A recent article detailed the 2012 sales of several highly successful medications. At the top of the list were two GI drugs:
Here’s the link:
Gastroenterology & Endoscopy News – Billion–Dollar Savings From
In the same issue as the vedolizumab phase 3 studies, there is a succinct review of tumor necrosis antagonist therapy (anti-TNF) therapy for IBD (NEJM 2103; 369: 754-62).
Useful points about IBD:
Anti-TNF agents:
Areas of uncertainty according to the authors:
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While yesterday’s post reviewed the data that indicate that vedolizumab is likely to be helpful for ulcerative colitis, only small improvements were noted for patients with Crohn’s disease (NEJM 2013; 369: 711-21, GEMINI 2 studies).
Vedolizumab, “a humanized immunoglobulin G1 monoclonal antibody to α4β7 integrin, modulates gut, but not brain, lymphocyte trafficking.” The GEMINI 2 studies for Crohn’s disease were similar to the GEMINI 1 studies for UC. However, even more medical centers (n=285) in more countries (n=39) and more patients (n=1115 with 967 receiving study drug) participated.
Baseline characteristics:
Results:
While the response rate to vedolizumab was modest in Crohn’s disease patients, there are some factors that need to be considered in interpreting this data. Unlike in many trials (According to the study which you would never … – gutsandgrowth), this trial included patients with more disease severity. The authors note that the effects of anti-integrin therapy could be relatively slower acting in Crohn’s disease due to the transmural nature of the disease. An alternative explanation would be that the gut-selective targeting by vedolizumab is ineffective in most patients with Crohn’s disease due to the need for a more systemic inhibition with transmural disease.
Bottom-line: Among the small percentage of patients who have a response to vedolizumab at week 6, the rates of clinical remission at week 52 were significantly higher than those who received placebo.
Vedolizumab!
Two articles indicate that Vedolizumab will be an important agent for treating Ulcerative Colitis (UC). The first article, NEJM 2013; 369: 699-710, describes two integrated studies (GEMINI 1 studies) in the use of this agent for induction and then for maintenance therapy of UC.
Background: Vedolizumab is a gut-selective blocker of lymphocyte trafficking (see previous post: Vedolizumab -another new IBD treatment | gutsandgrowth). It is similar to natalizumab which was approved in 2008 for Crohn’s disease. In phase 3 trials, natalizumab was demonstrated a response in 48% of patients with moderate-to-severe disease, but its large-scale use has been precluded by the potential for reactivation of the John Cunningham (JC) virus and progressive multifocal leukoencephalopathy (PML).
Study design: this study was a phase 3, randomized, double-blind, placebo-controlled study conducted at 211 medical centers in 34 countries from 2008-2012. At baseline some of the assessments included blood tests, stool for enteric pathogens, chest radiography, stool calprotectin, QuantiFERON-TB Gold assay and sigmoidoscopy. Intravenous vedolizumab was administered at a dose of 300 mg or placebo at days 1 and 15 during induction; also patients were stratified for glucocorticosteroids, use of immunosuppressives and prior use of TNF antagonists. In total, 746 patients received vedolizumab and 149 received placebo.
Some of the baseline patient characteristics:
Results:
Bottom-line: This large study shows that vedolizumab is effective in a large number of patients with UC, many who were refractory to other treatments, including anti-TNF agents.
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A recent article from Pediatrics, published online May 6, 2013
(doi: 10.1542/peds.2012-3567), confirms that influenza vaccination (injection/inactivated vaccine) is safe in patients with inflammatory bowel disease:
Abstract:
OBJECTIVE: Influenza immunization is recommended for children with IBD, however safety concerns may limit uptake. This study assessed whether immunization was associated with adverse events in IBD patients using a population-based database of children with IBD.
METHODS: All children <19 years diagnosed with IBD in Ontario, Canada between 1999–2009 were identified using health administrative data, and matched to non-IBD controls. Self-controlled case series (SCCS) analyses determined health services event rates (outpatient visits, hospitalizations and emergency visits) in any 2-week risk period to 180 days post-immunization compared to a no-risk control period. Relative incidence (RI) was calculated for overall and IBD-related events and rates were compared between IBD cases and controls using relative incidence ratios (RIR).
RESULTS: 4916 IBD patients were matched to 21,686 controls. IBD patients were more likely to have received immunization than controls (25.3% vs. 13.2%, P < .001). No increased event rates existed in IBD cases during risk periods (pooled RI 0.95, 95% CI 0.84–1.07), including hospitalizations and emergency visits. There was a slightly higher event rate in IBD cases versus controls for days 3–14 (RIR 1.60, 95% CI 1.05–2.44, P = .03). IBD-related visit rates were lower in risk periods compared to control period (pooled RI 0.81, 95% CI 0.68–0.96).
CONCLUSIONS: There was no increase in health services use in the post-vaccine risk period in IBD patients, and there was evidence for a protective effect of influenza immunization against IBD-related health services use. Influenza immunization is safe in children with IBD and should be encouraged to improve poor coverage rates.
