Category Archives: Pediatric Gastroenterology Intestinal Disorder

More on PPIs and Kidney Disease & Brain Disease

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The most recent information and perspective on proton pump inhibitors and kidney disease:

From AGA: More Data on PPI Use and Kidney Disease

An excerpt:

The most recent study related to PPIs and CKD was a meta-analysis by Wijarnpreecha et al. presented at the American Society of Nephrology annual meeting and published in Digestive Diseases and Sciences. They found that any use of PPIs was associated with a 33 percent relative increase in risk for CKD/ESRD whereas no such risk was seen with H2RAs.

Talking to Your Patients
  1. Inform patients that, while this study does raise some concern about long-term PPI use and the potential contributions to kidney disease, the study does not show that PPI use causes kidney disease. No decisions should be made in haste as a reaction to this study. A brief explanation of the meta-analysis may also be helpful. 
  2. Reassure patients that the benefits of using PPIs often outweigh the possible risks. Let them know that you prescribed a PPI for a clear-cut indication, in the lowest possible dose, and for an appropriate period of time (lowest dose, shortest time). 

From the published abstract:

Results: five studies (three cohort studies and two case-control studies) with 536,902 participants met the eligibility criteria and were included in the meta-analysis. We found that individuals with PPIs use had significantly increased the risk of CKD or ESRD when compared with non-PPIs users (pooled RR of 1.33, 95% CI, 1.18-1.51). There was no publication bias of overall included studies assessed by the funnel plots.

My take: (borrowed from the AGA) This is an association, not proof of a causal relationship. Patients who use PPIs differ at baseline than those who do not. For example, patients who use PPIs are more likely to have diabetes or hypertension than patients who do not use PPIs, and are more likely to use additional nephrotoxic medications. Large retrospective studies are unable to completely adjust for these baseline differences. These differences, rather than PPIs themselves, may explain the observed association.

Related study: DCF Klatte et al. Gastroenterol 2017; 153: 702-10.  In this retrospective analysis with more than 100,000 new PPI users (Swedish cohort), PPI users (compared to H2 blocker users) had an increased risk for doubled levels of creatinine with a HR of 1.26, and an increased risk of end-stage renal disease with HR of 2.40. The risk of chronic kidney disease was increased with higher cumulative PPI exposures.

Related study: Effects of PPI on dementia –recent large study shows no association: H Taipale et al. The American Journal of Gastroenterology(2017) 112, 1802–1808 (2017) doi:10.1038/ajg.2017.196.  (Thanks to Ben Gold for this reference. This study examined more than 70,000 Finnish patients with Alzheimer’s disease (AD) (2005-2011) and 280,000 controls.  Results: PPI use was not associated with risk of AD with 3-year lag window applied between exposure and outcome (adjusted odds ratio (OR) 1.03, 95% confidence interval (CI) 1.00–1.05). Similarly, longer duration of use was not associated with risk of AD (1–3 years of use, adjusted OR 1.01 (95% CI 0.97–1.06); ≥3 years of use adjusted OR 0.99 (95% CI 0.94–1.04)). Higher dose use was not associated with an increased risk (≥1.5 defined daily doses per day, adjusted OR 1.03 (95% CI 0.92–1.14)).

Sunrise over the South Rim at the Grand Canyon

Understanding the New Therapies for Spinal Muscular Atrophy

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Pediatric gastroenterologists follow children with spinal muscular atrophy type 1 (Wernig-Hoffman disease) mainly due to feeding problems associated with the profound weakness. Two recent studies show promise for spinal muscular atrophy and are summarized in a “quick take” video: Quick Take NEJM video on SMA type 1

While these new therapies have improved the outcomes, long term data are needed.  With the adenovirus vector gene therapy, if the expression of the gene therapy declines, it may not be possible to do further infusions due to antibody development against the adeonviral vector.

With nusinersen, which has been approved for clinical use, the anticipated cost of $750,000 for the first year of therapy alone and ongoing need for intrathecal administration are problematic.

CFTR Modulators for Cystic Fibrosis

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Two more studies have shown the effectiveness of CFTR modulators for subsets of patients with cystic fibrosis.

