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BACKGROUND: Preventing disease progression and viral suppression are the main goals of antiviral therapy in chronic hepatitis B (CHB). Liver stiffness measurement (LSM) by transient elastography is a reliable non-invasive method to assess liver fibrosis in patients with CHB. Our aim was to explore factors that may affect changes in LSMs during long term tenofovir (TDF) monotherapy in a well characterized cohort of patients with compensated CHB. METHODS: We analyzed serial LSMs in 103 adult patients with CHB who were on TDF monotherapy and had at least three LSMs over a period of 90 months. RESULTS: Twenty-five (24%) patients had advanced fibrosis at baseline. A significant decline in mean LSM between baseline and last visit (8.7 ± 6.2 kPa vs. 6.7 ± 3.3, p = 10- 3) was observed. Twenty-four (23%) patients had progression of liver fibrosis with mean increase in liver stiffness of 2.8 kPa (range: 0.2-10.2 kPa). Multivariate analysis showed that BMI ≥ 25 (OR, 0.014; 95% CI, 0.001-0.157; p = 0.001) and advanced fibrosis (OR, 5.169; 95% CI, 1.240-21.540; p = 0.024) were independently associated with a fibrosis regression of > 30% of liver stiffness compared to baseline value. CONCLUSIONS: In CHB patients TDF monotherapy resulted in liver fibrosis regression, especially in patients with advanced fibrosis. Despite the successful antiviral effect of TDF, 1 out of 4 patients had liver fibrosis progression. Obesity and advanced fibrosis at baseline were independently associated with significant liver fibrosis regression.
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Diagnóstico por Imagen de Elasticidad , Hepatitis B Crónica , Adulto , Humanos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , Cirrosis Hepática/diagnóstico por imagen , Tenofovir/uso terapéuticoRESUMEN
BACKGROUND: Optimization of treatment with biologics is currently an unmet need for patients with ulcerative colitis (UC). Real-world studies provide neutral estimates of drug efficacy and safety within unselected patient populations and allow for the recognition of specific characteristics that affect response to therapy. AIMS: We aimed to depict the efficacy of vedolizumab in patients with UC in a real-world setting and identify prognosticators of improved outcomes. METHODS: Patients with active UC who commenced treatment with vedolizumab were prospectively followed up. Patient-reported outcomes (PROs) and clinical/endoscopic-reported outcomes were recorded at baseline and at weeks 14 and 54. Predefined endpoints of early and persistent efficacy were analyzed against clinical characteristics to identify prognostic factors for response. RESULTS: We included 96 patients (anti-TNF-exposed = 38.5%). At week 14, 73 patients (76%) had clinical response and 54 (56.3%) clinical remission. At week 54, the primary endpoint of vedolizumab persistence was met by 72 patients (75%), whereas steroid-free clinical remission by 59.4%. Among patients who had endoscopy, rates for mucosal healing (Mayo endoscopic score of 0) were 29.8% at week 14 and 44.6% at week 54, respectively. Vedolizumab treatment led to significant improvements in quality of life. Corticosteroid-refractory or anti-TNF-refractory disease, articular manifestations, and high baseline UC-PRO2 were associated with decreased efficacy of vedolizumab in the primary and secondary outcomes. CONCLUSIONS: Vedolizumab is characterized by high efficacy and long-term treatment persistence in UC. More aggressive disease, as indicated by refractoriness to steroids or anti-TNFs and elevated baseline PROs, may predict suboptimal response and help pre-treatment prognostic stratification of patients.
