What We Know Now: Therapeutic Drug Monitoring for Inflammatory Bowel Disease

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This blog has discussed the utility of obtaining drug levels for both biologic agents and thiopurines.  A recent article (Inflamm Bowel Dis 2015; 21: 182-97) provides a concise up-to-date review.

Here are the key points:

  • Primary nonresponse to anti-TNF therapy (PNR) “is most commonly defined as lack of improvement of clinical signs and symptoms after the induction phase leading to discontinuation of the drug.”
  • “We think that patients who respond but fail to achieve remission…are likely almost all due to insufficient drug.”
  • Table 2 provides a list of predicting factors, both negative and positive, for PNR.  This list includes genetic mutations (e.g.. IL23R, NOD2/CARD15 variant), mucosal gene expression, clinical factors (e.g. young age, isolated colitis, smoking, nonstricturing disease, concomitant immunomodulators) and serologic (eg. CRP, hemoglobin, and presence of pANCA).
  • Patients with PNR to a TNF antagonist, “despite therapeutic concentrations of drug and no anti-drug antibodies (ADA), would likely benefit from a switch to an alternative drug with a different mechanism of action.”
  • “Patients with a high baseline inflammatory load…and increased clearance of drug because of a high turnover would likely benefit from higher induction doses.”  This hypothesis has been proven in rheumatoid arthritis patients in which patients with high TNF concentrations had a clinical response to 10 mg/kg that was “significantly better than the response to 3 and 6 mg/kg of infliximab.”
  • Patients (with ADA) with an “early immunogenic response against the TNF antagonist are unlikely to respond to dose escalation and thus should be switched to another TNF antagonist, and it should be considered to give higher induction doses in combination with an IMM [immunomodulator] to reduce the risk of immunogenicity.”

Take-home message: New definition of primary nonresponse to anti-TNF agent: “a lack of improvement of objectively assessed signs of active inflammation at baseline, after the induction phase despite the presence of adequate concentrations of drug and the absence of anti drug antibodies.”

Also noted: “Surgical management of ulcerative colitis in the era of biologicals” Inflamm Bowel Dis 2015; 21: 208-10. Key point: “Sacrificing the non responsive diseased colon is an underused or unnecessarily delayed chance to normalize ..health and life.”  “Deconditioning of patient with unreasonably long escalations of ineffective medications adds to the morbidity of surgical intervention.”

“Automimmune Features are Associated with Chronic Antibiotic-refractory Pouchitis”Inflamm Bowel Dis 2015; 21: 110-20. Key point: “Microsomal antibody expression and elevated IgG4-positive plasma cell infiltration were independent risk factors” for chronic antibiotic-refractory pouchitis.”

Update on MOC (recent blog:Resistance to Maintenance of Certification | gutsandgrowth) American Board of Internal Medicine “We Got It Wrong” “We launched programs that weren’t ready and we didn’t deliver an MOC program that physicians found meaningful. We want to change that.”

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“Using Drugs to Discriminate”

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A recent commentary (Jacobs DB, Sommers BD, NEJM 2015; 372; 399-402) highlighted a growing problem.  Many insurers are using drug benefit plans to dissuade sicker people from enrolling in their plans.

Prior to the Affordable Care Act (ACA), insurers charged high premiums to people with chronic conditions.  The ACA attempted to address this problem; in fact, the “individual mandate” was necessary to make sure that insurance companies had enough healthy people in their insurance pool to make it financially feasible.

Yet, insurance companies make more money if they can limit insuring sicker, chronically-ill people.  One way this is happening is through “Adverse Tiering” which substantially increases out-of-pocket expenses for individuals with HIV, cancer, diabetes, mental illness, and arthritis. The difference in out-of-pocket costs, for example, with for each HIV drug was more than $3000 (on average) between adverse-tiered plans and those that were not adverse-tiered.  Even for generic drugs, the cost was nearly a $2000 difference.

