Efficacy and Safety of Elective Switching from Intravenous to Subcutaneous Infliximab [CT-P13]: A Multicentre Cohort Study.

BACKGROUND: Intravenous [IV] infliximab is a well-established therapy for inflammatory bowel diseases [IBD] patients. A subcutaneous [SC] formulation of infliximab [CT-P13] has recently been shown to be as effective as IV infliximab after two doses of IV induction in a randomised trial, but there are no data to support elective switching of patients on maintenance IV infliximab therapy. We aimed to assess the effectiveness of an elective switching programme to SC CT-P13 in patients treated with IV infliximab. METHODS: Patients on established maintenance IV infliximab, who switched to SC CT-P13, were included in this retrospective multicentre cohort study. Disease activity was monitored serially with the Harvey-Bradshaw Index [HBI] for Crohn's disease [CD] and the Simple Clinical Colitis Activity Index [SCCAI] for ulcerative colitis (UC) for up to 12 months at months 3, 6, and 12. Faecal calprotectin [FC] and C-reactive protein [CRP] were recorded at baseline and follow-up, if available. Infliximab trough levels were measured prior to switch and at months 3, 6, and 12 following switch. The primary outcome measure was treatment persistence at latest follow-up. Secondary outcome measures included infliximab pharmacokinetics [PK], safety, need for corticosteroid rescue therapy, and need for surgery. RESULTS: We included 181 patients, of whom 115 [63.5%] had CD. The majority [72.4%] were on 8-weekly dosing of intravenous infliximab prior to switching, and more than half [59.1%] were on concomitant immunomodulatory therapy. The majority of patients (CD: 106, 92.2%; UC: 46, 76.7%; and IBD unclassified [IBD-U]: 5, 83.3%) were in clinical remission. Treatment persistence rate was high [n = 167, 92.3%] and only 14 patients [7.7%] stopped treatment during the follow-up period. There was no significant difference between baseline and repeat measurements at 3, 6, or 12 months for HBI, SCCAI, CRP, or FC. Of the total cohort, 25 patients (13.8%) had perianal CD. Of these, only two patients [8%] had worsening of perianal CD and required antibiotic therapy and further examination under anaesthesia [EUA]. Both these patients also switched back to intravenous infliximab. Median infliximab level increased from a baseline of 8.9 µg/dl [range 0.4-16] to 16.0 µg/dl [range 2.3-16, p <0.001] at 3 months. Serum levels stayed stable at 6 months [median 16 µg/dl, range 0.3-17.2] and 12 months [median 16 µg/dl, range 0.3-19.1, both p <0.001 compared with baseline]. Among the variables examined, only antibodies to infliximab [ATI] was associated with infliximab levels (odds ratio [OR] -13.369, 95% CI -15.405, -11.333, p <0.001]. A total of 14 patients [7.7%] developed ATI; of these, nine [64.3%] were on concomitant immunomodulatory therapy. Immunomodulatory therapy was not significantly associated with development of ATI [p = 0.15]. In a subset of patients receiving escalated IV infliximab dosing frequency prior to switching, no difference in treatment persistence was observed in patients receiving weekly versus alternate weekly SC CT-P13. Patient acceptance and satisfaction rates with SC CT-P13 were very high. CONCLUSIONS: Among patients on IV infliximab maintenance therapy switched to SC CT-P13, we observed high treatment persistence rates and low rates of immunogenicity, with no change in clinical disease activity indices or biomarkers. Infliximab levels increased after switch to SC CT-P13, and only ATI was associated with serum infliximab levels. Patient acceptance and satisfaction rates were high with SC CT-P13.

Intestinal failure-associated liver disease in adult patients.

PURPOSE OF REVIEW: The aim of this review is to give up-to-date information on intestinal failure-associated liver disease (IFALD) and how its investigation and management has evolved. Despite advances in treatment for patients with intestinal failure, IFALD remains a significant cause of mortality. RECENT FINDINGS: Liver biopsy remains as the gold standard for the diagnosis of IFALD, but its invasive nature has prompted assessment of noninvasive techniques. Risk factors for IFALD are both nonnutritional (e.g. sepsis) and nutritional. Strict protocols for the prevention of central venous catheter infections in patients with intestinal failure are well established, as is the optimization of the constituents of parenteral nutrition. Further research comparing the available lipid emulsions has become available. Novel approaches at maximizing intestinal absorption are discussed including glucagon-like peptide-2 analogues, as well as surgical approaches. SUMMARY: Although there are data on the novel investigative and therapeutic strategies for managing IFALD, further study is required to identify a suitable noninvasive technique for earlier diagnosis and then monitoring of IFALD. Further data are also required on the impact of novel therapies aimed at improving absorption and reducing parenteral nutrition load on IFALD occurrence and progression.

