Category Archives: Pediatric Gastroenterology Intestinal Disorder

Treating to Target

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As alluded to in a previous post (CCFA Conference Notes 2014 (part 2) | gutsandgrowth), there has been increasing discussion and efforts aimed at mucosal healing (MH) because it is associated with improved clinical outcomes in patient’s with Crohn’s disease (CD).  Even before its print publication, this study (Clin Gastroenterol Hepatol 2014; 12: 978-85) by William Sandborn’s group has influenced the discussion.

This retrospective study analyzed 67 patients with CD (2011-2012).  These 67 were selected from a population of 510 patients seen at UCSD who had at least several endoscopies and ulcers  seen at the initial procedure.  In this cohort of 67 patients, the median disease duration was 9.8 years.  Only 26 (38.8%) were naive to both immunosuppressives and biologics at referral.

Key findings:

  • Only half of the patients achieved MH.  “After a median follow-up of 62 weeks, 50.7% had MH and 61.1% had endoscopic improvement.”  79% of those who underwent adjustments achieved MH.
  • Clinical symptoms do not correlate with MH. “40.9% of patients experienced clinical symptoms despite MH and 18.8% of patients without clinical symptoms had significant endoscopic lesions.”
  • Biomarkers may be effective at predicting MH. “None of the patients with MH had an increased concentration of CRP.”
  • Adjusting treatment is needed if abnormal endoscopy; this is inherent in the philosophy of treating-to-target.

The authors conclude that “serial endoscopic procedures to guide treatment to the goal of MH is feasible in clinical practice.” Ultimately the goal is to influence the natural history of Crohn’s disease.

Study limitations:

  • retrospective study
  • small number of highly-selected patients
  • lack of randomization
  • definition of MH remains debated
  • no cost data
  • lack of data on stool biomarkers (e.g. calprotectin) which could serve as alternative
  • no answer to the question of what to do for the patient without MH who is receiving ‘maximal medical treatment’

From Dr. Sandborn: (from Healio Gastro summary):

“Evidence has accumulated that the complications of Crohn’s disease [CD] … are due to chronic inflammation that has not been fully treated,” William J. Sandborn, MD, chief of the gastroenterology division and director at the University of California, San Diego, IBD Center, told Healio.com. “This in turn has led to the concept of ‘treat to target’ in which patients are assessed with endoscopy for active inflammation prior to making important changes in therapy, and then reassessed with endoscopy within 4 to 6 months to ensure that the therapy change healed the bowel and resolved the inflammation.

“If active disease persists at endoscopy, even in the absence of clinical symptoms, then therapy is intensified and this cycle is repeated until mucosal healing (MH) is achieved.”

Take-home message: This study is one of many that are likely to influence the practice of clinicians to prove that the treatment is exerting a biologic effect and not solely improvement in clinical scoring indices.  With the emergence of multiple modalities to assess improvement, including biomarkers and imaging, it is not clear that repeated endoscopy will be the best assessment tool.

Related blog post: EXTEND & MUSIC: Optimizing Crohn Disease Care …

Also noted:

Clin Gastroenterol Hepatol 2014; 12: 986-94.  “Association Between Telephone Activity and Features of Patients with Inflammatory Bowel Disease.”  The authors found that 15% of patients were responsible for half of all telephone calls.  These patients were more likely to be seen in ED and hospitalized.

Clin Gastroenterol Hepatol 2014; 12: 929-34. “Histologic Remission: The Ultimate Therapeutic Goal in Ulcerative Colitis?” This article reviews definitions for histologic remission and highlights questions that need to be addressed before histologic remission is used more widely as a clinical endpoint in trials and in practice.

Antibiotics, Oral Contraceptives, and IBD

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Briefly noted:

“Physician Knowledge Regarding Concomitant Antibiotic and Oral Contraceptive Use in Patients with IBD.” Gastroenterology & Hepatology 2014; 10: 302-06.

