One year later

It has been one year and 300 posts since I’ve started this blog.  I’ve enjoyed putting together my thoughts about recent articles.  In addition, I like being able to search for previous blogs for information that I find helpful.

Currently there are close to ~35 hits per day in addition to the email/wordpress followers (about 30).  This number has been increasing and it is fascinating to see that people from all over the world will sometimes stumble across this blog.

If you have suggestions for topics, articles or other ways to improve this pediatric GI blog, please send me an email at jjhochman@gmail.com.

EoE: Drugs, Diets, Dilatation and PPI-REE

PPI-REE or proton pump inhibitor-responsive esophageal eosinophilia remains a problematic issue for our eosinophilic esophagitis (EoE) patients.  PPI-REE and the 3 D’s (Drugs, diet, and dilatation) have been reviewed recently (Clin Gastroenterol Hepatol 2012; 10: 1066-78).

The issues with PPI-REE that are problematic:

  • If a patient with suspected EoE is pretreated with a PPI and they do not have eosinophils present at the time of endoscopy then a diagnosis of PPI-REE cannot be established.
  • If patients are not pretreated, then determining that they have PPI-REE compared with typical EoE, requires repeat endoscopy.  Furthermore, response to PPI may be transient and/or natural variation in EoE could make definitive diagnosis of PPI-REE quite difficult.
  • If a patient presents with classic-appearing EoE, choosing to treat with a PPI is difficult as the response rate is much lower than with either dietary therapy or drug therapy.  In addition, many symptomatic patients may have been treated to some extent with a PPI.  Do they warrant repeat treatment and repeat endoscopy prior to using more typical treatment for EoE?

Beyond this topic, this review covers the recent consensus guidelines and the typical treatments: diets, drugs, and dilatation.

With regard to dilatation, the author notes that it may be safer than previously believed.  Furthermore, in a recent trial, 81% were symptom free at 3 months and 46% were symptom free at 1 year.  Despite better safety results, 74% of patients in one study complained of retrosternal pain after in endoscopy (moderate in 21% and severe in 17%).

With regard to drug or dietary therapy, the author recommends checking on the effectiveness after 6-8 weeks with a repeat endoscopy.  Until better tools for assessing response to therapy become available, endoscopy remains the only accurate way to determine if treatment is working.

Related blog entries:

Monitoring TNF antagonists in inflammatory bowel disease

Previously, this blog has discussed the use of drug monitoring in inflammatory bowel disease (Drug levels for inflammatory bowel disease | gutsandgrowth).  A good review of this topic has been published recently (Clin Gastroenterol Hepatol 2012; 10: 1079-87).

Some of the useful pointers:

  • Factors that influence clearance of TNF antagonists are reviewed:
  1. Antidrug antibodies (ADA) increase clearance and worsen outcomes
  2. Use of concomitant immunosuppressives reduces the likelihood of ADA formation and increase drug concentration.   In the SONIC trial, use of azathioprine was associated with trough infliximab (IFX) levels of 3.5 μg/mL compared with 1.6 μg/mL with monotherapy.  Also, ADA was reduce: 0.9% compared with 14.6% in the monotherapy group. [Other studies though have found variable effects of cotherapy.]
  3. Low serum albumin and high CRP are associated with increased drug clearance
  4. Individuals with high body size and males are more likely to have increased drug clearance.
  • Better assays for measurement of IFX and adalimumab (ADL) are now available.
  • Currently a trial evaluating trough levels is underway: Trough Level Adapted Infliximab Treatment (TAXIT).  With this study, the accepted target range for trough levels is 3-7 μg/mL.  Levels >7 μg/mL are considered supratherapeutic and allows for a prolongation of dosing interval.  Preliminary data confirm that trough levels inversely correlate with CRP.
  • Proposed algorithm in individuals with loss of response & positive ADA.  If ADAs present at high titer, then switch to different TNF antagonist.  If low  titer, could either switch or attempt drug escalation.
  • With IFX, when antibodies to infliximab (ATIs) are present, the likelihood of responding to increased dose is less than 20% whereas changing to different TNF antagonist has about an 90% response (in patients who were previous responders).
  • Proposed algorithm in individuals with loss of response & negative ADA.  If subtherapeutic trough levels (IFX ❤ μg/mL, ADL <8 μg/mL, or certolizumab <27.5 μg/mL), then dose escalation is worthwhile.  If drug levels are therapeutic, then dose escalation will not be effective.
  • With IFX, more than 85% of patients will respond to drug escalation when the trough level is subtherapeutic. This is much more favorable than switching agents.
  • One other issue with ADAs is that they may be transient is some patients.  Perhaps one-fourth of ATIs may be transient which may explain why some individuals with ATIs may still respond to dose escalation.

