Category Archives: Pediatric Gastroenterology Intestinal Disorder

Infliximab -Low Response in Young Kids (7 years and younger) with IBD

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 JPGN 2014; 59: 758-62. The full abstract for this reference follows but the message from this retrospective study of 33 children is clear –a much smaller percentage of the youngest children respond to infliximab compared to older children, adolescents and adults. In the discussion, the authors note that younger children may need higher dosing to maintain good infliximab levels or the disease pathogenesis may be much different (eg. underlying immunodeficiency and different gene mutations).

Here’s the abstract (from JPGN twitter feed):

Background: Infliximab (IFX) is efficacious for induction and maintenance of remission in pediatric patients with moderate-to-severe inflammatory bowel disease (IBD). It has, however, not been studied in patients 7 years old and younger. Our aim was to characterize efficacy and safety of IFX therapy in this cohort.

Methods: This was a retrospective study of patients with IBD ages 7 years and younger, treated with IFX between 1999 and 2011. Medical records were reviewed for age of diagnosis, disease phenotype, therapy, surgery, IFX infusion dates, dose, and intervals. Outcome measures included physician global assessment, corticosteroid requirement, and adverse events.

Results: Thirty-three children (ages 2.4–7 years) were included. Twenty patients had Crohn disease, 4 had ulcerative colitis, and 9 had indeterminate colitis. Maintenance of IFX therapy at 1, 2, and 3 years was 36%, 18%, and 12%, respectively. Patients of age 5 years and younger had the lowest rates of maintenance of therapy at 25% at year 1, and 10% at years 2 and 3 combined. Nine percent of all of the patients demonstrated response measured by the physician global assessment and were steroid free at 1 year. There were 8 infusion reactions. There were no malignancies, serious infections, or deaths.

Conclusions: IFX demonstrated a modest response rate and a low steroid-sparing effect in patients with IBD 7 years old and younger. Although this is a limited study, there appears to be a trend for decreased sustained efficacy with IFX in this age group, particularly in children 5 years old and younger, when compared with the previously published literature in older children.

IBD Update January 2015 (Part 2)

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1. A retrospective study (Inflamm Bowel Dis 2014; 20: 2292-98) of 217 patients with inflammatory bowel disease(108 infliximab-treated, 109 adalimumab-treated) provides data which indicates that combination therapy (mainly with thiopurines) resulted in higher trough levels and lower antibodies to infliximab (ATI) than monotherapy in patients treated with infliximab (IFX).  This was not evident in the adalimumab (ADA)-treated patients. Overall, approximately 90% of study population had Crohn’s disease.

Key points from this study:

  • The majority of trough level/antidrug antibody levels were drawn due to loss of response.  This is a major limitation of this study.
  • Among IFX-treated patients, those with combination therapy had trough level of 7.5 mcg/mL compared with 4.6 mcg/mL.  In combination therapy patients, the incidence of ATIs was 5.7% compared with 29.8% in monotherapy patients.
  • According to this study, the dose of the immunomodulator (IM) did not significantly influence the infliximab trough level or antibody formation; that is, more than half of patients were receiving “suboptimal dosed IM” and their infliximab levels/ATIs were similar to those who were optimally-dosed.
  • Among those who were receiving combination therapy, the incidence of antibody formation was lower in IFX-treated patients who started IM concurrently with IFX compared with those in which IM was added subsequently.
  • There were many other limitations in this study, including the finding that 94% of monotherapy patients had received previous immunomodulator therapy.

Bottomline: This study suggests that combination therapy is beneficial for patients receiving infliximab (in agreement with the previous SONIC study) and may not be beneficial for patients receiving adalimumab; however, only a well-designed prospective study

2. Inflamm Bowel Dis 2014; 20: 2266-70.  This study with 749 patients from Sweden showed that a large number of inflammatory bowel disease patients did not receive with iron supplementation: “Only 46% of patients with anemia were treated with iron supplementation or blood transfusion.”  This study showed frequent persistence of anemia one year after diagnosis, especially in children. At time of diagnosis, 55% of children and 27% of adults had anemia and 28% and 16% at one year followup, respectively.

My take: Treatment of the underlying IBD, often helps anemia.  However, in some patients treating the anemia with iron may help improve symptoms as much or more than other aspects of treatment.

3. Inflamm Bowel Dis 2014; 20: 2433-49.  Reviews pain management approaches for patients with IBD. The article emphasizes how pain can be multifactoral and that opiod-induced hyperalgesia may worsen pain.

