Impact of Epstein-Barr virus infection on inflammatory bowel disease (IBD) clinical outcomes.

OBJECTIVE: to evaluate the role of Epstein-Barr virus (EBV) on the intestinal mucosa in the evolution of inflammatory bowel disease (IBD). The risk factors for EBV infection and the frequency of EBV-associated lymphoproliferative disorders in IBD patients were also investigated. METHODS: intestinal biopsies of IBD patients with available EBV status determined by Epstein-Barr-encoding RNA (EBER) in situ hybridization were identified in the Pathology Database of our center. Clinical information, including phenotypic characteristics of IBD, previous treatments, diagnosis of lymphoma and patient outcome were reviewed in all cases. RESULTS: fifty-six patients with IBD (28 Crohn's disease, 27 ulcerative colitis and one unclassified colitis) were included. EBV in intestinal mucosa was positive in 26 patients (46 %) and was associated to a lymphoproliferative syndrome in one case. EBV positivity was associated with severe histological activity (52 % vs 17.2 %; p 0.007), the presence of a lymphoplasmacytic infiltrate (50 % vs 33.3 %; p 0.03) and active steroid treatment (61.5 % vs 33.3 %; p 0.03). Multivariate analyses only found an association between EBV and lymphoplasmacytosis (p 0.001). Escalation in previous treatment was significantly more frequent in the EBER+ group (53.8 % vs 26.7 %; p 0.038). No cases developed lymphoma during follow-up. CONCLUSIONS: EBV on the intestinal mucosa is associated with a poor outcome of IBD and the need for escalation of therapy. Lymphoplasmacytic infiltrate is associated with EBV infection. EBER+ patients used steroids more frequently compared with EBER- patients. No EBER+ patients developed lymphoma during follow-up.

Compliance, adverse effects and effectiveness of first line bismuth-containing quadruple treatment (Pylera®) to eradicate Helicobacter pylori infection in 200 patients.

INTRODUCTION AND OBJECTIVES: quadruple therapy with bismuth is recommended as a first line treatment for Helicobacter pylori (H. pylori) infection. The aim of this study was to evaluate the compliance, adverse effects and effectiveness of this treatment with the new galenic three-in-one capsule formulation containing bismuth subcitrate, metronidazole and tetracycline (Pylera®). METHODS: a prospective, non-controlled, single center observational study was performed in a cohort of 200 consecutive patients with an untreated H. pylori infection; 58% were female. The subjects were treated for ten days with Pylera® of three capsules four times daily with meals and a proton pump inhibitor taken before breakfast and dinner. The Pylera® capsule contains 140 mg of bismuth subcitrate, 125 mg of metronidazole and 125 mg of tetracycline. The compliance and adverse effects of the treatment were evaluated via telephone contact and via an interview during the clinical revision. Eradication of infection was controlled for at least four weeks after treatment termination via the urea breath test, the stool antigen test with monoclonal antibodies or by histology. RESULTS: treatment compliance was observed in 96% (192/200) of the patients. Only 28.5% (57/200) of the patients experienced adverse effects, which led to abandoning the treatment in only seven subjects. Severe adverse effects developed in only one case due to Clostridium difficile infection. The effectiveness based on intention to treat was 91.5% (183/200, 95% CI: 87.1-96.8) and per protocol was 95.2% (182/191, 95% CI: 90.9-98.9). CONCLUSIONS: in our experience, Pylera® is an effective and safe treatment that should be considered as a first line therapeutic option for the eradication of H. pylori infection.

A giant abdominal collection: when things are not what they seem.

Endoscopic ultrasound-guided transluminal drainage (EUS-TD) has become the standard of care for the treatment of peripancreatic fluid collections (PFCs). New lumen-apposing metal stents (LAMS) have facilitated the drainage technique . However, this fact should not cloud our view when planning a EUS-TD, as occasionally things are not what they seem.

Remission maintained by monotherapy after biological + immunosuppressive combination for Crohn's disease in clinical practice.

