Vedolizumab Study in IBD

Posted on November 16, 2016 by gutsandgrowth

From CGH Associated Editor Charles Kari:

Effectiveness and Safety of Vedolizumab Induction Therapy for Patients With Inflammatory Bowel Disease

Vedolizumab is a biologic agent which targets the integrin receptor and is approved for the treatment of patients with moderate-severe ulcerative colitis (UC) and Crohn’s disease (CD). Vedolizumab inhibits the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM–1).

In this [November] issue of Clinical Gastroenterology and Hepatology, Amiot and colleagues report the effectiveness and safety of vedolizumab induction therapy in patients with moderate-to-severe active UC and CD who previously failed anti-TNF therapy. Active IBD was defined according to the Harvey-Bradshaw index (HBI) >4 for CD patients and the Mayo Clinic score ≥6 for UC patients. Patients received intravenous vedolizumab at a dose of 300 mg at weeks 0, 2 and 6 and then every 8 weeks through week 52. Concomitant use of corticosteroids, immunomodulators, or methotrexate was permitted. The primary outcome measure was steroid-free clinical remission at week 14, which was defined as a HBI ≤4 for CD patients and a partial Mayo Clinic score ❤ with a combined stool frequency and rectal bleeding subscore of ≤1 for UC patients. A total of 294 patients were enrolled (CD, 173; UC, 121), of whom 276 completed the induction period. At week 14, 63 (36%) and 47 (39%) patients were in clinical remission in the CD and UC groups, respectively, of whom 53 (31%) and 43 (36%), respectively, were in steroid-free clinical remission. The clinical response rates at 14 weeks were 64% for CD patients and 57% for UC patients. Adverse events occurred in 93 patients (31.6%) out of 294 patients with serious adverse events in 24 (8.2%) and adverse events leading to vedolizumab discontinuation in 15 (5.1%) including one case of pulmonary tuberculosis.

In conclusion, in a cohort of IBD patients who failed anti-TNF therapy and received vedolizumab, about one third experienced steroid-free clinical remission at 14 weeks, with good safety profile (Figure 3).

Related Blog Posts:

Compared with Zika, CMV is a Greater Threat and Less Discussed

Posted on November 15, 2016 by gutsandgrowth

A recent article in NY Times provides another example of how a common infectious problem has been overshadowed by a more recent epidemic. CMV is A Greater Threat to Infants Than Zika

Two years ago, it was well-recognized that the flu virus is vastly more dangerous for U.S. than Ebola (Related post:Scarier than Ebola -the Flu | gutsandgrowth). This year, CMV should get more attention.

Here’s an excerpt:

Every year, 20,000 to 40,000 infants are born with CMV. At least 20 percent — up to 8,000 — have or develop permanent disabilities, such as hearing loss, microcephaly, intellectual deficits and vision abnormalities. There is no vaccine or standard treatment…

CMV is the most common congenital viral infection and the leading nongenetic cause of deafness in children. Roughly 400 children die from it annually. By contrast, roughly 900 pregnant women in the continental United States have contracted the Zika virus…

The American College of Obstetricians and Gynecologists used to encourage counseling for pregnant women on how to avoid CMV. But last year, the college reversed course, saying, “Patient instruction remains unproven as a method to reduce the risk of congenital CMV infection.”

My take: Perinatal CMV infection merits more discussion.

Related blog posts:

Trail to Iceberg Lake, Glacier Nat’l Park

Safer Than You Think: Biologic Therapies for IBD and Risk of Infection and Malignancy

Posted on November 14, 2016 by gutsandgrowth

While there have been a number of studies which have highlighted the potential risks of biologic agents, many studies have NOT identified any risk of infection or malignancy.

Another recent systematic review/meta-analysis (S Bonovas et al. Clin Gastroenterol Hepatol 2016; 14: 1385-97) provides reassuring data regarding the following biologics: infliximab, adalimumab, certolizumab, golimumab, natalizumab, and vedolizumab.

The authors identified 49 randomized placebo-controlled studies with 14,590 participants.

Key findings:

There was a moderate infection risk with odds ratio of 1.19 (19% increase in odds of developing an infection) and significant increase in opportunistic infections (eg. tuberculosis) OR 1.90
Risk of serious infections was NOT increased in patients treated with biologics with OR 0.89. In studies with low risk of bias, the risk of serious infections had OR of 0.56.
No increase in malignancy risk was identified with OR 0.90 but the authors note that data was insufficient in terms of exposure and follow-up to be conclusive.

