Optimism for New Treatment in Inflammatory Bowel Disease: AJM300

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Yesterday’s post on “Eternal Nutrition” had a link to podcasts on enteral nutrition as therapy for Crohn’s disease.  I listened to the podcasts and they were helpful (Enteral Therapy as Primary Therapy for Crohn’s Disease Podcast).  A few points that were made included the following:

  1. Try to have the right person teach/place the nasogastric feeding tube.  If the first experience is bad, this may make further attempts quite difficult.  At CHOP, their facility has an education center and they schedule 3-hour learning session for enteral feeds.  Teaching the teen to place the NG tube is preferred.
  2. Many pediatric gastroenterologists in U.S. are not informing their patients that enteral feedings are a treatment option.
  3. In most parts of the world, induction with enteral nutrition involves virtually 100% of diet as enteral nutrition for ~8-12 weeks.  CHOP modification involves 80-90% of calories delivered enterally, typically over an overnight drip.  If someone is not responding to enteral feeds, CHOP may increase calories delivered enterally.
  4. For maintenance with CHOP modification, gradually reduction from 7 days per week to 5 days per week is attempted.  At CHOP, they prefer hydrolysate for enteral tube feedings and think more rapid gastric emptying could be helpful.  However, the podcast state that specific formulas have not been shown to be superior in trials to date.  At CHOP, if formula is taken orally, then an intact protein formula is selected.
  5. If someone uses enteral formula for maintenance, then consideration of a gastrostomy tube (after 3 months) is reasonable.  They have not had local issues at sites due to Crohn’s disease.
  6. Resources include the Oley.org website and the Crohn’s Survival Guide.
  7. Enteral therapy seems to work in small bowel as well as colonic disease, despite early reports suggesting less efficacy with colonic disease.

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A recent phase II study (N Yoshimura et al. Gastroenterol 2015; 149: 1775-83) indicates that an oral antagonist of α4 integrin may be quite useful for ulcerative colitis.

This double-blind, placebo-controlled trial with 102 patients found the following:

  • A clinical response rate at 8 weeks of 62.7% in the treatment group and 25.5% for placebo)
  • Rates of remission were 23.5% in the treatment group  compared with 3.9% in the placebo group.
  • Mucosal healing were 58.8%% in the treatment group  compared with 29.4% in the placebo group.
  • No serious adverse events were noted.

In the commentary by  BG Levesque and S Ghosh (pg 1669-72), it is noted that subsequent oral integrins will be compared to vedolizumab and similar safety concerns exist; that is making sure that there are no cases of progressive multifocal leukoencephalopathy (PML) which has been associated with natalizumab therapy.  For vedolizumab, the RAMP safety monitoring program has NOT identified PML in 2884 IBD patients.

The commentary (in blue) discusses several integrins as potential therapeutic targets and outlines future therapies.

Nontargeted therapies:

  • A) Induction: corticosteroids, 5- aminosalicylates, cyclosporin, and tacrolimus
  • B) Maintenance: thiopurines, methotrexate, 5-aminosalicylates, and tacrolimus.

Targeted therapies (those in development phase in italics)

  • A) Monoclonal antibodies (induction and maintenance): tumor necrosis factor inhibitors, vedolizumab, other integrin/adhesion molecule inhibitors, interleukin-12/23 inhibitors, and interleukin-6 inhibitors.
  • B) Oral synthetic (induction and maintenance or stop and start): Jakinibs, integrin blockers, sphingosine-1-phosphate (s1P) regulators, and SMAD7 antisense oligonucleotide.

“The results of AJM300 demonstrate feasibility of such an approach, and we anticipate a proliferation of such approaches given the robust evidence supporting integrins as a target, especially if the drug can be targeted or delivered in a gut-specific manner.”

My take: There are a number of therapies being developed that are likely to transform the treatment of inflammatory bowel disease; future treatments will be more precise, more effective and have many more options.

Related blog posts:

Banning Mills

Banning Mills

 

“Eternal Nutrition” Therapy

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NASPGHAN twitter feed (with links to enteral therapy podcasts) was probably a typo &/or autocorrect issue:

“Podcast series must! Eternal Nutrition as Primary Therapy for Crohn’s disease. ”

Related blog posts:

Trying to Understand Gastroparesis

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…all I know is that I know nothing. –Socrates

Perhaps Socrates was a gastroenterologist.  So much of what we think we know, we are finding out is poorly understood.  This applies to gallbladder dyskinesia, sphincter of Oddi dysfunction and now gastroparesis.

