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IBD Update March 2019

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Briefly noted:

W El-Matary et al. Inflamm Bowel Dis 2019; 25: 150-5. This retrospective study of 667 children with Crohn’s disease who were prospectively enrolled in an inception study found that 85 (12.7%) had fistulizing perianal disease. The mean infliximab (pre-fourth dose) was 12.7 mcg/mL in responders compared with 5.4 mcg/mL in the active disease group.  My take: Higher trough levels are desirable in those with fistulizing disease.

LJT Smits et al. Inflamm Bowel Dis 2019; 25: 172-9. In a  prospective cohort with 83 patients with IBD (57 with Crohn’s disease) with at least 2 years of followup, 66% of IBD patients continued CT-P13 after switching from Remicade; two patients developed anti-drug antibodies.  The absolute numbers suggest no adverse impact of a single switch to the biosimilar product.

Related blog posts:

A Tinsley et al. Inflamm Bowel Dis 2019; 25: 369-76. This study documents the increased risk of influenza and increased influenza complications among IBD patients based on a database cohort of 140,480 patients (with and without IBD). The risk of hospitalization was 5.4% in patients with IBD compared with 1.85% in non-IBD patients.

Related blog post: Almost Everybody Needs Flu Shot -IBD Patients at Higher Risk

YY Xu et al. Inflamm Bowel Dis 2019; 25: 261-9. This meta-analysis included 18 nonrandomized controlled trial studies with 1407 patients who received preoperative infliximab and 4589 patients.  The authors showed that preoperative infliximab was not associated with any statistically significant differences for the 2 groups for any complications, reoperation, readmission or mortality.

CN Bernstein et al. Inflamm Bowel Dis 2019; 25: 360-8. This study, using population-based administrative health data (Manitoba) found increased burden of psychiatric disorders in IBD: compared with controls the incidence rate ratio for depression was 1.58, for anxiety 1.39, for bipolar disorder 1.82, and for schizophrenia 1.64.

Related blog post: #NASPGHAN17 Psychosocial Problems in Adolescents with IBD

View from Ryan Mountain, Joshua Tree National Park

More Cases of Hepatocellular Carcinoma after Fontan

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Several years ago, there were 4 cases of hepatocellular carcinoma (HCC) following Fontan procedure reported in the NEJM. (Reviewed in this blog: Hepatocellular carcinoma after Fontan Procedure).

Another recent report describes 3 patients who presented with HCC more than 10 years after Fontan procedure.  The age of these patients varied from 20 to 28 years. The authors use the term Fontan-Associated Liver Disease (FALD).  They note that FALD is strongly associated with the interval from the procedure, increasing in frequency with more time following surgery.  The risk of FALD is 4.4 times greater between years 11-15 years than in the first 10 years.

The authors recommend screening for HCC in patients 10 years after Fontan procedure. They suggest a baseline MRI followed by biannual ultrasounds and alpha-fetoprotein tests.

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Warren Peak, Joshua Trree National Park

Teaching an Old Liver New Tricks

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A recent retrospective study (JD de Boer et al. Liver Transplantation 2019; 25: 260-74) helps address the question of whether/when a geriatric liver is too old for donation.

The authors culled data from 2000-2015 from 17,811 first liver transplantations performed in the Eurotranplant region.

Key findings:

  • 2394 (13%) transplants were performed with livers ≥70 years old
  • Graft survival was reduced from donors with a history of diabetes (HR 1.3) and in recipients with hepatitis C virus (HCV) antibody (HR 1.5)
  • “Although donor age is associated with a linearly increasing risk of graft loss between 25 and 80 years old, no differences in graft survival could be observed when “preferred” recipients were transplanted” with older grafts (HR 1.1).
  • Preferred recipients: 1. HCV-Ab neg, 2. Recipient >45 years old, 3. BMI <35 kg/m2, 4. cold ischemia time < 8 hours. 26% of recipients were considered “preferred” recipients
  • Utilization of livers from donors ≥70 years old increased from 42% (2000-2003) to 76% (2013-2015).
  • The median donor age increased from 42 to 55 years old from 2000 to 2015.
  • The oldest transplanted liver was 98 years old!

