Venous Thromboembolism in Patients with Inflammatory Bowel Disease.

Patients diagnosed with inflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis, experience chronic inflammation of the gastrointestinal tract. Those with IBD face a higher risk of developing venous thromboembolism (VTE) compared to individuals without IBD. This escalated risk is associated with various factors, some modifiable and others non-modifiable, with disease activity being the primary concern. Interestingly, Janus Kinase inhibitors approved for the treatment of IBD may be associated with an increased risk of VTE but only in patients that have other underlying risk factors leading to an overall increased VTE risk. Several recognized medical societies have recommended the use of VTE prophylaxis for hospitalized individuals with IBD. The association between VTE and IBD and the need for pharmacologic prophylaxis remains under-recognized. Increased awareness of this complication can hopefully protect patients from a potentially deadly complication.

Current Venous Thromboembolism Chemoprophylaxis Practices After Surgery for Inflammatory Bowel Diseases.

Recent events shed light on the high risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease and the importance of prophylaxis in such patients. Protocols within the electronic medical record help improve compliance with VTE prophylaxis.

The Pathogenesis and Clinical Management of Stricturing Crohn Disease.

Stricturing of the gastrointestinal tract is a common complication in Crohn disease and is a significant cause of morbidity and mortality among this population. The inflammatory process initiates fibrosis, leading to aberrant wound healing and excess deposition of extracellular matrix proteins. Our understanding of this process has grown and encompasses cellular mechanisms, epigenetic modifications, and inherent genetic predisposition toward fibrosis. Although medications can improve inflammation, there is still no drug to attenuate scar formation. As such, management of stricturing disease requires a multidisciplinary and individualized approach including medical management, therapeutic endoscopy, and surgery. This review details the current understanding regarding the pathogenesis, detection, and management of stricturing Crohn disease.

Palliative Care in Inflammatory Bowel Disease: A New Partnership.

Background: Palliative care (PC) is being increasingly recognized for benefitting patients with a wide spectrum of chronic serious medical conditions. Methods: Care models and principles of PC for patient with inflammatory bowel disease were explored. Results: The use of a structured and systematic approach for emotionally laden conversations and the "Total Pain" paradigm are examples of PC expertise that can be applied through either primary or consultative PC models. Conclusions: PC should be considered in clinical practice and as a topic for further scholarly investigation to further define its role and benefits.

Financial Toxicity in People With Inflammatory Bowel Disease.

Financial toxicity is the term for problems our patients suffer related to the cost of medical care. It differs from both direct and indirect costs and is surprisingly common in patients that most would consider well-insured. This editorial discusses steps we can take to limit our patients' suffering.

How to Optimize Colon Cancer Surveillance in Inflammatory Bowel Disease Patients.

Colitis-associated colorectal neoplasia (CRN) is a well-known complication of chronic inflammation of the colon either with ulcerative colitis (UC) or colonic Crohn's disease (CD). Studies have shown that inflammatory bowel disease (IBD) patients have an overall higher risk for colorectal dysplasia and cancer compared to the general population and this risk is further increased by certain associated factors, including extent of disease, duration of disease, and age at onset. In addition, other risk factors not related to IBD can also further increase the risk for CRN, such as a family history of sporadic colon cancer and a concomitant diagnosis of primary sclerosing cholangitis. The society guidelines mostly agree on the appropriate time to begin CRN surveillance but vary somewhat on the appropriate intervals between surveillance colonoscopies. In addition, there is not yet a consensus on the appropriate method for surveillance. In this review, we discuss the risk for CRN in colonic IBD, the associated factors that further increase the risk for CRN, the current surveillance guidelines and the current methods available for CRN surveillance.

Vedolizumab for induction and maintenance of remission in ulcerative colitis: a Cochrane systematic review and meta-analysis.

