Combining Pentoxifylline With Vedolizumab for Crohn's Disease: Results of a Randomised, Placebo-controlled Pilot Study.

BACKGROUND AND AIMS: The efficacy of current biologics may be limited by targeting only one pathway. Pentoxifylline [PTX] interferes with tumour necrosis factor [TNF] gene expression. We performed a randomised, placebo-controlled pilot study to determine if PTX plus vedolizumab [VDZ] in patients with Crohn's disease [CD] is safe and improves response compared with VDZ monotherapy. METHODS: Thirty adult patients with active CD were randomised to VDZ/PTX or VDZ/placebo and followed for 24 weeks. Endoscopic activity and inflammatory cytokines were measured at baseline and Week 24. Descriptive statistics were used to determine estimates of effect. RESULTS: Demographics were similar but baseline disease activity was higher in the VDZ/PTX group. There was no difference in clinical remission at Week 14 (60.0% vs 66.67%, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.16, 3.51) or steroid-free clinical remission at Week 24 in patients receiving VDZ/PTX. Improved clinical response was noted in the VDZ/PTX group at Weeks 6, 14, and 24 [Week 6: 20% vs 6.67%, Week 14: 26.67% vs 6.67%, Week 24: 40% vs 20%]. The rate of endoscopic remission was similar between the groups [40% vs 33.33%], with a greater mean decrease in Simple Endoscopic Score-CD [SES-CD] and C-reactive protein [CRP] with VDZ/PTX [SES-CD -3.17 vs -0.15, CRP -5.56 vs 0.46]. An increase in serum TNF-α concentration was observed with VDZ/placebo group; PTX mitigated this effect. No serious adverse events occurred. CONCLUSIONS: VDZ/PTX did not provide benefit over VDZ monotherapy in clinical or endoscopic remission but appeared to improve clinical response and was safe. These data should inform a fully powered study.

Inflammatory Cytokine Profile in Crohn's Disease Nonresponders to Optimal Antitumor Necrosis Factor Therapy.

BACKGROUND: A significant number of patients receiving therapy with antitumor necrosis factor (TNF) agents for Crohn's disease experience primary or secondary nonresponse. The aim of this study was to assess whether patients with nonresponse to anti-TNF agents have increased expression of alternative cytokine pathways. METHODS: We designed a prospective, cross-sectional study that included patients with Crohn's disease receiving anti-TNF undergoing colonoscopy with adequate serum trough drug levels (≥8 µg/mL) and without anti-drug antibodies. Inflammatory cytokines and cell adhesions markers measured included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, interleukin (IL)-8, IL-1ß, and IL-6. The primary outcome was the presence of active endoscopic inflammation defined as the presence of at least 1 ulceration ≥5 mm. RESULTS: In total, 47 patients were included. Patients with active inflammation had significantly higher levels of ICAM-1 and IL-1ß when compared with those without intestinal inflammation (45.9 vs. 35.8 ng/mL, P<0.0001 and 3.2 vs. 1.5 pg/mL, P=0.002, respectively). There were no significant differences in the other study variables. Using receiving operating curves, ICAM and IL-1ß had a good correlation (receiver operating characteristic ≥0.8) with inflammation in this cohort of patients with "anti-TNF resistance." The results were similar in the group of patients with previous anti-TNF exposure. CONCLUSION: Our study suggests that patients who have active inflammation with seemingly adequate serum anti-TNF levels have increased levels of specific inflammatory pathways that may serve as biomarkers of nonresponse as well as potential targets of therapy in anti-TNF nonresponders.

[Update on chronic pancreatitis: review article]. / Una actualización de pancreatitis crónica: artículo de revisión.

Chronic pancreatitis is a progressive fibro-inflammatory disease of the pancreas characterized by irreversible fibrosis of the gland with eventual failure of exocrine and endocrine functions and hallmark features of abdominal pain, malabsorption, malnutrition, diabetes mellitus and pancreatic calcifications. In many patients this disease results from a complex mix of environmental (eg, alcohol, cigarettes, and occupational chemicals), genetic factors and a few patients with hereditary or autoimmune disease. The management includes medical, endoscopic and surgical approaches with the need for interaction between various specialties, calling for a concerted multidisciplinary approach. This review provides the reader with a comprehensive overview of the studies summarizing the epidemiology, etiology, physiopatology, clinical manifestation, diagnosis and treatments of the disease.