These points give several reasons why drug monitoring is useful in individuals with loss of response and may help determine whether patients responding to therapy may be able to prolong dose intervals.  At the same time, when an individual is not responding to therapy, it is also important to determine if in fact active inflammation is present with objective markers and to consider alternative explanations for GI symptoms (eg. Clostridium difficile infection, irritable bowel, bacterial overgrowth, etc.).

Related blog entries:

Only one chance to make first impression | gutsandgrowth

When nothing else is working | gutsandgrowth

Infliximab for children with Ulcerative Colitis | gutsandgrowth

Adalimumab for children with Crohn’s disease | gutsandgrowth

CHOOSE TNF TRIAL | gutsandgrowth

Facts or persuasion in health care decisions?

A thought-provoking perspective article in the NEJM 2012; 367: 1677-79 makes the argument that public health organizations/health professionals should be providing facts to inform people and not try to persuade or dissuade  them from screening for health conditions.

Examples of persuasion:

  • “The early warning signs of colon cancer: You feel great. You have a healthy appetite. You’re only 50.” (ad from New York Times Magazine from Memorial Sloan-Kettering Cancer Center)
  • “If you haven’t had a mammogram, you need more than your breasts examined.” (from American Cancer Society, 1970s)

The problem with persuasion messages is that they are ‘stripped of useful facts’ that indicate that screening can have harms as well as benefits.

For colon cancer, most 50-year-olds who feel great will not develop colon cancer.  The National Cancer Institute estimates that a 50-year-old has a 6 in 1000 chance of developing colon cancer in the next 10 years; the chance of death from colon cancer in that period 2 in 1000.  The advantages of colon screening would be to reduce that risk further: 67% with colonoscopy and 26% with sigmoidoscopy.  Screening, however, could result in bleeding, anesthetic complications, or perforation.

The tactics of persuasion rely on making people feel vulnerable and offering them hope.  Informed decisions allow appropriate expectations about the true benefits relative to harm.

Two new drugs for obesity

Undoubtedly, a safe, effective medication for obesity would be a pharmaceutical blockbuster.  The record so far on previous medications has been dismal.  Many have been abandoned due to safety concerns, including sibutramine (myocardial infarction and stroke) as well as dexfenfluramine/fenfluramine (valvulopathy).  Two new FDA-approved agents have shown promise but caution in their use will be needed (NEJM 2012; 367: 1577-79).  Neither agent has approval for pediatric usage.

Belviq (lorcaserin) is a selective agonist of the serotonin 5-HT-2C receptor and Qsymia (phentermine with topiramate) is a combination sympathomimetic amine (anorectic agent) with an antiepileptic drug.

In studies with lorcaserin, three studies (1-year placebo-controlled) have shown that the number of patients losing >5% of body weight was increased compared to placebo.  Mean percentage body weight loss with lorcaserin was -5.8% in first two studies and -4.5% in third study.  In contrast, placebo patients who received lifestyle counseling lost  -2.5% and -1.5% respectively.  Overall, up to 47% of patients receiving medication lost more than 5% body weight.

Potential safety concerns with lorcaserin:  initially there were concerns due to increased incidence of tumors in rats and possible valvulopathy (eg. mitral or aortic valve regurgitation).  However, the FDA has concluded that it is unlikely that these are likely to occur in humans.

With phentermine/topiramate, two placebo-controlled studies have shown an increase in patients losing >5% of body weight compared to placebo.  In the first study, the mean percentage change in body weight was -10.9% combination (dosage 15 mg/92 mg) compared with -1.6% for placebo.  In the second study, this dosage led to a -9.8% reduction compared with -1.2% in placebo patients. Overall, up to 70% of patients receiving medication lost more than 5% body weight.