The overall Kaplan-Meier survival curves are given in Figure 2 and there is a clear trend of better graft and patient survival with donors <70 years of age.  However, Figure 4 shows that graft survival with “preferred” recipients was essentially identical when comparing grafts from donors <70 compared to >70.  However, when comparing graft survival from donors <40 compared to donors >70, there appeared to be a small advantage for the younger organs, though this did not meet statistical significance. (HR 1.2 CI 0.96-1.37).

My take: Given the shortage of available livers, the use of older donor organs is a necessity and can be accomplished without significant loss of grafts in selected patients.

Related blog posts:

Joshua Tree National Park

 

NY Times: Five Things I Wish I’d Known Before My Chronic Illness

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A recent article describes some of the challenges of dealing with Crohn’s disease (thanks to Kayla Lewis for pointing out this reference).

NY Times: Five Things I Wish I’d Known Before My Chronic Illness

Key Points:

  • “Your relationships change” “It’s hard to be a good employee when you need extended time off. It’s hard to be a good friend when you cancel plans last minute. It’s hard to be a good partner or parent when you barely have the energy to get out of bed. “
  • “Everyone offers you advice” “So unless someone asks for your advice, don’t offer it. If you’re on the receiving end of misguided advice, say something like, “I appreciate that you’re trying to help, but my doctors and I think this treatment is best right now” or “There’s no known cure for my disease, but I’d love if you donated toward the research to find one!”
  • “You have to educate yourself — and everyone else“
  • “Support is everything”  Online communities can be helpful. ” The Crohn’s and Colitis Foundation has resources to help you find one. For a sometimes embarrassing “bathroom disease” like IBD, this is especially vital.”

Joshua Tree National Park

Economic Costs of Gluten Free Diet

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A recent study (AR Lee et al. Nutrients; 2019, 11, 399). Open access: Persistent Economic Burden of the Gluten Free Diet) quantifies the additional costs of a gluten free diet (GFD) in the U.S. Thanks to Kipp Ellsworth for this reference.

The authors conducted a “market basket” study to establish the cost of a GFD. “A market basket is a group of products that are purchased by consumers …for this study, the market basket was food that would necessitate a GF substitute, including staple foods, snack foods, and commonly used ready-made or convenience meals.”

Key findings:

  • GF products were more expensive, overall the increase was 183%.  This is an improvement from a 2006 study which found the increase overall at 240% (adjusted for inflation).
  • Mass-market products were 139%  more expensive than wheat-based versions

Discussion:

  • Cost is identified as a frequent reason for nonadherence with diet, cited by 33% in one study
  • Overall, the burden of GFD is more frequently related to the restrictive nature of the diet which leads to a negative impact on quality of life. According to the authors, in one study (Am J Gastroenterol 2014; 109: 1304-11), treatment burden for celiac was ranked higher than for diabetes hypertension, and congestive heart failure

My take: This study shows the significant economic burden of a GFD.  In Italy, the  “government offers celiac patients vouchers to buy gluten-free food — up to 140 euros per month.” (NPR: Italy, Land of Pizza and Pasta)

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FDA’s Very Limited Ability to Regulate Dietary Supplements

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NY Times: Supplement Makers Touting Cures for Alzheimer’s and Other Diseases Get F.D.A. Warning

An excerpt:

The Food and Drug Administration on Monday warned 12 sellers of dietary supplements to stop claiming their products can cure diseases ranging from Alzheimer’s to cancer to diabetes.

At the same time, Dr. Scott Gottlieb, the agency’s commissioner, suggested that Congress strengthen the F.D.A.’s authority over an estimated $40 billion industry, which sells as many as 80,000 kinds of powders and pills with little federal scrutiny…

The F.D.A.’s oversight is based on a 1994 federal law, which imposed minimal reporting and labeling requirements on the makers of vitamins, minerals and herbs — a fledgling industry at the time. To prevent a company from selling a product, the law requires the F.D.A. to prove that it is unsafe…

There are now between 50,000 and 80,000 dietary supplements on the market, according to the F.D.A. The agency also says that three of every four American consumers now take a dietary supplement regularly.

