Author Archives: gutsandgrowth

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About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

Integrating Mental Health into Pediatric IBD Care

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WE Bennett, MD Pfefferkorn. JAMA Pediatr. Published online August 19, 2019. doi:10.1001/jamapediatrics.2019.2669

Full Link: Editorial: “Mental Health Screening as the Standard of Care in Pediatric Inflammatory Bowel Disease” Thanks to Ben Gold for this reference.

An excerpt:

Butwicka and colleagues1 have published a fascinating, landmark cohort study in this issue of JAMA Pediatricsassessing the prevalence of psychiatric diagnoses and symptoms among children with inflammatory bowel disease (IBD) in Sweden. The authors used a rigorous design that compared a cohort of more than 6000 pediatric patients with IBD with hundreds of thousands of healthy controls, as well as a separate cohort comprising the patients’ own siblings who did not have IBD. Butwicka et al1 computed hazard ratios for any psychiatric disorder, as well as for multiple specific disorders, and found a hazard ratio of 1.6 for any psychiatric diagnosis when comparing children with IBD with healthy controls. The statistical analysis is stellar and represents the best data we currently have on the intersection of pediatric IBD and mental health. Their study highlights a substantial risk in a vulnerable population and should trigger revision of guidelines and allocation of resources to support widespread screening and treatment for these dangerous conditions.

Related Article:

A Butwicka et al. JAMA Pediatr. Published online August 19, 2019. doi:10.1001/jamapediatrics.2019.2662 

Full Text Link: Association of Childhood-Onset Inflammatory Bowel Disease With Risk of Psychiatric Disorders and Suicide Attempt

Related blog posts:

Crater Lake, OR

Briefly noted: Psoriasis due to Infliximab

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O Courbette et al. JPGN 2019; 69: 189-93. Infliximab Paradoxical Psoriasis in a Cohort of Children With Inflammatory Bowel Disease

From Abstract:

Results: One hundred and twenty-three CD patients and 24 UC patients were treated with IFX. Twenty patients (13.6%) experienced a paradoxical psoriasis. All of them were affected by CD. Perianal CD was more frequent in the psoriasis group (P = 0.033). Fourteen patients (70%) were in remission when skin lesions occurred. Paradoxical psoriasis was diagnosed 355 days (median, interquartile range [IQR] 239; 532) after the initiation of IFX corresponding to the eighth injection (median, IQR: 6; 15). Psoriasis lesions were controlled by local steroids in all cases and no patients discontinued IFX therapy.

Conclusions: 13.6% of our IBD patients treated with IFX developed psoriasis during a median follow-up of 23.9 months (IQR: 11.6; 36.5). Crohn disease patients with perianal disease were at a higher risk to develop this common side effect.

Combination Therapy Associated with Treatment Persistence

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Another large retrospective ‘real-world’ study (C Chen et al. Inflamm Bowel Dis 2019; 1417-27) examined persistence profiles of biologic therapies in newly diagnosed IBD patients.  This study, based on Truven Health MarketScan data (2008-2015) included 5612 patients with Crohn’s disease (CD) and 3533 with ulcerative colitis (UC). There were 1156 persons (20.6%) in the pediatric age range (0-18)

Key findings:

  • Less than half of the patients continued using their initial biologic treatment after 1 year (48.5% of CD cohort and 44.8% of UC cohort).
  • For infliximab (IFX) in the CD cohort, the 1 year continued rate was 47.6% and the 5 year rate was 20.0%. In the UC cohort, the rates were 44.9% and 15.7% respectively.
  • For adalimumab (ADA) in the CD cohort, the 1 year continued rate was 50.9% and the 5 year rate was 9.1%. In the UC cohort, the rates were 45.4% and 7.7% respectively.
  • Combination therapy with immunomodulators (IMM) significantly decreased the risk of discontinuation, especially if IMM was started more than 30 days before the biologic agent (HR 0.22).  Simultaneous starting had HR of 0.32.
  • The major predictors for noncompliance included infection and hospitalization.

Why did combination therapy result in higher medication persistence rates?

  • Potential reasons included improved efficacy by direct inflammatory effects and reduced drug antibodies to TNF antagonists.  It is possible that patients receiving combination therapy had more severe disease and thus less likely to discontinue therapy.

Limitation: This study may overestimate drug discontinuation as some patients may simply have had a dosing delay.

My take: This study shows a higher-than-expected rate of drug discontinuation indicating dissatisfaction related to efficacy, cost or complications. Those receiving immunomodulators (combination therapy) were much less likely to discontinue treatment.

Related blog posts:

Wizard Island, Crater Lake, OR

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

Combination Therapy Still Works for Inflammatory Bowel Disease (Part 1)

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There is speculation that the use of therapeutic drug monitoring (TDM) may obviate the advantages of combination therapy. However, there is plenty of data supporting combination therapy including a recent retrospective population-based study (LE Targownik et al. Clin Gastroenterol Hepatol 2019; 17: 1788-98).