Key finding:

  • IBD specialists and gynecologists were more likely to be aware that no evidence exists to support a link between a decrease in oral contraceptive pill (OCP) efficacy and concomitant use of ciprofloxacin or metronidazole.

Previous studies suggested that antibiotics reduced OCP efficacy.  The authors note that “more recent, prospective, pharmacokinetic studies in women demonstrate no evidence of an interaction between OCPs and most antibiotics, with the exception of rifampin.” (J Am Acad Dermatol 2002; 46: 917-23)

 

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

 

 

“If all you have is a hammer…”

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In my training, one of my mentors would be critical of the mentality “scope first, think second.”  He was concerned that too many gastroenterologists/pediatric gastroenterologists used endoscopy as a tool simply “because if all you have is a hammer, the world looks like a nail.”

A recent publication (Clin Gastroenterol Hepatol 2014; 12: 963-69) on first glance, however, provides ammunition to the “scope first” gastroenterologists and undermines the concept that “functional” GI disorders vastly outnumber “organic” GI disorders.  The key finding was that esophagogastroduodenoscopy (EGD) provided an “accurate” diagnosis in 38%.  This included reflux esophagitis in 21%, eosinophilic esophagitis (EoE) in 5%, eosinophilic gastroenteritis (EGE) in 4%, H pylori in 2%, celiac disease 0.6%, and Crohn’s disease 0.4%. This finding is dramatically higher than previous studies.  In fact, in a recent published study (Understanding Idiopathic Nausea | gutsandgrowth) on idiopathic nausea, a control group of patients with chronic abdominal pain had a normal endoscopy in 100%!

In this prospective study of 290 children (ages 4-18 years with a mean age of 11.9 years), the primary indication for upper endoscopy was chronic abdominal pain.  Of this 290, 216 had at least 1 alarm feature and 125 had at least 2 alarm features.  Alarm features were considered to be the following:

  • Nighttime awakening 33.3%
  • Weight loss 15.6%
  • Family history of IBD 8.4%
  • Vomiting 7.8%
  • Dysphagia 6.9%
  • Nocturnal diarrhea 6.7%
  • Gastrointestinal bleed 5.8%
  • Chronic diarrhea 5.8%
  • Unexplained fever 4.4%
  • Arthralgia 4.0%
  • Growth failure 2.4%
  • Perirectal disease 0.7%
  • Delayed puberty 0.2%

There is little debate that abdominal pain in combination with true alarm symptoms (True red flags in recurrent abdominal pain | gutsandgrowth) merits further evaluation.  The aspect of this report that is worthy of close inspection is the diagnostic yield in the 74 patients without alarm symptoms.  The authors note that 25 (33.7%) had a diagnosis established with EGD including 16 with reflux esophagitis, 4 with EGE, 2 with EoE, 1 with erosive esophagitis, 1 with celiac and 1 with H pylori.  The diagnostic criteria for EGE included ≥10 eosinophils per hpf in the stomach and ≥20 eosinophils per hpf in the duodenum.

The authors note that the diagnostic yield was based on gross endoscopic findings in procedure notes or histologic changes in biopsy reports; “final pathology report on biopsies provided the data source for histologic diagnosis.”

In my opinion there are multiple flaws of this prospective study.

1. There is a very high rate of reflux esophagitis in both the alarm group and the non-alarm group patients with chronic abdominal pain.  Of the entire cohort (n=290), the authors identified reflux esophagitis in 21% and this was “primarily histologic esophagitis.”  Furthermore, the authors state that “the presence or response to PPI therapy was not predictive of esophagitis or GERD.”  So, the obvious problems:

  • Presence of histologic reflux esophagitis varies widely based on the interpreting pathologist.  In a prospective study, more than one pathologist interpreting the histology would be useful.
  • Presence of histologic reflux esophagitis does not exclude the likelihood of coexisting functional disorders (related blog post: Why didn’t patient with documented reflux get better with PPI …).  As a practical matter, “slight” or “focal” esophagitis on histology has questionable real-world relevance in pediatric gastroenterology.
  • The authors acknowledge, “current expert consensus indicates that histology has limited value in evaluating pediatric GERD.”  Yet this diagnostic finding is one of the reasons why the authors claim that EGD is so valuable.

