and enzyme activity regulation (g-Profiler). Among the remaining 79 proteins, 14 were highly expressed in CD and 11 in CRC. These proteins clustered in DNA replication/expression and innate/adaptive immunity. In stool, endogenous peptides from 30 different proteins were identified, two being salivary and CD-associated: Basic Proline-rich Protein 1 (PRBs) and Acidic Proline-rich Phosphoprotein. Biological effects of the PRBs-related peptides GQ-15 and GG-17 found in CD stool were evaluated using CRC cell lines. These peptides induced cell proliferation and activated Erk1/2, Akt and p38 pathways. In conclusion, the salivary proteome unveiled DNA stability and immunity clusters shared between IBD and CRC. Salivary PRB-derived peptides, enriched in CD stool, stimulate CRC cell proliferation and the pro-oncogenic RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways suggesting a potential involvement of PRBs in IBD and cancer pathogenesis.
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Neoplasias Colorretais , Proteômica , Saliva , Humanos , Neoplasias Colorretais/metabolismo , Proteômica/métodos , Masculino , Feminino , Saliva/metabolismo , Pessoa de Meia-Idade , Adulto , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Idoso , Proteoma/metabolismo , Proteoma/análise , Fezes/química , Biomarcadores Tumorais/metabolismo , Linhagem Celular TumoralRESUMO
BACKGROUND: Recent studies showed that early surgery for Crohn's disease leads to a lower recurrence rate. However, the underlying mechanism is unknown. OBJECTIVE: The study aims to analyze the innate immunity microenvironment in ileal mucosa according to the duration of Crohn's disease. DESIGN: A prospective cohort study. SETTINGS: Tertiary referral center for IBD surgery. PATIENTS: A total of 88 consecutive patients with Crohn's disease undergoing ileocolonic resection were prospectively enrolled. Mucosal samples were obtained from both healthy and inflamed ileum. Data from a public data set were analyzed as an external validation cohort. MAIN OUTCOME MEASURES: Neutrophil infiltration was evaluated by histological asessment and macrophage subpopulation was assessed by immunohistochemistry. Expressions of TLR2 , TLR4 , TLR5 , DEFB1 , DEFB4A , DEFB103 , DEFA5 , and DEFA6 were quantified by real-time quantitative polymerase chain reaction. Concentrations of BDNF, CCL-11, ICAM-1, IL-1A, IL-1ß, IL-1RN, IL-12p40, IL-12p70, IL-15, IL-17A, IL-23A, MMP-3, CCL-3, KITLG, and VEGFA were determined with an immunometric assay. RESULTS: Neutrophil infiltration is inversely correlated with disease duration. DEFB4A mRNA expression tended to be higher in late-stage Crohn's disease ( p = 0.07). A higher number of macrophages expressed CD163 at low intensity in late-stage Crohn's disease ( p = 0.04). The concentration of IL-15 ( p = 0.02) and IL-23A ( p = 0.05) was higher in healthy ileal mucosa of early-stage patients. In the external cohort, expressions of DEFB1 ( p = 0.03), DEFB4A ( p = 0.01), IL-2 ( p = 0.04), and IL-3 ( p = 0.03) increased in patients with late-stage Crohn's disease. LIMITATIONS: A relatively small number of patients, especially in the newly diagnosed group. CONCLUSIONS: In newly diagnosed Crohn's disease, high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation. Moreover, M2 macrophages increase in the healthy mucosa of patients with late-stage Crohn's disease, suggesting that reparative and profibrotic processes are predominant in the long term, and in this phase, anti-inflammatory therapy may be less efficient. See Video Abstract . ACTIVACIN DE LA INMUNIDAD INNATA EN LA RECIENTEMENTE DIAGNOSTICADA ENFERMEDAD DE CROHN ILEOCLICA UN ESTUDIO DE COHORTE: ANTECEDENTES:Estudios recientes demostraron que la cirugía temprana para la enfermedad de Crohn (EC) conduce a una menor tasa de recurrencia. Sin embargo, se desconoce el mecanismo subyacente.OBJETIVO:El estudio tiene como objetivo analizar el microambiente de la inmunidad innata en la mucosa ileal según la duración de la EC.DISEÑO:Un estudio de cohorte prospectivo.AJUSTES:Centro terciario