From Kipp Ellsworth’s twitter feed:
The gluten-free, casein-free diet and autism: limited return on family investment
From Journal of Early Intervention
goo.gl/uulzis (link to entire article)
Excerpt:
Abstract
The gluten-free, casein-free (GFCF) diet is widely used by families of children with autism spectrum disorders (ASD). Despite its popularity, there is limited evidence in support of the diet. The purpose of this article was to identify and evaluate well-controlled studies of the GFCF diet that have been implemented with children with ASD. A review of the literature from 1999 to 2012 identified five studies meeting inclusion criteria. Research rigor was examined using an evaluative rubric and ranged fromAdequate to Strong. In three of the studies, no positive effects of the diet were reported on behavior or development, even after double-blind gluten and casein trials. Two studies found positive effects after 1 year but had research quality concerns. Reasons why families continue to expend effort on GFCF diets despite limited empirical evidence are discussed. Recommendations are that families should invest time and resources in more robustly supported interventions and limit GFCF diets to children diagnosed with celiac disease or food allergies.
A recent study questions the value of fundoplication in children with neurologic impairment who undergo gastrostomy tube placement (JAMA Pediatr doi:10.1001/jamapediatrics.2013.334).
This paper’s findings are limited by the study’s design as a retrospective, observational cohort study. However, the study has several strengths as well. First of all, this was a large study which identified 4163 neurologically-impaired infants who underwent either tube placement with (n=1404) or without fundoplication (n=2759). This population was drawn from 42,796 infants admitted to neonatal intensive care units from 42 children’s hospitals. Thus, a second advantage of this study was looking at a broad range of children from the same NICU population.
Findings:
The authors note that two previous studies had shown a reduction in reflux-related hospitalizations for children who had admissions due to reflux-related conditions. However, they note that in their study, these patients had fundoplication performed prophylactically based on clinical judgement.
But, “clinical symptoms, including dysfunctional swallowing and intolerance of gastric feedings, likely influence the decision to perform a concomitant fundoplication; however, these were unavailable in the database.” As such, the authors propensity score model could have failed to account for factors that are essential in deciding whether a concomitant fundoplication is worthwhile.
Bottom-line: A fundoplication may not effectively prevent reflux-related hospitalizations in neurologically-impaired infants; its expected benefits may be overstated. The only way to definitively determine how useful (or how ineffective) a fundoplication is would be a prospective study.
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As noted in a previous blog regarding NOTES (see link below), peroral endoscopic myotomy (POEM) has been investigated for treatment of achalasia. Now, a prospective study of 70 patients from 5 centers reports excellent results (Gastroeenterol 2013; 145: 309-11, editorial 272-73).
Results:
Potential benefits of POEM:
Early results suggest similar efficacy to surgery but with the recovery profile of an endoscopy Painless
For more widespread adoption, many questions need to addressed:
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With all the buzz regarding how a patient’s microbiome seems to affect everything from metabolic syndrome and colic to autoimmune diseases and inflammatory bowel disease, more attention has been paid in attempts to alter the microbiome for therapeutic benefits. In Crohn’s disease (CD), the fact that antibiotics have shown beneficial effects have led to a number of studies of probiotics. A recent study, like previous ones, did not demostrate any benefit with Saccharomyces boulardii (Clin Gastroenterol Hepatol 2013; 11: 982-87).
In this prospective double-blind, placebo-controlled study of 165 patients who achieved remission after steroids or salicylates, subjects were randomly assigned to groups given S boulardii (1 gram per day) or placebo for 52 weeks.
Results:
One important limitation of this study was not examining the effects of the probiotic on the microbiome of these patients. Perhaps, other probiotics would be more effective in restoring a “healthy” flora.
Based on these results, and others, the accompanying editorial (pg 988-89), advocates use of probiotics only for prevention of antibiotic-associated diarrhea, prevention of recurrent Clostridium difficile, and treatment/prevention of pouchitis.
Bottom-line: Probiotics have not been demonstrated to be helpful for Crohn’s disease.
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While the concept of gluten sensitivity without celiac disease has been recognized since 1980 (Gastroenterol 1980; 79: 801-06), a recent study indicates that gluten may not be the main culprit in inducing these symptoms (Gastroenterol 2013; 145: 320-28; editorial 276-79).
The authors of this double-blind crossover study were the same investigators who popularized the concept of nonceliac gluten sensitivity (NCGS) two years ago (Am J Gastroenterol 2011; 106: 508-14). In this current study, they demonstrate that in NCGS patients consuming a low FODMAPs diet (see previous post links below) gluten reintroduction did not cause specific or reproducible symptoms.
Methods: In this study, they enrolled 37 subjects with NCGS who fulfilled Rome III criteria for IBS and improved on a gluten-free diet (GFD). All participants continued their GFD and after a 1-week baseline, started on a low FODMAP diet for a 2-week run in period. Subsequently, patients were randomly assigned to 3 study arms: high gluten (16 g gluten/day), low gluten (2 g gluten & 14 g whey per day) or control (16 g whey/day). Each participant took this diet for 1 week, had a 2-week washout, then crossed over to each arm. In addition, at least 8 months, 22 subjects underwent another brief crossover study (high-gluten, whey only, or control with no additional protein). As part of the study, clinical, serological, and immunologic parameters were monitored during all aspects of the rechallenges.
Results: “Gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein.” There were no changes in any serological or immunologic parameters between the dietary challenges.
There were several limitations to this study of this highly-selected cohort which are well-described in their discussion.
Bottom-line: Gluten might not be a specific trigger once dietary FODMAPs are reduced.
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