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Bryce Canyon

Bryce Canyon

 

IBD Update January 2015 (Part 1)

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1. From the recent Advances in IBD Conference, Healio Gastroenterology reports on Dr. Baldassano’s update on PLEASE study which examined enteral nutrition in comparison to anti-TNF therapy.  Here’s the link: Enteral Nutrition Outcomes (Thanks to Kipp Ellsworth for this reference)

Here’s an excerpt:

Citing the findings from the Pediatric Longitudinal Study of Semi-Elemental Diet and Stool Microbiome (PLEASE), Baldassano demonstrated that greater mucosal healing was achieved in CD patients on exclusive enteral nutrition compared with partial enteral nutrition therapy. In this prospective cohort study, 38 children received enteral therapy with defined formula diet and 52 controls received anti-TNF-alpha therapy. The enteral nutrition group was further stratified to evaluate mucosal healing on a more restrictive diet; one subgroup received 80% to 90% of total caloric needs from enteral therapy, of which 14% achieved induction of remission at 8 weeks, the other subgroup received 90% to 100% of total caloric needs from enteral therapy, of which 45% achieved remission, and 62% of controls achieved remission.

2. NEJM 2014; 371: 2418-27. This is a case report of a 9-year-old with Crohn’s Disease and pulmonary nodules.  This report serves as a useful review.

3. Standardized use of fecal calprotectin (here’s the link -from KT Park’s Twitter feed):

Fecal calprotectin -use for identifying IBD and for identifying relapse risk

4. Inflamm Bowel Dis 2014; 20: 2247-59. Study examined factors associated with infliximab clearance.  Higher clearance noted with low albumin, high body weight, and the presence of antibodies to infliximab (ATI).  The authors note that higher concentrations with dose escalation are more likely when the dose interval was shortened than by increasing the administered dose.

5. Inflamm Bowel Dis 2014; 20: 2260-65. “Natural History of Perianal Crohn’s Disease After Fecal Diversion.”  Despite greater use of biologics, only 15 of 49 patients reestablished intestinal continuity between 2000-2011.  In this group of 15, only 5 remained reconnected and 3 of these 5 patients had procedures to control sepsis.  The likelihood of sustained intestinal continuity remains low in patients who have required a diverting procedure.

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Sandy Springs, Georgia

Sandy Springs, Georgia

IBD Incidence Increasing: 30 Years of Data from Manitoba

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A recent study (JPGN 2014; 59: 763-66) shows a steady trend of increased incidence of IBD in Manitoba. This figure is available online:

 

Increasing IBD Incidence in Children

Increasing IBD Incidence in Children from JPGNonline

Abstract:

Objectives: The aim of this study was to describe the incidence and prevalence of inflammatory bowel disease (IBD) in children <17 years of age in 30 years from 1978 to 2007.

Methods: From January 1, 1978, to December 31, 2007, the sex- and age-adjusted annual incidence and prevalence of pediatric IBD per 100,000 population were calculated based on the pediatric IBD database of the only pediatric tertiary center in the province. The annual health statistics records for the Province of Manitoba were used to calculate population estimates for the participants. To ensure validity of data, the University of Manitoba IBD Epidemiology Database was analyzed for patients <17 years of age from 1989 to 2000.

Results: The sex- and age-adjusted incidence of pediatric Crohn disease has increased from 1.2/100,000 in 1978 to 4.68/100,000 in 2007 (P < 0.001). For ulcerative colitis, the incidence has increased from 0.47/100,000 in 1978 to 1.64/100,000 in 2007 (P < 0.001). During the same time period, the prevalence of Crohn disease has increased from 3.1 to 18.9/100,000 (P < 0.001) and from 0.7 to 12.7/100,000 for ulcerative colitis (P < 0.001). During the last 5 years of the study the average annual incidence of IBD in urban patients was 8.69/100,000 as compared with 4.75/100,000 for rural patients (P < 0.001).

Conclusions: The incidence and prevalence of pediatric IBD are increasing. The majority of patients were residents of urban Manitoba, confirming the important role of environmental factors in the etiopathogenesis of IBD.

Unrelated: As a bonus for those who made it to the bottom of this post : there’s a new Bristol Stool App for iPhones.  Here’s the link: http://www.bristol-stool-scale.com (from John Pohl’s twitter feed)

 

Enthusiasm for Vedolizumab

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A recent GI & Hepatology News article quoted several leading IBD researchers stating that they consider Vedolizumab a first-line biologic therapy for ulcerative colitis.  Here’s the link:

Vedolizumab for UC

Here’s an excerpt:

Dr. Feagan presented outcome results after 80 and 104 weeks of vedolizumab treatment of 278 patients with ulcerative colitis who had completed a full year of treatment during the GEMINI 1 trial [Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Ulcerative Colitis] (N. Engl. J. Med. 2013;369:699-710). He reported that the percentage of patients in clinical remission grew from 66% after 52 weeks on treatment (the time of entry into the long-term phase of the study), to 77% after 80 weeks, which then dropped to 73% after 104 weeks. Patients with a clinical response increased from 78% after 52 weeks to 88% after 80 weeks, and then dropped to 83% after 104 weeks.

