Clinical Characteristics, Associated Malignancies and Management of Primary Sclerosing Cholangitis in Inflammatory Bowel Disease Patients: A Multicentre Retrospective Cohort Study.

BACKGROUND AND AIMS: Primary sclerosing cholangitis [PSC] is usually associated with inflammatory bowel disease [IBD]. An increased risk of malignancies, mainly colorectal cancer [CRC] and cholangiocarcinoma [CCA], has been reported in PSC-IBD patients. Our aim was to determine the clinical characteristics and management of PSC in IBD patients, and the factors associated with malignancies. METHODS: PSC-IBD patients were identified from the Spanish ENEIDA registry of GETECCU. Additional data were collected using the AEG-REDCap electronic data capture tool. RESULTS: In total, 277 PSC-IBD patients were included, with an incidence rate of 61 PSC cases per 100 000 IBD patient-years, 69.7% men, 67.5% ulcerative colitis and mean age at PSC diagnosis of 40 ± 16 years. Most patients [85.2%] were treated with ursodeoxycholic acid. Liver transplantation was required in 35 patients [12.6%] after 79 months (interquartile range [IQR] 50-139). It was more common in intra- and extrahepatic PSC compared with small-duct PSC (16.3% vs 3.3%; odds ratio [OR] 5.7: 95% confidence interval [CI] = 1.7-19.3). The incidence rate of CRC since PSC diagnosis was 3.3 cases per 1000 patient-years [95% CI = 1.9-5.6]. Having symptoms of PSC at PSC diagnosis was the only factor related to an increased risk of CRC after IBD diagnosis [hazard ratio= 3.3: 95% CI = 1.1-9.9]. CCA was detected in seven patients [2.5%] with intra- and extrahepatic PSC, with median age of 42 years [IQR 39-53], and presented a lower life expectancy compared with patients without CCA and patients with or without CRC. CONCLUSIONS: PSC-IBD patients with symptoms of PSC at PSC diagnosis have an increased risk of CRC. CCA was only diagnosed in patients with intra- and extrahepatic PSC and was associated with poor survival.

Short- and long-term clinical outcomes of self-expandable metal stents inserted for colorectal obstruction and efficacy of different insertion techniques / Resultados a corto y largo plazo de la colocación de prótesis metálicas autoexpandibles en la obstrucción colorrectal y eficacia de las diferentes técnicas de inserción

Objectives: (1) To evaluate the short- and long-term clinical outcomes of patients after colorectal stent placement and (2) to assess the safety and efficacy of the stents for the resolution of colorectal obstruction according to the insertion technique. Methods: Retrospective cohort study which included 177 patients with colonic obstruction who underwent insertion of a stent. Results: A total of 196 stents were implanted in 177 patients. Overall, the most common cause of obstruction was colorectal cancer (89.3%). Ninety-two stents (47%) were placed by radiologic technique and 104 (53%) by endoscopy under fluoroscopic guidance. Technical success rates were 95% in both groups. Clinical success rates were 77% in the radiological group and 81% in the endoscopic group (p>0.05). The rate of complications was higher in the radiologic group compared with the endoscopic group (38% vs 20%, respectively; p=0.006). Among patients with colorectal cancer (158), 65 stents were placed for palliation but 30% eventually required surgery. The multivariate analysis identified three factors associated with poorer long-term survival: tumor stage IV, comorbidity and onset of complications. Conclusions: Stents may be an alternative to emergency surgery in colorectal obstruction, but the clinical outcome depends on the tumor stage, comorbidity and stent complications. The rate of definitive palliative stent placement was high; although surgery was eventually required in 30%. Our study suggests that the endoscopic method of stent placement is safer than the radiologic method

