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

Posted on February 4, 2015 by gutsandgrowth

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”

Posted on February 3, 2015 by gutsandgrowth

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

Related blog post:

ACA -A Report Card | gutsandgrowth

Not So Promising: FMT for Ulcerative Colitis

Posted on January 30, 2015 by gutsandgrowth

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

Posted on January 28, 2015 by gutsandgrowth

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.

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NASPGHAN Postgraduate Course 2014 -3rd Module | gutsandgrowth

Prucalopride -Not Better Than Placebo for Children with Constipation

Posted on January 27, 2015 by gutsandgrowth

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

Helpful Position Paper: Percutaneous Endoscopic Gastrostomy in Children

Posted on January 25, 2015 by gutsandgrowth

A recent European Society for Pediatric Gastroenterology Hepatology and Nutrtition (ESPGHAN) position paper provides some useful advice regarding the management of percutaneous endoscopic gastrostomy (PEG) in children and adolescents (JPGN 2015; 60: 131-41).

Table 1 provides a succinct description of the potential benefits of PEG compared with nasogastric tube including less dislodgement, reduces risk of aspiration, better appearance, safer/more reliable enteral access, optimizes development of oral skills, less blockage/clogging, cost-effective, less interference with daily activities, avoids nasal irritation/trauma, reduced anxiety at mealtimes, and shorter meal times.

Table 2 provides a good summary of clinical indications including optimizing nutritional status, maintaining hydration, supporting unpalatable diet, decompressing stomach, improving medication adherence, ensuring safe feedings/prevent aspiration, and improving quality of life.

The position paper reviews relative and absolute contraindications (uncorrectable coagulopathy, interposition of enlarged organs, frank peritonitis); I did not see any mention of high dose steroids as a relative contraindication. Given high dose steroids’ impact on healing, PEG needs to be avoided if possible in this setting (in my opinion).

The authors provide extensive information on potential complications (table 6 and table 7).

Other key points:

“In the United Kingdom, it is accepted by the National Institute of Clinical Effectiveness that expectation of continuous NGT use for a minimum of 4 weeks (www.nice.org.uk/CG032 –this reference provided by authors focuses on NGT in adults), or even 2 to 3 weeks, should prompt consideration of PEG insertion.”
“The use of a routine preoperative upper GI contrast study is NOT advised to rule out malrotation.”
“Asymptomatic children do not require investigation for GERD before PEG insertion.” However, the authors note that in the presence of significant symptomatic reflux, or reflux in the presence of an unsafe swallow/progressive neurologic disease, or chronic respiratory disease, this should prompt discussion around the need for a surgical antireflux procedure.
The authors suggest that PEG change to a button can occur “after a period of 2 months or more.” Our institution generally does not change prior to 3 months.
The authors state that formula (rather than clears) can be started within 4 to 6 hours of PEG insertion.
One aspect of their recommendations that I disagreed with was their advice on preventing a ‘buried bumper.’ “To prevent a ‘buried bumper,’ the PEG should be carefully pushed into the stomach by 1 to 2 cm and then rotated once a week from day 7 postinsertion.”
Perhaps this advice is offered as the guideline also suggests that patients do not need much follow-up: “The child will require follow-up, typically provided by nurse specialists 3 months after placement of the gastrostomy. Thereafter, annual review of the device is usually adequate…between routine appointments caregivers should have access to appropriately trained professionals.” In my view, if the tube is appropriately sized (checked early on) and patients are followed (for excessive weight gain), then pushing in the tube should be unnecessary.

Take-home message: Overall, this is a useful reference/summary for PEG tube management, though some recommendations are based on practice patterns rather than high-quality data.

Are there others who would like to relay their experience and advice?

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Not Happy With Functional GI Diseases

Posted on January 21, 2015 by gutsandgrowth

A recent study (J Pediatr 2015; 166: 85-90, editorial 11-14) finds that children with functional gastrointestinal diseases (FGID) had more impaired “quality of life” than children with organic gastrointestinal diseases. For those of us taking care of these children, this finding does not come as a surprise, but there is a lot to learn from this study nonetheless.

Using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales, the authors completed a 9-site study with 689 families for patients with physician-diagnosed GI disorders including functional problems like irritable bowel syndrome and dyspepsia as well as organic diseases like Crohn’s disease and ulcerative colitis. These patients were compared with a healthy control sample of 1114 families.

In addition to obtaining health-related quality of life (HRQOL) data, the authors reported information on school days missed, days in bed, parent missed workdays, and healthcare utilization.

Key findings:

FGID and organic GI diseases demonstrated lower HRQOL than healthy controls across all measures (emotional, physical, social, and school; P<0.001 for all) with larger effect sizes for FGID.
FGID and organic GI diseases also had more school days missed, days in bed, parent missed workdays, and healthcare utilization, again with larger effect sizes for FGID.

The associated editorial tries to work through the reasons why the impact of FGID is greater than an organic disease.