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Colitis Ulcerosa , Anticuerpos Monoclonales Humanizados , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/efectos adversos , Grecia , Humanos , Calidad de Vida , Inducción de Remisión , Estudios Retrospectivos , Esteroides/uso terapéutico , Resultado del Tratamiento , Inhibidores del Factor de Necrosis TumoralRESUMEN
BACKGROUND & AIMS: The level of fecal calprotectin (FC) correlates with endoscopic evidence of inflammation in Crohn's disease (CD). A treat-to-target algorithm for patients with CD, that incorporates FC, outperforms a treatment strategy based on symptoms alone in the induction of mucosal healing at 12 months. We investigated whether normalization of FC within 12 months of diagnosis of CD is associated with a reduction in disease progression. METHODS: We performed a retrospective cohort study at a tertiary IBD centre in the United Kingdom. We identified all incident cases of CD diagnosed from 2005 through 2017. Patients with a FC measurement ≥250 µg/g at diagnosis who also had at least 1 follow-up FC measurement within the first 12 months of diagnosis and >12 months of follow up were included. The last FC measurement within 12 months of diagnosis was used to determine normalization (cut-off <250 µg/g). The primary endpoint was time to first disease progression (composite of progression in Montreal disease behavior B1 to B2/3, B2 to B3, or new perianal disease; CD-related surgery; or CD-related hospitalization). Cox proportional hazards regression analysis was used to determine independent factors associated with time to first disease progression. RESULTS: A total of 375 patients out of 1389 incident cases were included, with a median follow up of 5.3 years (interquartile range, 3.1-7.4 years). Normalization of FC within 12 months of diagnosis was confirmed in 43.5% of patients. Patients with normalized levels of FC had a significantly lower risk of composite disease progression (hazard ratio [HR], 0.36; 95% CI, 0.24-0.53; P < .001). They also had a lower risk of reaching any of the separate progression endpoints (progression in Montreal behavior or new perianal disease HR, 0.22; 95% CI, 0.11-0.45; P < .001; hospitalization HR, 0.33; 95% CI, 0.21-0.53; P <.001; surgery HR, 0.39; 95% CI, 0.19-0.78; P = .008) CONCLUSIONS: Normalization of FC within 12 months of diagnosis is associated with a reduced risk of progression of CD.
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Enfermedad de Crohn , Complejo de Antígeno L1 de Leucocito , Biomarcadores , Enfermedad de Crohn/diagnóstico , Progresión de la Enfermedad , Heces , Humanos , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND AND AIM: Ustekinumab is a monoclonal antibody that targets interleukin-12/23. In Scotland, it was approved for the treatment of moderate to severe Crohn's disease in 2017. The objective of this study was to establish the real-world effectiveness and safety of ustekinumab in the treatment of Crohn's disease. METHODS: We conducted a retrospective study of patients receiving ustekinumab across eight Scottish National Health Service health boards between 2017 and 2019. Inclusion criteria included a diagnosis of Crohn's disease with symptoms attributed to active disease plus objective signs of inflammation at baseline (C-reactive protein ≥ 5 mg/L or fecal calprotectin ≥ 250 µg/g or inflammation on endoscopy/magnetic resonance imaging) and completion of induction plus at least one clinical follow-up at 8 weeks. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, deep remission, and perianal fistula response. Rates of serious adverse events were described quantitatively. RESULTS: Our cohort consisted of 216 patients (female sex, 37.9%; median age, 39.0 years, interquartile range [IQR] 28.8-51.8 years; disease duration, 9.9 years, IQR 6.0-16.5 years; prior biologic, 98.6%) with a median follow-up of 35.0 weeks (IQR 17.4-52.0 weeks). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission plus mucosal healing) were 32.0%, 32.7%, and 19.3%, respectively. In patients with active perianal disease (n = 37), the 12-month cumulative perianal response rate was 53.1%. The serious adverse event rate was 13.6 per 100 patient-years of follow-up. CONCLUSION: Ustekinumab is a safe and effective treatment for the treatment of complex Crohn's disease.