BACKGROUND AND AIM: The optimal time to withdraw combined biological + immunosuppressive therapy in Crohn's disease is debated. Following remission of 6 months with the combined therapy, we assessed the efficacy of monotherapy in maintaining remission. METHODS: Crohn's disease patients (n = 75) were retrospectively selected from clinical records for having achieved remission within 6 months of receiving combined biological + immunosuppressive therapy. Treatment continued for a further year with one or the other of the combination drugs withdrawn. Clinical remission was defined as Crohn's Disease Activity Index (CDAI) < 150 and endoscopic remission as CDAI < 150 + absence of mucosal lesions + no signs of active inflammation on ileocolonoscopy. Crohn's disease relapse was defined as CDAI > 250. RESULTS: Twenty-eight percent (21/75) patients were relapsers. Withdrawal of biological therapy was more frequent than immunosuppressive (73.3% vs 26.7%) with no significant differences in relapse rates (30.9% vs 20%; P = 0.401). Endoscopic remission was more accurate than clinical remission (relapse rates: 10.5% vs 33.9%; P = 0.05). C-reactive-protein was higher in relapsers (19.2 ± 23.7 mg/L vs 2.5 ± 4.7 mg/L; P = 0.009). Multivariate analysis indicated C-reactive protein > 5 mg/L (odds ratios [OR]: 30.12; 95% confidence intervals [95% CI]: 5.91-153.38; P = 0.0001) and younger age at diagnosis (OR: 1.10; 95% CI: 1.01-1.19; P = .047) as independent factors predicting relapse. There was a strong trend toward a protective effect of endoscopic remission (OR: 0.17; 95% CI: 0.02-1.22; P = 0.077). CONCLUSION: A subgroup of Crohn's disease patients treated with combination therapy can be identified (C-reactive protein < 5 mg/L, endoscopic remission, and older age at Crohn's disease diagnosis) who would continue in remission despite cessation of the biological (expensive) component of the combination therapy.

Predictive factors for erythema nodosum and pyoderma gangrenosum in inflammatory bowel disease.

BACKGROUND AND AIM: To identify predictive factors related to the development of erythema nodosum and pyoderma gangrenosum, in patients with inflammatory bowel disease (IBD). METHODS: Epidemiological and clinical data from 270 patients with Crohn's disease (CD) and 125 patients with ulcerative colitis (UC) were collected between 2003 and 2011. The variables retrospectively analyzed were: gender, age at diagnosis, type of IBD (CD or UC), smoking habit, pattern of disease (IBD), location and extension, family history, previous IBD-related surgery, other extraintestinal manifestations (EIMs), and previous biological and immunosuppressive therapy. RESULTS: Thirty-seven patients showed at least one cutaneous manifestation. These lesions were more frequent in women (15.4%) than in men (4.2%; P = 0.0001) and in CD (12.2%) than in UC patients (3.2%; P = 0.005). These manifestations were more frequently associated with other EIMs (25% vs 7.2%; P = 0.0001), and they were less frequent in patients who received a previous biological therapy for IBD (6.8% vs 11.2%; P = 0.1). Patients with skin manifestations were younger at diagnosis of IBD than those patients without them (26.3 ± 10 vs 32.9 ± 14.5, P = 0.008). Independent variables significantly associated with development of skin manifestations were: female (P = 0.008), previous biological therapy (P = 0.007), age at diagnosis (young, P = 0.026), type of IBD (CD, P = 0.043) and presence of other EIMs (P = 0.0001). CONCLUSION: Predictive factors involved in the development of main cutaneous manifestations are: female, CD, young age at diagnosis of IBD, and presence of other EIMs. Early use of biological therapies prevents the development of cutaneous manifestations.

The Natural History of Patients With Pre-Existing and De Novo Inflammatory Bowel Disease After Solid Organ Transplantation: EITOS Study of GETECCU.

BACKGROUND: Limited data are available on the outcome of inflammatory bowel disease (IBD) in patients with solid organ transplantation (SOT). We describe the natural history of pre-existing IBD and de novo IBD after SOT. METHODS: This was a retrospective, multicenter study that included patients with pre-existing IBD at the time of SOT and patients with de novo IBD after SOT. The primary outcome was IBD progression, defined by escalation of medical treatment, surgical therapy, or hospitalization due to refractory IBD. Risk factors were identified using multivariate Cox proportional hazard analysis. RESULTS: A total of 177 patients (106 pre-existing IBD and 71 de novo IBD) were included. Most patients with pre-existing IBD (92.5%) were in remission before SOT. During follow-up, 32% of patients with pre-existing IBD had disease progression, with a median time between SOT and IBD progression of 2.2 (interquartile range, 1.3-4.6) years. In the de novo cohort, 55% of patients had disease progression with a median time to flare of 1.9 (interquartile range, 0.8-3.9) years after diagnosis. In the pre-existing IBD cohort, active IBD at the time of SOT (hazard ratio, 1.80; 95% confidence interval, 1.14-2.84; P = .012) and the presence of extraintestinal manifestations (hazard ratio, 3.10; 95% confidence interval, 1.47-6.54; P = .003) were predictive factors for IBD progression. CONCLUSIONS: One-third of patients with pre-existing IBD and about half of patients with de novo IBD have disease progression after SOT. Active IBD at the time of SOT and the presence of extraintestinal manifestations were identified as risk factors for IBD progression.