de referencia para cirugía de EII.PACIENTES:Fueron registrados de manera prospectiva y consecutiva 88 pacientes con EC sometidos a resección ileocolónica. Se obtuvieron muestras de mucosa ileal, tanto del íleon sano como del íleon inflamado. Los datos se analizaron como una cohorte de validación externa.PRINCIPALES MEDIDAS DE RESULTADO:Fueron evaluados la infiltración de neutrófilos por histología y la subpoblación de macrófagos por inmunohistoquímica. La expresión de TLR2, TLR4, TLR5, DEFB1, DEFB4A, DEFB103, DEFA5 y DEFA6 fueron cuantificados mediante qPCR en tiempo real. Las concentraciones de BDNF, CCL-11, ICAM-1, IL-1A, IL-1B, IL-1RN, IL-12 p40, IL-12 p70, IL-15, IL-17A, IL-23A, MMP-3, CCL-3, KITLG, VEGFA se determinaron con ensayo inmunométrico.RESULTADOS:La infiltración de neutrófilos se correlaciona inversamente con la duración de la enfermedad. La expresión del ARNm de DEFB4A mostro una tendencia a ser mayor en la EC en etapa tardía ( p = 0,07). Un mayor número de macrófagos expresaron CD163 a baja intensidad en la etapa tardía ( p = 0,04). La concentración de IL15 ( p = 0,02) e IL23A ( p = 0,05) fue mayor en la mucosa ileal sana de pacientes en estadio temprano. En la cohorte externa, la expresión de DEFB1 ( p = 0,03) y DEFB4A ( p = 0,01), IL2 ( p = 0,04) e IL3 ( p = 0,03) aumentó en pacientes en etapa tardía.LIMITACIONES:Un número relativamente pequeño de pacientes, especialmente en el grupo recién diagnosticado.CONCLUSIONES:En la EC recién diagnosticada, los altos niveles de IL-15 e IL-23 en la mucosa sana sugieren que la inmunidad innata es el promotor de la inflamación aguda. Además, los macrófagos M2 aumentan en la mucosa sana de pacientes con EC en etapa tardía, lo que sugiere que los procesos reparadores y profibróticos son predominantes a largo plazo y en esta fase, la terapia antiinflamatoria puede ser menos eficiente. (Traducción-Dr. Osvaldo Gauto ).
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Doença de Crohn , Molécula 1 de Adesão Intercelular , beta-Defensinas , Humanos , Estudos de Coortes , Interleucina-15 , Interleucina-17 , Metaloproteinase 3 da Matriz , Fator Neurotrófico Derivado do Encéfalo , Doença de Crohn/cirurgia , Estudos Prospectivos , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptor 5 Toll-Like , Imunidade Inata , Interleucina-12 , Interleucina-23 , Estudos RetrospectivosRESUMO
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.
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PURPOSES: Stricture is a common complication of Crohn's disease (CD) and may be treated with bowel-sparing procedures. Our study analyzed what happens in terms of intestinal and systemic inflammation when the diseased bowel is left behind following surgery. METHODS: In this retrospective study, we enrolled 42 consecutive patients who underwent strictureplasty (alone or with resection) for stricturing CD. Control patients who underwent complete diseased bowel resection were identified and propensity score-matched for the sex, age, and history of abdominal surgery. Biohumoral values were collected at follow-up examinations at 1, 6, and 12 months after surgery. Magnetic resonance imaging (MRI) was performed before and after strictureplasty in 19 patients. RESULTS: In the strictureplasty group, fecal calprotectin levels were decreased at 12 months (p = 0.03), whereas in the resectiongroup, they were decreased at 6 months (p = 0.02). On MRI, the ADC [apparent diffusion coefficient] (p < 0.001), wall thickness (p = 0.046) and Magnetic Resonance Index of Activity (MaRIA) (p < 0.001) and Clermont (p < 0.001) scores were improved after strictureplasty. Surgical recurrence was more frequent in the strictureplasty group than in the resection group (p = 0.003). CONCLUSIONS: Our retrospective study showed that even if the diseased bowel was left behind after surgery, the intestinal inflammatory activity still decreased. However, the permanence of the diseased bowel still increased the risk of reoperation, probably because of the fibrotic nature of the stenosis and the multifocality of CD.