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Enfermedad de Crohn , Ustekinumab , Adulto , Estudios de Cohortes , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Escocia , Medicina Estatal , Resultado del Tratamiento , Ustekinumab/efectos adversosRESUMEN
Relapses are observed in most hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients who discontinue treatment with nucleos(t)ide analogues (NAs); however, the rates of relapse vary widely among studies, and whether all patients with relapse need retreatment is unclear. The aim of this study was to assess the impact of different definitions on the rates of posttreatment relapse and therefore on the probability of retreatment in patients who have discontinued effective long-term NA therapy. In total, 130 HBeAg-negative chronic hepatitis B patients without cirrhosis and before NA treatment were included. All had on-therapy virological remission for ≥24 months and close follow-up for ≥12 months after stopping NA treatment or until retreatment, which started on stringent predefined criteria. Relapses rates based on several predetermined definitions of virological and perhaps biochemical criteria were assessed. The median duration of therapy was 60 months and the median duration of on-therapy virological remission was 43 months. During a median off-NAs follow-up of 15 months, no patient experienced liver decompensation or died. Cumulative relapse rates were 2%-49%, 4%-73%, 11%-82%, and 16%-90% at 3, 6, 12, and 24 months, respectively, whereas cumulative retreatment rates were 15%, 22%, and 40% at 6, 12, and 24 months, respectively, after discontinuation of NA therapy. No patient characteristic was independently associated with the probability of relapse based on at least two definitions or of retreatment. CONCLUSION: In HBeAg-negative chronic hepatitis B patients who discontinue NA therapy, the definition of relapse has a great impact on off-NAs relapse rates and potentially on the probability of retreatment. Regardless of definition, off-NAs relapses cannot be easily predicted by patient characteristics. A substantial proportion of such patients may not require retreatment if stringent criteria are adopted. (Hepatology 2017).
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Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Adulto , ADN Viral , Femenino , Estudios de Seguimiento , Antígenos e de la Hepatitis B , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Retratamiento/estadística & datos numéricos , Resultado del Tratamiento , Privación de Tratamiento/estadística & datos numéricosRESUMEN
BACKGROUND & AIMS: The effects of long-term antiviral therapy on survival have not been adequately assessed in chronic hepatitis B (CHB). In this 10-centre, ongoing cohort study, we evaluated the probability of survival and factors affecting survival in Caucasian CHB patients who received long-term entecavir/tenofovir therapy. METHODS: We included 1,951 adult Caucasians with CHB, with or without compensated cirrhosis and without hepatocellular carcinoma (HCC) at baseline, who received entecavir/tenofovir for ≥12â¯months (median, six years). Kaplan-Meier estimates of cumulative survival over time were obtained. Standardized mortality ratios (SMRs) were calculated by comparing death rates with those in the Human Mortality Database. RESULTS: The one-, five-, and eight-year cumulative probabilities were 99.7, 95.9, and 94.1% for overall survival, 99.9, 98.3, and 97.4% for liver-related survival, and 99.9, 97.8, and 95.8% for transplantation-free liver-related survival, respectively. Overall mortality was independently associated with older age and HCC development, liver-related mortality was associated with HCC development only, and transplantation-free liver-related mortality was independently associated with HCC development and lower platelet levels at baseline. Baseline cirrhosis was not independently associated with any type of mortality. Compared with the general population, in all CHB patients mortality was not significantly different (SMR 0.82), whereas it was lower in patients without HCC regardless of baseline cirrhosis (SMR 0.58) and was higher in patients who developed HCC (SMR 3.09). CONCLUSION: Caucasian patients with CHB and compensated liver disease who receive long-term entecavir/tenofovir therapy have excellent overall and liver-related eight-year survival, which is similar to that of the general population. HCC is the main factor affecting their overall mortality, and is the only factor affecting their liver-related mortality. LAY SUMMARY: Caucasian patients with chronic hepatitis B with or without compensated cirrhosis who receive long-term entecavir or tenofovir therapy have excellent overall eight-year survival, which is similar to that of the general population. Hepatocellular carcinoma is the main factor affecting their overall mortality, and is the only factor affecting liver-related mortality in this setting.