The authors note that the studies including in this review challenge some of the findings of observational studies. “However, observational studies lack the experimental random allocation of participants…the discrepancies between observational studies and randomized trial evidence might be explained by the inability of observational designs to fully address the complex and important differences between the IBD patients receiving and those not receiving biologics.”

Study limitations include “sponsorship bias -because the trials were supported by pharmaceutical companies and limited followup of 24 months. In addition, most of the trials in the meta-analysis were judged to be at high or unclear risk of bias because of their methodological characteristics.

My take: This study indicates that biologic therapies do not appear to increase the risk of serious infections and may not increase the overall risk of malignancy.

Related blog posts:

Portland Fish Market

Image: Duodenal Ulcer due to an Unusual Cause

Posted on November 13, 2016 by gutsandgrowth

This ulcer was identified in a 26 year old and determined to be due to Strongyloides stercoralis infection. From Clin Gastroenterol Hepatol Nov 2016; DOI: http://dx.doi.org/10.1016/j.cgh.2016.04.019 “This case also highlights the importance of including strongyloidiasis in the differential diagnosis when a patient presents with ulcer bleeding and eosinophilia.”

Image Only: Middle Schoolers as Likely to Die From Suicide as From Traffic Accidents

Posted on November 12, 2016 by gutsandgrowth

From NY Times: Full Text

It is now just as likely for middle school students to die from suicide as from traffic accidents.

That grim fact was published on Thursday by the Centers for Disease Control and Prevention. They found that in 2014, the most recent year for which data is available, the suicide rate for children ages 10 to 14 had caught up to their death rate for traffic accidents.

Explaining Differences in Disease Severity for Alagille Syndrome

Posted on November 11, 2016 by gutsandgrowth

A recent study (DOI: http://dx.doi.org/10.1016/j.jcmgh.2016.05.013) has shown a gene which may help explain the difference in disease severity in Alagille syndrome.

Here’s a link to full text: THBS2 is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome

Here’s the abstract:

Background & Aims

Alagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder.

Methods

We performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus.

Results

We identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions.

Conclusions

Based on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1–NOTCH2 signaling in patients harboring a JAG1mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome.

Related blog posts:

Fatty Liver Improved with Exercise

Posted on November 10, 2016 by gutsandgrowth

A recent study (LA Orci et al. Clin Gastroenterol Hepatol 2016; 14: 1398-1411) analyzed data from 28 randomized trials (>1600 patients) and performed a meta-analysis regarding the utility of exercise for nonalcoholic fatty liver disease (NAFLD).

Key finding:

Physical activity, independently from diet change, was associated with improvement in intrahepatic lipid content (-0.69) and with reduction in alanine aminotransferase.

The authors note that the effects of lipid reduction due to exercise is considered moderate-to-large. In several trials, another effect of exercise that was measured was a reduction in insulin resistance.

Limitations:

The duration of the effect of exercise is not known and there is not a clear “dose” of exercise.
Lack of histologic data (only 2 studies had histology data)

My take: This study suggests that exercise by improving metabolic status is important in improving NAFLD; thus, a fatty liver is not just about being fat.

Bar Harbor at Sunset

Is It Time To Start Testing HBsAg Levels in Hep B Patients?

Posted on November 9, 2016 by gutsandgrowth

Two recent studies show that HBsAg levels may help determine therapeutic decisions:

WP Brower et al. Clin Gastroenterol Hepatol 2016; 14: 1481-89
Y-C Hsu et al. Clin Gastroenterol Hepatol 2016; 14: 1490-98.

The first study was a retrospective study of 292 HBeAg-negative patients with chronic hepatitis B virus (HBV) infection. This cohort had normal ALT values and HBV DNA <20,000 IU/mL. Patients were considered to be carriers of inactive HBV if their HBV DNA was <2000 IU/mL and serum levels of ALT remained normal.

Key findings with regard to likelihood of having inactive HBV at following year:

“odds were 97% for initial level of HBsAg <100 IU/mL”
“odds were 85% for patients with initial levels 100-1000 IU/mL and 76% for patients with initial levels >1000 IU/mL”

Also, “patients with HBV activity who had levels of HBV DNA <5000 IU/mL and decreases in HBsAg of 0.5 log IU/mL or more for 1 year had a high probability of becoming carriers of inactive HBV in the next year.” Figure 2 in an easy graphic form shows cumulative probabilities of becoming inactive or active HBV over the three-year period.

In the second study, Hsu et al performed a prospective study of 161 consecutive patients with undetectable HBV DNA following 3 or more years of entecavir. After stopping therapy, patients were monitored for relapse.