Una actualización de pancreatitis crónica: artículo de revisión / Update on chronic pancreatitis: review article

La pancreatitis crónica es una enfermedad fibro-inflamatoria progresiva del páncreas caracterizada por la fibrosis irreversible de la glándula con el eventual fallo de las funciones exocrinas y endocrinas. Las características distintivas de la enfermedad son el dolor abdominal, la malabsorción, la desnutrición, la diabetes mellitus y las calcificaciones pancreáticas. En muchos pacientes el origen de esta enfermedad se debe a una compleja mezcla de factores ambientales (por ejemplo, alcohol, cigarrillos y productos químicos en el trabajo), factores genéticos y en algunos casos origen hereditario o autoinmune. El manejo incluye enfoques médico, endoscópico y quirúrgico con la necesidad de la interacción entre diversas especialidades para dar un enfoque multidisciplinario coordinado. Esta revisión ofrece una visión general de los estudios recientes resumiendo la epidemiología, etiología, fisiopatología, manifestaciones clínicas, diagnóstico y tratamiento de la enfermedad.

Chronic pancreatitis is a progressive fibro-inflammatory disease of the pancreas characterized by irreversible fibrosis of the gland with eventual failure of exocrine and endocrine functions and hallmark features of abdominal pain, malabsorption, malnutrition, diabetes mellitus and pancreatic calcifications. In many patients this disease results from a complex mix of environmental (eg, alcohol, cigarettes, and occupational chemicals), genetic factors and a few patients with hereditary or autoimmune disease. The management includes medical, endoscopic and surgical approaches with the need for interaction between various specialties, calling for a concerted multidisciplinary approach. This review provides the reader with a comprehensive overview of the studies summarizing the epidemiology, etiology, physiopatology, clinical manifestation, diagnosis and treatments of the disease.

Serum Amyloid A as a Surrogate Marker for Mucosal and Histologic Inflammation in Patients with Crohn's Disease.

BACKGROUND: Serum amyloid A (SAA) is an acute-phase protein, but its role as a biomarker of disease activity in Crohn's disease is unclear. The aim of the study was to assess the correlation between SAA, inflammatory cytokines, and mucosal inflammation in patients with Crohn's disease and to investigate whether this marker might be useful in patients who do not have elevated C-reactive protein (CRP) levels despite having active disease. METHODS: Cross-sectional study including patients with Crohn's disease who underwent colonoscopies for assessment of disease activity. Predictive variables were recorded at the time of the procedure and included demographics, phenotype of disease, medications, and collection of serum for cytokine analysis (SAA, CRP, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukins 8, 1ß, and 6). The primary outcome was the presence of mucosal healing (MH) (absence of macroscopic and microscopic inflammation). RESULTS: Ninety-four patients were included. Sixty-eight (72.3%) had not achieved MH. SAA, CRP, intercellular adhesion molecule, and interleukin-6 levels were significantly lower in those patients with MH. SAA was the only test that performed well in the sensitivity/specificity analysis (receiver operating characteristic: 0.81, P = 0.046). A high SAA was able to identify 70% of the patients with a normal CRP but active inflammation. CONCLUSIONS: High circulating SAA levels can correlate with lack of MH and may be used as a surrogate marker for disease activity, even in those patients in whom CRP levels do not correlate with disease activity.

Type 1 autoimmune pancreatitis: case scenario and review of the disease.

Autoimmune pancreatitis (AIP) is an uncommon disease that represents a diagnostic challenge unless it is considered as a cause of acute pancreatitis, pancreatic exocrine insufficiency and a pancreatic mass. This entity is under diagnosed and successful medical therapy is available. In this paper, we will describe a case of a 59 year-old, Hispanic woman diagnosed with autoimmune pancreatitis, a disease previously believed to affect typically older men. We will review the definition, types, clinical manifestations, radiological features, serology, histopathological findings, treatment strategies and diagnostic criteria of autoimmune pancreatitis.

Quality of Care Provided by Hepatologists to Patients with Cirrhosis at Three Parallel Health Systems.

BACKGROUND: Evidence-based guidelines and quality indicators for cirrhosis care have been established. Whether there are variations in adherence to these cirrhosis standards at different specialty settings has not been investigated. AIMS: To evaluate the quality of cirrhosis care delivered at diverse hepatology care sites. METHODS: We conducted a retrospective study comparing the quality of care at three hepatology specialty clinics: a Faculty Practice, safety-net hospital, and Veterans Affairs (VA) Medical Center. Consecutive patients with cirrhosis (85 Faculty Practice, 81 safety-net, and 76 VA) between 2010 and 2011 were included. Median follow-up was 2.3 years. Outcome measures were the adherence to six cirrhosis-specific quality-of-care indicators. RESULTS: Adherence to hepatitis A and B vaccinations was highest at the safety-net hospital, 81 and 74 %, compared to 46 and 30 % at the Faculty Practice (P < .001). Adherence to yearly hepatocellular carcinoma surveillance was highest at the safety-net site (79 %) versus the VA (50 %) and Faculty Practice (42 %), P = .001. In contrast, screening rates for esophageal varices were 75 % at the Faculty Practice and only 58 and 43 % at the VA and safety-net sites, respectively (P < .001). Liver transplant discussions were documented most consistently at the Faculty Practice (82 %) compared to the safety-net site (53 %) and VA (54 %), P < .001. CONCLUSIONS: Disparities in cirrhosis quality measures existed by site. Strategies to overcome these disparities need to be developed to improve the delivery of quality cirrhosis care as we face a rise in cirrhosis-related complications over the next two decades.

Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis.

BACKGROUND: Gastroparesis (GP) is a disabling chronic gastroenterologic disorder with high morbidity that severely impacts patients' quality of life. GP can present acutely after a viral-like gastrointestinal illness resulting in speculation that in some patients, neurologic damage caused by the infection might underlie the pathogenesis of idiopathic gastroparesis (IGP). AIMS: The aim of this study is to document case reports of Enterovirus (EV) infection as a possible cause of IGP. METHODS: Eleven patients referred with a diagnosis of GP underwent workup to exclude known causes of GP. Those with a history of flu-like symptoms or gastroenteritis prior to onset of GP symptoms had gastric biopsies taken during upper endoscopy to assess for the presence of gastric mucosal EV infection. Data on presenting symptoms, extra-intestinal symptoms and conditions, prior nutritional support requirements, upper endoscopy findings, and response to therapy were cataloged. RESULTS: Eleven patients were diagnosed as IGP. Nine had active EV infection on gastric biopsies and were included (7/9 female, mean age 43 years). Eight out of nine received EV treatment with antivirals and/or immune therapies, with a wide degree of variability in treatment regimens. Four out of eight who received EV treatment had symptomatic improvement. One patient had stable symptoms. Three patients are currently undergoing therapy. CONCLUSIONS: Gastric EV infection was frequently detected (82 %) in patients undergoing investigation for IGP. Antiviral and/or immune therapies against EV seem to be favorable, as most of our patients had resolution of their GP symptoms after treatment. This is the first study to identify EV as a possible infectious etiology of IGP.

Noninvasive Markers to Assess Liver Fibrosis.

Chronic liver disease represents a major public health problem, accounting for significant morbidity and mortality worldwide. Their prognosis and management greatly depends on the amount and progression of liver fibrosis with time and the risk of development of cirrhosis. Historically, liver biopsy was considered to be the gold standard for the detection of fibrosis. Nevertheless, liver biopsy is an invasive procedure that has limitations in terms of patient acceptance, risk-benefit ratio, cost-effectiveness, and its availability in various geographic regions. Moreover, it is a questionable gold standard due to significant sampling error and intraobserver and interobserver variability. These limitations have led to the development of noninvasive techniques for assessing the presence and the degree of liver fibrosis. This review aims to revise the most recent data from the literature about noninvasive methods useful in the evaluation of liver fibrosis.

Age of Diagnosis is Associated with Disease Presentation and Therapeutic Complications in Patients with Crohn's Disease.

BACKGROUND: Although Crohn's disease (CD) is usually diagnosed at a younger age, a growing population of patients with inflammatory bowel disease is diagnosed above age 60 (elderly). The aim of this study was to compare disease phenotype, behavior, and therapy in elderly patients with CD to young patients diagnosed between 18 to 25 years. METHODS: This retrospective case-control study identified patients diagnosed with CD at age 60 or above (elderly) and matched them by gender and disease duration with 2 "young" controls diagnosed between 18 and 25 years. Demographic data, disease information, and medical and surgical history were collected from the University of Chicago Medicine inflammatory bowel disease database. RESULTS: Thirty-two patients were identified in the "elderly" group and matched to 64 "young" patients. Crohn's colitis was more common in older patients (37.5% versus 15.6%, P = 0.02) who were also less likely to have ileocolonic, perianal, or penetrating disease with less extraintestinal manifestations. After 1998, there was no difference in the use of steroids, 5-aminosalicylates, immunomodulators, biologics, or immunomodulators + biologics. No difference was found in the rates of bowel surgery between the 2 groups. Elderly patients developed fewer therapy-related noninfectious complications and Crohn's-related abscesses. Three serious infections (staphylococcal septicemia, pneumonia, and cryptococcal meningitis) were identified in 3 elderly patients on combination immunomodulators + biologics. CONCLUSIONS: Elderly CD is more likely to present with Crohn's colitis and less likely to present with ileocolonic, perianal, or penetrating disease with less extraintestinal manifestations. Elderly are more likely to develop serious therapy-related infectious complications. Larger prospective trials are needed to evaluate the risks of CD immunosuppressive therapy in elderly patients.