2. In the entire cohort, the authors try to validate their findings by indicating that identification of a diagnosis led to medical therapy that was “effective in approximately 67%” of children with short-term followup. (Only 81% had short-term followup outcomes available).  Yet, there is no control group.  How many children with chronic abdominal pain will improve for a short period without an EGD-based diagnosis?  The answer: a lot of them.

3. Limitations include selection bias toward those with more severe symptoms or alarm symptoms.  In addition, this study included only a small number who were considered to have no alarm symptoms.  Finally, the short-term followup makes conclusions about the response to therapy questionable.

This study will be a useful reference for any pediatric gastroenterologist who wants to justify the need for an endoscopy.  The authors note “the majority of children in our study (93%) met criteria for functional gastrointestinal disorders, and a significant proportion (38%) still had significant histologic findings.  Therefore, we conclude the Rome III criteria alone are not sufficient to identify children who require upper endoscopy, and screening for alarm symptoms has limited utility.”

In my opinion, the reliance on histology as well as selection bias weaken the findings of this study.  If a patient with a histologic diagnosis of reflux (or several other entities) and a presentation of chronic abdominal pain does not improve, the pediatric gastroenterologist should remember that only “a poor carpenter blames his tools.”

Bottomline: EGD remains an important tool in evaluating abdominal pain.  However, I think this study substantially overestimates its utility.

Related blog posts:

 

 

 

 

Specific Carbohydrate Diet in Children -Ahead of Print

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Here is a link, bit.ly/1xb1kk8, (from JPGN) and the abstract to an article on the Specific Carbohydrate Diet in Children.  This study shows clinical improvement and mucosal healing, confirmed by capsule endoscopy, in response to the specific carbohydrate diet (SCN). Congratulations to my colleagues/partners from GI Care for Kids who published this study in JPGN:

Objective: To prospectively evaluate clinical and mucosal responses to the specific carbohydrate diet (SCD) in children with Crohn’s disease (CD).

Methods: Eligible patients with active CD (Pediatric Crohn’s Disease Activity Index, PCDAI >= 15) underwent a patency capsule and if passed intact, capsule endoscopy (CE) was performed. Patients were monitored on SCD for 52 weeks while maintaining all prescribed medications. Demographic, dietary and clinical information, PCDAI, Harvey Bradshaw (HB) and Lewis score (LS) were collected at 0, 12 and 52 weeks. CE’s were evaluated by an experienced reader blinded to patient clinical information and timing.

Results: Sixteen patients were screened; 10 enrolled; and 9 completed the initial 12 week trial; receiving 85 % of estimated caloric needs prior to, and 101%, on the SCD. HB significantly decreased from 3.3 + 2.0 to 0.6 + 1.3 (p = 0.007) as did PCDAI (21.1 + 5.9 to 7.8 + 7.1; p = 0.011). LS declined significantly from 2153 + 732 to 960 + 433 (p = 0.012). Seven patients continued the SCD to 52 weeks with HB (0.1 + 0.4) and PCDAI (5.4 + 5.5) remaining improved (p = 0.016 and 0.027 compared to baseline) with mean LS at 1046 + 372 and 2 patients showing sustained mucosal healing.

Impressions: Clinical and mucosal improvements were seen in children with CD using the SCD over 12 and 52 weeks. Additionally, CE can monitor mucosal improvement in treatment trials for pediatric CD. Further studies are critically needed to understand the mechanisms underlying SCD’s effectiveness in children with CD.

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Benefits of Gluten-Free Diet for “Asymptomatic” Celiac

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Here’s a link to the abstract: gastrojournal.org/article/S0016-…

Methods: “We performed a prospective trial of 3031 individuals at risk for celiac disease based on screens for EmA. Of 148 seropositive individuals, 40 fulfilled inclusion criteria and were randomly assigned to groups placed on a GFD or gluten-containing diets.”

