Ursodeoxycholic Acid, Cystic Fibrosis, and the Problem with Surrogate Markers

Posted on by

A recent study (C Colombo et al. J Pediatr 2016; 177: 59-65) examined 20 patients with cystic fibrosis-associated liver disease (CFLD) who were receiving ursodeoxycholic acid (UDCA) for at least 2 years.  Specifically, they wanted to focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid.  The possibility that long-term UDCA therapy could be detrimental was propelled by a primary sclerosing cholangitis study (K Lindor et al. Hepatology 2009; 50: 808) which indicated that high doses of UDCA resulted in worse outcomes despite better “liver function tests.”

Dosing of UDCA: 20 mg/kg/day

Key findings: UDCA became the predominant serum bile acid; 2 hours after UDCA administration, “both UDA and chenodeoxycholic acid significantly increase (P< .01), but no significant changes in serum lithocholic acid concentrations were observed.”

What does this study prove?

Well, not very much.  There are other potential mechanisms for UDCA toxicity and as the editorial notes, “we still lack the necessary endpoints in CF liver disease with which to assess the efficacy of UDCA or any therapy that is on the horizon.”

My take: Because our surrogate markers are unreliable for CFLD, there really is no way to know with certainty whether UDCA therapy is beneficial.

gardenpic3

Landmark Publication for Ustekinumab (Stelara)

Posted on by

A recent study (BG Feagan, WJ Sandborn et al NEJM 2016; 375: 1946-60) provides extensive data regarding the effectiveness of ustekinumab for Crohn’s disease.

This publication combines three trials (industry-sponsored): UNITI-1, UNITI-2, and IM UNITI.  The first two trials with 741 and 628 patients respectively examined intravenous ustekinumab for induction.  Patients (18 years or older with Crohn’s disease) received either 130 mg, 6 mg/kg or placebo.  UNITI-1 were patients with primary or secondary nonresponse to TNF antagonists.  UNITI-2 were patients in whom conventional therapy failed or in which unacceptable side effects developed. The majority of UNITI-2 patients had not received a TNF antagonist.

IM UNITI with 397 patients followed patients who completed the first two trials for maintenance (90 mg SC every 8 weeks or every 12 weeks).  For this study, the primary end point was remission at week 44 (CDAI score <150).

The IM UNITI study involved 260 sites in 27 countries.

Key findings:

  • With the induction trials, ustekinumab outperformed placebo at 6 weeks.  For UNITI-1, 130 mg dosing resulted in 34.3% response, 6 mg/kg resulted in 33.7% response and placebo 21.5%.
  • For UNITI-2, 130 mg dosing resulted in 51.7% response, 6 mg/kg resulted in 55.5% response and placebo 28.7%.
  • For IM UNITI, every 8 weeks dosing resulted in 53.1% remission at week 44, compared with 48.8% dosed every 12 weeks, and 35.9% who received placebo.
  • For IM UNITI, among those who started in remission at week 0, 66.7% (q 8 weeks), 56.4% (q12 weeks) and 45.6% (placebo) remained in remission at 44 weeks.

When looking at more objective results, both UNITI-1 and UNITI-2 showed significant drops in calprotectin and CRP values; both of these objective markers favored 6 mg/kg over 130 mg fixed induction dose.

  • UNITI-1 at 6 weeks, calprotectin dropped 38.6 in 130 mg dosing group, 41.3 in 6 mg/kg group and 0 in placebo.
  • UNITI-2 at 6 weeks, calprotectin dropped 55.0 in 130 mg dosing group, 106.3 in 6 mg/kg group and 0 in placebo.
  • For the IM UNITI objective markers, it was noted that the median CRP values generally were unchanged in both treatment groups (q8 weeks, and q12 weeks) but increased in the placebo group by ~4 mg/L.  Also, calprotectin remained <250 mg in both ustekinumab treatment groups at a much higher percentage than those who received placebo.

Safety:

Extensive safety data are reported and more than 60% of all patients, including placebo-treated patients reported potential adverse effects.  Adverse effects and serious adverse effects were similar in treatment and control groups. During 1 year of therapy, there were no deaths or instances of the reversible posterior leukoencephalopathy syndrome.

Other points:

  • Response to ustekinumab was observed as early as week 3
  • UNITI-2 patients, most of whom had not failed a TNF antagonist, had higher response than UNITI-1 likely due to disease which was less refractory and of shorter duration

My take: These data support the use of ustekinumab for Crohn’s disease, particularly in patients who have not responded to other therapies.

stelarastudy

 

Learned Fear of Gastrointestinal Sensations Plus Two

Posted on by

Briefly noted: The authors of a recent study (E Ceunen et al. Clin Gastroenterol Hepatol 2016; 14: 1552-58) set out to study whether it is likely that healthy adults could learn to fear “innocuous visceral sensations.”  Fifty-two healthy subjects received  2 types of esophageal balloon distentions –one that was perceptible and non-painful and one that was painful.  Not surprisingly, when the researchers paired these two interventions in the experimental group, the experimental group learned to fear the innocuous stimulation as well as the painful distention.  This study provides theoretical support for one mechanism that could trigger ongoing functional gastrointestinal symptoms and a potential rationale for therapies, like cognitive behavioral therapy, which attempt to extinguish these symptoms.

