Category Archives: Pediatric Gastroenterology Intestinal Disorder

Vedolizumab: summary of latest data

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BG Feagan et al. Clin Gastroenterol Hepatol 2017; 15: 229-39.

From Clin Gastroenterol Hepatol, Feb 2017 Issue Highlights Link from AGA twitter feed:Vedolizumab in Anti-Tumor Necrosis Factor Naïve or Previously Exposed Ulcerative Colitis Patients

“Feagan et al present data comparing patients based on past exposure to anti-TNF agents. This post-hoc analysis compared 464 patients who received vedolizumab or placebo who were naïve to TNF antagonists to 367 patients who had been exposed but had an inadequate response, loss of response, or intolerance to TNF antagonists…

The investigators describe greater differences in efficacy for vedolizumab (versus placebo) in patients who were naïve to TNF inhibitors than for patients with prior exposure to anti-TNF agents.

Week 6 reponse rates to vedolizumab or placebo were 53% vs 26% amongst patients naïve to TNF antagonists (absolute difference 26%) compared to 39% vs 21% in patients with prior anti-TNF exposure (absolute difference 18%).

Week 52 remission rates with vedolizumab and placebo were 47% and 19%, respectively, for patients naïve to TNF antagonists (absolute difference 28%) compared with 36% and 5%, respectively, in patients with prior exposure to TNF biologics (absolute difference 29.5%).

Thus, while vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC patients whether or not they had previously received therapy with anti-TNF agents, there were numerically greater treatment benefit at week 6 among patients who had never received prior biologic therapy.“

My take: Given the higher response in anti-TNF naive patients along with the favorable safety profile, vedolizumab could be considered as a first-line therapy.

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Induction endpoints in TNF-failure patients by type of failure. Forest plots show difference from placebo and 95% CIs for percentages of patients with (A) clinical response, (B) clinical remission, and (C) mucosal healing at Week 6. Patients with more than one type of TNF antagonist failure were evaluated by each type of failure; thus the number of patients in the subgroups may total more than the number of enrolled patients.

Induction endpoints in TNF-failure patients by type of failure. Forest plots show difference from placebo and 95% CIs for percentages of patients with (A) clinical response, (B) clinical remission, and (C) mucosal healing at Week 6. Patients with more than one type of TNF antagonist failure were evaluated by each type of failure; thus the number of patients in the subgroups may total more than the number of enrolled patients.

Closer Look at Ustekinumab Data

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At a recent dinner, we had the opportunity to hear a review of some of the recent data on ustekinumab.  These notes may include some errors in transcription and errors of omission.  Most of this data is derived from a recent publication that has been summarized in this blog: Landmark Publication for Ustekinumab (Stelara) | gutsandgrowth

Some key points:

  • In numerous studies of biologic agents, longer duration of disease is associated with a much lower response to therapy.  For the UNITI-1/UNTI-2 studies, the patients enrolled had long duration of disease (~10 years in UNIT1-1, ~8 years in UNITI-2)
  • Recent data indicate that vedolizumab is effective for Crohn’s disease, but works slowly. It likely takes ~6 months to determine if it is working.
  • With ustekinumab, most patients respond within 3 weeks of the induction dose; however, among nonresponders, many responded after the first maintenance dose.  Thus, probably need to give at least the induction dose and the first maintenance dose for determining whether ustekinumab is effective.
  • Overall safety profile looks very good for ustekinumab.  More than 4000 patients in a psoriasis registry showed no serious safety signals (though psoriasis patients receive a lower dose).
  • Overall, the 6 mg/kg induction dose outperformed the 130 mg dose with regard to objective measures.
  • High placebo rate in the IM-UNITI study likely is due to some residual response to the initial induction dose.
  • Every 8 week dosing for ustekinumab was more effective than every 12 week dosing in these studies, though, there are likely patients who need more frequent and some who could benefit from less frequent dosing.
  • 2.3% of patients in IBD studies had detectable antibody to ustekinumab but this did not preclude efficacy.
  • ~20% of IBD patients do not develop increased CRP
  • Pediatric studies of ustekinumab are ongoing testing different dosing regimens.
  • One other anecdote in regards to magical thinking about which premedications are most effective:  A man with a ridiculous hat was approached as he walked in an Atlanta.suburb.  A lady asked him why he wore such an unusual hat. He replied that “the hat keeps elephants far away.”  The lady said, “there are no elephants around here.” He said, “See it is working.”