Results: “The GFD group also had reduced indigestion (P=.006), reflux (P=.05), and anxiety (P=.025), and better health, based on the visual analog scale (P=.017), than the gluten-containing diet group.”

Take-home message: A gluten free diet improves symptoms (even in “asymptomatic” patients) with celiac disease

Comparing Biologics for Ulcerative Colitis

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A recent study has reviewed biologic therapies for ulcerative colitis (Ann Intern Med. 2014;160(10):704-711). Here’s the abstract link: bit.ly/1o5PpRX.

Data Synthesis: ..There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo.

Limitation: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials.

Conclusion: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option.

Related blog posts:

 

Infliximab Compared to Adalimumab -Which is Better?

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Pharmaceutical companies are not motivated to provide a definitive answer on the title question.  A recent study (Clin Gastroenterol Hepatol 2014; 12: 811-17) states that “head-to-head clinical trials of anti-TNF therapies are unlikely to ever be undertaken because of the extreme cost to conduct such studies and the financial risk that such trials would entail for the manufacturers.”  The two most popular biologics, infliximab (IFX) and adalimumab (ADA), for inflammatory bowel disease have been incredibly successful (Multi-billion dollar biologics | gutsandgrowth).

The current study is “one of the first to directly compare the effectiveness” of IFX and ADA for Crohn’s disease.  The authors retrospectively examined a U.S. Medicare data cohort from 2006-2010 and identified new users with 1459 IFX and 871 ADA patients.  While 94% of Medicare enrollees are >65 years, this study had a range of patient ages due to those who received Medicare due to disability.  In fact, in the ADA group, ~60% were between 30-60 years and in the IFX group, ~44% were in this age group.

Key result:

  • After 26 weeks of treatment, 49% of patients receiving IFX remained on drug compared with 47% of those receiving ADA.
  • Fewer patients with IFX underwent surgery (5.5 vs 6.9 surgeries per 100 person-years) but this did not reach statistical significance.
  • Rates of hospitalization did not differ among the two groups

While persistence is an imperfect measure of effectiveness, the fact that surgeries and hospitalizations were similar indicates that the medications are likely to have similar clinical effectiveness, at least in this population.  Data on mucosal healing, more direct measures of effectiveness, and longer followup certainly would strengthen this conclusion.

My First Take: It is Hard to Save $$$ at a Rolls-Royce Dealership

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A recent article looked at a crucial issue –trying to deliver “best care at lower cost” (Inflamm Bowel Dis 2014; 20: 946-51).  “The goal of this report is to answer the primary question: What are implementable strategies and exploratory considerations for cost-efficient anti-TNF use while maintaining the highest quality of IBD care?”

The strategies that are discussed include the following:

  • Reduce costs of avoidable dose intensification of class switching by eliminating episodic anti-TNF use and improving patient education
  • Reduce over-utilization costs by accurately determining indication for escalating anti-TNF use
  • Reduce nondrug infliximab costs through shortened infusion times after initial safety is clearly established

Exploratory considerations:

  • Self-injectable anti-TNFs
  • Combination therapy
  • Monitoring anti-TNF drug levels and autoantibodies
  • Assessing mucosal healing as a clinical endpoint

The authors discuss both the exploratory issues and the strategies.  Some of each could easily increase costs, at least in the short-term, rather than reduce them.  The authors also make note of the development of an infliximab biosimilar (Inflecta) which could be approved in U.S. by 2015.

While the review article is a good read, in my opinion the authors fail to address in a meaningful way the larger context.  The costs for hospital-based care are enormous; pediatric hospitals are like Rolls-Royce dealerships; and by the way, if you have to ask how much it costs, you probably cannot afford it.  With regard to charges/costs, there is little transparency, high variability, and little accountability.  Understanding health care costs and trying to get a good deal is much harder than buying a car.

For IBD care, as an example, the authors make note of the cost of infliximab at one pediatric tertiary care center.  At this institution, “77% of the total health care cost for each infusion encounter” was for non-drug costs.  Given how expensive the drug cost is, the expense for an infusion is very high, but probably similar to many other pediatric hospitals.