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The role of biomarkers in the diagnosis of inflammatory bowel disease is not fully characterized. C-reactive protein has a short half-life and elevates quickly after the onset of an inflammatory process; the performance is better in Crohn's disease than in ulcerative colitis. Erythrocyte sedimentation rate is easy to determine, widely available, and cheap, but the long half-life, the influence of age, anemia, smoking, and drugs limit its usefulness. Fecal markers have good specificity, but suboptimal accuracy. Microbial antibodies and novel immunological markers show promise but need further evidence before entering clinical practice. Proteomic methods could represent the dawn of a new era of stool protein/peptide biomarker panels able to select patients at risk of inflammatory bowel disease.
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Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a complex, immune-mediated, disorder which leads to several gastrointestinal and systemic manifestations determining a poor quality of life, disability, and other negative health outcomes. Our knowledge of this condition has greatly improved over the last few decades, and a comprehensive management should take into account both biological (i.e., disease-related, patient-related) and non-biological (i.e., socioeconomic, cultural, environmental, behavioral) factors which contribute to the disease phenotype. From this point of view, the so called 4P medicine framework, including personalization, prediction, prevention, and participation could be useful for tailoring ad hoc interventions in IBD patients. In this review, we discuss the cutting-edge issues regarding personalization in special settings (i.e., pregnancy, oncology, infectious diseases), patient participation (i.e., how to communicate, disability, tackling stigma and resilience, quality of care), disease prediction (i.e., faecal markers, response to treatments), and prevention (i.e., dysplasia through endoscopy, infections through vaccinations, and post-surgical recurrence). Finally, we provide an outlook discussing the unmet needs for implementing this conceptual framework in clinical practice.
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The cost of caring for patients with inflammatory bowel disease (IBD) continues to increase worldwide. The cause is not only a steady increase in the prevalence of Crohn's disease and ulcerative colitis in both developed and newly industrialised countries, but also the chronic nature of the diseases, the need for long-term, often expensive treatments, the use of more intensive disease monitoring strategies, and the effect of the diseases on economic productivity. This Commission draws together a wide range of expertise to discuss the current costs of IBD care, the drivers of increasing costs, and how to deliver affordable care for IBD in the future. The key conclusions are that (1) increases in health-care costs must be evaluated against improved disease management and reductions in indirect costs, and (2) that overarching systems for data interoperability, registries, and big data approaches must be established for continuous assessment of effectiveness, costs, and the cost-effectiveness of care. International collaborations should be sought out to evaluate novel models of care (eg, value-based health care, including integrated health care, and participatory health-care models), as well as to improve the education and training of clinicians, patients, and policy makers.
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Colite Ulcerativa , Doença de Crohn , Gastroenterologia , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/terapia , Doença de Crohn/epidemiologia , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/terapia , Custos de Cuidados de SaúdeRESUMO
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.
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Anemia Ferropriva , Anemia , Deficiência de Vitaminas , Doenças Inflamatórias Intestinais , Deficiências de Ferro , Masculino , Adulto , Feminino , Humanos , Prevalência , Qualidade de Vida , Estudos Prospectivos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/epidemiologia , Anemia/epidemiologia , Anemia/etiologia , Anemia/terapia , Deficiência de Vitaminas/complicações , Inflamação/complicações , Fadiga/etiologia , Anemia Ferropriva/epidemiologia , Anemia Ferropriva/etiologia , Anemia Ferropriva/terapiaRESUMO
BACKGROUND: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease. METHODS: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 µg/L), 24 h urinary copper excretion (100-900 µg/24 h), and alanine aminotransferase (ALT; <2 × upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 µg/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting). FINDINGS: Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9·1 µg/L (95% CI -24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237·5 µg/24 h (99% CI 115·6 to 359·4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15·5 µg/L [95% CI -34·5 to 3·6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124·8 µg/24 h [99% CI -37·6 to 287·1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17·6 µg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 µg/L (-34·7 to 22·1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1·8 mg/L (-19·2 to 22·8) with penicillamine and -2·2 mg/L (-6·1 to 1·7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy. INTERPRETATION: The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease. FUNDING: Orphalan.