Key findings;

49.2% of patients had a clinical relapse (defined by elevation of both HBV DNA >2000 IU/mL and by elevated ALT >2-fold ULN)
81.7% had virological relapse (HBV DNA >2000 IU/mL).
All patients with HBeAg-positivity had clinical relapse and were retreated.
For HBeAg negative patients at end of treatment, 39.2% had a clinical relapse & 77.4% had a virological relapse.
Serum HBsAg level predicted relapse among HBeAg-negative patients: 11 patients with HBsAg <10 IU/mL did not relapse. The lower the serum level of HBsAg at the end of treatment, the lower the rate of clinical relapse (see Figure 1). Of those with HBsAg 100-1000, there was ~25% clinical relapse at 30 months f/u and more than 50% virological relapse.

My take: HBsAg level is becoming important in truly determining who has inactive HBV and reflects the likely natural history. It is expected that using HBsAg levels will be increasingly used to determine management of HBeAg-negative HBV.

Related blog posts:

Pushback on AAP SIDS -Sleeping Guidelines

Posted on November 8, 2016 by gutsandgrowth

Recently, this blog summarized AAP SIDS recommendations. These recommendations have been reviewed in a NY Times commentary: Should Your Baby Really Sleep in the Same Room as You?

This opinion piece provides a good background on the issue os whether having a baby sleep in the same room is beneficial and explains some of the flaws in the studies behind the recommendations. Here’s an excerpt:

So when the American Academy of Pediatrics recently issued new infant sleep guidelines — highlighting a recommendation that babies sleep in their parents’ rooms for at least six months but ideally a full year — some parents despaired…

Yet the recommendation drew skepticism from some doctors, who argued that a close look at the evidence showed that the benefits of room-sharing didn’t always justify its costs to parents, who would have to sacrifice privacy, sex and, above all, sleep…

Depriving parents of good sleep can also endanger babies. Sleep-deprived people can have decreased empathy. Sleep deprivation is associated with anincrease in car accidents (which are a top killer of older children). It stresses marriages and families and is significantly associated with an increased riskof postpartum depression.

And with regard to the studies:

The first thing to note is that they all collected data in the 1990s, when SIDS was much more common than it is today. The academy said room-sharing “decreases the risk of SIDS by as much as 50 percent,” but that was before the significant improvement in SIDS rates. It’s not clear that sharing a bedroom would make as much of a difference today as it did then.

The second is these were all studies in Europe, where room-sharing is much more common. Only about 20 percent to 41 percent of infants in the control group slept in their own rooms. That makes it hard to pinpoint the reason they survived, and to generalize the findings to the United States.

My take: While the risk of SIDS may improve when infants sleep in the same room, this article makes a compelling argument that it may cause more harm than benefit.

Salivary Pepsin Doesn’t Pass Muster for Evaluation of Reflux

Posted on November 7, 2016 by gutsandgrowth

For quite a long time, I thought the expression was “Pass Mustard”.

A recent study (F Dy et al. J Pediatr 2016; 177: 53-8) shows that testing salivary pepsin is probably a waste of time in assessing for extraesophageal reflux disease. The authors prospectively recruited 50 children who underwent multiple studies including 24-hour pH-MII testing. The idea of pepsin as a biomarker has some plausibility since it is produced in the stomach and its presence in the oropharynx (or airway) would be unexpected. Since salivary pepsin does not require invasive diagnostic testing, it would be useful if it had adequate sensitivity and specificity.

Key findings:

21 of 50 (42%) were salivary pepsin-positive with a median concentration of 10 ng/mL. Pepsin was detected in 6 of 21 with abnormal impedance testing and 8 of 21 with abnormal pH results (per Table 1 –the discussion used a denominator of 11 for each of these results)
There was no significant correlation between salivary pepsin-positivity compared with salivary pepsin-negative for reflux episodes, acid reflux, nonacid reflux or any other reflux variable.
The authors also reiterate in the discussion that clinical trials, evaluating reflux and chronic cough, “have failed to find a consistent relationship between measure dreflux and clinical response.”
The authors note that bronchoscopy pepsin correlation with esophageal reflux monitoring was similarly low in sensitivity
The authors note that “one-third of healthy asymptomatic adults have pepsin detected in their saliva.” In this study, 38% (15 of 39) of children had pepsin detected despite normal impedance results.

My take: While this study mainly shows that pepsin detected in the saliva has no practical use in correlation with reflux, the bigger picture is the uncertain relationship of reflux as a causal association with chronic cough.

Any of the reflux-esophageal gurus care to comment?

Related blog posts:

Carriage Road in Acadia National Park