Category Archives: Pediatric Gastroenterology Intestinal Disorder

Vaccination and Inflammatory Bowel Disease -Resources Targeted for Adult Patients

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From a recent Gastroenterology & Hepatology –Full Link:

Gastroenterology & Hepatology  July 2017 – Volume 13, Issue 7; Vaccination of Patients With Inflammatory Bowel Disease.  Francis A. Farraye, MD, MSc

Thanks to John Pohl’s twitter feed for this link that provides recommendations for Adults with IBD.

An excerpt:

G&H  What specific resources for vaccinations are available to help gastroenterologists?

FF  It is helpful for providers to keep a copy of the Crohn’s and Colitis Foundation’s health maintenance recommendations posted in their office. This 1-page checklist (available at http://www.crohnscolitisfoundation.org/science-and-professionals/programs-materials/ccfa-health-maintenance.pdf) includes all recommended vaccines and also comments on other important health maintenance items, such as screening for cervical and skin cancer, depression, and osteoporosis. In addition, Cornerstones Health has a vaccination checklist (available at http://www.cornerstoneshealth.org/wp-content/uploads/2017/06/Monitoring-and-Prevention-3.10.2017.pdf) that can be downloaded, printed, and placed in each examination room to reinforce the importance of vaccination. Primary care providers as well as gastroenterologists can use these checklists as reminders in their busy practices.

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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.

Two Viewpoints: Anti-TNF Therapy Shortly After Crohn’s Disease Surgery

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A recent AGA perspectives issue provides two viewpoints on when to start/resume anti-TNF therapy after Crohn’s disease surgery:

Dr. Bressler states that he considers anti-TNF therapy for patients with ongoing immune dysfunction after surgery who are at high risk for recurrence.  Attributes of high risk disease include the following:

  • younger age (<30 years)
  • smoker
  • two or more surgeries for penetrating disease.

His commentary indicates that a “‘wait and see’ approach is appropriate for most patients. He frequently will measure a calprotectin three months postoperatively and every three months and perform a colonoscopy typically 6-9 months postoperatively. Those with endoscopic recurrence will be placed on anti-TNF therapy.

Dr. Requiero states:

  • The most effective way to prevent recurrence is to initiate an anti-TNF within four weeks of surgery. It has been my practice that patients at high risk for postoperative Crohn’s disease recurrence initiate anti-TNF shortly after they are discharged from the hospital.
  • If a patient had been on an anti-TNF prior to the surgery, I will usually resume the same anti-TNF after the surgery. In these patients, I do not give a re-induction course unless they had not received the anti-TNF for more than three months prior to surgery.
  • Concomitant therapy: “In the majority of patients, I treat with an anti-TNF, I will use a concomitant immunomodulator…One year after surgery, if there is no disease recurrence, I will decrease and often stop the immunomodulator. With the advent of therapeutic drug monitoring, I have a number of postoperative anti-TNF patients on monotherapy without an immunomodulator.
  • [In] patients at moderate risk for postoperative recurrence… I perform an ileocolonoscopy six months postoperatively and, if there is evidence of endoscopic recurrence, I add an anti-TNF agent. After finding a high rate of recurrence in these patients, I am beginning to shift my practice to initiating anti-TNFs in this moderate-risk group as well.

My take: I tend to favor Dr. Reguieiro’s approach in my patient population.

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Diagnosis and Misdiagnosis of Constipation

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A personal pet peeve is having to explain to so many parents that their child is not constipated.  The typical scenario is that their child went to the ER for abdominal pain and had an abdominal radiograph (AXR); then, the parents are informed that their child is constipated based on ‘fecal loading’ noted on the AXR.  In this scenario, it is common for the child to have the following:

  • regular bowel movements
  • lack of a rectal exam
  • lack of improvement with laxatives (though some do improve, perhaps due to the fact that symptoms often have regression to the mean)
  • often a normal AXR when interpreted by radiologist rather than ED physician (it is normal to have some stool in the colon)

So, I like to see publications that support my viewpoint that this approach is misguided. Two recent studies provide some insight into this topic:

  • SB Freedman et al. J Pediatr 2017; 186: 87-94
  • CC Ferguson et al. Pediatrics 2017; 140 (1):e20162290 (thanks to Ben Gold for this reference)

Freedman et al performed a retrospective cohort study (children <18 yrs) who were diagnosed with constipation at 23 EDs from 2004-2015. This study used the PHIS database. Key findings:

  • 185,439 of 282,225 had AXR at index ED visit
  • Revisits to ED occurred in 3.7%
  • 0.28% returned with a clinically important alternate diagnosis, most commonly appendicitis (34% in this category)
  • Children who had AXR were more likely to have a 3-day revisit with a clinically important alternate diagnosis (0.33% vs. 0.17%)

Recognizing that AXRs are “unnecessary and potentially misleading,” Ferguson et al aimed to decrease AXR utilization in low-acuity patients who were suspected of having constipation. Using quality tools, the authors performed four plan-do-study-act cycles which included holding grand rounds, sharing best practices, metrics reporting, and academic detailing. Key finding:

  • Over 12 months, we observed a significant and sustained decrease from a mean rate of 62% to a mean rate of 24% in the utilizaiton of AXRs in the ED for patients suspected of having constipation.