A recent study (PJ Pasricha et al. Gastroenterol 2015; 149: 1762-74, commentary 1666-68) and commentary show how little we understand about gastroparesis.

The study was a large prospective surgery of 262 adult patients with gastroparesis (either diabetic or idiopathic).

Key findings:

  • 28% had improvement in the gastroparesis cardinal symptom index (GCSI) at 48 weeks.  Beyond 48 weeks, there were no significant reductions through week 192.
  • Favorable characteristics: male gender, age 50 and older, initial infectious prodrome (18% of cohort), antidepressant usage, and 4-hour gastric retention greater than 20%.
  • Unfavorable characteristics: obesity, smoking, use of pain modulators, moderate to severe abdominal pain, severe reflux, and moderate to severe depression.

The commentary suggests that those with the higher GCSI improved, in part, because of a regression toward the mean bias.  Other important commentary:

  • “More severely delayed gastric emptying was associated with a greater likelihood of improvement”
  • “There was no differences in outcome between diabetic or idiopathic gastroparesis.”
  • Gastric emptying tests are not reliable:  “Pathophysiologic tests are useful in clinical practice if they are reproducible, explain the symptoms, guide therapeutic choices, and determine response to therapy and long-term prognosis.  Despite its popularity, the gastric emptying test scores low on most of these criteria.”
  • “A metaanalysis found no correlation between the change in gastric emptying rate and the symptom response during prokinetic therapy…A 5-year prospective follow-up study of …functional dyspepsia…found that more than 50% improved…with no relation to the presence of delayed gastric emptying.”
  • “Using the term gastroparesis also can lead to premature closure in our efforts to understand the pathophysiology of symptoms…can lead to botulinum injections into the pylorus or placement of gastric stimulators (formerly called gastric pacemakers) for gastroparesis, both of which have been shown to be nonefficacious in controlled trials.”

My take: It is unclear “when to consider gastric emptying testing and how to use it in patient management.”  For the pediatric population, gastroparesis is more likely to be associated with a prodromal infection which increases the likelihood of recovery.

Related blog posts:

Banning Mills

Banning Mills

Using Ustekinumab for Crohn’s Disease

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From GI & Hepatology News: New targeted Crohn’s therapy performs well in phase III trial.

This study of Ustekinumab (aka Stelara) was different than previous studies (see previous gutsandgrowth blog from 2012: Ustekinumab for Crohn’s disease) in that this study targeted patients who were NOT ant-TNF failures; however, about 80% of patients had failed corticosteroids.

An excerpt:

Ustekinumab, a monoclonal antibody targeted against interleukins 12 and 23 (IL-12 and IL-23)…

 The trial, called UNITI-2, enrolled patients with moderate to severe Crohn’s disease who had failed traditional therapies but were naive to or at least had not failed a tumor necrosis factor (TNF) inhibitor…

In UNITI-2, 628 patients were randomized to placebo, 130 mg of ustekinumab in a fixed subcutaneous dose of 130 mg, or a weight-based dose of 6 mg/kg of subcutaneous ustekinumab…The primary endpoint was a CDAI reduction of at least 100 points at 6 weeks. Clinical remission at 8 weeks, defined as CDAI less than 150, was a secondary endpoint.

The primary endpoint was reached by 28.7% randomized to placebo, 51.7% of those randomized to the fixed dose of ustekinumab, and 55.5% of those randomized to weight-based dosing. The advantage for the active treatment arms was statistically significant (both P less than .001). For the secondary endpoint of clinical remission at 8 weeks, the rates were 19.6% for placebo, 30.6% (P = .009 vs. placebo) for fixed-dose ustekinumab, and 40.2% (P less than .001 vs. placebo) for the weight-based dose…

Ustekinumab was well tolerated with similar rates and types of adverse events reported in the active treatment and placebo groups.

My take: This study indicates that ustekinumab is likely to be another treatment option for patients with Crohn’s disease.

“Aging Elephant in the Room”

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Happy New Year!