This ‘real-world’ study (2001-2016) utilized the Manitoba IBD database and included 852 persons with Crohn’s disease (CD) and 303 with ulcerative colitis (UC).

Key findings: 

  • In persons with CD, combination therapy (immunomodulator with a TNF antagonist) was associated with lower treatment ineffectiveness with an adjusted hazard ratio (aHR) for ineffectiveness at 0.62.  The ineffectiveness in UC persons was lower at 0.82 but did not reach statistical significance.
  • When looking at specific time frames, among patients with CD, at 1 year, combination therapy the rate of ineffectiveness-free treatment was 74.2% for combination therapy compared to 68.6% for monotherapy; at 2 years, the rates were 64.0% and 54.5% respectively.
  • Combination therapy in CD was associated with increased time to first IBD-related hospitalization with aHR of 0.53 and with lower rates of switching anti-TNF agents (aHR 0.63).  Lower rate of surgery (aHR 0.76) did not reach statistical significance.
  • The choice of immunomodulator (6-MP/AZA vs MTX) and the choice of anti-TNF agent (IFX or ADA) did not significantly influence the overall benefit of combination therapy.  Though, AZA was the main concomitant treatment (92%).
  • 90% of the patients in the study who received combination therapy had received immunomodulator therapy prior to combination therapy.  This is in contrast to the SONIC study in which patients were naive to both agents.
  • 57% of IFX users and 43% of ADA users received concomitant therapy.

My take: Combination therapy has been associated with higher response rates to IBD therapy.  This advantage has to be weighed against potential adverse effects.

Related blog posts:

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.

Wizard Island. Crater Lake, OR

SMOFlipid vs. Intralipid for Intestinal Failure Patients

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A recent study (C Belza et al. JPEN 2019; https://doi.org/10.1002/jpen.1692) showed that SMOFlipid reduced the frequency of cholestasis in intestinal failure patients. Thanks to Kipp Ellsworth for reference.

An Observational Study of Smoflipid vs Intralipid on the Evolution of Intestinal Failure–Associated Liver Disease in Infants With Intestinal Failure. From Abstract:

Methods

This was a retrospective cohort study of infants with IF with a minimum follow‐up of 12 months in 2008–2016. Patients were stratified into 2 groups: group 1 received SMOFlipid; group 2 was a historical cohort who received Intralipid. The primary outcome was liver function evaluated using conjugated bilirubin (CB) levels…

Results

Thirty‐seven patients were evaluated (17 = SMOFlipid, 20 = Intralipid). SMOFlipid patients were less likely to reach CB of 34 (24% vs 55%, P = 0.05), 50 µmol/L (11.8% vs 45%; P = 0.028), and did not require Omegaven (0% vs 30%; P = 0.014). CB level at 3 months after initiation of parenteral nutrition (PN) was lower in patients receiving SMOFlipid (0 vs 36 µmol/L; P = 0.01). Weight z‐scores were improved for patients receiving SMOFlipid at 3 months (−0.932 vs −2.092; P = 0.028) and 6 months (−0.633 vs −1.614; P = 0.018).

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Crater Lake, OR

Modeling Trough Levels to Predict Optimal Infliximab Dosing

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A recent study for optimizing infliximab  dosing: LE Bauman et al.  2019 Jul 9. pii: izz143. doi: 10.1093/ibd/izz143. [Epub ahead of print]

The authors identified 228 pediatric patients with IBD and developed a pharmocokinetic model using weight, albumin, sedimentation rate and antibodies to infliximab (ATI) to help predict infliximab dosing that would achieve a therapeutic trough level (>5 mcg/mL).

In their study, they also simulated 1000 patients and found that only 24% of patients receiving 5 mg/kg q8weeks achieved a therapeutic level; this increased to 56% for 10 mg/kg q8weeks.  Shortening dose interval more reliably achieved therapeutic levels: 5 mg/kg q4 weeks had a target level in 84% and 10 mg/kg q6 weeks had a target level in 80%.

The image above corresponds to Figure 5 in the manuscript.  This figure shows the difference between proactive and reactive dosing strategy.  In the first panel, a higher initial dose prevents suboptimal dosing whereas the second panel shows suboptimal troughs until adjustment of dose after identifying a low trough.  Avoiding low troughs may reduce the likelihood of developing antibodies to infliximab and therapeutic failure

My take: This study and several others indicate that most pediatric patients need either more frequent inflixmab dosing or higher initial doses to achieve therapeutic levels and to improve outcomes.

Study: Soda (even diet soda) May Increase Mortality

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From Reuters –Link: Soft drinks – sugared or low-calorie – may raise the risk of early death

Link to abstract: Association Between Soft Drinks Consumption and Mortality in 10 European Countries

Excerpt:

In a study that followed more than 400,000 European adults for more than 16 years, the risk of premature death was heightened in those who consumed 2 or more glasses per day of soft drinks, according to the report published in JAMA Internal Medicine…

The new findings don’t mean that soft drinks cause early death, because “in these types of studies (observational epidemiology) there are other factors which may be behind the association we observed,” Murphy added in an email. “For instance, high soft drink consumption may be a marker of overall unhealthy diet”…

Participants who consumed two or more glasses of soft drinks per day were 17% more likely to die early compared to those who drank less than a single serving of soft drinks per month…

Those who consumed two or more glasses of artificially sweetened soft drinks a day were 26% more likely to die prematurely compared to those who drank less than a glass per month.