BACKGROUND: We performed a systematic review to evaluate the efficacy and safety of vedolizumab for induction and maintenance of remission in ulcerative colitis. METHODS: A literature search to June 2014 identified all applicable randomized trials. Outcome measures were clinical and endoscopic remission, clinical and endoscopic response, quality of life, and adverse events. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome. Study quality was evaluated using the Cochrane risk of bias tool. The GRADE criteria were used to assess the quality of the evidence. MAIN RESULTS: Four studies (606 patients) were included. The risk of bias was low. Pooled analyses indicated that vedolizumab was significantly superior to placebo for induction of remission (RR = 0.86, 95% CI, 0.80-0.91), clinical response (RR = 0.82, 95% CI, 0.75-0.91), endoscopic remission (RR = 0.82, 95% CI, 0.75-0.91), and for achieving remission at 52 weeks in week 6 responders (RR = 2.73, 95% CI, 1.78-4.18). GRADE analyses suggested that the overall quality of the evidence was high for induction of remission and moderate for maintenance therapy (due to sparse data consisting of 246 events). No statistically significant difference was observed in the incidence of adverse events between vedolizumab and placebo. CONCLUSIONS: Vedolizumab is superior to placebo as induction and maintenance therapy for ulcerative colitis. Future studies are needed to define long-term efficacy and safety of this agent.

Tumor necrosis factor-alpha antagonists twenty years later: what do Cochrane reviews tell us?

In 1998, the U.S. Food and Drug Administration granted regulatory approval to the first tumor necrosis factor-α antagonist, infliximab, for the treatment of moderately to severely active Crohn's disease. As of 2013, there were 3 additional tumor necrosis factor-α antagonists commercially available for the treatment of inflammatory bowel disease in the United States: adalimumab, certolizumab pegol, and golimumab. Despite a vast literature describing both clinical trial and clinical practice experience with these agents, there remain important questions regarding the efficacy and safety of tumor necrosis factor-α antagonists for the treatment of inflammatory bowel disease. These questions and the best available evidence to answer them were discussed during a Cochrane Collaboration session held at the 2013 Digestive Diseases Week annual meeting. This article reviews the data from that session.

Vedolizumab for induction and maintenance of remission in ulcerative colitis.

BACKGROUND: Cellular adhesion molecules play an important role in the pathogenesis of ulcerative colitis, making selective blockade of these molecules a promising therapeutic strategy. Vedolizumab, a recombinant humanized IgG1 monoclonal antibody, inhibits adhesion and migration of leukocytes into the gastrointestinal tract by binding the alpha4beta7 integrin. Animal studies have suggested that vedolizumab may be a useful therapy for ulcerative colitis. This updated systematic review summarizes the current evidence on the use of vedolizumab for induction and maintenance of remission in ulcerative colitis. OBJECTIVES: The primary objectives were to determine the efficacy and safety of vedolizumab used for induction and maintenance of remission in ulcerative colitis. SEARCH METHODS: A computer-assisted search for relevant studies (inception to 15 June 2014) was performed using PubMed, MEDLINE, EMBASE and CENTRAL. References from published articles and conference proceedings were searched to identify additional citations. SELECTION CRITERIA: Randomized controlled trials comparing vedolizumab to placebo or a control therapy for induction or maintenance of remission in ulcerative colitis were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias for each trial. The primary outcomes were failure to induce clinical remission and relapse. Secondary outcomes included failure to induce a clinical response, failure to induce endoscopic remission, failure to induce an endoscopic response, quality of life, adverse events, serious adverse events and withdrawal due to adverse events. We calculated the relative risk (RR) and 95% confidence intervals (CI) for each outcome. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Four studies (606 patients) were included. All of the studies were rated as having a low risk of bias. Pooled analyses revealed that vedolizumab was significantly superior to placebo for induction of remission, clinical response, and endoscopic remission and prevention of relapse. After 4 to 6 weeks of therapy 77% (293/382) of vedolizumab patients failed to enter clinical remission compared to 92% (205/224) of placebo patients (RR 0.86, 95% CI 0.80 to 0.91; 4 studies 606 patients). After 6 weeks of therapy 48% of vedolizumab patients failed to have a clinical response compared to 72% of placebo patients (RR 0.68, 95% CI 0.59 to 0.78; 3 studies 601 patients). After 4 to 6 weeks of therapy 68% of vedolizumab patients failed to enter endoscopic remission compared to 81% of placebo patients (RR 0.82, 95% CI 0.75 to 0.91; 3 studies, b583 patients). After 52 weeks of therapy, 54% of vedolizumab patients had a clinical relapse compared to 84% of placebo patients (RR 0.67, 95% CI 0.59 to 0.77; 1 study, 373 patients). One small study (28 patients) found no statistically significant difference in endoscopic response (RR 1.00, 95% CI 0.62 to 1.61). GRADE analyses indicated that the overall quality of the evidence for the primary outcomes was high for induction of remission and moderate for relapse (due to sparse data 246 events). There was no statistically significant difference between vedolizumab and placebo in terms of the risk of any adverse event (RR 0.99, 95% CI 0.93 to 1.07), or serious adverse events (RR 1.01, 95% CI 0.72 to 1.42). There was a statistically significant difference in withdrawals due to adverse events. Six per cent of vedolizumab patients withdrew due to an adverse event compared to 11% of placebo patients (RR 0.55, 95% CI 0.35 to 0.87; 2 studies, 941 patients). Adverse events commonly reported across the studies included: worsening ulcerative colitis, headache, nasopharyngitis, upper respiratory tract infection, nausea, and abdominal pain. AUTHORS' CONCLUSIONS: Moderate to high quality data from four studies shows that vedolizumab is superior to placebo for induction of clinical remission and response and endoscopic remission in patients with moderate to severely active ulcerative colitis and prevention of relapse in patients with quiescent ulcerative colitis. Moderate quality data from one study suggests that vedolizumab is superior to placebo for prevention of relapse in patients with quiescent ulcerative colitis. Adverse events appear to be similar to placebo. Future trials are needed to define the optimal dose, frequency of administration and long-term efficacy and safety of vedolizumab used for induction and maintenance therapy of ulcerative colitis. Vedolizumab should be compared to other currently approved therapies for ulcerative colitis in these trials.