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“Adults are just obsolete children” –Theodor Seuss Geisel

So, begins an interesting commentary (B Kinnear. JAMA pediatrics 2015; 169: 1081-2 -thanks to Ben Gold for this reference).

This editorial discusses a growing problem of patients older than 21 years of age seeking care in pediatric institutions.  Currently, ~15,000 admissions occur annually in the U.S..  At the author’s institution (Cincinnati Children’s), the average daily hospital census was 15.7 patients between 2012-2014.  In fact, at Cincinnati, which has an adult care hospital across the street, they have developed a team to care for these patients: “the Hospital Medicine Adult Care team.” In addition, they have established protocols to recognize and initiate treatment on problems like acute coronary syndrome, pulmonary embolism, and acute stroke.

The author argues that age should not be the only factor determining which institution would offer the best care.  Some cognitively impaired adults with cerebral palsy may be better-suited at a pediatric facility and some obese teenagers with type 2 diabetes and hypertension may fit better at an adult care hospital.

Common barriers to transitioning to adult care hospitals:

  • Lack of adult health care professional knowledge and comfort by adult health care physicians
  • Poor communication between pediatric and adult care providers
  • Families fear of leaving established care settings

These adults in pediatric care settings do have increased length of stays and greater odds of mortality than adolescents, even when adjusting for  the increased number of chronic conditions.  Thus, it is not entirely clear that outcomes will be improved by retaining this vulnerable population at pediatric institutions.  Much of this question will be determined by the institutional resources available for their care.

My take: I worry that keeping adults (patients >21 years) in pediatric institutions is a mistake.  There are increasing numbers of vulnerable patients and their needs should be addressed by adult care providers.

Isle of Palms, SC

Isle of Palms, SC

My Favorite Posts 2015

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I want to thank all of those who have provided input to this blog this year.  Best wishes to all for a happy and healthy 2016.

Here’s my list of favorite posts in the past year:

On being a doctor:

Nutrition posts:

Gastroenterology posts:

IBD posts:

Liver posts:

Screen Shot 2015-12-09 at 8.21.20 PM

Popular Posts 2015

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Today and tomorrow I am posting the most popular posts and my personal favorite posts from 2015.  I am labeling the most popular posts as those posts that had the highest number of visits in the past year.

Most popular posts:

Shem Creek, SC

Shem Creek, SC

‘Don’t Believe Our Study’

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The message I inferred from a recent study (CA Siegel et al. Clin Gastroenterol Hepatol 2015; 13: 2233-40) was to disregard their results which generally showed a lack of benefit of combination therapy (aka “concomitant immunomodulator” or dual therapy) compared with anti-tumor necrosis factor (anti-TNF) monotherapy for Crohn’s disease.

Specifically, the authors state the following in their discussion:

Although our results challenge the clinical importance of combination therapy in this specific scenario, it is hard to ignore the preponderance of data to date relating to the pharmacokinetics of anti-TNF medications that support the approach of combination therapy over monotherapy.

Here’s the background for this study.  The authors performed a meta-analysis of placebo-controlled trials (n=1601 subjects) to examine the question of whether continued use of immunomodulators (IMs) would be of benefit in patients who had failed monotherapy with IMs (“IM-experienced”).  The authors note that the SONIC study showed that combination therapy (infliximab and azathioprine) was more beneficial in patients who were IM-naive than monotherapy.  This meta-analysis included data from 3 anti-TNF agents: infliximab, adalimumab, and certolizumab.

Key findings:

  • Combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio 1.02) or in maintaining a response (OR 1.53).
  • In subgroup analysis, there was a statistically-significant protective effect of baseline IM exposure versus no baseline IM exposure among those treated with infliximab.
  • Generally, combination therapy was not associated with any change in adverse reactions; however, combination therapy with infliximab had lower adverse events, which was driven by infusion reactions.

My take: This study indicates that combination therapy is likely helpful in IM-experienced patients who are starting infliximab and possibly not effective with the other anti-TNF agents.  The authors emphasize the need for well-designed, prospective, randomized, placebo-controlled trial for a definitive answer.  Until then, don’t believe their study.

Of interest: Recently I became aware of a college scholarship opportunity for young adults with IBD: Abbvie Scholarship Program.

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Clever Marketing or Truth in Advertising?

Clever Marketing or Truth in Advertising?

Yosemite National Park

Yosemite National Park