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Antivirales/uso terapéutico , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/mortalidad , Tenofovir/uso terapéutico , Adulto , Anciano , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/mortalidad , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Guanina/uso terapéutico , Hepatitis B Crónica/complicaciones , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana EdadRESUMEN
Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long-term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10-center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for ≥1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5-10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5-10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years (P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness ≥12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender-Hepatitis B score at baseline or year 5 developed HCC. CONCLUSION: The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development. (Hepatology 2017;66:1444-1453).
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Antivirales/administración & dosificación , Carcinoma Hepatocelular/epidemiología , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/epidemiología , Adulto , Anciano , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/virología , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Guanina/administración & dosificación , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Incidencia , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Tenofovir/administración & dosificación , Población BlancaRESUMEN
PURPOSE OF REVIEW: Immune checkpoint inhibitors are monoclonal antibodies against the inhibitory, co-stimulatory molecules CTLA-4 and PD-1/PD-L1. Their use in oncology has been associated with frequent and diverse immune-related adverse events. In the digestive tract, such toxicity presents primarily as colonic inflammation, resembling inflammatory bowel disease (IBD). This review presents recent developments regarding the characteristics of checkpoint inhibitor colitis (CIC) and its relation to IBD. RECENT FINDINGS: Several reports from patient cohorts with CIC have outlined its similarities and differences with IBD. Clinically and endoscopically, there is high overlap, including the negative prognostic significance of deep ulceration. Histologically, CIC may present as either acute colitis or demonstrate features of chronic damage, including IBD-like and lymphocytic colitis-like phenotypes. CIC immunopathogenesis appears to be associated with a predominance of mucosal Th1/Th17 effector responses, and may also be influenced by input from the gut microflora. Finally, current treatment of CIC is based on steroids and infliximab, although other biologics such as vedolizumab may also be effective. SUMMARY: CIC represents a distinct form of colitis with characteristics reminiscent of IBD flares. Clarification of the mechanisms involved in its pathogenesis will greatly enhance our understanding and therapeutic management of immune-mediated colitides, including IBD.
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Colitis/diagnóstico , Colitis/etiología , Inmunoterapia/efectos adversos , Enfermedades Inflamatorias del Intestino/diagnóstico , Anticuerpos Monoclonales/efectos adversos , Antígeno B7-H1/inmunología , Antígeno CTLA-4/inmunología , Colitis/inmunología , Colitis/microbiología , Diagnóstico Diferencial , Microbioma Gastrointestinal/inmunología , Humanos , Inmunofenotipificación , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Anti-CTL4-A therapy is associated with development of colitis. We characterized ipilimumab-associated colitis in nine melanoma patients (6 male, mean age: 55.3-yrs). Median value for diarrhea grade was 2, number of ipilimumab doses 2, and interval since last administration 3-wks. Endoscopic characteristics resembled inflammatory bowel disease and histology revealed predominance of plasmacytes or CD4+ T-cells. We observed significant upregulation of Th1 and Th17 effector pathways (>10-fold increase for IFN-γmRNA, >5-fold for IL-17A, p < 0.01 vs. controls). Significant elevation of FoxP3 was also detected. In conclusion, ipilimumab administration results in elevations of effector lymphocytes and pro-inflammatory mediators in the gut lamina propria.