During weeks 53-104 on treatment the rates of adverse events, serious adverse events, serious infections, adverse events resulting in treatment discontinuation, enteric infections, and malignancies were all low and similar to the event rates seen among the patients randomized to placebo in the GEMINI 1 study.

The results suggest that with vedolizumab treatment of inflammatory bowel disease “once you achieve an effect it is long-lasting,” Dr. Rutgeerts said in an interview. But he cautioned that the long-lasting efficacy was achieved with treatment every 4 weeks. While this approach was safe, it would also be expensive in routine practice, he noted. “The safety looks good, but the cost would be very high.”

“A key concept of vedolizumab is that it builds efficacy over time,” commented Dr. Silvio Danese during a talk at the meeting. “Vedolizumab is not the fastest runner, but [treating inflammatory bowel disease] is a marathon, and the important thing is getting to the finish”

Bottomline: Head-to-head trials would be helpful to determine which biologic agent should be considered first-line.

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Moving to MRE

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A recent review (JPGN 2014; 59: 429-39) regarding imaging for inflammatory bowel disease reiterates the accepted view that magnetic resonance enterography (MRE) is typically the most useful imaging test for children with inflammatory bowel disease; in Table 5, MRE is listed for each indication, though CT scan is recommended “if emergent or after hours.”  The review reviews prior pediatric publications, radiation risks (with non-MRE studies), and alternative imaging.  The discussion on costs is minimized, though the authors note that MRE is the most expensive and can be compromised by motion artifact. As a practical matter, I think giving a typical charge (or range) for each of the imaging techniques would be helpful.  Also, another important issue is assuring that radiologists have the technical expertise to obtain quality imaging.

Another study (Clin Gastroenterol Hepatol 2014; 12: 1702-07) retrospectively looked at 1095 emergency room visits by 613 individuals (average age ~40 years) to determine if they could develop a model to limit unnecessary CT scans.  Of the 1095 CT scans, 24.8% were normal; 10.9% had either perforation or non-perianal abscess.  In their discussion, they note that the equation “no scan for ESR (mm/h) + 5*CRP (mg/dL) ≤10” would avoid 18.5% of CT scans.  Implementation of a more complex model could eliminate up to 43% of the CT scans.  The algorithm (Figure 2) suggested by the authors:

  • Assess for obstruction.  If suggestive symptoms, obtain abdominal X-rays.  If concerns for obstruction remain, consider CT scan.
  • If not concerned about obstruction, is there a high likelihood of perforation or abscess? If yes proceed with CT scan.  If not, consider anti-inflammatory therapy if CD symptoms present (without imaging).

Here’s the link to the abstract –supplementary materials can be obtained by those who log in.   http://dx.doi.org/10.1016/j.cgh.2014.02.036

Bottomline: Cross-sectional imaging is particularly helpful at determining whether complications are developing in patients with inflammatory bowel disease.  Increasing use of MRE will reduce radiation risks.

With regard to costs, a recent NPR story discussed “How Much Is That MRI, Really? Massachusetts Shines A Light.” While this story discussed costs related to a Massachusetts law which mandates that insurers reveal the costs of various tests, it did not relate any information regarding quality.  The study implied that an MRI at one institution would be equivalent to an MRI at another.  This is not the case.

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What is Panayiotopoulos Syndrome?

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Recently, Panayiotopoulos syndrome was mentioned on the GI Listserv as a possible explanation for a child with seizures following vomiting and gagging.  I hope that I was not the only one to wonder what that was.

According to Pediatrics Review Article:

Panayiotopoulos syndrome is a common idiopathic childhood-specific seizure disorder formally recognized by the International League Against Epilepsy. An expert consensus has defined Panayiotopoulos syndrome as “a benign age-related focal seizure disorder occurring in early and mid-childhood. It is characterized by seizures, often prolonged, with predominantly autonomic symptoms, and by an EEG [electroencephalogram] that shows shifting and/or multiple foci, often with occipital predominance.”

Autonomic epileptic seizures and autonomic status epilepticus are the cardinal manifestations of Panayiotopoulos syndrome. Autonomic seizures in Panayiotopoulos syndrome consist of episodes of disturbed autonomic function with emesis as the predominant symptom. Other autonomic manifestations include pallor (or, less often, flushing or cyanosis), mydriasis (or, less often, miosis), cardiorespiratory and thermoregulatory alterations, incontinence of urine and/or feces, hypersalivation, and modifications of intestinal motility.