My take: These studies support my view that routine use of AXR in the diagnosis of constipation is a mistake and can be misleading.

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How Good is Your Probiotic for Antibiotic-Associated Diarrhea?

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The enthusiasm for probiotics is generally greater than expected based on the data available to support their use for many indications.  This has been discussed several times on this blog (see below).  The reasons why probiotics are sometimes not effective can be related to being poorly regulated/lack rigorous production standards; even in conditions in which there is some effectiveness (eg. antibiotic-associated diarrhea [AAD]), the number of persons needed to treat for one person to benefit is fairly high. Furthermore, as a recent study (A Olek et al. J Pediatr 2017; 186: 82-6) shows, even in conditions like AAD in which probiotics have proven efficacy, the effects may be strain-specific and/or dose-related.

Olek et al showed that Lactobacillus planatarum DSM9843 (LP299V) was NOT beneficial compared to placebo in reducing the incidence of loose/watery stools or mean number of stools among 438 children receiving outpatient antibiotic therapy.

Specifics: This was a prospective, double-blind, randomized, placebo-controlled parallel-group study.  The treatment group received LP299V during antibiotic therapy and for 1 week afterwards.  In addition to monitoring the number of stools, the authors determined the frequency of AAD which they defined according to WHO guidelines (>3 loose/watery stools/24 hours after initiation of antibiotics).  In this study, AAD was confined to study duration rather than over 2 months.

  • Overall, 44.5% of children developed loose/watery stools among placebo group and 39% among probiotic group
  • 4.1% developed AAD among placebo group and 2.8% among LP299V
  • LP299V showed no significant beneficial effects in reducing AAD or loose/watery stools

The authors note that LP299V has been effective in studies involving adult hospitalized patients.  They question whether healthy children, therefore, may be less likely to benefit from probiotics and whether a higher dose could have been more effective.

My take: “Data from clinical studies on probiotics are conflicting” for many conditions, including antibiotic-associated diarrhea.

Lovers Leap, near Ashville (Appalachian Trail)

 

 

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Pediatric Views on Biosimilars and Interchangeability

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A recent commmentary (D Patel, KT Park. JPGN 2017; 134-6) explains the topic of interchangeability and its relationship to biosimlars. While biosimilars are expected to reduce the cost of biologic therapy, there are concerns regarding immunogenicity and whether switching to these products could reduce therapeutic sustainability.

The authors explain that some products are truly interchangeable and produce the same clinical result.  An interchangeable medicine (eg. typical generic) does not increase safety risk and switching from originator drug can be done by pharmacists or government payers without intervention of the prescribing health provider.

CT-P13 (Inflectra) has been approved as a biosimilar but has not been deemed an interchangeable product.  This is important.  Biosimilars “could have clinical consequences and repeated switches may increase immunogenicity.” Also, biosimilar products are much more complicated products than typical generic drugs.

Other key points:

  • The assumption that CT-P13 is interchangeable in pediatric IBD is “highly debatable.” Biosimilars undergo fewer studies than originator products.  CT-P13 has data from PLANETRA and PLANETAS trials “which may not be applicable for IBD, particularly pediatric IBD, given the inherent differences in disease pathophysiology.”
  • “No long-term, multiple-switch (eg. originator to biosimilar to originator) studies in pediatric or adult patients have been performed.”
  • “It is premature and possibly risky to assume that interchangeability will not cause differences in immunogenicity without long-term evidence in the pediatric population.” Pediatric patients likely have a “higher probability of developing autoantiantibodies” and need effective therapy for a longer duration.

My take: We still have a lot to learn.  Until more studies are available, switching stable patients could increase risk of losing response.

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Dry Falls, Highlands NC

AGA Recommendations on Biosimilars

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The AGA has made several recommendations regarding biosimilars –#2 and #6 are particularly of interest to pediatric gastroenterologists. More on this topic will follow tomorrow.

Link: AGA Makes Six Recommendations to FDA on Interchangeable Biosimilars

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Abstract Only: Mucosal Healing in Pediatric Inflammatory Bowel Disease

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This post provides the full abstract from today’s earlier post.

 

A retrospective study (Inflamm Bowel Dis 2017; 23: 1447-53) describes assessment of mucosal healing in pediatric patients with inflammatory bowel disease.

Here is abstract:

Background: Mucosal healing (MH) is associated with improved clinical outcomes in patients with Crohn’s disease (CD) and ulcerative colitis (UC). MH as a target for treatment has been suggested, although there is little pediatric data. The goal of this study was to evaluate MH in clinical practice in pediatric patients with inflammatory bowel disease in clinical remission.