Novel Therapies on Primary Biliary Cirrhosis.

All patients with primary biliary cirrhosis (PBC) and abnormal liver biochemistry should be considered for specific therapy. Ursodeoxycholic acid (UDCA) is the only FDA-approved drug for treating PBC. Approximately 40% of patients with PBC respond incompletely to treatment with UDCA, thus having increased risk of death or need for liver transplantation. No second-line therapies for patients with inadequate response to UDCA therapy have been approved. This review provides a current perspective on potential new approaches to treatment in PBC, and highlights some of the challenges we face in evaluating and effectively implementing those treatments.

Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.

BACKGROUND & AIMS: In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI). METHODS: We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohn's and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, and biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI. RESULTS: Levels of 6-TGN correlated with those of infliximab (ρ, 0.53; P < .0001). The cut-off point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8 × 10(8) red blood cells (RBCs) (area under receiver operating characteristic, 0.86; P < .001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/mL, respectively; P = .8). An infliximab level of 8.3 mcg/mL or greater was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with 6-TGN levels less than 125 pmol/8 × 10(8) RBCs were significantly more likely to have ATI (odds ratio, 1.3; 95% confidence interval, 2.3-72.5; P < .01). CONCLUSIONS: Although 6-TGN levels of greater than 230 pmol/8 × 10(8) RBCs have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine of 125 pmol/8 × 10(8) RBCs or greater may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.

Leopard skin sign: the use of narrow-band imaging with magnification endoscopy in celiac disease / Signo de la "piel de leopardo": el uso de endoscopía con magnificación y narrow banding en enfermedad celiaca

Celiac disease (CD) is an immune reaction to gluten containing foods such as rye, wheat and barley. This condition affects individuals with a genetic predisposition; it targets the small bowel and may cause symptoms including diarrhea, malabsorption, weight loss, abdominal pain and bloating. The diagnosis is made by serologic testing of celiac-specific antibodies and confirmed by histology. Certain endoscopic characteristics, such as scalloping, reduction in the number of folds, mosaic-pattern mucosa or nodular mucosa, are suggestive of CD and can be visualized under white light endoscopy. Due to its low sensitivity, endoscopy alone is not recommended to diagnose CD; however, enhanced visual identification of suspected mucosal abnormalities through the use of new technologies, such as narrow band imaging with magnification (NBI-ME), could assist in targeting biopsies and thereby increasing the sensitivity of endoscopy. This is a case series of seven patients with serologic and histologic diagnoses of CD who underwent upper endoscopies with NBI-ME imaging technology as part of their CD evaluation. By employing this imaging technology, we could identify patchy atrophy sites in a mosaic pattern, with flattened villi and alteration of the central capillaries of the duodenal mucosa. We refer to this epithelial pattern as ôLeopard Skin Signõ. Since epithelial lesions are easily seen using NBI-ME, we found it beneficial for identifying and targeting biopsy sites. Larger prospective studies are warranted to confirm our findings.

La enfermedad celiaca (EC) es una reacción inmune a los alimentos que contienen gluten como el centeno, el trigo y la cebada. Esta condición afecta a las personas con predisposición genética, comprometiendo al intestino delgado causando síntomas como diarrea, mala absorción, pérdida de peso, dolor abdominal y meteorismo. El diagnóstico se hace con estudios serológicos de anticuerpos específicos celiacos y es confirmado por histología. Algunas características endoscópicas tales como ôscallopingõ, reducción en el número de pliegues, patrón mucoso tipo mosaico o mucosa nodular, son sugestivos de EC y se pueden observar con endoscopía de luz blanca. Debido a su baja sensibilidad la endoscopía por sí sola no se recomienda para diagnosticar EC, sin embargo, una visualización cuidadosa de las anormalidades mucosas sospechosas a través de nuevas tecnologías como ôNarrow Band Imaginingõ con magnificación (NBI-ME) puede ayudar a dirigir las biopsias y así incrementar la sensibilidad de la endoscopía. Esta es una serie de siete casos con diagnóstico serológico e histológico de EC a quienes se les realizó una endoscopía digestiva alta con NBI-ME. En ellos se pudo identificar sitios de atrofia parcelar en un patrón de mosaico, con vellosidades aplanadas y alteración de los capilares de la mucosa duodenal. Nos referimos a esta alteración como el ôSigno de la Piel de Leopardoõ. Como las lesiones epiteliales se ven fácilmente usando NBI-ME, lo encontramos beneficioso para identificar y dirigir los sitios donde tomar las biopsias. Estudios prospectivos más grandes deben realizarse para confirmar nuestros hallazgos.