Adalimumab treatment in Crohn's disease: an overview of long-term efficacy and safety in light of the EXTEND trial.

The advent of anti-tumor necrosis factor (TNF) therapies revolutionized the treatment of inflammatory bowel disease. Adalimumab is a subcutaneous anti-TNF agent indicated for use in patients with moderate-to-severe Crohn's disease and those with moderate-to-severe ulcerative colitis. In both diseases, it can be used for both induction of remission and for maintenance of remission. This review focuses on its use in Crohn's disease as described in the EXTEND (Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing) trial. Several clinical trials using traditional instruments to measure clinical response have had endoscopic substudies looking for endoscopic healing. The EXTEND trial is the first to use mucosal healing on endoscopy as a primary endpoint for patients with moderate-to-severe Crohn's disease and baseline ulcerative disease treated with continuous adalimumab. In this well designed trial, the primary endpoint was narrowly missed, but the secondary endpoints further the notion that mucosal healing should be a more mainstream measure of drug efficacy. How this will translate from clinical trials to the clinic is not yet clear, but identifying noninvasive markers for mucosal healing, and understanding the implications of mucosal healing for safety, resource utilization, and quality of life are all worthy targets for further study. The aim of this review is to understand the role of mucosal healing, safety profile, and efficacy in patients treated with anti-TNF therapy, with particular attention to adalimumab and the EXTEND trial.

Tetomilast: new promise for phosphodiesterase-4 inhibitors?

INTRODUCTION: Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD. AREAS COVERED: Peer-reviewed publications, including Phase I and II clinical trials, all other formats included. EXPERT OPINION: Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast.

Natalizumab for the treatment of Crohn's disease.

Natalizumab (Tysabri, formerly known as Antegren, Elan Pharmaceuticals [Elan; San Francisco, CA, USA] and Biogen Idec [Biogen; Cambridge, MA, USA]) is a humanized monoclonal antibody against alpha4 integrin, which inhibits leukocyte adhesion and migration into inflamed tissue. The drug has been shown to be more efficacious than placebo in inducing response and maintaining remission in moderate-to-severe Crohn's disease. There have been reports of progressive multifocal leukoencephalopathy after treatment with natalizumab in Crohn's disease and multiple sclerosis. It has been otherwise well tolerated, although it is associated with an increased risk of infections, especially influenza and influenza-like illness. The drug is not approved in Europe for the treatment of Crohn's disease, but it is approved in the USA for the treatment of both multiple sclerosis and moderate-to-severe Crohn's disease. Owing to the risk of progressive multifocal leukoencephalopathy, it can only be given under the TOUCH program, which is a special restricted distribution program available only to prescribers, infusion centers, pharmacies associated with infusion sites and patients who are enrolled in the program.