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Degeneração Hepatolenticular , Adulto , Humanos , Quelantes/efeitos adversos , Cobre , Degeneração Hepatolenticular/tratamento farmacológico , Penicilamina/efeitos adversos , Trientina/efeitos adversosRESUMO
Background: In 10%-20% of cases it is impossible to make a differential diagnosis between ulcerative colitis and Crohn's colitis. A 50% failure rate of J pouch ilea-anal anastomosis is observed in Crohn's colitis. In 2009, we created the Padua Prognostic Score for Colitis (PPSC) to predict the long-term clinical and functional outcome and quality of life of patients undergoing restorative proctocolectomy with J pouch. The aim of the present study is to establish and validate the accuracy of a prognostic score for chronic inflammatory bowel diseases (IBD). Patient population and methods: The PPSC was created in 2009 by integrating clinical and histological information of patients undergoing RPC. It included preoperative perianal abscess or fistula, rectal sparing, terminal ileum involvement, skip lesions and histological diagnosis of indeterminate colitis or Crohn's colitis on the operative specimen. The validity of this score was tested in predicting postoperative abscess or fistula, anal canal disease, pouchitis, pouch failure and new diagnosis of Crohn's disease. Correlation analysis, ROC curve analysis and survival analysis were used to validate the PPSC in a different cohort from the previous one. Results: We retrospectively enrolled in this study 138 consecutive patients undergoing CPR for ulcerative colitis (n = 127) or indeterminate colitis (n = 11) in our institution since 2005 to 2020. In this period, we observed 11 patients with postoperative abscess or fistula, 3 with anal canal disease, 40 with pouchitis, 6 with pouch failure and 6 with new diagnosis of Crohn's disease. In the new validation cohort, the PPSC confirmed to have a good accuracy in predicting the onset of postoperative CD (AUC = 74.5%, p = 0.018). Kaplan Meier curves demonstrate how a PPSC over 1 can reliably predicts the long-term onset of, pouchitis (p = 0.002) and anal abscess or fistulae (p = 0.04). Conclusions: In this validation study we confirmed the accuracy of the PPSC in predicting postoperative fistulas or abscesses and pouchitis. Therefore, we believe that in clinical practice patients with a PPSC score greater than 1 should be warned of this risk of possible Crohn's disease diagnosis and pouch failure.
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Previous investigations have increased the knowledge about the pathological processes of inflammatory bowel diseases. Besides the complex organization of immune reactions, the mucosal epithelial lining has been recognized as a crucial regulator in the commencement and persistence of intestinal inflammation. As the intestinal epithelium is exposed to various environmental factors, the intestinal epithelial cells are confronted with diverse cellular stress conditions. In eukaryotic cells, an imbalance in the endoplasmic reticulum (ER) might cause aggregation of unfolded or misfolded proteins in the lumen of ER, a condition known as endoplasmic reticulum stress. This cellular mechanism stimulates the unfolded protein response (UPR), which elevates the potential of the endoplasmic reticulum protein folding, improves protein production and its maturation, and also stimulates ER-associated protein degradation. Current analyses reported that in the epithelium, the ER stress might cause the pathogenesis of inflammatory bowel disease that affects the synthesis of protein, inducing the apoptosis of the epithelial cell and stimulating the proinflammatory reactions in the gut. There have been significant efforts to develop small molecules or molecular chaperones that will be potent in ameliorating ER stress. The restoration of UPR balance in the endoplasmic reticulum via pharmacological intervention might be a novel therapeutic approach for the treatment of inflammatory bowel diseases (IBDs). This review provides novel insights into the role of chemical chaperone UPR modulators to modify ER stress levels. We further discuss the future directions/challenges in the development of therapeutic strategies for IBDs by targeting the ER stress. Figure depicting the role of endoplasmic reticulum stress-mediated inflammatory bowel disease and the therapeutic role of endoplasmic reticulum stress inhibitors in alleviating the diseased condition.