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Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Antígeno CTLA-4/antagonistas & inhibidores , Colitis/inducido químicamente , Colon/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Biopsia , Antígeno CTLA-4/inmunología , Colitis/inmunología , Colitis/metabolismo , Colitis/patología , Colon/inmunología , Colon/metabolismo , Colon/patología , Colonoscopía , Diarrea/inducido químicamente , Diarrea/inmunología , Esquema de Medicación , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ipilimumab , Masculino , Melanoma/inmunología , Persona de Mediana Edad , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Estudios Retrospectivos , Neoplasias Cutáneas/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/metabolismo , Factores de TiempoRESUMEN
PURPOSE: To assess whether use of Impedance Threshold Device (ITD) during cardiopulmonary resuscitation (CPR) reduces the degree of post-cardiac arrest Acute Kidney Injury (AKI), as a result of improved hemodynamics, in a porcine model of ventricular fibrillation (VF) cardiac arrest. METHODS: After 8 min of untreated cardiac arrest, the animals were resuscitated either with active compression-decompression (ACD) CPR plus a sham ITD (control group, n=8) or with ACD-CPR plus an active ITD (ITD group, n=8). Adrenaline was administered every 4 min and electrical defibrillation was attempted every 2 min until return of spontaneous circulation (ROSC) or asystole. After ROSC the animals were monitored for 6 h under general anesthesia and then returned to their cages for a 48 h observation, before euthanasia. Two novel biomarkers, Neutrophil Gelatinase-Associated Lipocalin (NGAL) in plasma and Interleukin-18 (IL-18) in urine, were measured at 2 h, 4 h, 6 h, 24 h and 48 h post-ROSC, in order to assess the degree of AKI. RESULTS: ROSC was observed in 7 (87.5%) animals treated with the sham valve and 8 (100%) animals treated with the active valve (P=NS). However, more than twice as many animals survived at 48 h in the ITD group (n=8, 100%) compared to the control group (n=3, 37.5%). Urine IL-18 and plasma NGAL levels were augmented post-ROSC in both groups, but they were significantly higher in the control group compared with the ITD group, at all measured time points. CONCLUSION: Use of ITD during ACD-CPR improved hemodynamic parameters, increased 48 h survival and decreased the degree of post-cardiac arrest AKI in the resuscitated animals.
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Lesión Renal Aguda/complicaciones , Reanimación Cardiopulmonar/instrumentación , Impedancia Eléctrica , Paro Cardíaco/terapia , Fibrilación Ventricular/terapia , Animales , Biomarcadores/orina , Modelos Animales de Enfermedad , Epinefrina/uso terapéutico , Femenino , Hemodinámica , Interleucina-18/orina , Lipocalina 2/orina , Monitoreo Fisiológico , PorcinosRESUMEN
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.
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BACKGROUND: The UNITI trial reports efficacy of ustekinumab (UST) dose intensification in Crohn's disease (CD) from 12- to 8-weekly, but not 4-weekly. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly, 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness of this strategy. METHODS: We performed a retrospective, observational cohort study in NHS Lothian including all UST treated CD patients (2015-2020). RESULTS: 163 CD patients were treated with UST (median follow-up: 20.3 months [13.4-38.4]), of whom 55 (33.7%) underwent dose intensification to 4-weekly (n = 50, 30.7%) or 6-weekly (n = 5, 3.1%). After 1 year 29.9% were dose intensified. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3-70.9), and concomitant steroid use at UST start (HR 1.8; 1.0-3.1) were associated with dose intensification. Following dose intensification, 62.6% patients (29/55) remained on UST beyond 1 year. Corticosteroid-free clinical remission was achieved in 27% at week 16 and 29.6% at last follow-up. CONCLUSION: One third of CD patients treated with UST underwent dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed both anti-TNF and vedolizumab, or required steroids at initiation were more likely to dose intensify.