If one is interested in reducing the costs of infliximab and other infusions, the first practical step would be to consider infusion outside of a hospital-based setting, such as an infusion center.  In such a setting, the patient safety would still be excellent but the costs would be less.

In Atlanta, there have been some high-profile hospital acquisitions that have increased health care costs (When doctors sell out, hospitals cash in | www.myajc.com).  In many circumstances, when a hospital acquires a physician practice, infusion center, or endoscopy center, the charges and reimbursement increase despite no change in clinical care.  In this way and many others, the current system promotes cost-inefficient care.

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AJG Celiac Practice Guidelines 2013 -Useful Link

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This full-text link to AJG Practice Guidelines for Celiac Disease 2013 (Am J Gastroenterol 2013; 108:656–676; doi:10.1038/ajg.2013.79) provides 45 evidence-based recommendations for diagnosis and management of celiac disease along with 264 references.  

Table of Contents for Article

Table of Contents for Article

Topics of particular interest

  • Whether to test first-degree relatives.  The article recommends testing in symptomatic individuals and consideration of testing in asymptomatic individuals
  • When to perform genetic testing
  • When to use tests besides tissue transglutaminase antibody (TTG IgA) (mainly in children less than 2 years)
  • Recommends against use of stool or salivary testing
  • How to approach refractory celiac disease
  • The limited circumstances which justify followup endoscopy

Potential Reasons for Genetic Testing:

Potential Reasons for Genetic Testing

Celiac vs. Gluten Sensitivity:

Celiac vs. Gluten Sensitivity

Bottomline: This practice guideline covers most of the issues dealing with celiac and gluten sensitivity –it is a useful reference.

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Understanding Idiopathic Nausea

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A recent article describes a retrospective chart review of 45 children with chronic nausea and compares them to 49 children with chronic abdominal pain (J Pediatr 2014; 164: 1104-09).

Key findings:

  • While onset of symptoms was similar, the chronic nausea cohort presented at a median age of 15 years compared with 12 years for the pain cohort.
  • Comorbid conditions like anxiety, dizziness and fatigue were common in chronic nausea cohort.
  • Family history of migraines was note in 71% of nausea cohort compared with 22% in pain cohort
  • Extensive laboratory and imaging was much more frequent in nausea cohort.  With nausea cohort, 78% had abdominal ultrasound, 60% an upper GI, 58% brain imaging with either a CT scan or MRI, 38% gastric emptying, 31% abdominal CT or MRI, and 24% had HIDA.
  • Almost all endoscopies were normal (98% of chronic nausea group and 100% of pain cohort)
  • For nausea cohort treatment, tricyclic antidepressants showed a good response (=at least 50% symptom improvement) in 44% with a mean maximal dose of 50 mg. In contrast, with proton pump inhibitors, only 22% had some improvement (=at least 25% symptom improvement).  Similarly, ondansetron showed some improvement in 50% –though none had a “good response.”
  • Twelve patients (27%) of the nausea cohort met diagnostic criteria for cyclic vomiting syndrome (CVS) (with interepisode nausea) and another nine (20%) developed chronic nausea after ‘outgrowing’ CVS.
  • Postural (orthostatic) tachycardia syndrome (POTS) was noted in 16 of 45 in the nausea cohort based on an orthostatic screen (heart rate ≥30 beats/min during positional changes from 10 minutes in supine position to standing.

As the authors note, their study, conducted between 2006-2012, had numerous limitations, particularly the relative small size and retrospective nature.  In addition, the physician expertise in nausea/vomiting at Children’s Hospital of Wisconsin predisposes to a selection bias.

Take-home message: Nausea can be a severe symptom but is often difficult to manage. Extensive workup has a low yield in absence of other complaints or physical exam findings.

An AGA technical review on nausea and vomiting was published in 2001: GASTROENTEROLOGY 2001;120:263–286 

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.