Objetivos: 1) Evaluar los resultados clínicos a corto y largo plazo de los pacientes después de la colocación de una prótesis a nivel colorrectal y 2) Evaluar la eficacia y la seguridad de las prótesis en la resolución de la obstrucción en función de la técnica de inserción. Métodos: Estudio de cohortes retrospectivo que incluyó 177 pacientes con obstrucción cólica que fueron tratados incialmente con colocación de prótesis. Resultados: Se colocaron 196 prótesis en 177 pacientes. La causa más frecuente de obstrucción fue el cáncer colorrectal (89,3%). Noventa y dos prótesis (47%) se colocaron mediante técnica radiológica y 104 (53%) mediante endoscopia bajo guía fluoroscópica. Las tasas de éxito técnico fueron del 95% en ambos grupos. Las tasas de éxito clínico fueron del 77% en el grupo radiológico y del 81% en el grupo endoscópico (p>0,05). La tasa de complicaciones fue mayor en el grupo radiológico en comparación con el grupo endoscópico (38 vs. 20%, respectivamente; p=0,006). Entre los pacientes con cáncer colorrectal (158), 65 prótesis se colocaron con un fin paliativo, pero el 30% requirió finalmente cirugía. El análisis multivariante identificó 3 factores asociados a una peor supervivencia: estadio tumoral IV, comorbilidad y aparición de complicaciones. Conclusiones: Las prótesis pueden ser una alternativa a la cirugía urgente en la obstrucción colorrectal, pero el resultado clínico depende del estadio tumoral, de la comorbilidad y de las complicaciones de la prótesis. La tasa de colocación de prótesis paliativa definitiva fue alta; aunque en un 30% se requirió cirugía, finalmente. Nuestro estudio sugiere que el método de implantación con visión endoscópica es más seguro que el método radiológico

Short- and long-term clinical outcomes of self-expandable metal stents inserted for colorectal obstruction and efficacy of different insertion techniques.

OBJECTIVES: (1) To evaluate the short- and long-term clinical outcomes of patients after colorectal stent placement and (2) to assess the safety and efficacy of the stents for the resolution of colorectal obstruction according to the insertion technique. METHODS: Retrospective cohort study which included 177 patients with colonic obstruction who underwent insertion of a stent. RESULTS: A total of 196 stents were implanted in 177 patients. Overall, the most common cause of obstruction was colorectal cancer (89.3%). Ninety-two stents (47%) were placed by radiologic technique and 104 (53%) by endoscopy under fluoroscopic guidance. Technical success rates were 95% in both groups. Clinical success rates were 77% in the radiological group and 81% in the endoscopic group (p>0.05). The rate of complications was higher in the radiologic group compared with the endoscopic group (38% vs 20%, respectively; p=0.006). Among patients with colorectal cancer (158), 65 stents were placed for palliation but 30% eventually required surgery. The multivariate analysis identified three factors associated with poorer long-term survival: tumor stage IV, comorbidity and onset of complications. CONCLUSIONS: Stents may be an alternative to emergency surgery in colorectal obstruction, but the clinical outcome depends on the tumor stage, comorbidity and stent complications. The rate of definitive palliative stent placement was high; although surgery was eventually required in 30%. Our study suggests that the endoscopic method of stent placement is safer than the radiologic method.

Genetic susceptibility in the development of colorectal adenomas according to family history of colorectal cancer.

Our study aimed to evaluate the relevance of genetic susceptibility in the development of colorectal adenomas (CRA) and its relationship with the presence of family history of colorectal cancer (CRC). Genomic DNA from 750 cases (first degree relatives of patients with CRC) and 750 controls (subjects with no family history of CRC) was genotyped for 99 single nucleotide polymorphisms (SNPs) previously associated with CRC/CRA risk by GWAS and candidate gene studies by using the MassArray™ (Sequenom) platform. Cases and controls were matched by gender, age and histological lesion. Eight hundred and fifty-eight patients showed no neoplastic lesions, whereas 288 patients showed low-risk adenomas, and 354 patients presented high-risk adenomas. Two SNPs (rs10505477, rs6983267) in the CASC8 gene were associated with a reduced risk of CRA in controls (log-additive models, OR: 0.67, 95%CI:0.54-0.83, and OR:0.66, 95%CI:0.54-0.84, respectively). Stratified analysis by histological lesion revealed the association of rs10505477 and rs6983267 variants with reduced risk of low- and high-risk adenomas in controls, being this effect stronger in low-risk adenomas (log-additive models, OR:0.63, 95%CI:0.47-0.84 and OR:0.64, 95%CI:0.47-0.86, respectively). Moreover, 2 SNPs (rs10795668, rs11255841) in the noncoding LINC00709 gene were significantly associated with a reduced risk of low-risk adenomas in cases (recessive models, OR:0.22, 95%CI:0.06-0.72, and OR:0.08, 95%CI:0.03-0.61) and controls (dominant models, OR:0.50, 95%CI:0.34-0.75, and OR:0.52, 95%CI:0.35-0.78, respectively). In conclusion, some variants associated with CRC risk (rs10505477, rs6983267, rs10795668 and rs11255841) are also involved in the susceptibility to CRA and specific subtypes. These associations are influenced by the presence of family history of CRC.