My take: Whether drinking soda directly impacts one’s health or is a marker for an unhealthy lifestyle is not settled by this study.  Yet, I feel confident that preferentially drinking water is a healthy habit.

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Proactive Therapeutic Drug Monitoring -Different Time Points

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Yesterday’s post outlined expert recommendations for proactive therapeutic drug monitoring (pTDM).  Today’s post reviews a study (NV Casteele et al. Clin Gastroenterol Hepatol 2019; 17: 1814-21) which identifies optimal levels at earlier time points. The authors note that “higher infliximab (IFX) concentrations during induction therapy  are correlated with long-term relapse-free and colectomy-free survival.”

The authors analyzed data from 484 patients with active ulcerative colitis (UC) from two double-blind, placebo-controlled, parallel group studies: ACT-1 and ACT-2.

Key findings:

  • IFX levels ≥18.6 mcg/mL at week 2, ≥10.6 mcg/mL at week 6, and ≥34.9 mcg/mL at week 8 were associated with Mayo endoscopic scores (MES) of ≤1 at week 8.
  • IFX level of ≥5.1 mcg/mL at week 14 was associated with MES of ≤1 at week 30
  • IFX level of ≥6.7 mcg/mL at week 14 was associated with MES of 0 at week 30

My take: In pediatric patients receiving monotherapy with an anti-TNF agent, checking earlier levels (week 6, week 8, or week 10) may help avoid low troughs which are associated with a higher likelihood of treatment failure.  This study provides guidance on target levels at earlier time points.

Related blog posts:

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.

Crater Lake, OR. The blue color is amazing !

 

Appropriate Proactive Therapeutic Drug Monitoring

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This blog post and tomorrow’s post highlights two articles on proactive therapeutic drug monitoring (pTDM) for inflammatory bowel disease.  The first article (K Papmichael et al.  Clin Gastroenterol Hepatol 2019; 17: 1655-68) summarizes a meeting of 13 international IBD specialists who reached consensus on 24 statements after a review of the literature.

Full Text Link:  Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases

Key Recommendations:

  • For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics.
  • Reactive TDM was appropriate for all biologic agents both for primary non-response and secondary loss of response

Background/Rationale for pTDM:

  • “Numerous studies have demonstrated a positive correlation between serum biologic drug.concentrations and favorable therapeutic outcomes”
  • “Low or undetectable drug concentrations can lead to immunogenicity and treatment failures”
  • “TDM…is an important tool for optimizing biologic therapy…Data suggest that pTDM, with drug titration to a target trough concentration, performed in patients with clinical response/remission can also improve the efficacy of anti-TNFs”

Table 4  Scenarios of Applying Therapeutic Drug Monitoring of Biological Therapy in Patients With Inflammatory Bowel Disease

1-4: Anti-TNFs:

  • It is appropriate to order drug/antibody concentration testing in responders at the end of induction for all anti-TNFs.
  • It is appropriate to order drug/antibody concentration testing at least once during maintenance for patients on all anti-TNFs.
  • It is appropriate to order drug/antibody concentration testing of anti-TNFs at the end of induction in primary non-responders.
  • It is appropriate to order drug/antibody concentration testing for all anti-TNFs in patients with confirmed secondary loss of response.

5-8: Vedolizumab -agreement only on ordering TDM in non-responders or those with loss of response

9-12: Ustekinumab  -agreement only on ordering TDM in non-responders or those with loss of response

From Table 5: Biological Drug Concentrations and Anti-Drug Antibodies When Applying Therapeutic Drug Monitoring in Inflammatory Bowel Disease

  • Infliximab: 15. In the presence of adequate trough drug concentrations, anti-drug antibodies are unlikely to be clinically relevant.
  • Infliximab: 19. The minimal trough concentration for infliximab post-induction at week 14 should be greater than 3 μg/mL, and concentrations greater than 7 μg/mL are associated with an increased likelihood of mucosal healing.
  • Adalimumab: 22. The minimum drug concentration at week 4 for adalimumab should at least be 5 μg/mL. Drug concentrations greater than 7 μg/ml are associated with an increased likelihood of mucosal healing.
  • Certolizumab: 24 & 25: The minimum concentrations for certolizumab pegol at week 6 should be greater than 32 μg/mL and 15 μg/mL during maintenance.
  • Golimumab 26 & 27: The minimum drug concentration at week 6 for golimumab should at least be 2.5 μg/mL and 1 μg/mL.during maintenance

My take: This article provides extensive literature to reinforce their recommendations.  Most of the trough levels mentioned are minimum levels that need to be achieved.