Comparative effectiveness of antitumour necrosis factor agents and vedolizumab in ulcerative colitis.

INTRODUCTION: Antitumour necrosis factor (TNF) agents and vedolizumab are used to treat ulcerative colitis (UC) but the response is variable and there is little data on comparative effectiveness. Apart from previous exposure to anti-TNF agents, predictors of response have not been identified. We aimed to (i) compare the efficacy of anti-TNF agents and vedolizumab in UC and (ii) investigate the utility of clinical and biochemical parameters in predicting response. PATIENTS AND METHODS: Patients commencing any biological therapy for ambulant UC were included. Disease activity was monitored serially with the Simple Clinical Colitis Activity Index for up to 12 months. We compared the efficacy of anti-TNF agents and vedolizumab for induction and maintenance of response and remission on an intention-to-treat basis. We examined the utility of faecal calprotectin (FC) and early normalization of FC to predict response. RESULTS: Ninety-seven patients commencing anti-TNF and 42 commencing vedolizumab therapy were included. Vedolizumab-treated patients had significantly greater previous anti-TNF therapy exposure and a lower baseline FC. Response, remission and steroid-free remission rates were comparable between both groups at 6 weeks, 6 and 12 months. Clinical remission but not steroid-free remission at 12 months was higher in the vedolizumab group. There was a significant reduction in the Simple Clinical Colitis Activity Index and FC at 6 weeks, 6 and 12 months compared with baseline in both groups. Baseline FC and early normalization did not predict response at 6 and 12 months. CONCLUSION: The efficacy of anti-TNF and vedolizumab in UC appear comparable. We could not identify any predictors of response and remission.

Monitoring long-term parenteral nutrition.

PURPOSE OF REVIEW: This review discusses the monitoring aimed at achieving good long-term outcomes in people dependent on home parenteral nutrition (HPN). RECENT FINDINGS: There have been recent studies highlighting the importance of treating low bone mineral density in HPN-dependent patients, methods of screening for liver disease, assessment of quality of life (QoL) and the need for early assessment for intestinal transplantation and growth factor therapy. SUMMARY: High-quality HPN services require expert multidisciplinary teams with a focus on strict aseptic catheter care protocols alongside regular monitoring and management of clinical, laboratory and patient-related factors. Areas that should be considered in the routine monitoring of HPN include regular laboratory measurements, QoL, assessment for intestinal failure-associated liver disease, treatment of metabolic bone disease and consideration of evolving treatments, alongside management of any underlying condition leading to intestinal failure.

Home Parenteral Nutrition: Vascular Access and Related Complications.

Patients with chronic intestinal failure are dependent on parenteral nutrition (PN) to maintain health and preserve life. Maintaining safe vascular access is vital to prevent life-threatening complications such as catheter-related bloodstream infection or central venous occlusion. Dedicated central venous catheters with rigorous catheter care aseptic protocols are vital in obtaining good long-term outcomes that allow continuation of PN over many years. Good catheter care requires an experienced multidisciplinary team using appropriate vascular devices, trained to identify and aggressively treat catheter-related bloodstream infections, catheter occlusions, and catheter-related thrombosis. Consideration must also be given to evolving strategies to prevent recurrent infections, including prophylactic central venous catheter locks.

Survival and nutritional dependence on home parenteral nutrition: Three decades of experience from a single referral centre.

BACKGROUND: Home parenteral nutrition (HPN) is the mainstay of treatment for patients with Type 3 intestinal failure (IF), however long term data on mortality and nutritional outcomes are limited. OBJECTIVES: To assess the long-term survival and requirements for ongoing HPN in patients receiving treatment at a UK national referral centre for intestinal failure. METHODS: Patients with IF who received HPN for more than 3 months at this Intestinal Failure Unit between 1978 and 2011 had their clinical records reviewed. SPSS 20 was utilised to perform Cox regression analysis and generate Kaplan Meier curves, with the aim of identifying factors associated with death and the continued need for HPN. RESULTS: Case notes from 545 patients were reviewed. Overall survival (OS) in patients without malignancy at commencement of IF was 93%, 71%, 59% and 28% at 1, 5, 10 and 20 years after starting treatment. Crohn's disease, mesenteric ischaemia and chronic intestinal pseudo-obstruction were associated with a better OS than scleroderma and radiation enteritis on multivariate analysis. Older age at onset of IF was associated with poor OS, while shorter small bowel length or central line sepsis was not. 15% (25/170) of deaths were due to complications of HPN (central line sepsis = 10, IF-associated liver disease = 15). Continued HPN dependence in survivors was 83%, 63%, 59% and 53% at 1, 5, 10 and 15 years, respectively. Among the 153 patients without malignancy who achieved nutritional independence from HPN, 77 (50.3%) did so after surgical reconstruction of the alimentary tract (HPN duration mean 19 months, range 3-126 months). 76 patients (49.7%) weaned from HPN without undergoing surgical reconstruction. CONCLUSION: This is the largest reported data set on long-term survival and dependence on HPN and will inform the indications, benefits and risks of treatment in disease specific groups. A significant proportion of patients achieved nutritional autonomy without surgical intervention.