  • JL Taylor-Cousar et al. NEJM 2017; 377: 2013-23
  • SM Rowe et al. NEJM 2017; 377: 2024-35.

In the Taylor-Cousar study, the authors treated patients with homozygous Phe508del cystic fibrosis with either combination tezacaftor-ivacaftor or placebo for 24 weeks. Combination therapy resulted in FEV1 that was 4% higher along with a 35% lower rate of pulmonary exacerbations than placebo.

In the Rowe study which examined patients some retained CFTR function (which occurs ~5% of CF patients), a prospective trial of tezacaftor-ivacaftor had a greater effect on increasing FEV1 than ivacaftor alone.  Ivacaftor monotherapy and tezacaftor-ivacaftor combination therapy were both more effective than placebo.

A related editorial (H Grasemann. pgs: 2085-8) helps provide context to help understand the importance of these studies.  His key point:

“Although CFTR modulator therapies have measurable beneficial effects on some aspects of the disease, there is still an unmet need for truly effective new therapies to be developed for all persons with cystic fibrosis.  The clinical efficacy of the current combination therapies for patients with cystic fibrosis who have the most common CFTR genotype (Phe508del/Phe508del) is suboptimal and falls within the range of established symptomatic therapies, such as nebulized inhaled hypertonic saline or recombinant human DNAse.”

This figure depicts the types of molecular defects: No functional CFTR with framshifts for deletions or insertions (class 1), CFTR trafficking defect due to misfolded protein (class II), defective channel regulation (class III), reduced cholirde conductance (class IV) , reduced synthessis (class V) or decreased CFTR stability (class VI)

Research for Fatty Liver Disease

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Recently the AASLD Postgraduate Course discussed emerging treatments for nonalcoholic fatty liver disease/nonalchoholic steatohepatitis. From AASLD News: Emerging Treatments for NASH 

Key point:

  • Quentin Anstee: “It is important to remember that our patients with fatty liver disease will most likely die of cardiovascular disease, not liver disease.”

Four principles in treating nonalcoholic fatty liver disease (NAFLD) to address both cardiovascular and liver risks.

  • Target obesity with lifestyle changes and, possibly, bariatric surgery.
  • Target metabolic syndrome to reduce cardiovascular disease risk using medications with additional liver-directed benefits.
  • Target liver disease to prevent progression of steatohepatitis to fibrosis and cirrhosis.
  • Minimize downstream complications such as hepatocellular carcinoma.

More than 60 phase 3 trials are underway –Primary Therapeutic Targets:

  • PPAR signaling (insulin signaling, glucose and lipid metabolism, energy homeostasis, inflammation)
  • FXR signaling (insulin sensitivity, glucogenesis, lipogenesis)
  • ASK1 signaling (apoptosis)
  • CCR2/CCR5 signaling (inflammation and fibrogenesis).

TPN Amino Acid Shortages Following Hurricane Maria

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Thanks to Kipp Ellsworth for this link: FDA Announcement Regarding Medical Product Shortages Related to Puerto Rico Production

An excerpt: the hurricane disrupted Baxter’s amino acids production facilities in Puerto Rico; Baxter is one of the largest manufacturers of this product serving the U.S. market. In order to help mitigate this shortage, the FDA has worked with Baxter to facilitate the temporary importation of amino acids for pediatric and adult formulations of IV amino acids from Baxter facilities in the United Kingdom and Italy. 

IBD Short Takes -Fall 2017

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From ImproveCareNow: Real-World Experience with Adalimumab

An excerpt:

A total of 174 children and adolescents were treated with adalimumab as their first anti-TNF therapy…The mean age at the time of Crohn’s disease diagnosis was 13 years and, on average, they started adalimumab at 14.5 years of age…

  • At 3 months after adalimumab was started, all 174 were still on the medication, and 69-71% were in steroid-free remission
  • At 6 months after adalimumab was started, of the 174 who had a clinic visit, 95% were still on the medication, and 75-77% were in steroid-free remission
  • At 12 months after adalimumab was started, of the 154 who had a clinic visit, 94% were still on the medication, and 79-80% were in steroid-free remission
  • At 24 months after adalimumab was started, of the 71 who had a clinic visit, 97% were still on the medication, and 91-94% were in steroid-free remission
  • At 36 months after adalimumab was started, of the 39 who had a clinic visit, 80-86% were still on the medication, and 81-86% were in steroid-free remission

No positive or negative effect on remission was seen with concomitant immunomodulator therapy. However, the number of patients studied during the retrospective analysis is too small to detect all but the greatest impact of this approach.