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Guideline Links: Infant Cholestasis and Esophageal Atresia-Tracheoesophageal fistula

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One way that I use this blog is to use the search function for previous posts with useful links.  For example, I know if I search “foreign” that I will come across a post that has a summary as well as a link to the NASPGHAN recommendations on Foreign Bodies (Foreign Bodies in Children -Expert Guidance).

This post has two links :

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oneboatcostamaya

 

Picture Quiz: Intestinal Cause of Edema

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Link to full text from AGA twitter feed:  A Rare Cause of Generalized Edema

Background: “A 19-year-old boy presented to our hospital because of a 6-month history of progressive dyspnea and generalized edema. He developed cough, abdominal fullness, diarrhea, and leg edema 5 years ago. Liver cirrhosis was suspected at that time…Chest radiography showed bilateral pleural effusions (Figure A). Abdominal computed tomography demonstrated large amount of ascites (Figure B). … Subsequently, antegrade double-balloon enteroscopy …demonstrated nodular mucosal lesions with a milk-like surface in the duodenum (Figure C). Moreover, snow flake appearance of mucosa was found in the jejunum and proximal ileum (Figure D). However, a normal appearance of mucosa was identified in the middle ileum (Figure E).”

The Answer: 

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“Histologic examination shows chronic inflammation of the ileum characterized by increased lymphoplasma cell infiltration of lamina propria without malignancy. Moreover, marked dilatation of lymphatic ducts that involved the mucosa was identified (Figure F)… a diagnosis of primary intestinal lymphangiectasia (PIL) was made.

Orphan Drugs –Very Profitable

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Did you know that Remicade and Humira are orphan drugs?  For those concerned about pharmaceutical costs, a recent NPR article is a must.

From NPR: Drugs For Rare Diseases Have Become Uncommonly Rich Monopolies

Here’s an excerpt:

Lucrative financial incentives created by the Orphan Drug Act signed into law by President Reagan in 1983 succeeded far beyond anyone’s expectations. More than 200 companies have brought almost 450 so-called orphan drugs to market since the law took effect.

Yet a Kaiser Health News investigation shows that the system intended to help desperate patients is being manipulated by drugmakers to maximize profits and to protect niche markets for medicines already being taken by millions. The companies aren’t breaking the law but they are using the Orphan Drug Act to their advantage in ways that its architects say they didn’t foresee or intend. Today, many orphan medicines, originally developed to treat diseases affecting fewer than 200,000 people, come with astronomical price tags…

More than 70 were drugs first approved by the Food and Drug Administration for mass market use. These medicines, some with familiar brand names, were later approved as orphans. In each case, their manufacturers received millions of dollars in government incentives plus seven years of exclusive rights to treat that rare disease, or a monopoly…

When a drugmaker wins approval of a medicine for an orphan disease, the company gets seven years of exclusive rights to the marketplace, which means the FDA won’t approve another version to treat that rare disease for seven years, even if the brand name company’s patent has run out. The exclusivity is compensation for developing a drug designed for a small number of patients whose total sales weren’t expected to be that profitable…

Industry-wide, orphan drug tax credits cost the federal government $1.76 billion in fiscal 2016

My take: Any objective observer would recognize that the goals of the Orphan Drug Act are being subverted by current practice and changes are needed to achieve the goals of targeting rare diseases and reasonable medication costs.