In a retrospective study (AM Moon et al. Clin Gastroenterol 2016; 14: 1629-37) with 6451 patients with cirrhosis (mean age 60.6 yrs), the authors note that use of antibiotics during upper gastrointestinal bleeding (which is currently recommended) is associated with reduced mortality by ~30% at 30 days.  Despite its benefit, this intervention is often overlooked.  In the current study, only 48.6% of admissions received timely antibiotics; however, during the course of the study, the rate of antibiotic use improved from 30.6% in 2005 to 58.1% in 2013.

A recent retrospective study (N Goossens et al. Clin Gastroenterol 2016; 14: 1619-28) with 492 subjects showed that histologic NASH (in 12% of cohort) was associated with increased risk of death in patients who underwent bariatric surgery compared to patients without NASH.  Overall, bariatric surgery reduced the risk of death during the study period with HR of 0.54; the median follow-up was 10.2 years, with surgery taking place 1997-2004.  However, in patients with NASH the HR 0.90 which indicated that there was not a significant reduction in the risk of death.

Bar Harbor, ME (low tide)

Bar Harbor, ME (low tide)

Is there a link between the microbes in your colon and depression?

Posted on by

A recent study (Y Liu et al. Clin Gastroenterol Hepatol 2016; 14: 1602-11) showed that fecal microbiota signatures were similar between patients with diarrhea-predominant irritable bowel syndrome (IBS-D) and in patients with depression.

The authors analyzed stool samples from 100 Chinese subjects.  In addition to analyzed stool microbiota, the authors evaluated visceral hypersensitivity with a barostat and assessed for mucosal disease with immunohistochemical analyses of sigmoid biopsies.

In both IBS-D patients and patients with depression, the stool diversity was much less than controls and had similar abundance of many alterations, including higher proportions of Bacteroides and Prevotella (see below).

My take: It is interesting to speculate on whether changes in our microbiome could trigger/be related to the pathogenesis of not only IBS-D but other non-GI disorders like depression.

In the screenshot below, the term “COMO” refers to the 25 subjects who had both IBS and depression.

screen-shot-2016-11-14-at-12-10-03-pm

The President-Elect and the Anti-Vaccine Crowd

Posted on by

Multiple sources have reported that the anti-vaccine crowd is pleased with the results of the 2016 presidential election.

From Slate (11/22/16): Trump reportedly assured vaccine skeptics of of his support

An excerpt:

The president-elect has a long history of vaccine misinformation; he first began to express his beliefs that there might be a relationship between vaccines and autism nearly a decade ago—years after this association was scientifically discredited. He’s repeated these ideas over the years, and he never found it necessary to correct or refine his position during the election…

Jennifer Larson, CEO of the autism-focused Holland Center, in which she explained that she and other vaccination skeptics discussed their concerns with Trump at a donor event in August. According to her account, Trump assured them that he’s on their side.

From StatNews (11/30/16): Meeting with Trump emboldens anti-vaccine activists, who see an ally in the Oval Office

An excerpt:

“For the first time in a long time, I feel very positive about this, because Donald Trump is not beholden to the pharmaceutical industry,” movement leader Andrew Wakefield told STAT in a phone interview…

A former doctor whose medical license was revoked, Wakefield launched the movement to question the safety of vaccines nearly two decades ago with a fraudulent study (which has since been retracted) suggesting that a widely administered vaccine against measles, mumps, and rubella can cause autism…

Those who seek to undercut trust in vaccines “see in Donald Trump a fellow traveler — someone who, like them, is willing to basically ignore scientific studies and say, ‘This is true. Vaccines cause autism because I believe it’s true,’” said Dr. Paul Offit, the head of the infectious diseases department at Children’s Hospital of Philadelphia.

My take: There is a reason anti-vaxxers see Donald Trump as a fellow traveler.

Acadia Natl Park

Acadia Natl Park

Nonpartisan Fear of GMOs

Posted on by

A recent NPR report: Americans Don’t Trust Scientists’ Take On Food Issues

This reports how frequently misinformed the US public is about is about food safety issues but at least this information is not associated with partisan political views.

An excerpt:

39 percent of the survey participants believe that genetically modified foods are worse for your health than non-GM food. However, there’s essentially no scientific evidence to support that belief — a conclusion confirmed most recently by a National Academy of Sciences report…

Americans believe that there’s no scientific consensus on GMOs. Just over 50 percent of respondents believe that “about half or fewer” of scientists agree that GM foods are safe to eat. Only 14 percent’s beliefs match the reality — that “almost all” scientists agree that GM foods are safe to eat…

Roughly equal shares of Republicans and Democrats (39 percent versus 40 percent) feel that GMOs are worse for people’s health. More Democrats than Republicans (60 percent versus 50 percent) believe that organic foods are healthier. It’s significant, but not a huge difference….