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Enfermedad de Crohn , Fármacos Dermatológicos , Ustekinumab , Enfermedad de Crohn/tratamiento farmacológico , Ustekinumab/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Masculino , Femenino , Adolescente , AdultoRESUMEN
OBJECTIVE: It is unclear how the compounding prevalence of inflammatory bowel disease (IBD) has translated into the causes and rates of hospitalisation, particularly in an era of increased biologic prescribing. We aimed to analyse these trends in a population-based IBD cohort over the last 10 years. DESIGN: The Lothian IBD registry is a complete, validated, prevalent database of IBD patients in NHS Lothian, Scotland. ICD-10 coding of hospital discharge letters from all IBD patient admissions to secondary care between 1 January 2010 and 31 December 2019 was interrogated for admission cause, with linkage to local/national data sets on death and prescribed drugs. RESULTS: Fifty-seven per cent (4673/8211) of all IBD patients were admitted to secondary care for >24 h between 1 January 2010 and 31 December 2019. In patients <40 years, IBD was the commonest reason for admission (38% of admissions), whereas infection was the most common cause in those >60 years (19% of admissions). Three per cent (243/8211) of IBD patients accounted for 50% of the total IBD bed-days over the study period. Age-standardised IBD admission rates fell from 39.4 to 25.5 admissions per 100,000 population between 2010 and 2019, an average annual percentage reduction of 3% (95% CI -4.5% to -2.1%, p < 0.0001). Non-IBD admission rates were unchanged overall (145-137 per 100,000 population) and specifically for serious (hospitalisation) and severe (ITU admission or death) infection over the same period. CONCLUSION: Despite compounding prevalence and increased biologic use, IBD admission rates are falling. The cause of admission varies with age, with infection the predominant cause in older patients.
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Productos Biológicos , Enfermedades Inflamatorias del Intestino , Anciano , Enfermedad Crónica , Estudios de Cohortes , Hospitalización , Humanos , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/terapia , Estudios Retrospectivos , Escocia/epidemiologíaRESUMEN
BACKGROUND AND AIMS: Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients. METHODS: We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8-14 weeks) and maintenance (16-26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models. RESULTS: Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41-60%) and 37% (26-45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31-50%) and 29% (23-36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%). CONCLUSION: Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.
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BACKGROUND: Patients with primary biliary cholangitis (PBC) who have advanced disease are hypercoagulable, with no thrombophilic factors compared to non-cholestatic cirrhotics. We investigated whether hypercoagulability is present in early-stage PBC. METHODS: PBC patients with biopsy-documented early disease and healthy controls matched by sex and age were asked to participate in the study. All were evaluated using rotational thromboelastometry (ROTEM), platelet aggregation, and flow cytometry. Four ROTEM parameters were evaluated (clotting time, clotting formation time, α-angle, and maximum clot firmness [MCF]). Platelet aggregation was determined as the maximal change in light transmission after the addition of adenosine diphosphate, collagen and epinephrine. Flow cytometry was used to evaluate the expression of glycoprotein (GP) IIb, GPIIa, and P-selectin on the platelet surface. RESULTS: We enrolled 50 individuals in the study (25 PBC patients, 25 controls). Prothrombin time and activated partial thromboplastin time did not differ significantly between PBC patients and controls (P-value not significant). In ROTEM, aaaaaaaa-angle and MCF parameters were abnormally elevated in 9 (36%) PBC patients compared to 3 (12%) healthy controls and the difference was statistically significant (P=0.026). Platelet aggregation in PBC patients was not significantly different from controls. In flow cytometry, GPIIb and P-selectin expression was greater in PBC patients than in the control group and the difference was statistically significant (P=0.005 and P=0.006 respectively). CONCLUSION: In this study, we used a combination of sophisticated methods to detect evidence of platelet activation and hypercoagulability in patients with early PBC. Our findings may have important clinical implications and merit further investigation.