Oral Cyanocobalamin is Effective in the Treatment of Vitamin B12 Deficiency in Crohn's Disease.

Cobalamin deficiency is common in patients with Crohn's disease (CD). Intramuscular cobalamin continues to be the standard therapy for the deficiency and maintenance treatment in these patients, although oral route has been demonstrated to be effective in other pathologies with impaired absorption. Our aims were to evaluate the efficacy of oral therapy in the treatment of cobalamin deficiency and in long-term maintenance in patients with Crohn's disease. We performed a multicenter retrospective cohort study that included 94 patients with Crohn's disease and cobalamin deficiency. Seventy-six patients had B12 deficiency and 94.7% of them normalized their cobalamin levels with oral treatment. The most used dose was 1 mg/day, but there were no significant differences in treatment effectiveness depending on the dose used (≥1 mg/24 h vs. <1 mg/24 h). Eighty-two patients had previous documented B12 deficiency and were treated with oral B12 to maintain their correct cobalamin levels. After a mean follow-up of 3 years, the oral route was effective as maintenance treatment in 81.7% of patients. A lack of treatment adherence was admitted by 46.6% of patients in who the oral route failed. In conclusion, our study shows that oral cyanocobalamin provides effective acute and maintenance treatment for vitamin B12 deficiency caused by CD with or without ileum resection.

Biosimilars in inflammatory bowel disease.

The introduction of biologic therapies has revolutionized the treatment of inflammatory bowel disease (IBD) and has significantly improved the disease course and outcomes for many patients. Biologics are the main drivers of cost in many IBD units and biosimilars, although are not better than originators, are usually cheaper and thus can increase the availability of this type of therapy. Biosimilar are highly similar to innovator but, due to the complex structures of innovators and the variability inherent in the manufacturing process, they are no identical. This fact cause concerns with respect to the efficacy and safety in medical community, especially in the medical indications in which no specific clinical trials with biosimilars have been performed as IBD. Nowadays, two biosimilars to infliximab, CT-P13 and SB2, has been approved by European Medicines Agency in all the indications of the reference product. To date, the available evidence suggests that switch from reference medicinal product (infliximab) to the biosimilar (CT-P13 or SB2) is feasible since published studies have not observed significantly difference in terms of efficacy, immunogenicity and safety. However, the experts agreed that by now there is not sufficient evidence to consider infliximab biosimilars interchangeable with the originator compound. In this manuscript, we will review the processes involved in the manufacturing and regulatory approval of biosimilars and examine the evidence presently available on approved biosimilars in Europe for IBD.

Management of low-dose aspirin and clopidogrel in clinical practice: a gastrointestinal perspective.

Low-dose aspirin, alone or combined with other antiplatelet agents, is increasingly prescribed for cardiovascular prevention. However, the cardiovascular benefits should be evaluated together with the gastrointestinal risks. Low-dose aspirin is associated with upper and lower gastrointestinal injury, although lower gastrointestinal effects are poorly characterized. This gastrointestinal risk differs among antiplatelets drugs users. The most important risk factors are history of peptic ulcer, older age, and concomitant use of non-steroidal anti-inflammatory drugs or dual antiplatelet therapy. Effective upper gastrointestinal prevention strategies are available and should be used in at-risk patients taking low-dose aspirin or clopidogrel. Proton pump inhibitors seem to be the best gastroprotective agents, whereas the benefits of Helicobacter pylori eradication are still unclear. Low-dose aspirin has additional effects in the gastrointestinal tract. A large body of evidence indicates that it can protect against different cancers, in particular colorectal cancer. This effect could modify the future indications for use of low-dose aspirin and the risk-benefit balance.

Prevention and Treatment of NSAID Gastropathy.