A few problems with this approach:

  • Insurer’s drug prices are not usually available to public when choosing a plan; thus, these higher out-of-pocket costs are often unanticipated. (*Price transparency could accelerate rather than hinder this process.)
  • If sicker patients flock to plans without “adverse tiering,” this could make these non-adverse-tiered plans lose money and result in similar design to avoid “adverse selection.”

Conclusion: “Preventing [this adverse tiering and] other forms of financial discrimination on the basis of health status — with the attendant risks of adverse selection in the marketplace –will require ongoing oversight.”

Here’s the NY Times Report on this study: Study Finds HIV Drugs Priced Out of Reach

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“Weekend Effect” –From the Other Side of the Bed

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Many times when I’m working at the hospital on a weekend I’ve wondered how long hospitals can continue to offer fewer services during weekends than during the work week.  Usually if I’m there, I don’t want to hear that something has to wait until Monday.  It also puts me in the uncomfortable position of deciding whether something is urgent enough that on-call staff (eg. radiology, anesthesiology) need to be called in.  At the same time, some services in the hospital, for example, interventional radiology may have only one or two people who are qualified and it is unrealistic to expect them to be available 24/7/365.

A recent commentary (Klass P, NEJM 2015; 372: 402-405) helps provide a family’s perspective regarding this situation. Here are some of the key points:

  • “It can be shocking to hear, over and over, about the ways that weekends are slower and things don’t get done.”
  • Often many services are absent like physical therapy and psychiatry.  Most other services are understaffed and “cross-covering” patients with less familiarity.
  • For many conditions, morbidity and mortality are higher on weekends. (J Pediart Surg 2014; 49: 1087-91, NEJM 2001; 345: 1580, JAMA 2008; 299: 785-92))
  • “When you’re sick and scared, Sunday is the same as Tuesday.”

Bottomline: This commentary makes a strong case for saying “the hospital is not actually about patients. It’s about doctors and nurses, physical therapists and nutritionists.”

Question: Do you think weekend staffing should change or will change to address these shortcomings?

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Related link:

 

Cool Mirror at High Museum

Cool Mirror at High Museum

What to Fear in 2015

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From Parade Magazine,  What to Fear in 2015:

An excerpt:

Here are a few of the things you should and should not fear in 2015:

  • Flu not Ebola
  • Domestic violence not serial killers, pedophiles
  • Heart disease not Mercury in fish
  • Not getting enough dietary fiber not gluten
  • The re-appearance of measles, whooping cough, and other preventable diseases not vaccine side effects
  • Texting while driving not air travel
  • Malware on your cell phone not bulk password theft
  • Gun violence among young people not school shootings/mass murders
  • Sitting too much not heart attacks during exercise

Another link on the measles epidemic from NY Times: Vaccine Critics Defensive. Another editorial remarked on how Ebola which is much less contagious than the measles alarmed so many people in this country; it stated that if a terrorist, rather than parents refusing vaccinations, had unleashed a highly contagious virus on our communities, many would be calling for military retaliation. Unfortunately, it takes a measles epidemic to provide a passionate argument for immunizations. Related blog post: 1400 Different Immunization Schedules -What Could Go Wrong …

From NBC News Measles Vaccine FAQ

Leptin Deficiency and Early-Onset Extreme Obesity

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A brief report (NEJM 2015; 372: 48-54) details a case of 2.5 year old who weighed 33.7 kg (>99.9% and z score of 7.2) and had BMI of 38.6 (>99.9% and z score of 5.8).

Link to article (and picture/growth curve)

The authors determined that he had a mutation which caused biologically inactive leptin.  Subsequently, treatment with metreleptin injections, improved eating behavior and resulted in substantial weight loss.

Key points:

  • “Current clinical recommendations advise that leptin serum concentrations be measured in children who have rapid weight gain in the first months of life.” (“The severely obese patient –a genetic work-up.” Nat Clin Pract Endocrinol Metab 2006; 2: 172-7)
  • This case report demonstrates that normal circulating levels of the hormone “do not rule out disease-causing mutations in the gene encoding leptin.”