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Pushing the Boundaries on Dietary Therapy for Crohn’s Disease (CD-TREAT)

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A recent study (available online in advance of publication) (V Svolos et al. Gastroenterology https://doi.org/10.1053/j.gastro.2018.12.002) examines the feasibility and science of modifying a diet to mimic exclusive enteral nutrition.

Full text accepted manuscript (from ScienceDirect/Gastroenterology website): Treatment of Active Crohn’s Disease With an Ordinary Food-based Diet That Replicates Exclusive Enteral Nutrition (PDF 135 pages)

Background: The authors note that exclusive enteral nutrition (EEN) is the only established dietary treatment for Crohn’s disease.

This complicated study had three main parts:

  1. Examining the effects of their CD-TREAT diet compared to EEN in 25 healthy adults in a randomized control trial
  2. Animal experiments (rat model) to explore the anti-inflammatory effect of CD-TREAT
  3. Pilot open-label study of 5 children with CD-TREAT diet (8-weeks)

In the first part of this study, the authors modeled a diet based on the components of the formula modulen. This diet continued to exclude gluten, lactose, and alcohol and tried matching other components (macronutrients, vitamins, minerals, fiber).  In place of maltodextrin (the commonest carbohydrate in EEN feeds), the authors substituted foods high in starch and low in fiber.  Also, the authors decreased carbohydrates in CD-TREAT (particularly complex carbohydrates) in favor of protein.  This diet was given to 25 healthy adults.

Key findings:

  • CD-TREAT induced similar effects to EEN on fecal microbiome, composition,metabolome, mean total sulfide, pH, and short-chain fatty acids (SCFA)

In the second part of this study, in the rat model, CD-TREAT and EEN produced similar changes in bacterial load, short-chain fatty acids, microbiome, and in ileitis severity.

In the third part of the study with 5 children, after 8 weeks —Key findings:

  • 4 (80%) had a clinical response
  • 3 (60%) entered a clinical remission with concurrent reductions in calprotectin (mean decrease of 918 +/- 555 mg/kg)

The CD-TREAT diet appears to affect the taxon abundance of many species of the microbiome in a manner similar to EEN therapy.  The authors noted that CD-TREAT also changed the abundance of genera belonging to Actinobacteria, Bacteroides, and Firmicutes.

Unlike EEN, the CD-TREAT diet is subject to more variable individual intakes; it is not identical in all individuals.

My take: The mechanism of action of EEN therapy remains poorly understood.  The CD-TREAT diet, which is far more diverse than EEN, appears to replicate many of the effects of EEN: “the microbial composition, fecal pH, SCFA, total sulfide, fecal bacterial load and fecal metabolome significantly changed in the same direction for both diets.” A larger clinical study is needed to confirm the effectiveness of the CD=TREAT diet.

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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

Joshua Tree National Park

 

 

Plasma miR-1290 -Specific Biomarker for Necrotizing Enterocolitis

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Briefly noted: P Cheung, et al. J Pediatr 2019; 205: 83-90.  This study showed that a plasma biomarker for necrotizing enterocolitis (NEC), miR-1290, was very useful in a cohort of 301 neonates.

  • Of 20 infants with miR-1290 > 650 copies/microliter, 15 were diagnosed with NEC.
  • In those with intermediate values (220-650 copies/microliter) adding CRP (>1.58 mg/dL) allowed for a sensitivity of 0.83, specificity of 0.96, a positive predictive value of 0.75, and a negative predictive value of 0.98.
  • The authors state that 7 of 36 infants had NEC diagnosed earlier by 8-32 hrs based on the availability of miR-1290 testing.

My take: Biomarkers are helping us identify serious diseases more quickly and changing how we practice.  Hopefully, work in this area will help us identify NEC sooner and improve outcomes.