EC Maxwell et al. JPGN 2017; 65: 299-305  CHOP experience with diverting ileostomy for severe IBD (2000-2014).

  • In this retrospective study, a diverting ileostomy in 24 patients had improvement: 71% –>22% on chronic steroids, improved growth, hemoglobin, blood transfusion and hospitalization.
  • 10 patients underwent subsequent colectomy, 7 had successful reanastomosis, and 7 remain diverted.
  • Diversion allowed a definitive diagnosis in 7 subjects (initially 13 patients were considered IBD-U).
  • Surgical complications were common (n=13 in 7 subjects) and included stoma obstruction, stoma prolapse, and resection of ischemic bowel.
  • One notable feature regarding this cohort was that 50% were 5 or younger when diagnosed with IBD.
  • The authors conclude that a diverting ileostomy can induce clinical stability and allow time to clarify diagnosis.

A Assa et al. JPGN 2017; 65: 293-98. In this study involving findings from 234 patients extracted from the ImageKids database (prospective multicenter cohort), the authors found that pediatric patients with perianal Crohn’s disease have a greater inflammatory burden; however, this was driven mainly by those who had fistulizing disease.

L Lian et al. Clin Gastroenterol Hepatol 2017; 15: 1226-31. This retrospective study from the Cleveland Clinic compared outcomes of endoscopic balloon dilation (EBD) (n=176) or surgery (n=131) for Crohn’s disease-related strictures (1998-2013). Patients who had EBD had an “average time to surgery delayed by 6.45 years.” Immediate success rate for EBD was 91.3%; the perforation rate was 1.1%.. Ultimately, 52% of patients who had EBD required surgery.  Earlier surgery lowered the risk of further surgery but also was associated with significant perioperative complications. In the operative group, 8.8% of patients experienced complications, mainly intra-abdominal abscesses and enterocutaneous fistula. Thus, in the right hands and with careful selection, EBD may be useful.

I Lawrance et al. Clin Gastroenterol Hepatol 2017; 15: 1248-55. This study reported the results of 11 patients who received rectal tacrolimus for resistant ulcerative proctitis. Dosing: The concentration of tacrolimus was 0.5 mg/mL and 3 mL was administered twice a day.Clinical response, using the Mayo Clinic score, was achieved in 73% of tacrolimus subjects compared with 10% (n=1) of placebo-treated subjects.  Mucosal healing at week 8 was noted in 73% of tacrolimus-treated patients, as well.

Soapes Creek Trail

Therapeutic Drug Monitoring: Ustekinumab (Stelara)

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The ability to measure drug levels has changed how we think about refractory medical disease, particularly in patients with inflammatory bowel disease.  Prior to the availability of therapeutic drug monitoring (TDM), in some situations poor response to therapy could be ascribed to variability in host immune response. Now, it is clear that many cases of refractory medical disease are due to insufficient drug level.  TDM allows for dose individualization to target the right amount of medication.

TDM has an accepted role in anti-TNF therapy.  Now, a study (R Battat et al. Clin Gastroenterol Hepatol 2017; 15: 1427-34) extends the concept of TDM to ustekinumab.  This study which took place between 2014-2015 examined ustekinumab use in 62 patients with refractory Crohn’s disease (CD).  Ustekinumab dosing: 90 mg SC at weeks 0, 1, and 2 for induction, then 90 mg every 4 or 8 weeks for maintenance.