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Estresse do Retículo Endoplasmático , Doenças Inflamatórias Intestinais , Humanos , Resposta a Proteínas não Dobradas , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Retículo Endoplasmático , Chaperonas Moleculares/metabolismoRESUMO
Colorectal cancer (CRC) risk is increased in Inflammatory Bowel Disease (IBD) and surveillance needs to be tailored according to individual risk. The open issues include the role of the characteristics of IBD and CRC in determining the long-term outcome. These issues were assessed in our multicenter study, including a cohort of 56 IBD patients with incident CRC. The clinical and histopathological features of IBD patients and of CRC were recorded. Incident CRC in IBD occurred at a young age (≤40 years) in 25% of patients (median age 55.5 (22-76)). Mucinous signet-ring carcinoma was detected in 6 out of the 56 (10.7%) patients, including 4 with Ulcerative Colitis (UC) and 2 with Crohn's disease (CD). CRC was more frequently diagnosed by colonoscopy in UC (85.4% vs. 50%; p = 0.01) and by imaging in Crohn's Disease CD (5.8% vs. 31.8%; p = 0.02). At onset, CRC-related symptoms occurred in 29 (51.9%) IBD patients. The time interval from the diagnosis of IBD to CRC was shorter in UC and CD patients with >40 years (p = 0.002; p = 0.01). CRC-related death occurred in 10 (29.4%) UC and in 6 (27.2%) CD patients (p = 0.89), with a short time interval from CRC to death (UC vs. CD: 6.5 (1-68) vs. 14.5 (8-40); p = 0.85; IBD: 12 months (1-68)). CRC occurring at a young age, a short time interval from the diagnosis of IBD to CRC-related death in the elderly, CRC-symptoms often mimicking IBD relapse and the observed high mortality rate may support the need of closer surveillance intervals in subgroups of patients.
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BACKGROUND/GOAL: Ulcerative colitis (UC) is characterized by chronic inflammation and progressive course, with potential extraintestinal complications including cardiovascular mortality. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels have been recently recognized as biomarkers of low-grade inflammation and cardiovascular disease. The aim of our study was to evaluate PCSK9 levels in patients with UC and different degrees of disease activity. METHODS: We prospectively recruited consecutive patients with UC attending our center at the University Hospital of Padua. Demographics, clinical characteristics, and biochemical data, including PCSK9, high sensitivity C-reactive protein, and fecal calprotectin, were recorded. Moreover, endoscopic procedures were performed in all subjects. RESULTS: We included 112 patients with UC (mean age=52.62±12.84 y; 52.62% males). Patients with UC and abnormal fecal calprotectin (≥250 µg/g) and/or C-reactive protein (≥3 mg/L) had greater levels of PCSK9 compared with UC patients with normal fecal calprotectin and high sensitivity C-reactive protein ( P =0.03 and 0.005, respectively). Higher endoscopic scores in UC were characterized by greater levels of PCSK9 ( P =0.03). Furthermore, we found a positive correlation between PCSK9 levels and fecal calprotectin ( r =0.18, P =0.04), endoscopic Mayo Score ( r =0.25, P =0.007), and UC-Riley Index ( r =0.22, P =0.01). We also found a positive correlation between PCSK9 levels and both total and low-density lipoprotein cholesterol values ( P <0.05). CONCLUSIONS: Serum PCSK9 levels are increased in patients with biochemical and endoscopic evidence of active disease in UC. Further longitudinal studies are necessary to evaluate the role of PCSK9 as a potential biomarker of disease activity and cardiovascular risk in UC.
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Colite Ulcerativa , Adulto , Idoso , Biomarcadores , Proteína C-Reativa/análise , Colite Ulcerativa/diagnóstico , Colonoscopia , Estudos Transversais , Fezes/química , Feminino , Humanos , Inflamação , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/análise , Pró-Proteína Convertase 9/metabolismo , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Adalimumab is used to treat ulcerative colitis, but additional effectiveness and safety data are needed. PATIENTS AND METHODS: This retrospective study considered adults with ulcerative colitis treated with adalimumab at 19 hospitals. Clinical data were collected from the start of treatment, after 2, 6 and 12 months, and at the last visit. Outcome measures of effectiveness were treatment duration, reasons for discontinuation and colectomy. RESULTS: We studied 381 patients treated with adalimumab for a median of 12.1 months. Disease activity at the start of treatment was moderate to severe in 262 cases (68.8%) and endoscopic activity was moderate to severe in 339 cases (89.0%). At week 8, clinical responses were observed in 177 cases (46.5%) and clinical remission in 136 cases (35.7%). At 12 months, remission was observed in 128 cases (33.6%). Overall, 44 patients required colectomy, and 170 patients (44.6%) were still taking adalimumab when data were collected. Variables associated with adalimumab discontinuation were concomitant steroid treatment, severe clinical-endoscopic activity at baseline, need for adalimumab intensification and drug-related adverse events. Variables associated with colectomy were concomitant steroid treatment and high baseline C-reactive protein. CONCLUSION: Adalimumab is safe and effective for the treatment of ulcerative colitis.