Below is a visual abstract indicating that transfusion for platelet count less than 25 K was associated with a lower rate of death/major bleeding that a platelet count threshold of 50 K.

Visual abstract indicates that most preterm infants do not need platelet transfusions as long as the platelet count is >25 K.

Oral Antibiotics For Refractory Inflammatory Bowel Disease

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A recent retrospective study (J Breton et al. Inflamm Bowel Dis 2019; https://doi.org/10.1093/ibd/izz006) currently available online in advance of publication is likely to influence current practice in children with refractory inflammatory bowel disease (IBD). Thanks to Ben Gold for sharing this reference.

Link to abstract: Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease

Here are some of the details:

  • There were 63 patients who met inclusion criteria.
  • 27 (43%) with colonic (n=18) or ileocolonic (n=9) Crohn’s disease (CD)
  • 23 (36.5%) with ulcerative colitis
  • 13 (21% classified with IBD-U.
  • 34 (54%) were corticosteroid-refractory or dependent
  • 62/63 with previous or present loss of response or primary nonresponse to anti-tumor necrosis factor (anti-TNF) therapy
  • 48 (76.2%) were receiving anti-TNF therapy at time of antibiotic initiation
  • Of the 37 with available anti-TNF trough, 23 (62.%) were considered therapeutic  (IFX ≥5, or ADA ≥7.5)
  • Medical refractoriness “was defined by corticosteroid resistance, as shown by no or partial response to more than 7 days of hgih-dose corticosteroids (≥ 1 mg/kg/day prednisone equivalent) or primary nonresponse or loss of response to a biologic”

Antibiotic regimens: A=Amoxicillin, D =Doxycycline, M =Metronidazole, C= Ciprofloxacin, V= vancomycin. Antibiotic therapy was based on previous study which used ADM. A =50 mg/kg/day divided TID to max 500 mg/dose; D =4 mg/kg/day divided BID to max 100 mg/dose; M 15 mg/kg/day divided TID to max of 250 mg/dose. In children <8 yrs, C =20 mg/kg/day divided BID to max of 250 mg.  Vancomycin 125 mg/dose QID in <8 y and 250 mg/dose QID in ≥8 yo could be added as a 4th drug and Gentamicin cold be substituted in those with a drug allergy.

  • 45% ADM
  • 8% ADMV
  • 8% CMV
  • 8% AMV
  • 8% ACM
  • 6% ADV
  • 17% Other

Improvement with Regimen:

  • Median PUCAI dropped from 55 at baseline to 10 (P<0.0001) by 3 weeks ± 1 week after antibiotic initiation
  • 40 (63.5%) experienced a clinical response with a change in PUCAI of ≥20 points
  • 25 (39.7%) entered clinical remission, including 6 who achieved corticosteroid-free remission
  • Other markers of improvement: increased median hemoglobin (10.7–>11.6), Improved median CRP (1.1 –> 0), improved median ESR (38 –>21)
  • Use of doxycycline (OR 0.25) and high PUCAI ≥ 65 (OR 0.2) were both associated with a much lower odds of clinical remission

Outcomes:

  • Among the 25 entering clinical remission, 13 (65%) had successful rescue of current anti-TNF therapy, 6 were transitioned to another biologic (vedolizumab or ustekinumab)
  • No serious adverse drug-related toxicities were evident.  No cases of Clostridium difficile. One patient had a vaginal yeast infection

Implications:

  • The authors interpret their findings as indicating that antibiotics could serve as an effective rescue therapy in some and potentially rescue anti-TNF therapy in patients with refractory disease.
  • The discussion speculates that improvement is related to microbial modulation as dysbiosis “may play a causative role in perpetuating inflammation”
  • In those placed on antibiotics, the authors state that “clinical response should be assessed frequently and therapy discontinued if no improvement is documented within 1 week”

Safety and Antibiotic Choice:

  • While there were no safety signals evident in this study over 1 year, the long-term risks of using antibiotics is uncertain. For example, with ciprofloxacin, a fluoroquinolone, there is a well-recognized risk of permanent damage to tendons/joints (link to FDA update) and fluoroquniolones increase the risk of aortic tear/rupture.  Because aortic rupture is rare, this increased risk represents a very low absolute risk.
  • The authors indicate that doxycycline, used in 45%, had a much lower response rate.  This makes the choice of antibiotic regimen uncertain –none of the other regimens were used in more than 8%.
  • Given the retrospective nature, it is unclear whether some of the improvement could be related to additional time for the adjunctive/non-antibiotic treatments to work. Though, the authors found that the effect of antibiotics seemed to be independent of therapy optimization.

My take: This is an important study for children with limited treatment options in the setting of refractory disease and may act to salvage current anti-TNF treatment or facilitate a bridge to an alternative treatment.  Though, the optimal antibiotic regimen in this setting is unclear.

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.

Heart-shaped Cactus, Joshua Tree National Park

Joshua Tree National Park. This image selected since this article discusses a ‘bridge’ therapy,

 

How (Un)Helpful is AD Manometry in Children with Orthostatic Intolerance?

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A recent retrospective study (LN Zhang et al. J Pediatr 2019; 205: 133-44) reviewed the records of 103 consecutive children with orthostatic intolerance and gastrointestinal symptoms, all of whom had undergone antroduodenal manometry (ADM). The median age was 17 years with a 3:1 female predominance. The same group has published a smaller study in 2016 with 35 children (A Darbari et al JPGN 2016; 63: 329-35).

In their methods, the authors stated that neurogenic intestinal dysmotility was diagnosed if there was

1. lack of fasting MMC III
2. presence of simultaneous nonpropagative or retrograde phases
3. prolonged >30 min high amplitude clusters in duodenum
4. increase in basal tone >30 mmHg for >3 minutes during phase II MMC in a fasting state
5. lack of conversion from fasting MMC-III to fed MMC-II after meals
6. bursts of nonpropagating phase contractions w/in 30 minutes of meals

Key findings:

  • At baseline, the authors state that 12 (12%) had neurogenic intestinal dysmotility and 8 (8%) had significant antral hypomoility.
  • When ADM was undertaken in conjunction with tilt testing, the authors identified neurogenic intestinal dysmotility in 51 (50%), rumination/regurgitation in 23 (22%), and visceral hyperalgesia in 11 (11%).
  • Abnormalities in ADM did not have any correlation with abnormal gastric emptying studies (GES)s (which were performed in 83 of 103).  For example, among those with abnormal ADM (n=83), 48 (73%) had normal GES. And, among those with normal GES (n=58), 48 (83%) had abnormal ADM.
  • “Analysis of EGD biopsy samples revealed nonspecific esophagitis and/or gastritis in 16 of 103 patients (15%)”

While this research provides some insight into why children with orthostatic intolerance may have gastrointestinal symptoms, I remain skeptical of the usefulness of ADM as a routine study in clinical practice. The authors claim that ADM has ‘potential importance…in its utility in targeting future therapies.’

There are many hurdles, in my view, in making these studies worthwhile clinically:
  1. More uniformity in interpretation of ADM studies.  I do not have specialized neurogastroenterology training, but my understanding is that the difference between normal and abnormal is often blurry.
  2. More effective motility agents including prokinetics and agents to improve visceral hyperalgesia. How helpful is it to identify subtle manometric abnormalities without effective therapeutic agents?
  3. If GI problems are only demonstrated during tilt testing, how important is this?  I suspect that many individuals would have abnormalities if ADM was done while they were on a roller coaster, but I doubt that this would help me determine treatment for GI symptoms induced by this type of stimulus.
My take: This study confirms that EGDs are rarely useful in this setting and suggests that ADM could be.  While the study identifies frequent abnormalities when ADM was combined with tilt testing, it remains uncertain whether this will improve clinical management.
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Cholla Cactus, Joshua Tree National Park
Don’t get too close -often called the ‘jumping cactus’