Bottomline: If a parent is convinced that vomiting or retching is triggering seizures, the child’s neurologist needs to consider this disorder.

Lack of Meaningful Improvement in Crohn’s Patients with Tofacitinib

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As noted in a previous blog (see below for link), tofacitinib, an oral Janus Kinase Inhibitor has shown promise as an agent for ulcerative colitis. However, its results thus far for Crohn’s disease (CD) have been discouraging.  Another study (Clin Gastroenterol Hepatol 2014; 12: 1485-93) reiterates that message.

In brief, 139 patients with moderate-to-severe active CD were randomly assigned to 3 dosage groups of tofacitinib (1-, 5-, and 15-mg) and compared with placebo.  There were no significant differences in response or remission between tofacitinib and the placebo group, though there were reductions in both C-reactive protein and fecal calprotectin among patients given the 15-mg dose.

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Liver Disease Associated with Inflammatory Bowel Disease

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A useful review on the hepatobiliary manifestations of inflammatory bowel disease (IBD): Inflamm Bowel Dis 2014; 1655-67.

A few topics/comments from review:

Primary sclerosing cholangitis (PSC):

  • “among those with PSC, about 70% to 80% have UC and 15% to 20% have CD.  Those IBD patients with PSC are more likely to develop malignant complications and to require liver transplantation. Conversely, only about 0.4% to 7.5% of patients with IBD will develop PSC.”
  • “Currently, no medical treatment has been proven to decrease the progression of PSC.”
  • “At the time of diagnosis of PSC, IBD must be ruled out and a complete colonoscopy with multiple segmental biopsies of the mucosa needs to be performed.”  Among PSC-IBD patients, “annual surveillance colonoscopy is recommended.”
  • Further surveillance recommendations (eg. annual imaging/CA 19-9 annually) discussed in Table 2.

Cholelithiasis: Gallstones are reported in 13% to 24% of all patients with CD.  In UC, the risk of cholelithiasis “does not seem to be increased.”

Drug-induced liver disease: (see liver tox website)

  • Thiopurines
  • Methotrexate
  • Sulfasalazine/mesalamine
  • Biologic agents

Viral hepatitis in immunosuppressed IBD patients:

Hepatitis B reactivation -algorithm for screening/management of latent hepatitis B provided in Figure 3

Other liver problems seen in IBD patients:

  • Portal Vein Thrombosis
  • Nonalcoholic Fatty Liver Disease
  • Secondary amyloidosis
  • Hepatic abscess

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Work on Both Ends

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Two articles provide some insight into endoscopic interventions on both ends of the gastrointestinal tract.

In the first article (JPGN 2014; 59: 608-11), the authors retrospectively studied 11 children who received mitomycin-C concurrently with endoscopic dilatation for the treatment of anastomotic strictures after esophageal atresia repair.  Key finding: 8 of 11 achieved resolution of their strictures, 2 remained with stenosis, and 1 needed surgical correction. However, the authors found no benefit of mitomycin C in the resolution of the strictures compared with endoscopic dilatation alone in historical controls (n=10). In fact, in this small study, the control group patients had fewer endoscopic dilatations (3.7 vs. 5.4 dilatations per patient) and 9 of 10 achieved stricture resolution.

In the second article (JPGN 2014; 59: 604-08), the authors retrospectively reviewed the outcome of children (n=33) with surgically-treated Hirschsprung’s disease (HD) who were treated with intrasphincteric Botox injections for obstructive symptoms. In these children with median age of first Botox injection was 3.6 years; a median of 2 injections were given.  26 (79%) had had a transanal endorectal pull-through.  Key finding: initial improvement was noted in 76% and “good/excellent” long-term response was evident in 52% (Table 2).

Bottomline: Botox therapy appears helpful for non-relaxing sphincters in HD whereas mitomycin-C remains an unproven therapy for esophageal strictures.

Also briefly noted: JPGN 2014; 59: 674-78.  “Use of cyproheptadine in young children with feeding difficulties and poor growth in a pediatric feeding program.” n=127.  Of the 82 who took cyproheptadine regularly, 96% reported a positive change in feeding behaviors and there was a significant improvement in weight gain.

Also, with regard to stooling problems, Sana Syed (Emory GI fellow) pointed out a useful website that emphasizes proper positioning for functional constipation: squattypotty.com.  While the website promotes their product to provide proper foot support (with elevation), there are other ways to get a similar result.  As noted previously (“Poo in You” Video | gutsandgrowth) proper positioning can help a lot.

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