Related blog posts:

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Not So Promising: FMT for Ulcerative Colitis

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After initial reports suggesting that fecal microbiota transplantation (FMT) may be helpful for ulcerative colitis (UC), more recent data suggest that it is not so promising (JPGN 2015; 60: 27-29, editorial 3).

In this open-label, prospective study of four patients, all boys aged 13-16 years, patients tolerated a single-dose FMT (via nasogastric tube) without adverse effects but there was no significant clinical or laboratory improvement.

The article provides a number of references regarding the experience of FMT for UC.

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1400 Different Immunization Schedules -What Could Go Wrong?

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A recent study (J Pediatr 2015; 166: 151-6) has examined the frequency of “alternative” (non-standard) vaccination schedules among 222,628 children in New York (2009-2011), using a statewide mandatory immunization information system.

Key findings:

  • 25% of children followed an non-standard immunization schedule.
  • At 9 months of age, children on an non-standard schedule were less likely to be up-to-date (15% compared with 90%, P<0.05).

The authors note that in a separate study that there were “1400 individualized vaccination patterns.”  These patterns break down into three: delays of vaccine, selective refusal of specific vaccines, and reduction in the number of vaccines.

In a brief summary, Sarah Long notes that for parents/doctors –“Although their intent is heightened protection of their children/patients from harm, the result is the opposite.  Alternative “schedules” are completely untested for immunogenicity or safety.”

One limitation of this study is that it was conducted in New York.  There is wide variability in the resistance to vaccination among states.

Bottomline: Their has been an increase in the use of non-standard vaccine schedules.  This is contributing to community vulnerability to vaccine preventable diseases.

A related story: “Disneyland” Measles Outbreak (from USA Today) and from NY Times (1/21/15): Measle cases linked to Disneyland (& unvaccinated students).  1/28/15 Measles in Arizona reaches ‘critical point’

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Which is Safer –Drip Feeds or Bolus Feeds in Healthy Preterm Infants?

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A recent provocative study (J Pediatr 2014; 165: 1255-7) takes a look at the frequency of cardiorespiratory events in healthy neonates <33 weeks gestation who needed supplemental enteral tube feeds.

It is generally accepted that continuous or “drip” feedings are less likely to provoke reflux events (and reflux-induced cardiorespiratory events) by limiting the amount of formula in the stomach at any time point.  If there is less formula, presumably there would be less stomach distention and a lower likelihood of reflux.  In addition, a continuous amount of formula would serve to buffer stomach acid.

Despite the sound theoretical underpinnings, is this really true?  In this study, the authors detected fewer cardiorespiratory events with polysomnographic monitoring in healthy premature neonates who were fed with bolus feedings rather than with drip feedings.

Study design: Each of 33 infants served as its own control.  During a 6-hour monitoring period, noninvasive polysomnographic recordings were performed.  Each infant was fed twice via an orogastric tube.  The first meal was given as a 10-minute bolus (by gravity) and the second was delivered over 3 hours. It is noted that the tube was removed after the bolus feeding (this is not routinely done in clinical practice).

Demographics: Median gestational age was 31 weeks and median postnatal age was 16 days.  Fortified human milk was given in 12, premature formula in 7, and 14 had mixed feeding.

Results (Table 2): “continuous feeding was associated with a greater number of prolonged apneas and apnea-related hypoxic episodes.”

  • Median Apnea Frequency: 4 in continuous versus 2 in bolus group (no obstructive apneas were noted)
  • Median hypoxic episodes: 3 in continuous versus 2 in bolus group.

The authors speculate that leaving the tube in place for continuous feeds could increase GER-related apnea or trigger ‘protective upper airway reflexes in response to the irritating stimulus.’

Bottomline: The assumption that continuous feedings will reduce cardiorespiratory events is not supported by this study.  The findings warrant cautious interpretation; the small sample size and specific ages of the premature infants are significant limitations.   In addition, leaving an enteral tube in place after a bolus feeding would be a better design as this is a routine practice.