Humanized antibody to the alpha4beta7 integrin for induction of remission in ulcerative colitis.

BACKGROUND: Cellular adhesion molecules play an important role in the pathogenesis of ulcerative colitis, making selective blockade of these molecules a promising therapeutic strategy. MLN-02, a recombinant humanized IgG1 monoclonal antibody, inhibits adhesion and migration of leukocytes into the gastrointestinal tract by binding the alpha4beta7 integrin. Animal studies have suggested that MLN-02 may be a useful therapy for ulcerative colitis. This systematic review summarizes the current evidence on the use of MLN-02 for induction of remission in ulcerative colitis. OBJECTIVES: To determine the efficacy and safety of MLN-02 for induction of remission in ulcerative colitis. SEARCH STRATEGY: A computer-assisted search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Specialized Trial Register was performed to identify relevant publications. References from recent reviews and published articles were searched to identify additional citations. Manual searches to identify key conference abstracts were performed. Unpublished data from on-going trials were identified by correspondence with authors and experts in the field and from the manufacturer of MLN-02. SELECTION CRITERIA: Randomized controlled trials comparing MLN-02 to placebo or a control therapy for the induction of remission in ulcerative colitis were included. DATA COLLECTION AND ANALYSIS: Two independent reviewers performed data extraction and assessment of the methodological quality of each trial. Data were analyzed using Review Manager (RevMan 4.2). MAIN RESULTS: One study satisfied the inclusion criteria for this review. In this study, MLN-02 was found to be effective for induction of clinical response (RR = 1.78, 95% CI 1.22 to 2.60) and remission (RR = 2.25, 95% CI 1.17 to 4.36) in patients with moderately severe ulcerative colitis. Patients receiving MLN-02 had higher IBDQ scores than patients receiving placebo. There was a trend toward increased endoscopic remission with MLN-02 relative to placebo, although this difference was not statistically significant (total MLN-02 20% versus placebo 8%; P = 0.05; RR = 2.46, 95% CI 0.98 to 6.15). Adverse events occurred in a similar proportion of patients treated with MLN-02 compared to placebo (RR = 1.60, 95% CI 0.67 to 3.83). Neutralizing antibodies were found in a significant proportion of patients receiving MLN-02, and in the group of patients with high antibody titers clinical remission rates were no different than placebo. No opportunistic infections were reported. AUTHORS' CONCLUSIONS: Data from one trial suggests that MLN-02 may be effective for induction of clinical response and remission in patients with moderately severe ulcerative colitis. Adverse events appear to be similar to placebo, although immunogenicity may be an issue. Further trials are needed to confirm the results of this study and to define the optimal dose and frequency of administration of MLN-02.