Clinical outcome after anti-tumour necrosis factor therapy discontinuation in 1000 patients with inflammatory bowel disease: the EVODIS long-term study.

BACKGROUND: The long-term outcome of patients after antitumour necrosis factor alpha (anti-TNF) discontinuation is not well known. AIMS: To assess the risk of relapse in the long-term after anti-TNF discontinuation. METHODS: This was an extension of the evolution after anti-TNF discontinuation in patients with inflammatory bowel disease (EVODIS) study (Crohn's disease or ulcerative colitis patients treated with anti-TNFs in whom these drugs were withdrawn after achieving clinical remission) based in the same cohort of patients whose outcome was updated. Clinical remission was defined as a Harvey-Bradshaw index ≤4 points in Crohn's disease, a partial Mayo score ≤2 in ulcerative colitis and the absence of fistula drainage despite gentle finger compression in perianal disease. RESULTS: This was an observational, retrospective, multicenter study. A total of 1055 patients were included. The median follow-up time was 34 months. The incidence rate of relapse was 12% per patient-year (95% confidence interval [CI] = 11-14). The cumulative incidence of relapse was 50% (95% CI = 47-53): 19% at one year, 31% at 2 years, 38% at 3 years, 44% at 4 years and 48% at 5 years of follow-up. Of the 60% patients retreated with the same anti-TNF after relapse, 73% regained remission. Of the 75 patients who did not respond, 48% achieved remission with other therapies. Of the 190 patients who started other therapies after relapse, 62% achieved remission with the new treatment. CONCLUSIONS: A significant proportion of patients who discontinued the anti-TNF remained in remission. In case of relapse, retreatment with the same anti-TNF was usually effective. Approximately half of the patients who did not respond after retreatment achieved remission with other therapies.

Modulation of faecal metagenome in Crohn's disease: Role of microRNAs as biomarkers.

BACKGROUND: The gut microbiota plays a key role in the maintenance of intestinal homeostasis and the development and activation of the host immune system. It has been shown that commensal bacterial species can regulate the expression of host genes. 16S rRNA gene sequencing has shown that the microbiota in inflammatory bowel disease (IBD) is abnormal and characterized by reduced diversity. MicroRNAs (miRNAs) have been explored as biomarkers and therapeutic targets, since they are able to regulate specific genes associated with Crohn's disease (CD). In this work, we aim to investigate the composition of gut microbiota of active treatment-naïve adult CD patients, with miRNA profile from gut microbiota. AIM: To investigate the composition of gut microbiota of active treatment-naïve adult CD patients, with miRNA profile from gut microbiota. METHODS: Patients attending the outpatient clinics at Valme University Hospital without relevant co-morbidities were matched according to age and gender. Faecal samples of new-onset CD patients, free of treatment, and healthy controls were collected. Faecal samples were homogenized, and DNA was amplified by PCR using primers directed to the 16S bacterial rRNA gene. Pyrosequencing was performed using GS-Junior platform. For sequence analysis, MG-RAST server with the database Ribosomal Project was used. MiRNA profile and their relative abundance were analyzed by quantitative PCR. RESULTS: Microbial community was characterized using 16S rRNA gene sequencing in 29 samples (n = 13 CD patients, and n = 16 healthy controls). The mean Shannon diversity was higher in the healthy control population compared to CD group (5.5 vs 3.7). A reduction in Firmicutes and an increase in Bacteroidetes were found. Clostridia class was also significantly reduced in CD. Principal components analysis showed a grouping pattern, identified in most of the subjects in both groups, showing a marked difference between control and CD groups. A functional metabolic study showed that a lower metabolism of carbohydrates (P = 0.000) was found in CD group, while the metabolism of lipids was increased. In CD patients, three miRNAs were induced in affected mucosa: mir-144 (6.2 ± 1.3 fold), mir-519 (21.8 ± 3.1) and mir-211 (2.3 ± 0.4). CONCLUSION: Changes in microbial function in active non-treated CD subjects and three miRNAs in affected vs non-affected mucosa have been found. miRNAs profile may serve as a biomarker.

Prognosis of Patients with Ulcerative Colitis in Sustained Remission After Thiopurines Withdrawal.