With regard to safety, it is known that topiramate is teratogenic and increases the risk of orofacial cleft.  Due to this, approval for this combination requires a risk evaluation and mitigation strategy (REMS) which permits only specially-certified pharmacies to dispense along with formal training for prescribers. In addition, this combination has been associated with mildly increased heart rate. Due to favorable changes in blood pressure, the FDA concluded that this medication had a good benefit-risk balance.  But, the manufacturer recommends against it use in patients with cardiac issues or cerebrovascular disease.

With both new medications, other safety concerns include the risk of increased psychiatric effects.  In addition, specific recommendations include the following:

  • Only recommended in adults with BMI ≥30 or adults with BMI ≥27 with at least one weight-related comorbidity
  • With both medications, if weight loss not adequate after 12 weeks then discontinue medication.  With lorcaserin, if weight loss is not ≥5%, then discontinue.  With phentermine/topiramate, if weight loss is not ≥3% at 12 weeks (with 7.5 mg/46 mg), consider dosage increase and/or discontinuation.

Related blog entries:

Can NALFD be improved with bile acid sequestration?

Probably not (Hepatology 2012; 56: 922-32).

Because bile acid sequestrants like colesevelam (& cholestyramine) lower plasma low density lipoprotein (LDL) levels and can improve glycemic control, a recent study tested the hypothesis that this would result in improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH).

Methods: 50 patients were randomly assigned to either colesevelam 3.75 g/d or placebo for 24 weeks.  All patients had a liver biopsy within 6 months as a baseline study.  The primary outcome was liver fat as measured by a MRI technique (proton-density fat-fraction or PDFF) and by MR spectroscopy. At the start and conclusion of the study patients had biochemical assays, MRI-PDFF & MR spectroscopy; also, patients had a liver biopsy at completion of study.

Results: The colesevelam group had increased fat at the conclusion of the study period by a mean difference of 5.6% with PDFF and 4.9% with MR spectroscopy, both compared with placebo group.  In addition, liver biopsy did not detect any effect of treatment.  Looking at the biochemical indices, there was also a trend of increased transaminases in the treatment group compared to the control group (Table 3 in study).

Conclusions: The authors indicate that the increased fat may be due to a compensatory increase in bile acid synthesis.  Also, as the changes in fat were only detected on MRI, future NASH studies may benefit from this technique as well.

Related blog entries:

NAFLD Guidelines 2012 | gutsandgrowth

Pediatric NAFLD Position Paper | gutsandgrowth

PEG vs. Fiber for constipation

Which is better for childhood constipation, polyethylene glycol 3350 (PEG) or fiber? A recent study weighs in (J Pediatr 2012; 161: 710-15).

This randomized, prospective, open-label study compared PEG (with electrolytes) to a fiber supplement (acacia fiber, psyllium fiber, and fructose [AFPFF]) in 100 children with chronic functional constipation (Rome III criteria).  Mean age was 6.5 years.  Study design allowed for dosage adjustment.  Initial PEG dosing was 0.5 g/kg but could be increased to 1 g/kg. AFPFF was dosed at 16.8 g daily but could be increased to 22.4 g.  Primary outcome was ≥3 bowel movements per week and improved stool consistency (≥2 on Bristol stool scale).

Key findings:

  • Compliance was better with PEG than AFPFF: 96% for 72%.
  • After 8 weeks, improvement noted in 83% of PEG patients compared to 78% of AFPFF (P=0.788).  At this time point, PEG were having ~5.8 stools/week vs. 5.6 for AFPFF.  Mean Bristol scores were 3.7 and 3.5 respectively.
  • Conclusion: similar efficacy but PEG had better acceptance.  No mention of relative costs of these agents is noted.

Additional references:

Diagnosis and management of idiopathic childhood constipation – BMJ  NICE (Nat’L institute for Health and Clinical Excellence) recommendations 2010

Also, a recent previous post (ACE report -10 year effectiveness | gutsandgrowth) has links to multiple related blog entries.