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Adalimumab/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Adulto , Idoso , Colectomia/estatística & dados numéricos , Feminino , Humanos , Quimioterapia de Indução , Itália , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Inflammatory bowel diseases, namely ulcerative colitis and Crohn's disease, occur worldwide and affect people of all ages, with a high impact on their quality of life. Sex differences in incidence and prevalence have been reported, and there are also gender-specific issues that physicians should recognize. For women, there are multiple, important concerns regarding issues of body image and sexuality, menstruation, contraception, fertility, pregnancy, breastfeeding and menopause. This practice-based review focuses on the main themes that run through the life of women with inflammatory bowel diseases from puberty to menopause. Gastroenterologists who specialize in inflammatory bowel diseases and other physicians who see female patients with inflammatory bowel diseases should provide support for these problems and offer adequate therapy to ensure that their patients achieve the same overall well-being and health as do women without inflammatory bowel diseases.
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Colite Ulcerativa/complicações , Doença de Crohn/complicações , Doenças dos Genitais Femininos/etiologia , Saúde Reprodutiva , Saúde da Mulher , Adulto , Feminino , Humanos , Gravidez , Qualidade de VidaRESUMO
BACKGROUND: Current literature still lacks studies evaluating the effectiveness and safety of switching from Infliximab originator to SB2 biosimilar in Inflammatory Bowel Diseases (IBDs). We aimed to verify the ability of SB2 to maintain the clinical and biochemical response induced by originator after switching. As secondary outcome, we aimed to verify safety, tolerability and immunogenicity of SB2 biosimilar compared with its IFX originator. METHODS: We prospectively enrolled all patients who switched from originator to SB2 at three Italian IBD Units from August 2018 to April 2020. We collected clinical and biochemical data at the time of switch (T0), and at the first (T1) and the second (T2) visits after switching (mean time from switching: 135 and 329 days, respectively). In addition, data regarding therapeutic drug monitoring at T0 and T1 were recorded. RESULTS: Eighty-five IBD patients (28 with Ulcerative Colitis and 57 with Crohn's Disease) were included in the study. At T1, we observed statistically significant modifications in clinical activity of disease (70 patients were in clinical remission at baseline and 60 at T1 p = 0.02), but not at T2 (p = 0.3). Fecal calprotectin values were not different both at T1 and T2 (both p = 0.9) as well as the rate of concomitant treatment with steroids (p = 0.2 and p = 0.1) or immunosuppressants (p = 0.1 and p = 1.0). Moreover, the need for therapeutic optimization from T0 to T1 and from T1 to T2 was found significant (both p = 0.01). No anti-drug antibodies were identified at T1, and no serious adverse events were recorded. CONCLUSIONS: Overall, our data show that most of the patients switching from Infliximab originator to SB2 maintain the clinical and biochemical remission for at least 1 year. Further data are necessary to understand the clinical implications of these findings in the long term.