BACKGROUND: The ideal length of treatment with thiopurines in patients with ulcerative colitis (UC) in sustained remission remains unknown. It is widely accepted that the drug withdrawal is associated with a worse outcome. The aim of this study was to analyze the outcome after this withdrawal and to identify predictors of relapse. METHODS: A multicenter and retrospective study was designed. A total of 102 patients with UC who discontinued thiopurines in a situation of sustained remission were included. All the patients were followed up until last revision or until relapse (understood as the occurrence of signs and symptoms of UC that required a rescue treatment). RESULTS: After thiopurines withdrawal, overall relapse was recorded in 32.35% of the patients: 18.88% in the first year, 36.48% in the third, and 43.04% in the fifth year after withdrawal. On multivariate analysis, predictors of relapse were the time from diagnosis of UC until the starting of thiopurines (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.01-1.02; P = 0.039), the number of relapses before the withdrawal (HR, 1.3; 95% CI, 1.01-1.66; P = 0.029), pancolitis (HR, 5.01; 95% CI, 1.95-26.43; P = 0.028), the duration of treatment with thiopurines (HR, 0.15; 95% CI, 0.03-0.66; P = 0.013) and the situation of biological remission at withdrawal (HR, 0.004; 95% CI, 0.0001-0.14; P = 0.002). CONCLUSIONS: The withdrawal of thiopurines in patients with UC, although in sustained remission, is related to a high relapse rate. Clinical variables such as the extent of the disease, the duration of treatment or time from diagnosis to the start of thiopurines should be considered before stopping these drugs.

Colección abdominal gigante: cuando no todo es lo que parece / A giant abdominal collection: when things are not what they seem

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Hepatobiliary manifestations in inflammatory bowel disease: the gut, the drugs and the liver.

Abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and therefore become a diagnostic challenge. Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn's disease and ulcerative colitis (UC), and typically do not correlate with intestinal activity. Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of IBD, and is more prevalent in UC. Approximately 5% of patients with UC develop PSC, with the prevalence reaching up to 90%. Cholangiocarcinoma and colon cancer risks are increased in these patients. Less common disorders include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease. Hepatitis B reactivation during immunosuppressive therapy is a major concern, with screening and vaccination being recommended in serologically negative cases for patients with IBD. Reactivation prophylaxis with entecavir or tenofovir for 6 to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen (HBsAg) positive, independently from viral load. HBsAg negative and anti-HBc positive patients, with or without anti-HBs, should be closely monitored, measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy, and should be treated if the viral load increases. On the other hand, immunosuppressive therapy does not seem to promote reactivation of hepatitis C, and hepatitis C antiviral treatment does not influence IBD natural history either. Most of the drugs used for IBD treatment may induce hepatotoxicity, although the incidence of serious adverse events is low. Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant. Methotrexate-related hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner. Liver biopsy is not routinely recommended. Biologics-related hepatotoxicity is rare, but has been shown most frequently in patients treated with infliximab. Thiopurines have been associated with veno-occlusive disease, regenerative nodular hyperplasia, and liver peliosis. Routine liver biochemical tests are recommended, especially during the first month of treatment. All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement. Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.

Cutaneous lymphoma in a patient with ulcerative colitis after immunosuppressive therapy.

INTRODUCTION: Biologics are generally safe and well tolerated. However, the risk of haematopoietic cancer in patients with inflammatory bowel disease receiving infliximab has been a growing concern. CASE PRESENTATION: We report the first case of cutaneous lymphoma after short use of infliximab in 75-year old Caucasian man with a 7-year history of ulcerative colitis. CONCLUSION: Our current knowledge is not sufficient to rule out an increased risk of lymphoma associated with biologics, or allow definitive conclusions to be drawn about the association of infliximab and lymphoma. However, this case and others direct the attention to that both higher index of suspicion and closer follow up are required if patients are maintained on long-term infliximab together with other immunosuppressive therapy.

Tetania y convulsiones, síntomas de debut de la enfermedad de Crohn / Tetany and convulsions: onset symptoms in Crohn’s disease

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Cumplimiento, efectos adversos y efectividad del tratamiento cuádruple con bismuto (Pylera(R)) como tratamiento erradicador de primera línea en 200 pacientes con infección por Helicobacter pylori / Compliance, adverse effects and effectiveness of first line bismuth-containing quadruple treatment (Pylera(R)) to eradicate Helicobacter pylori infection in 200 patients