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BACKGROUND: Long-term monotherapy with nucleos(t)ide analogs (NAs) represents the treatment option for the majority of patients with chronic hepatitis B (CHB), an aging population with a greater likelihood of comorbidities. We assessed the prevalence of concurrent non-hepatic diseases and the safety monitoring in a large cohort of CHB patients receiving NAs and their potential impact on disease outcomes. METHODS: We included 500 consecutive CHB patients from 5 major tertiary Greek centers, under long-term therapy with an NA. Epidemiological/clinical characteristics and data on concomitant disease, drug use and investigations ordered were collected. RESULTS: The mean age was 58 years and 66% were male. Most patients were receiving tenofovir disoproxil fumarate (TDF, 60%) or entecavir (ETV, 37%) monotherapy. Decompensated cirrhosis at baseline was present in 10%, while hepatocellular carcinoma (HCC) under therapy developed in 21 patients. The median duration of total NA therapy was 56 and of latest therapy 42 months. The most common (prevalence >10%) comorbidities were hypertension (28%), non-HCC cancer(s) (12%), and diabetes (11%). Patients with a longer duration of latest therapy (≥4 vs. <4 years) were older (mean age: 58 vs. 56 years, P=0.004), had more frequent history of prior use of NA(s) (53% vs. 35%, P<0.001), and less frequent liver decompensation (5% vs. 13%, P=0.008) and non-HCC cancers (8% vs. 15%, P=0.020). HCC developed more frequently in patients with than in those without diabetes (11% vs. 3%, P=0.022). CONCLUSION: Greek CHB patients currently treated with NAs, almost exclusively ETV or TDF, are often older than 60 years, have several comorbidities, and thus require careful management.
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BACKGROUND AND AIMS: Fibrosis-4 (FIB-4) index is a HCC predictor in chronic hepatitis B (CHB) patients. However, little is known about whether FIB-4 helps identify non-cirrhotic CHB patients with minimal HCC risk after prolonged nucleos(t)ide analogue (NA) therapy. METHODS: A total of 1936 ethnically diverse, non-cirrhotic CHB patients were enrolled in this retrospective multi-national study. All patients received prolonged NA treatment, including entecavir and tenofovir disoproxil fumarate. We explored whether FIB-4 cutoff of 1.30, a marker indicative of mild fibrosis severity, could stratify HCC risks in these patients. RESULTS: A total of 48 patients developed HCC after a mean follow-up of 6.98 years. FIB-4 level at 1 year after treatment (1-year FIB-4) was shown to be associated with HCC development and was superior to pre-treatment FIB-4 value. When patients were stratified by 1-year FIB-4 of 1.30, the high FIB-4 group was at an increased HCC risk compared to the low FIB-4 group, with a hazard ratio of 4.87 (95% confidence interval: 2.48-9.55). Multivariable analysis showed that sex and 1-year FIB-4 were independent predictors, with none of the 314 female patients with low 1-year FIB-4 developing HCC. Finally, 1-year FIB-4 of 1.30 consistently stratified HCC risks in patients with low PAGE-B score, a score composed of baseline age, sex and platelet count, and the annual incidence rate of HCC was 0.11% in those with PAGE-B < 10 + 1-year FIB-4 < 1.30. CONCLUSIONS: In non-cirrhotic CHB patients receiving prolonged NA therapy, 1-year FIB-4 < 1.30 is useful for identifying those with minimal HCC risk by combining with female sex or low PAGE-B score.
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Carcinoma Hepatocelular , Hepatitis B Crónica , Cirrosis Hepática , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Femenino , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/etiología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIMS: Multiple adalimumab [ADA] biosimilars are now approved for use in inflammatory bowel disease [IBD]; however, effectiveness and safety data remain scarce. We aimed to investigate long-term outcomes of the ADA biosimilar SB5 in IBD patients following a switch from the ADA originator [SB5-switch cohort] or after start of SB5 [SB5-start cohort]. METHODS: We performed an observational cohort study in a tertiary IBD referral centre. All IBD patients treated with Humira underwent an elective switch to SB5. We identified all these patients in a biological prescription database that prospectively registered all ADA start and stop dates including brand names. Data on IBD phenotype, C-reactive protein [CRP], drug persistence, ADA drug and antibody levels, and faecal calprotectin were collected. RESULTS: In total, 481 patients were treated with SB5, 256 in the SB5-switch cohort (median follow-up: 13.7 months [IQR 8.6-15.2]) and 225 in the SB5-start cohort [median follow-up: 8.3 months [4.2-12.8]). Of the SB5-switch cohort, 70.8% remained on SB5 beyond 1 year; 90/256 discontinued SB5, mainly due to adverse events [46/90] or secondary loss of response [37/90]. In the SB5-start cohort, 81/225 discontinued SB5, resulting in SB5-drug persistence of 60.3% beyond 1 year. No differences in clinical remission [p = 0.53], CRP [p = 0.80], faecal calprotectin [p = 0.40] and ADA trough levels [p = 0.55] were found between baseline, week 26 and week 52 following switch. Injection site pain was the most frequently reported adverse event. CONCLUSION: Switching from ADA originator to SB5 appeared effective and safe in this study with over 12 months of follow-up.