Key findings:

  • At week 26, 80.7% of patients had a clinical response, 66.1% had a clinical remission, and 58.9% had an endoscopic response.
  • In those with an endoscopic response, the mean trough concentration of ustekinumab was 4.7 mcg/mL compared with 3.8 mcg/mL those without an endoscopic response.
  • Using a trough threshold of 4.5 mcg/mL at week ≥26, 75.9% had an endoscopic response whereas those with a level below this trough had a 40.7% endoscopic response
  • The authors did not detect antibodies to ustekinumab in any patient. The authors note that ustekinumab has low immunogenicity and prior UNITI studies indicated antibody formation in 0.2% after induction and 2.3% at 1 year.
  • Unlike combination therapy with anti-TNF therapy, “concurrent immunosuppressive therapy does not explain low immunogenicity, as only 25.8% of patients received these and had neither improved clinical outcomes nor higher drug concentrations.”

Thus far, no clinical studies have demonstrated improved clinical outcomes with dose escalation in the setting of low ustekinumab levels.  A prospective trial would be helpful.

My take: This study shows promising results for ustekinumab for refractory CD.  The low immunogenicity indicates that monotherapy is likely appropriate.  A target level of >4.5 mcg/mL indicates a higher likelihood of response.

Related blog posts:

#NASPGHAN17 Celiac Disease and Mucosal Healing

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This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Celiac disease: treat to target! Where should we aim and how do we get there?

Ivor Hill  Nationwide Children’s Hospital

Key point:

  • Dr. Hill asserted that long-term outcomes are related to ongoing intestinal inflammation and thus our goal should be mucosal healing rather than normalized symptoms/normalized serology

At this lecture, I asked Dr. Hill what he would recommend for an asymptomatic pediatric patient with ongoing intestinal inflammation who was strictly adherent to a gluten-free diet, who had no other recognizable diseases, and who had normalized their serology on treatment.  His response was that in adults that ~50% of patients improve with better attention to diet.  Thus, currently besides further dietary scrutiny, it is unclear what should be done in the pediatric population should one find ongoing mucosal disease in an asymptomatic adherent patient.

My take: Until prospective pediatric studies are published to determine the frequency of ongoing intestinal inflammation in those on a strictly GFD in asymptomatic patients and until we have additional management options, it does not make sense to look for mucosal healing.  “Don’t hunt what you cannot kill.”

Related blog posts:

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.

 

#NASPGHAN17 Therapeutic Drug Monitoring Associated with Increased Clinical Remission

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In support of Dr. Baldassano’s talk (NASPGHAN17: Treat to Target and Tight Control), this poster from the Cincinnati group (A Mulgand et al) showed that therapeutic drug monitoring has been associated with improved clinical remission scores (80% to 87%).  Correlation with a more objective marker of remission along with longer followup is now needed. One of the authors, Dana Dykes, has joined our group in Atlanta!

 

Related blog posts:

#NASPGHAN 17 More Abstracts

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This link for the NASPGHAN abstracts :NASPGHAN 2017 Scientific Abstracts

The following slides are from some of the abstract posters. This first poster (next 5 pics) showed that symptom association with meals is not predictive of aspiration among a selected group of children who underwent swallow study evaluations. In the figures, the blue bars are children who passed the swallow study whereas the red bars indicate the children who failed the swallow study.

This next slide demonstrated that a six food diet for EoE could be administered blenderized via a gastrostomy tube.

The next slide showed that irritable bowel syndrome was more frequent (overall hazard ratio of 1.52) following a urinary tract infection in the first year of life.

The next pictures are from a poster discussing high rates of recurrent C difficile infection following fecal microbial transplantation in pediatric patients with inflammatory bowel disease (mainly ulcerative colitis).  An inference from this study would be that many cases of C difficile that were attributed as causing symptoms could in fact have been from a flare up of their IBD.  More details about the diagnosis of C difficile (based on PCR or ELISA) would be helpful

The next poster provides data from CHOP experience with Ustekinumab.  Overall, in this highly-selected (refrcactory) population the long term improvement was low; while one-third had steroid-free remission at week 8, this was not maintained at week 16 and week 24.  In addition, among the 22 patients, one developed transverse myelitis.

This study that follows (next two pics) documented the relative safety of liver biopsies (mainly percutaneous without interventional radiology) in the post-transplant period.  The two most serious adverse events, cholangitis and bile leak, helped identify biliary strictures.

The following collaborative study examined the neurocognitive status of children with Alagille syndrome.  Overall, this study shows that children with Alagille syndrome are at increased risk of low IQ compared to children with other cholestatic diseases.