Introducción y objetivos: la cuádruple terapia con bismuto se recomienda como primera línea de tratamiento de la infección por Helicobacter pylori (H. pylori). El objetivo del estudio es valorar el cumplimiento, los efectos adversos y la efectividad de este tratamiento con la nueva forma galénica de cápsulas que contienen subcitrato de bismuto, metronidazol y tetraciclinas (Pylera(R)). Métodos: estudio observacional, prospectivo, unicéntrico, no controlado. Se incluyen 200 pacientes consecutivos, el 58% mujeres, con infección por H. pylori y sin tratamiento erradicador previo, tratados durante diez días con Pylera(R) (tres cápsulas cuatro veces al día con las comidas) asociado a un inhibidor de la bomba de protones antes de desayuno y cena. La cápsula de Pylera(R) contiene 140 mg de subcitrato de bismuto, 125 mg de metronidazol y 125 mg de tetraciclina. El cumplimiento y los efectos adversos del tratamiento se valoran mediante contacto telefónico y entrevista en la revisión clínica. El control de erradicación se realiza, al menos, tras cuatro semanas de finalizado el tratamiento, mediante la prueba del aliento con urea, la prueba de antígenos fecales con anticuerpos monoclonales o por histología. Resultados: a) cumplimiento del tratamiento en el 96% (192/200) de los pacientes; b) efectos adversos en el 28,5% (57/200) de los pacientes, motivando en siete casos el abandono del tratamiento y con gravedad en un solo caso por infección por Clostridium difficile; y c) efectividad por intención de tratamiento (183/200) del 91,5% (IC 95%: 87,1-96,8) y por protocolo (182/191) del 95,2% (IC 95%: 90,9-98,9). Conclusiones: el tratamiento con Pylera(R), en nuestra experiencia, es efectivo y seguro, debiéndose considerar como una opción terapéutica de primera línea en la erradicación de la infección por Helicobacter pylori

Introduction and objectives: quadruple therapy with bismuth is recommended as a first line treatment for Helicobacter pylori (H. pylori) infection. The aim of this study was to evaluate the compliance, adverse effects and effectiveness of this treatment with the new galenic three-in-one capsule formulation containing bismuth subcitrate, metronidazole and tetracycline (Pylera(R)). Methods: a prospective, non-controlled, single center observational study was performed in a cohort of 200 consecutive patients with an untreated H. pylori infection; 58% were female. The subjects were treated for ten days with Pylera(R) of three capsules four times daily with meals and a proton pump inhibitor taken before breakfast and dinner. The Pylera(R) capsule contains 140 mg of bismuth subcitrate, 125 mg of metronidazole and 125 mg of tetracycline. The compliance and adverse effects of the treatment were evaluated via telephone contact and via an interview during the clinical revision. Eradication of infection was controlled for at least four weeks after treatment termination via the urea breath test, the stool antigen test with monoclonal antibodies or by histology. Results: treatment compliance was observed in 96% (192/200) of the patients. Only 28.5% (57/200) of the patients experienced adverse effects, which led to abandoning the treatment in only seven subjects. Severe adverse effects developed in only one case due to Clostridium difficile infection. The effectiveness based on intention to treat was 91.5% (183/200, 95% CI: 87.1-96.8) and per protocol was 95.2% (182/191, 95% CI: 90.9-98.9). Conclusions: in our experience, Pylera(R) is an effective and safe treatment that should be considered as a first line therapeutic option for the eradication of H. pylori infection

Asynchrony between the circular and the longitudinal muscle contraction in patients with nutcracker esophagus.

BACKGROUND & AIMS: The increases in intraluminal pressure and muscle cross-sectional area (CSA) during esophageal contraction are markers of circular and longitudinal muscle contractions. The goal of our study was to determine temporal synchrony between circular and longitudinal muscle contraction in healthy subjects and patients with nutcracker esophagus. METHODS: Pressure and high-frequency intraluminal ultrasound (HFIUS) images were recorded simultaneously in healthy subjects and patients with nutcracker esophagus at 2 and 10 cm above the lower esophageal sphincter during wet swallow. HFIUS images were digitized and analyzed for the muscle CSA. The time interval (delta-t) between the peak muscle CSA and the peak pressure was determined. RESULTS: In healthy subjects, a close temporal correlation existed between the peak contraction pressure and the peak muscle CSA with a maximum delta-t of 0.5 seconds at the 2- and 10-cm levels (0-0.5 seconds). On the other hand, the patient group had a median delta-t of 1.25 seconds (0.75-3.5 seconds) at the 2-cm level and 0.75 seconds (0-2.0 seconds) at the 10-cm level. Ninety-eight of 103 contractions in patients showed a delta-t >0.5 seconds. There was a significant correlation between delta-t and the amplitude of pressure wave, the duration of pressure wave, and the peak muscle CSA. The duration of pressure wave but not the duration of CSA wave was longer in patients with nutcracker esophagus as compared with healthy subjects. CONCLUSIONS: Patients with nutcracker esophagus show temporal asynchrony between the contractions of circular and longitudinal muscle layers.