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Adalimumab/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Adalimumab/administración & dosificación , Adolescente , Adulto , Biosimilares Farmacéuticos/administración & dosificación , Estudios de Cohortes , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Fármacos Gastrointestinales/administración & dosificación , Humanos , Masculino , Estudios Prospectivos , Estudios Retrospectivos , Escocia , Medicina Estatal , Adulto JovenRESUMEN
Decoy receptor-3 (DcR3) is a member of the TNF receptor superfamily of proteins, which has been implicated in anti-apoptotic and anti-inflammatory pathways, via binding to TL1A, LIGHT and Fas-L. The role of the TL1A/DcR3 ligand/receptor pair in ulcerative colitis (UC) has not been studied. We investigated the systemic (peripheral blood) and local (large intestine) expression of DcR3 and TL1A in 64 patients with UC and 56 healthy controls. DcR3 serum concentrations were highly elevated in patients with active UC (P<0.0001 vs. healthy controls). This elevation was clearly related to the presence of intestinal inflammation as it was less frequently observed in patients in remission (P=0.003 vs. active UC) whereas effective treatment resulted in disappearance or significant decrease of serum DcR3 (P=0.006 vs. pre-treatment). Furthermore, DcR3 mRNA transcripts were significantly elevated in inflamed areas of the colon (P=0.002 vs. non-affected of the same patient). In addition to DcR3 elevation, we found increased circulating levels of TL1A in patients with either active or inactive UC in comparison to healthy controls (P<0.001 for both). We conclude that elevated serum DcR3 may serve as an indicator of active colonic inflammation in patients with UC. TL1A/DcR3-mediated pathways may participate in the pathogenesis of UC.
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Colitis Ulcerosa/sangre , Colitis Ulcerosa/metabolismo , Mucosa Intestinal/metabolismo , Miembro 6b de Receptores del Factor de Necrosis Tumoral/análisis , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/análisis , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Adolescente , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Colitis Ulcerosa/terapia , Femenino , Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Miembro 6b de Receptores del Factor de Necrosis Tumoral/sangre , Miembro 6b de Receptores del Factor de Necrosis Tumoral/genética , Miembro 6b de Receptores del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/genética , Adulto JovenRESUMEN
BACKGROUND/AIMS: The incidence of celiac disease (CD) has increased in recent years due to the recognition of atypical forms and the identification of silent cases through serological screening. Our aim was to detect temporal trends in the presentation of pediatric CD in Greece. METHODS: We reviewed the medical files of all children diagnosed with CD between 1978 and 2007 at a single academic pediatric center. Cases were classified according to the year of diagnosis. We examined demographic data, presenting symptoms, delay to diagnosis, and the prevalence of associated conditions. RESULTS: During the study period, 284 new cases of CD were diagnosed. The incidence of CD was significantly increased in recent years (p < 0.05). We observed significant trends towards older age at diagnosis (p < 0.001), longer delay to diagnosis (p < 0.05) and decreased frequency of the classical and/or gastrointestinal predominant mode of presentation (p < 0.001). In recent years, diagnosis of CD was significantly more frequent due to testing of asymptomatic children with a positive family history for CD or personal history of associated conditions (p < 0.001). CONCLUSION: We report a changing pattern in the presentation of pediatric CD in Greece. CD is diagnosed more frequently in older children, oftentimes presents with atypical symptoms, and is increasingly detected through serological screening. CD should be considered in the presence of atypical presentations.