The authors hypothesize that two factors play a big role:

1. Issue of control:

FGID -the cause is less evident
FGID -very few effective treatments
These factors may contribute to families feeling helpless and ‘out of control’

2. Issue of response shift:

The authors explain that response shift indicates a circumstance in which a “patient is compelled to adjust to this new reality.”
Response shift often involves a change in expectations
Response shift often involves a change in prioritization
Thus, response shift could explain why patients with organic GI disease have higher quality of life scores.

In addition, the authors note that with many FGID, that physicians often “suspect constipation is the cause…when laxative therapy is not helpful, this leads to more frustration.” They advocate shifting the focus for these families from “finding a cure to managing day-to-day symptoms.”

In my view, there are a lot of other factors at play that may help explain why HRQOL is lower in patients with FGIDs. This can include a high incidence of emotional disturbances (eg. anxiety, depression) and poor coping skills (eg. catastrophizing). This study also is another example showing that the physical severity of the medical disease does not correlate with the severity of the impact.

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Will I Have This Stomach Pain Forever? (Part 2)

Posted on January 20, 2015 by gutsandgrowth

The article reviewed earlier today on this blog (Clinical Gastroenterology and Hepatology 2014; 12: 2026-32) has been reviewed on the AGA blog as well (some of this information is redundant from earlier post):

Here’s a link to a summary of the article: AGA blog on RAP and here’s an excerpt: Sara Horst et al investigated whether pediatric functional abdominal pain leads to functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS) in adulthood. They performed a longitudinal analysis of 392 children (8−16 years old) initially seen at a subspecialty clinic for recurrent abdominal pain. Horst et al assessed the contribution of gastrointestinal symptoms, extra-intestinal somatic symptoms, and depressive symptoms to FGIDs 5−15 years later. They found that on average 9 years later, 41% met symptom criteria for FGID—mostly irritable bowel syndrome and functional dyspepsia. Levels of depressive symptoms in childhood correlated a greater likelihood of FGID later in life (see figure).

Will I Have This Stomach Pain Forever? (Part 1)

Posted on January 20, 2015 by gutsandgrowth

More data (Clin Gastroenterol Hepatol 2014; 12: 2026-32) helps answer the question about the persistence of functional abdominal pain from childhood into young adulthood.

Using a longitudinal study design, consecutive new pediatric patients (8-16 years) with functional abdominal pain from a subspecialty clinic were contacted on average 9.2 years (n=392) after their initial evaluation.

Key findings:

41% continue to meet criteria for a functional GI disorder, most commonly irritable bowel syndrome (110 of 169 patients).
Severity of pain was not a predictive factor of persistence
Extraintestinal somatic complaints and depressive symptoms increased the risk of having persistent functional abdominal pain.

The associated editorial (pages 2033-36) comments on the strengths of the study and the potential opportunity of intervening to prevent persistence of abdominal pain. It notes that anxiety and hypervigilance can lower the brain’s perception threshold and lead to increased pain. “From this perspective, centrally targeted treatments such as psychological treatment or psychopharmacological treatments will likely have therapeutic value.”

Take-home message: 59% of patients resolve their symptoms with time.

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What’s Wrong with “I Want My Kid Tested For Food Allergies”

Posted on January 16, 2015 by gutsandgrowth

Most parents, and many physicians, do not understand the limitations of food allergy testing. As I am sure is common among physicians, I frequently receive requests for food allergy testing; parents do not realize that the strategy for food allergy testing is not straight-forward and has not advanced significantly for decades. This information is detailed in a recent study and associated editorial (J Pediatr 2015; 166: 97-100, editorial 8-10: “Pitfalls in Food Allergy”).

The study was a retrospective review of all new patients seen at a pediatric food allergy center (2011-2012). This involved a review of 797 new patients.

Key findings:

Of 284 patients who had received a food allergy panel, only 90 (32.8%) had a history warranting evaluation for food allergy.
Among 126 individuals who had food restrictions imposed based on food allergy panel testing, 112 (88.9%) were able to re-introduce at least 1 food into their diet.
The positive predictive value of food allergy testing was 2.2%.

So what can we learn from this study and editorial?

Misdiagnosis often relates to a lack of understanding regarding serum IgE-based testing. First of all, many children with atopic dermatitis (and other atopic conditions) have elevated total IgE which results in more false positives. In addition, a positive IgE test for a specific food indicates sensitization but not necessarily an allergy.

Strategy for testing (recommended by editorial):

“The key to the diagnosis of food allergy cannot be overstated; it begins with a detailed clinical history”
Testing should be “limited in general to the food(s) in question.”
When there is uncertainty, oral food challenges can be performed by specialists.
“If a patient is consuming a food without clinical symptoms of allergy, allergy testing should not be done to that food.”

Bottomline (from authors’ conclusion): “Food allergy panel testing often results in misdiagnosis of food allergy, overly restrictive dietary avoidance, and an unnecessary economic burden on the health system.”

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