Related blog post:

Prucalopride -Not Better Than Placebo for Children with Constipation

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Background: There were high expectations for prucalopride for the treatment of constipation based on previous small studies as well as a placebo-controlled trial in adults.  In adults, after 12 weeks of treatment, between 19.5-29% were responders compared to 9.6-12.1% in placebo patients. Prucalopride is a 5-hydroxytryptamine receptor-4  (5HT4) agonist which has been shown to accelerate colonic motility and is similar structurally to agents like cisapride and tegaserod; these latter medications have shown effectiveness as prokinetics but were limited by life-threatening cardiovascular side effects.

Design: Large (n=213), multicenter, placebo-controlled trial (Mugie SM, et al. Gastroenterol 2014; 147: 1285-95, editorial 1214-16). Response to medication indicated by >3 spontaneous bowel movements per week and <1 episode of fecal incontinence every 2 weeks.

Findings:

  • 17% of prucalopride subjects and 17.8% of placebo subjects were considered responders.
  • If based solely on bowel movement frequency, 29.2% of prucalopride achieved >3 BMs/week, whereas 35.5% of placebo-treated patients achieved this frequency.
  • Adverse effects were similar

Why did Prucalopride not work?

The authors and editorial make several speculations.  In children, withholding behavior is much more important in the pathophysiology of functional constipation (FC) than in adults.  In addition, slow transit constipation is much more common in adults than in children. In the adolescents (≥12 to <18) there was a mild response noted: 18.5% compared with 14.8% of placebo-treated patients (P=.38). The editorial notes that the short length of the trial (8 weeks) could explain the negative results, though this is unlikely.

The editorial, by Samuel Nurko and Miguel Saps, notes a much higher response to polyethylene glycol which “is the mainstay of treatment.”  “PEG-based solutions achieved a successful outcome in 56% of participants compared with 29% in the lactulose group.”

Take-home message: “This study does not provide new data to justify a change in the indication of PEG as first line of treatment for FC in children.”

In followup to questions regarding Miralax safety, here is a link from NASPGHAN’s Neurogastroenterology and Motility Committee: Miralax FAQ

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A Sign in Our Office --Needs Clarification

A Sign in Our Office –Needs Clarification

AAP -Behind the Scenes (Part 2)

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Besides the focus on legislation and access to care, the AAP meeting provided an infectious disease update from Dr. Harry Keyserling, membership update by Dr. Roma Klicius, the Pediatric Foundation Report by Dr. Bob Wiskind, an update on oral health care by Dr. Chevron Brooks, a brief update on AAP Friends of Children by Dr. Jay Berkelhammer, and discussion about transitional care.

With regard to the infectious diseases update, Dr. Keyserling noted that despite the flu vaccine’s lower “match” this year and its reduced effectiveness, it is still quite important to receive the flu vaccine.

  • Each year, about 1/3rd ot the population gets the flu.
  • About 1 in 10,000 people die due to the flu.
  • In 2012-13, there were 171 pediatric deaths across the country due to influenza.  90% of these deaths occurred in children who were not immunized; in other words, for a child with the flu, the risk of death is more than 10 times higher in those who do not receive the immunization.

Here are a couple of slides (used with permission) regarding the flu:

Risk of Death from the Flu

Risk of Death from the Flu

Flu Data thru Jan 2015

Flu Data thru Jan 2015

Flu Vaccine Coverage

Flu Vaccine Coverage

Bottomline: The AAP is working on preventing deaths from all vaccine-preventable deaths, including the flu.

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Since my job at the AAP is to work on nutrition-related issues, I would welcome suggestions for areas of concern.  As there are separate areas devoted to obesity and breastfeeding, my goal is to work on other aspects of nutrition in children.  Some ideas that have come up already include an update on gluten-related disorders and nutritional supplements.  Any other advice?

Upcoming AAP Schedule

Upcoming AAP Schedule