Hepatobiliary manifestations of inflammatory bowel disease.

Patients with inflammatory bowel diseases (IBDs) may present with several hepatic abnormalities. Some of these liver diseases are benign and only require observation, whereas others may cause liver failure and require liver transplantation. The aim of this review was to present and summarize the latest evidence on the most common liver diseases seen in patients with IBD. These manifestations can be divided in to 3 groups: those that are seen in association with IBD, those that are due to metabolic and physiologic changes induced by the IBD and those that are secondary to the drugs used in the treatment of IBD. Primary sclerosing cholangitis is one of the most common hepatobiliary manifestations of IBD that is more prevalent in patients with ulcerative colitis. There is no approved medical treatment for primary sclerosing cholangitis and about 50% of patients will require liver transplantation within 10 to 15 years from the time of diagnosis. Among the drugs that are commonly used in the treatment of IBD, thiopurines and methotrexate impose the higher risk of hepatotoxicity. In most cases, dose adjustment and avoidance of hepatotoxins will normalize the liver tests and discontinuation of the drug is required in a minority of cases. Reactivation of hepatitis B virus during immunosuppressive therapy is a major concern and adequate screening and vaccination is warranted. The approach to a patient with IBD who presents with abnormal liver chemistries can be challenging not only because 2 or more conditions can co-exist but also because management must be individualized.

"Leopard skin sign": the use of narrow-band imaging with magnification endoscopy in celiac disease.

Celiac Disease (CD) is an immune reaction to gluten containing foods such as rye, wheat and barley. This condition affects individuals with a genetic predisposition; it targets the small bowel and may cause symptoms including diarrhea, malabsorption, weight loss, abdominal pain and bloating. The diagnosis is made by serologic testing of celiac-specific antibodies and confirmed by histology. Certain endoscopic characteristics, such as scalloping, reduction in the number of folds, mosaic-pattern mucosa or nodular mucosa, are suggestive of CD and can be visualized under white light endoscopy. Due to its low sensitivity, endoscopy alone is not recommended to diagnose CD; however, enhanced visual identification of suspected mucosal abnormalities through the use of new technologies, such as narrow band imaging with magnification (NBI-ME), could assist in targeting biopsies and thereby increasing the sensitivity of endoscopy. This is a case series of seven patients with serologic and histologic diagnoses of CD who underwent upper endoscopies with NBI-ME imaging technology as part of their CD evaluation. By employing this imaging technology, we could identify patchy atrophy sites in a mosaic pattern, with flattened villi and alteration of the central capillaries of the duodenal mucosa. We refer to this epithelial pattern as "Leopard Skin Sign". Since epithelial lesions are easily seen using NBI-ME, we found it beneficial for identifying and targeting biopsy sites. Larger prospective studies are warranted to confirm our findings.

Predictive factors for clinically actionable computed tomography findings in inflammatory bowel disease patients seen in the emergency department with acute gastrointestinal symptoms.

BACKGROUND: The wide use of abdomino-pelvic computed tomography (APCT) in emergency departments (ED) has raised the concern for radiation exposure, costs and potential reactions to contrast agents. The aim of this study was to determine the yield and predictive factors for clinically actionable findings (CAF) in APCTs performed in patients with inflammatory bowel disease (IBD) who visit the ED. METHODS: We performed a cross-sectional study including patients with IBD who visited the ED. Variables considered were demographics, IBD phenotype, clinical symptoms, IBD medication use prior to ED visit, laboratory values, and imaging results. The primary outcome was a composite of CAF, defined as new, intra-abdominal abscess or tumor, bowel obstruction, fistulae, diverticulitis, choledocholithiasis, or appendicitis. RESULTS: 354 patients were included. One or more CAF were reported in 26.6% of the APCTs (32.1% in CD and 12.8% in UC [p<0.01]). Independent predictive variables of CAF in CD were: CRP level ≥5mg/dl (p=0.04), previous history of IBD surgery (p=0.037), Black race (p<0.01) and low body mass index (p<0.01). None of the study variables predicted CAF in UC. CONCLUSIONS: The yield for CAF with APCT in the ED was high for CD patients but minimal for those with UC and was not improved by the use of contrast. Elevated CRP, low BMI, Black race and previous history of IBD surgery predicted CAF in CD but no variables were predictive of CAF in UC.