Validation of a Simple 0 to 10 Numerical Score (IBD-10) of Patient-reported Inflammatory Bowel Disease Activity for Routine Clinical Use.

BACKGROUND: Various physician- and patient-reported instruments exist for quantification of disease activity in inflammatory bowel diseases (IBD) but none are widely used in routine clinical practice. A simple patient-reported outcome measure might help inform clinical decision making. We evaluated a patient-reported 0 to 10 score of IBD activity (IBD-10) by correlation with conventional multicomponent activity indices. METHODS: A single-center prospective cross-sectional study was conducted in ambulant patients with IBD. Patients were asked to verbally rate the control of Crohn's disease (CD) or ulcerative colitis (UC) on a numerical scale from 0 to 10, with 10 indicating perfect control. Disease activity was assessed using Harvey-Bradshaw index for CD and simple clinical colitis activity index for UC. RESULTS: A total of 405 patients were included, of whom 209 (52%) had CD and 196 (48%) had UC. The median age was 41 (interquartile range, 27-55) years. IBD-10 correlated well with Harvey-Bradshaw Index (rs = -0.69, P < 0.001) and simple clinical colitis activity index (rs = -0.79, P < 0.001). An IBD-10 score of ≥7 predicted remission (defined by Harvey-Bradshaw index/simple clinical colitis activity index) with 90% sensitivity (95% confidence interval [CI], 86-94) and 75% specificity (95% CI, 67-82). The discriminatory ability of IBD-10 for remission was better for UC (area under the receiver operating characteristic curve, 0.93; 95% CI, 0.89-0.97) than for CD (area under the receiver operating characteristic curve, 0.86; 95% CI, 0.81-0.91; P = 0.035). An IBD-10 score of <7 correlated with treatment escalation. CONCLUSIONS: The IBD-10 score correlates well with more complex clinical activity indices. Correlation was less strong for CD than for UC, possibly reflecting a weaker link in CD between stool frequency and the patient perspective of disease activity. The IBD-10 score could readily be used in routine clinical practice.

Central Venous Catheter Salvage in Home Parenteral Nutrition Catheter-Related Bloodstream Infections: Long-Term Safety and Efficacy Data.

BACKGROUND: Catheter-related bloodstream infections (CRBSIs) are a serious complication in the provision of home parenteral nutrition (HPN). Antibiotic salvage of central venous catheters (CVCs) in CRBSI is recommended; however, this is based on limited reports. We assessed the efficacy of antibiotic salvage of CRBSIs in HPN patients. MATERIALS AND METHODS: All confirmed CRBSIs occurring in patients receiving HPN in a national intestinal failure unit (IFU), between 1993 and 2011, were analyzed. A standardized protocol involving antibiotic and urokinase CVC locks and systemic antibiotics was used. RESULTS: In total, 588 patients were identified with a total of 2134 HPN years, and 297 CRBSIs occurred in 137 patients (65 single and 72 multiple CRBSIs). The overall rate of CRBSI in all patients was 0.38 per 1000 catheter days. Most (87.9%) infections were attributable to a single microorganism. In total, 72.5% (180/248) of CRBSIs were salvaged when attempted (coagulase-negative staphylococcus, 79.8% [103/129], Staphylococcus aureus, 56.7% [17/30]; polymicrobial infections, 67.7% [21/30]; and miscellaneous, 66.1% [39/59]). CVC salvage was not attempted in 49 episodes because of life-threatening sepsis (n = 18), fungal infection (n = 7), catheter problems (n = 20), and CVC tunnel infection (n = 4). Overall, the CVC was removed in 33.7% (100/297) of cases. There were 5 deaths in patients admitted to the IFU for management of the CRBSI (2 severe sepsis at presentation, 3 metastatic infection). CONCLUSIONS: This is the largest reported series of catheter salvage in CRBSIs and demonstrates successful catheter salvage in most cases when using a standardized protocol.

Nutritional management of the patient with Crohn's disease.

Active Crohn's disease often co-exists with malnutrition and requires input from the inflammatory bowel disease multidisciplinary team in order to assess, prevent and treat the complications of both malnutrition and active disease.

Body Mass Index and Smoking Affect Thioguanine Nucleotide Levels in Inflammatory Bowel Disease.