Administrative claims analysis of all-cause annual costs of care and resource utilization by age category for ulcerative colitis patients.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease with peak incidence in the third decade of life and a second peak in the sixth or seventh decade. While drug therapy can be used to control the inflammation and reduce symptoms, patients with UC may be treated surgically. There is little information in the published literature evaluating the all-cause health care costs of patients with UC according to age. OBJECTIVE: To assess from administrative claims the direct all-cause (not disease-related) costs of care and resource utilization for patients with UC compared with members without UC by 3 age categories. METHODS: A retrospective analysis was conducted using the PharMetrics database of patients with a diagnosis of UC (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 556.x) from January 1, 2000, through June 30, 2005. This database contains enrollment data and pharmacy and medical claims from more than 85 different managed care organizations and more than 55 million patients in the United States. Patients had to be continuously enrolled for 6 months before and 12 months after the initial UC diagnosis and have at least 2 distinct claims with a diagnosis code for UC. The mean per-patient health care resource utilization and costs were calculated for patients in the year following their initial UC diagnosis and compared with the same measures for a group of age- and gender-matched members (without UC claims) at a ratio of 4:1. Three age groups were analyzed: pediatric-adolescent (aged < 18 years), adults (aged 18 to 64 years), and older adults (aged e 65 years). Differences in the measures of all-cause health care resource utilization (claims and costs) between the UC and non-UC groups were tested for statistical significance using the Wilcoxon signed-rank test, a non-parametric alternative to the paired t test. Differences between the 3 age cohorts were tested using the Mann-Whitney U test. RESULTS: Data were collected for 15,105 patients with UC and for 59,159 members in the comparator cohort without UC matched by age and gender. The average age for both cohorts was 44 years, and 54% were female. Mean ([SD], median) annual all-cause total health care costs in 2005 dollars for patients with UC were $13,233 ([$40,715], $5,190) versus $3,214 ([$12,741], $753) for the comparator group (P < 0.001). For all UC patients, all-cause inpatient hospitalization costs constituted the largest component ($5,771, 43.6%) of the mean annual total costs, followed by prescription medications ($2,423, 18.3%); miscellaneous services, such as hospice, psychiatric facility, and nursing home care ($2,092, 15.8%); outpatient hospital visits ($1,310, 9.9%); physician office visits ($899, 6.8%); laboratory procedures ($470, 3.6%); and emergency department visits ($268, 2.0%). Resource utilization (e.g., physician visits, laboratory claims, pharmacy claims) was highest for older adults aged e 65 years, followed by pediatricadolescent patients and adults aged 18 to 64 years (all comparisons P < 0.01). The mean ([SD], median) all-cause total health care costs were highest for pediatric-adolescent patients with UC (n = 589, 3.9%) at $23,113 ([$70,999], $6,214), followed by older adults (n = 650, 4.3%) at $15,811 ([$23,882], $6,886, P < 0.001), while adults aged 18 to 64 years (n = 13,866, 91.8%) incurred the lowest cost at $12,693 ([$39,505], $5,108, P < 0.001). CONCLUSION: Patients with UC identified from medical claims incurred significantly higher all-cause health care costs for all 3 age categories than did the comparator group of health plan members without diagnosis for UC.

Efficacy of infliximab for luminal and fistulizing Crohn's disease and in ulcerative colitis.

Infliximab is arguably the first major advance in therapy for inflammatory bowel disease in more than a quarter of a century. Although it is important to distinguish efficacy from effectiveness, the data from clinical practice mirror those from randomized controlled trials. Infliximab has proven efficacious for luminal manifestations of Crohn's disease (CD) regardless of location. It also has proven efficacy in the subset of penetrating disease to the skin and perianal area, and it increases rates of steroid-free remission. These benefits are reflected in improved quality of life, with limited data showing that infliximab can decrease rates of hospitalization and CD-related surgery. Infliximab also has proven to be efficacious in patients with ulcerative colitis (UC) and has increased rates of steroid-free remission. Whether infliximab will have an impact on the risk of colorectal cancer in UC and Crohn's colitis has yet to be determined. The combination of strong evidence from large randomized controlled trials with substantial examination of use in the practice setting has moved biologic therapy with infliximab from novel to mainstream. In this review, the data for the efficacy of infliximab in controlled trials will be discussed in the context of real world effectiveness.

Rifaximin for the treatment of active pouchitis: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: The efficacy of the nonabsorbable antibiotic rifaximin in patients with active acute or chronic pouchitis is unknown. METHODS: We performed a placebo-controlled pilot trial to evaluate the efficacy and safety of rifaximin in patients with active pouchitis. Eighteen patients with active pouchitis were randomized to receive oral rifaximin 400 mg or placebo 3 times daily for 4 weeks. Active pouchitis was defined as a total Pouchitis Disease Activity Index (PDAI) score = 7 points. Clinical remission was defined as a PDAI score <7 points and a decrease in the baseline PDAI score = 3 points. The primary analysis was clinical remission at week 4. RESULTS: Eight patients were randomized to rifaximin and 10 patients were randomized to placebo. One patient in the placebo group did not have a post-baseline efficacy evaluation and was excluded from the efficacy analysis. Two of 8 patients (25%) treated with rifaximin were in clinical remission at week 4 compared to 0 of 9 patients (0%) treated with placebo (P = 0.2059). None of 8 patients in the rifaximin group withdrew from the trial prior to week 4. Two of 9 patients in the placebo group withdrew prior to week 4 due to lack of efficacy and were categorized as treatment failures. CONCLUSIONS: Clinical remission occurred more frequently in patients treated with rifaximin 400 mg 3 times daily but the difference was not significant in this pilot study. A larger trial would be required to determine if rifaximin is effective for the treatment of active pouchitis. Rifaximin was well tolerated.