Related posts:

Here’s another related link: NY Times Stop Bashing GMO Foods

Ft Knox, Maine

Ft Knox, Maine

Truly Penicillin Allergic?

Posted on by

Here’s a link to the video story regarding misdiagnosis of penicillin allergy: Your Allergy to Penicillin May Be Non-Existent

Link to print version: Allergy to Penicillin?

An excerpt: Dr. Thanai Pongdee, an allergist at the Mayo Clinic in Jacksonville, Florida and colleagues tested 384 people who said they were allergic to penicillin. Tests showed 94 percent of them were in fact, not allergic.

pcn-allergy

Predicting Short Bowel Syndrome Enteral Autonomy: Small Bowel Diameter

Posted on by

In a small retrospective single-center study (GC Ives et al. J Pediatr 2016; 178: 275-7), the authors found that small bowel diameter, as measured on calibrated luminal contrast studies was predictive of enteral autonomy.

Measurements of >35 mm of bowel lumen was considered dilated.  29 patients had adequate imaging for the study.  Necrotizing enterocolitis was the most common etiology of short bowel syndrome in this study.  16 (55%) of the intestinal failure group achieved enteral autonomy in an average of 1.3 years.  11 (38%) of patients underwent an intestinal lengthening procedure.

Key findings:

  • Small bowel diameter correlated negatively with residual small bowel length
  • Larger small bowel diameter predicted failure to achieve enteral autonomy.  In fact, only one patient in this study with a dilated small bowel diameter achieved enteral autonomy.

My take: Bigger (diameter) is not better.

Related blog posts:

Lighthouse in Rockland

Lighthouse in Rockland

Weak Link in Liver Transplantation Survival

Posted on by

A recent article and editorial (DH Leung et al. Liver Transpl 2016; 22: 1584-92 & editorial by JC Bucuvalas, S Feng 1466-68) provides a better picture of long-term survival for pediatric patients facing the prospect of liver transplantation.

Among patients less than 2 years in the UNOS data sharing registry, there were 994 with biliary atresia (BA) and 221 with other chronic liver disease.

The key data:

  • The overall postlisting mortality was 19.6% with most of this due to wait-list mortality (12.4%).  Posttransplant mortality was 8%.
  • The non-BA patients had a higher wait-list mortality compared with BA patients: 23.9% vs 9.8%
  • Risk factors for mortality included lack of exception points (HR 5.8), and initial creatinine >0.5.  In addition, BA patients without prior abdominal surgery (eg Kasai) was higher (risk was 1.6 times greater) than in those with BA with presumed Kasai.

Reviewing the article, it is not clear to me if patients removed the waitlist (eg due to sepsis and other causes) are included in this analysis.  Thus, the true postlisting mortality may be higher than 20% if all needy individuals are considered.

From the editorial -other aspects:

  • Only one-third of pediatric recipients have optimal outcomes which would include normal LFTs, maintained on monotherapy immunosuppression, normal growth, and free of comorbidity.  In addition, even among those with ‘optimal’ outcomes, many would still have histologic injury.
  • The “incidence of nonstandard exception requests has increased 5-fold and is now used on behalf of 44% of wait-listed children.”  Importantly, children with public insurance were less likely to have petitions for exception PELD points.

My take (with help from editorial): To improve outcomes, this means starting with candidate selection and working on each step: traversing wait-list management and optimizing posttransplant care.

Related blog posts:

Mural in Rockland, ME

Mural in Rockland, ME

Notable Briefs for IBD -December 2016

Posted on by

MI Abdalla et al. Inflamm Bowel Dis 2016; 22: 2658-64.  This article reviewed the impact of an ostomy on QOL (quality of life) for Crohn’s disease patients. n=402 with ostomy compared with 4331 CD patients without.

Key findings:

  • Patients with ostomy were more likely to be in remission: 48.5% versus 31.35%.
  • Having an ostomy did not impact overall health-related quality of life but did reduce social role satisfaction.
  • Conclusion: “ostomy is well tolerated…particularly when clinical remission is achieved.”

WKM Liew et al. J Pediatr 2016; 178: 227-32. In this study with 16 patients (aged 6-24 years) who received thalidomide, more information on neuropathy is provided.  “All subjects with cumulative doses greater than 60 g developed polyneuropathy.”  4 of 5 subjects receiving the drug for >20 months developed neuropathy. Two important points:

V Collij et al. Inflamm Bowel Dis; 2016; 22: 2562-70. “We identified drugs that target the proteins encoded by IBD candidate genes.” Key finding: There were 113 drugs that could potentially be used in IBD treatment, including 14 known IBD drugs, 48 drugs that are/have been tested for IBD, 19 being tested for other inflammatory diseases, and 32 new investigational medications.

from one of the best days all year

from one of the best days all year on board “Bufflehead”