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INTRODUCTION: Appropriate treatment is critical in elderly inflammatory bowel disease (IBD) subjects since they are at higher risk of complications such as infections, malignancies and mortality. EVIDENCE ACQUISITION: We conducted an extensive PUBMED search for guidelines, systematic reviews and primary studies to perform a critical analysis of the existing literature on the efficacy and safety of conventional and biological therapies for elderly IBD patients. EVIDENCE SYNTHESIS: Due to the exclusion of elderly population from clinical trials, most evidences comes from real-life studies. While aminosalicylates remain a cornerstone treatment of elderly patients with ulcerative colitis (UC), for their effectiveness and safety, their use in Crohn's disease (CD) should not be further supported. Corticosteroid use should be limited for the induction of remission, while as maintenance treatment it should be avoided, due to the low safety profile. Although as efficacious as in the younger population, immunosuppressant use has been associated with higher risk of infective/malignant issues and further use should be carefully evaluated. Biologics have demonstrated high effectiveness in the elderly. However, due to increased morbidity and mortality described in elderly subjects treated with anti-TNF alpha agents, vedolizumab and ustekinumab should be favoured over anti-TNF alpha agents. CONCLUSIONS: Treatment of elderly IBD patients remains challenging, since comorbidities and the risk of adverse events can complicate the effectiveness and safety of therapy. Close monitoring of such patients in a multidisciplinary team is advocated to reduce the risk of infections and optimize the treatment, choosing a suitable agent.
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To date, data on effectiveness and safety of Adalimumab (ADA) biosimilars in inflammatory bowel diseases (IBDs) are lacking. Therefore, we aimed to verify the ability of ABP501 and SB5 to maintain the clinical and biochemical response induced by the ADA originator, after switching to them. We prospectively analyzed data collected from 55 patients with IBD who switched to ABP501, and 25 patients with IBD who switched to SB5, from ADA originator at four IBD Units between 2018 and 2020. In addition, we included an age and sex-matched control group (n = 38) who continued ADA originator for at least two years and who did not switch to a biosimilar drug. Clinical and biochemical data (C-Reactive Protein (CRP), fecal calprotectin (FC)), concomitant steroid and/or immunosuppressant therapy at the time of the switch and after six months were collected. At six months, in the ABP501 group, we did not observe statistically significant modifications in clinical activity of disease (p = 0.09) and FC values (p = 0.90). Some patients (n = 8) needed to add steroids at six months after switching (p = 0.01), however the need for optimization was not significant between the two timepoints (p = 0.70). Finally, 14.5% patients stopped therapy after six months. Similarly, in the SB5 group we observed a stability of clinical activity and FC values (p = 0.90 and p = 0.20), and a concomitant statistically significant decrease in CRP (p = 0.03). There were no differences in steroids/immunosuppressants need or optimizing biological therapy in this group. Finally, drug survival curves of patients who switched from originator to ABP501 and those who continued ADA originator were similar (p = 0.20). Overall, biosimilar drugs seem to be as effective and safe as the originator. Further larger and longer studies are mandatory to understand the clinical implications of these findings.
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Adalimumab/administração & dosagem , Medicamentos Biossimilares/administração & dosagem , Substituição de Medicamentos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Adalimumab/efeitos adversos , Adulto , Biomarcadores/análise , Medicamentos Biossimilares/efeitos adversos , Proteína C-Reativa/análise , Fezes/química , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/diagnóstico , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Head-to-head comparison studies evaluating the effectiveness and tolerability of anti-tumor necrosis factor (anti-TNF) drugs in inflammatory bowel disease patients are lacking. AIM: To compare the effectiveness and tolerability of anti-TNF-α drugs used in clinical practice in a cohort of patients with moderate-to-severe ulcerative colitis (UC). METHODS: Retrospectively, 122 UC patients treated with infliximab (IFX) originator and biosimilar, adalimumab (ADA), and golimumab (GOL) were included. We performed an ITT analysis to evaluate clinical response and remission, steroid-free clinical remission, and endoscopy response according to the different time points of the follow-up. Baseline and post induction predictor factors of these outcomes were evaluated using multivariate logistic regression models. Moreover, a propensity score-based weighting analysis was performed. Data were analyzed using R and STATA11 software. RESULTS: The overall clinical response was 77% after induction, 81.4% at 30 weeks, and 76.9% at 52 weeks, while the steroid-free clinical remission was 39.7, 46, and 54.6%, respectively. After induction, a higher rate of treatment failure was observed in the GOL group. At the end of follow-up, lower rates of steroid-free clinical remission and clinical response were obtained by GOL. At week 52, endoscopic response was achieved by 46.5% of the population. CONCLUSIONS: Among the different anti-TNF treatments, moderate-to-severe UC seems to respond better to IFX and ADA, whereas GOL seems to be less effective, despite a similar good safety profile.