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Cystic Fibrosis Expert Update 2017

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During one of our recent group clinical meetings, one of my partners (Edith Pilzer, MD) presented an update on cystic fibrosis.

Here is a link to her slides:Link: cf-presentation

Here are a few of my notes:

There has been a great improvement in survival of cystic fibrosis patients..  From the Cystic Fibrosis Foundation:

  • ” Today the median predicted survival age is close to 40. This is a dramatic improvement from the 1950s, when a child with CF rarely lived long enough to attend elementary school.”

cftr2org  —website provide information on specific genotypes, including whether genotype is associated with pancreatic insufficiency

From the website:

  • This website provides information for members of the general public, including cystic fibrosis patients and their family members, about what is currently known about specific genetic variants related to cystic fibrosis.
  • Patients and their family members are encouraged to visit the section, “For patients and family members” first.
  • This website also provides more in-depth research-related information for health care professionals and researchers

Pancreatic enzyme replacement therapy (PERT) (see slides)

  • Creon 3000 beads are small enough to go through Gastrostomy tube
  • Pertzye has bicarbonate; thus, additional acid blocker administration is usually not needed
  • Viokase is hard to obtain
  • Relizorb –external lipase cartiledge.  This allows formula, delivered by NG, to run through column and obviates the need for additional PERT dosing.  One cartridge designed for 500 cc but several cartridges can be ‘piggy-backed.’ Here is website: relizorb.com.  Relizorb intent is to eliminate enzymes for night feeds, though it only has lipase; yet, there still could be a need additional PERT for protease and amylase.  Potentially PERT could be administered before or after and hopefully avoid awakening at night for enzymes..

Cystic Fibrosis Related Diabetes (CFRD)

  • Frequent reason for poor growth
  • Now, with increased survival, ~35% of Cystic Fibrosis patients develop CFRD

Distal Intestinal Obstruction Syndrome (DIOS)

  • If mild, treatment with miralax is reasonable
  • If vomiting, consider surgery consult
  • If more than mild, consider water-soluble enema with 10% mucomyst

My take: Great update.  Edith has been taking care of children with cystic fibrosis for more than 30 years and has witnessed/participated in the improvement in the survival of these patients.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

 

Puerto Rico

Puerto Rico

Constipation Video from Primary Children’s Hospital

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This is a really good educational video (< 8min) -now on YouTube: Constipation in Children: Understanding and Treating This Common Problem (Thanks to John Pohl’s twitter feed for this resource)

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Cost Effectiveness & Underpowered Studies

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A recent study (ALT Ma et al. J Pediatr 2016; 179: 216-8) reaches a conclusion that questions the cost-effectiveness of pretreatment TPMT activity in pediatric patients. In my opinion, this retrospective study is ridiculous. Here’s why:

The authors examined thiopurine transmethyltransferase (TPMT level) in 228 children before starting a thiopurine. They found the following:

  • Only 2 patients experienced mild neutropenia
  • 12% of their cohort had intermediate activity and 88% normal TPMT activity

I agree with their conclusion that routine blood tests are needed following institution of thiopurines, I think stating that “from an economic point of view –the cost for testing TPMT enzyme activity was high without major clinical benefit” cannot be made with such a small study.  Deficient TPMT activity occurs in about 1 in 300.  If a single patient develops bone marrow suppression due to a thiopurine medication, this can lead to a horrific and prolonged hospitalization.  The cost of such a hospitalization, both economically and emotionally, is enormous.

My take: If I were taking a thiopurine, I would want to know if I metabolized this medication at a slower rate and was at increased risk for bone marrow suppression.  My hunch is the authors would not forgo checking a TPMT level on themselves despite their study’s conclusion, particularly if they have ever witnessed a patient with thiopurine-induced bone marrow suppression.

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Grand Prismatic Spriing, Yellowstone

Grand Prismatic Spriing, Yellowstone