OPINION STATEMENT: Nonsteroidal anti-inflammatory drug (NSAID) treatment will be necessary as part of our therapeutic armamentarium for many years to come. Therefore, safe prescription is mandatory in order to prevent adverse events. In the last two decades, new strategies and new drugs have been developed to reduce NSAID-associated upper gastrointestinal (GI) adverse events. Although the implementation of guidelines into clinical practice takes time, several studies have shown a recent and profound decrease in hospitalizations due to upper GI complications, which has been linked to widespread use of proton pump inhibitors (PPIs), better NSAID prescription, and decreased prevalence of Helicobacter pylori infection. This is encouraging.Safe NSAID prescription should be straightforward since the most relevant aspects are clinical in nature. Before issuing any prescription, three key questions should be considered:1) Is NSAID treatment necessary for this patient?2) What cardiovascular (CV) and GI risk factors does this patient have?3) What is the most suitable NSAID for this patient?GI and CV risk are easy to estimate, and we know that these risks are not the same for all NSAIDs. Selective cyclooxygenase (COX)-2 inhibitors, like celecoxib at usual doses, carry the lowest GI risk and are the best option in patients with moderate/high GI risk without high CV risk. Gastroprotective therapy (PPI as the drug of choice) should be considered if a non-selective NSAID is prescribed. For those at the highest risk, a combination of PPI plus a coxib is the best option. Also, eradication of H. pylori infection in patients with previous peptic ulcer or in NSAID-naïve users must be considered. Naproxen is the best option in patients with high CV risk and low/moderate GI risk.Patients taking aspirin represent a real challenge for treatment, since interaction with frequently prescribed NSAIDs (e.g. ibuprofen/naproxen) may alter its antiplatelet effect, representing a potential clinical problem. Switching treatment (e.g. taking aspirin before NSAID dosing) may not be an alternative since interaction may persist, especially when taking enteric-coated aspirin. Changing NSAID treatment to diclofenac/celecoxib/etoricoxib may also not be an option in patients with high or previous CV event history. Under these circumstances, careful prescription should be considered at the individual patient level.When dyspepsia develops in an NSAID user, PPI co-therapy plus reduction of the NSAID dose or a change in the type of NSAID are valid alternatives, but clinical experience shows that, for some patients, stopping NSAID therapy may be the only option. After a bleeding episode, most patients can be managed with alternative therapy to NSAIDs, but if needed, a coxib plus a PPI and H. pylori eradication is a safe alternative.

Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage.

NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal (GI) adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies.

Is NSAIDs-related gastrointestinal damage preventable?

Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most commonly used drugs worldwide; however, they are not innocuous. The spectrum of upper gastrointestinal (GI) tract damage caused by NSAIDs has been well established, and strategies to prevent this have been widely studied and implemented. Removing modifiable risk factors, the selection of less toxic NSAIDs and treatment with gastroprotective drugs, if necessary, are the main strategies employed. However, injury of the NSAIDs-related lower GI tract remains poorly characterized. In the last decade, there has been an increasing interest in this field and the search for effective preventive treatments is under way. Use of cyclooxygenase-2 inhibitor, prostaglandin, antibiotic or drugs that are not yet commercially available such as nitric oxide-releasing and hydrogen sulfide (H(2) S)-releasing NSAIDs compounds seem to reduce lower GI injury, but more evidence are needed before any of them are recommended in high-risk patients.

Gastrointestinal lesions and complications of low-dose aspirin in the gastrointestinal tract.

Low dose aspirin (ASA) use has been associated with a wide range of adverse side effects in the upper gastrointestinal (GI) tract, which range from troublesome symptoms without mucosal lesions to more serious toxicity, including ulcers, GI bleeding, perforation and even death. Upper GI symptoms in low dose ASA users are common but often careless or misinterpreted and they are not always related to the presence of mucosal injury. Usually, low dose ASA related ulcers are reasonably small and asymptomatic, and probably heal over a period of weeks to a few months. But, the real clinical problem occurs when the ulcer results in a GI complication (mostly bleeding). The estimated average excess risk of symptomatic or complicated ulcer related to low dose ASA is five cases per 1000 ASA users per year. Death is the worst outcome of GI complications in low dose ASA users, but data about this aspect are scarce. Current evidence indicates that low dose ASA can damage the lower GI tract also, but the real size of the problem is still unknown.

Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed medication in the world. Their main benefit derives from their anti-inflammatory and analgesic effect, but the use of these agents is not innocuous since they mainly increase the risk of gastrointestinal (GI) and cardiovascular complications compared with non-NSAID users. NSAIDs injures the upper and lower gut by depleting COX-1 derived prostaglandins and causing topical injury to the mucosa. The risk of upper GI complications varies, depending on the presence of one or more risk factors. Among them, the three main risk factors are prior history of peptic ulcer, the single most important risk factor, age, the most common, and concomitant aspirin use, due to their GI and cardiovascular implications. Those individuals at-risk should be considered for alternatives to NSAID therapy and modifications of risk factors. If NSAID therapy is required, patients at risk will need prevention strategies including co-therapy of NSAID with gastroprotectants (PPI or misoprostol) or the prescription of COX-2 selective inhibitors. The probable introduction of NO-NSAIDs in the market in the near future may open a new therapeutic option for patients with hypertension who need NSAIDs.