INTRODUCTION: Optimal levels of the thiopurine metabolite, 6-thioguanine nucleotides [6-TGN] correlate with remission of inflammatory bowel disease [IBD]. Apart from variations in the thiopurine methyl transferase [TPMT] gene, little is known about other predictors of 6-TGN levels. Obesity adversely affects response to infliximab and adalimumab and clinical course in IBD, but little is known about the interaction of thiopurines and obesity. We investigated the relationship between body mass index [BMI] and 6-TGN levels and sought to examine other predictors of 6-TGN levels. METHODS: This retrospective cohort study included patients with concurrent measurements of 6-TGN and BMI. The association between 6-TGN and clinical variables including BMI was estimated using a multivariable linear regression model. RESULTS: Of 132 observations, 77 [58%] had Crohn's disease and 55 [42%] ulcerative colitis. BMI, smoking, and TPMT levels were associated with 6-TGN levels in multivariable analysis. Every 5kg/m(2) increase in BMI was associated with an 8% decrease in 6-TGN (0.92; 95% confidence interval [CI] 0.87-0.98; p = 0.009). Smokers had higher 6-TGN levels in comparison with non-/ex-smokers [1.43; 95% CI 1.02-2.02; p = 0.041]. Patients with intermediate TPMT had higher 6-TGN compared to those with normal levels [2.13; 95% CI 1.62-2.80; p < 0.001]. Obese patients were more likely to have sub-therapeutic 6-TGN levels and a higher methyl mercaptopurine nucleotide [MMPN/TGN] ratio despite a similar dose of thiopurines. CONCLUSIONS: Active smoking and intermediate TPMT values were associated with higher 6-TGN levels but increasing BMI resulted in lower 6-TGN and higher MMPN levels. This may explain the worse outcome that has been reported previously in obese IBD subjects.

Long-term outcome of patients with systemic sclerosis requiring home parenteral nutrition.

BACKGROUND & AIMS: Patients with systemic sclerosis may develop intestinal failure requiring home parenteral nutrition. However, few outcome data have been reported. This study aimed to review the outcome of patients with systemic sclerosis receiving home parenteral nutrition. METHODS: Records of all patients with systemic sclerosis who commenced home parenteral nutrition, at a national intestinal failure unit were retrospectively reviewed. Disease characteristics, survival and outcome data were evaluated. RESULTS: Twenty five patients (20% male; median age: 55 years) were included over a 22-year period (37,200 central venous catheter days). All patients had small intestinal involvement. Prior to home parenteral nutrition, 16 failed enteral feeding. Nine patients were trained to self-administer their home parenteral nutrition; carers/relatives were trained for the remainder. Cumulative survivals on home parenteral nutrition at 2, 5 and 10 years were 75%, 37%, and 23%. Sixteen patients died from causes unrelated to home parenteral nutrition. Two patients were weaned off home parenteral nutrition. Seven patients survive on home parenteral nutrition (median: 41 months; range 9-178). Central venous catheter-related complications were low; these included occlusion (0.70 episodes per 1000 central venous catheter days), sepsis (0.19 episodes per 1000 central venous catheter days) and central venous thrombosis (0.11 episodes per 1000 central venous catheter days). CONCLUSIONS: This is the longest, largest reported series of patients with systemic sclerosis receiving home parenteral nutrition. It shows that home parenteral nutrition can be used safely and effectively in patients with very severe systemic sclerosis-related gastrointestinal involvement.

Anaemia in inflammatory bowel disease.

Anaemia is a common manifestation in inflammatory bowel disease (IBD) and impairs quality of life. Anaemia in IBD is typically caused by iron deficiency or anaemia of chronic disease. Treatment of iron deficiency with oral iron may lead to gastrointestinal intolerance though this may be related to the dose of iron replacement. New intravenous formulations have emerged which allow safe, rapid and effective correction of iron deficiency in IBD. In this article, we provide a review on the topic and cover recent progress in the field for the practicing gastroenterologist.

Targeting the cell cycle in esophageal adenocarcinoma: an adjunct to anticancer treatment.

Esophageal adenocarcinoma is a major cause of cancer death in men in the developed world. Continuing poor outcomes with conventional therapies that predominantly target apoptosis pathways have lead to increasing interest in treatments that target the cell cycle. A large international effort has led to the development of a large number of inhibitors, which target cell cycle kinases, including cyclin-dependent kinases, Aurora kinases and polo-like kinase. Initial phase I/II trials in solid tumors have often demonstrated only modest clinical benefits of monotherapy. This may relate in part to a failure to identify the patient populations that will gain the most clinical benefit. Newer compounds lacking the side effect profile of first-generation compounds may show utility as adjunctive treatments targeted to an individual's predicted response to treatment.