Methods: A retrospective review of electronic health record data was performed on all patients with CD or UC who underwent at least 2 colonoscopies from 2010 through 2016. Only patients in clinical remission undergoing a scope for MH were included in our study. The incidence of MH and histologic healing (HH) was analyzed, along with cumulative rates of MH in each group. MH was defined by both physician assessment of MH and an endoscopic score of zero for CD and UC.

Results: A total of 76 patients with CD and 28 patients with UC underwent at least one MH scope while in clinical remission. Of the 76 patients with CD, 51 patients (67%) demonstrated MH by physician assessment, 34 patients (45%) demonstrated MH by a simple endoscopic score for CD of zero, and 35 patients (46%) demonstrated HH. Of the 28 patients with UC, 20 patients (71%) demonstrated MH by physician assessment, 10 patients (36%) demonstrated MH by a Mayo score of zero, and 10 patients (36%) demonstrated HH. Nineteen patients underwent a second MH scope and 11 (58%) demonstrated MH by physician assessment, 7 patients (37%) demonstrated MH by simple endoscopic score for CD or Mayo scores of zero, and 5 patients (26%) demonstrated HH. Of those patients with active disease, 21 of 25 patients with CD underwent escalation of therapy, whereas 8 of 8 patients with UC underwent escalation of therapy. Cumulative rates of MH when defined by physician assessment were 79% (60 of 76 patients) in CD and 79% (22 of 28 patients) in UC.

Conclusions: MH is feasible in pediatric CD and UC, and rates of cumulative MH in pediatric patients are similar to previously published adult data. In children with inflammatory bowel disease in clinical remission, approximately one-third demonstrate active disease at endoscopy.

Pediatric IBD: Treating to Target

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In 2014, an influential study by Sandborn et al (Clin Gastroenterol Hepatol 2014; 12: 978-85) described the importance of mucosal healing in a strategy termed “treating to target.”  The main findings (reviewed in a previous post Treating to Target) were the following:

  • 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.

Now, my colleagues at Emory have published a single-center experience on mucosal healing (MH) (SL Santha, PR Shankar, A Pan, B Schoen, S Kugasthasan, CG Sauer. Inflamm Bowel Dis 2017; 23: 1447-53).  While this study has the typical limitations of a retrospective study, it makes several useful points.  It takes a little extra effort to interpret their findings as they describe their results based only on the 104 patients with clinical remission rather than based on the total of 182 patients who had at least two colonoscopies.  78 were excluded due to ‘acute GI symptoms.’

Of the 104 patients considered to be in clinical remission, 76 had Crohn’s disease and 28 patients had ulcerative colitis.

Key findings:

  • For patients with ulcerative colitis (UC) who were in clinical remission, 20 (71%) had MH per physician assessment, though only 10 patients (36%) had MH based on Mayo score of zero.  10 patients (36%) demonstrated histologic healing.
  • For patients with Crohn’s disease (CD) who were in clinical remission, 51 (67%) had MH per physician assessment, 34 (45%) had MH base on simple endoscopic score for CD, and 35 (46%) had histologic healing.
  • 21 of 25 CD patients and 8 of 8 patients with UC underwent escalation of therapy based on endoscopic evaluation. 9 patients underwent dose optimization of their biologic as the modification in their therapy; this step is now routinely done in pediatrics without followup endoscopy.

The discrepancy in MH rates based on physician assessment, endoscopic scores, and histologic healing is explained.  Generally, MH based on physician assessment would include normal and those with very mild mucosal disease.  “For CD, this included small and rare aphthous ulcers, and for UC, this included mild Mayo 1 erythema in only one segment of bowel.”

Questions about the approach to ‘treating to target:’

  • This study does not describe other alternative modalities to assess for mucosal healing. Is it feasible to use a biomarker like an abnormal calprotectin to target those in need of further evaluation? In those with abnormal biomarkers, dose escalation would not require a repeat scope.
  • The Emory group has used MRE extensively, but does not report MRE findings in this population.  Would MRE (which does not require sedation) be more useful in some patients?

As in adult patients, this study does show the need for objective markers in pediatric inflammatory bowel disease; 30% of patients who were considered to be in clinical remission had active disease with further investigation.  This finding has implications for ImproveCareNow which uses physician global assessment in tracking remission rates for pediatric IBD.

In their discussion, the authors state that “changes in medical therapy can increase the MH rate to nearly 80%, which could be even higher with additional changes in those who did not demonstrate MH on a second endoscopy.”  This sentence needs to be carefully interpreted.  The authors were able to show MH based on physician assessment in 82 of 104 patients (79%) who were in clinical remission.  This rate would be MUCH lower if the entire cohort of 182 were included, possibly no greater than 50%.

The authors conclude with “endoscopy should be considered in pediatric patients with IBD in clinical remission to identify those without MH who may require medication escalation despite the absence of clinical symptoms.”

My take: I agree with the authors that objective markers of clinical remission need to be obtained to assess the effectiveness of therapy.  However, I am not convinced that endoscopy is needed in every patient who is doing well on therapy; other biomarkers and imaging may be more beneficial.

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Sign at Pisgah Fish Camp Restaurant: “On this site in 1897 nothing happened.”