Vedozlizumab -Detectable in Breastmilk

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A recent correspondence (M Julsgaard et al.Gastroenterol 2018; 154: 752-65) shows that vedolizumab is detectable in varying concentrations in breastmilk.  The authors collected samples from 5 mothers who were receiving vedolizumab (VDZ) for inflammatory bowel disease.

Key findings:

  • Peak VDZ concentration in breastmilk was 0.318 mcg/mL which was 1/179th of the corresponding concentration of the maternal serum levels.
  • The authors calculated a maximum oral dose of 0.048 mg/kg/day for breastfed infants based on this peak level. “This minute quantity is furthermore anticipated to undergo proteolysis in the stomach” and be bound/excreted in GI tract.
  • VDZ was detectable in all samples for 30 minutes prior to infusion (trough) through 14 days.

This study is in agreement with another study showing that levels in the breastmilk were minute (~1/100) of serum levels (A Lahat et al. J Crohns Colitis. 2018 Jan 5;12(1):120-123).

My take: These are low levels of VDZ –nevertheless further monitoring of infants to determine conclusively whether VDZ enterally causes any adverse effects is warranted.

Views from Mike O’Callahan -Pat Tillman Bridge

 

Pediatric Home and Office Biologic Infusions -What is Needed

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A recent clinical report (E Barfield et al. JPGN 2018; 66: 680-86) will be influential.  This guideline is from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.  Congratulations to my partner, Chelly Dykes, who is one of the coauthors.

Full text: Assuring Quality for Non-Hospital Based Biologic Infusions in Pediatric Inflammatory Bowel Disease: A Clinical Report from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

For many years, our office has had an office-based infusion center which has provided infusions in a safe and cost-effective manner.  Recently, there have been some situations in which home-based infusions have been proposed either to lower costs and/or for convenience.  This report succinctly describes the hurdles that need to be addressed before recommending this treatment pathway. As noted below, patient safety encompasses a great deal more than infusion reactions. Delays in infusions (which can increase risk of loss of response) due to reactions and lapses in communication are additional issues.

Recommendation 1: Home- or office-based infusions should ensure safe administration of the biologic infusion, provide reliable execution of infusion-related orders (eg, laboratories for therapeutic drug monitoring, dose optimization protocols, etc), and be equipped to recognize and respond to potential complications.

  • Infusion reactions:  ” Infusion reactions associated with infliximab and vedolizumab can range from mild reactions such as fever and chills, dyspnea, pruritus, or urticaria (in approximately 5%–10%), to severe reactions including anaphylaxis, convulsions, and hypotension (<1%)”
  • Emergencies: “In the event of an urgent or emergent reaction during home- or office-based infusions, the in-home services agency (IHSA) nurse needs to be able to contact the appropriate ordering medical team member expeditiously by phone or pager to review/clarify specific concerns or needs to have an established clear policy on how to proceed with managing the reaction.” 
  • Communication: “We identified the lack or inconsistency of on-call coverage by the primary medical team when home- or office-based infusions occur as a significant barrier to safely initiating or continuing home- or office-based infusion programs. Difficulty in reaching a knowledgeable team member is a breach in reliable care and represents serious patient risk.”
  • Related work: “In addition to administering the biologic infusion, executing all other infusion-related orders is an important safety consideration. Implementing unique home infusion protocols is linked to treatment efficacy.”  

Recommendation 2: Pediatric home- or office-based infusions, particularly for patients 12 years and younger, should be staffed by a pediatric nurse professional with Pediatric Advanced Life Support (PALS) certification and clinical experience with pediatric patients.

Recommendation 3: Evidence-based standard of care for biologic therapy maximizing effectiveness and treatment sustainability should be established before initiating home or office-based infusions.

Recommendation 4: Home- or office-based infusion pathways that decrease opportunity loss for patients and families and deliver high-quality, patient-centered care should be supported and reproduced.

Recommendation 5: Pediatric gastroenterologists should ensure appropriate shared liability with IHSAs to deliver high-quality care in home-based infusions for children by executing pragmatic steps as outlined below:

  1. “Document discussion with the patient and family about the indication, risks, and adverse event management …
  2. Refer the patient to an accredited, licensed IHSA based on patient’s insurance coverage. If no accredited, licensed IHSA for the pediatric patient exists, this is grounds for not initiating home- or office-based infusions…
  3. & 4. Use an infusion protocol… with clear directives on recognition of signs/symptoms of reactions and administration of reaction medications and use of EMS or parent transport to an emergency room.
  4. Maintain accurate documentation and communication of therapy type, dose, and frequency.
  5. Provide a reliable communication mechanism for the IHSA to notify provider of changes or infusion-related events
  6. Regularly reviewing ongoing IHSA performance with regard to delivery of services, accurate laboratory ordering and turnaround time, safety and quality concerns and timely redressal of these issues.
  7. Switch to another IHSA if the performance reliability is unsatisfactory. …we acknowledge that changing IHSAs may be difficult.”

Recommendation 6: A more equitable division of labor should be established to offset increased administrative burden placed on the pediatric gastroenterologist and medical team to effectively facilitate and maintain home- or office-based infusions, especially when driven by payer-mandated policies.

Recommendation 7: …Among patients receiving home- or office-based infusions, unreliable follow-up care with the provider as scheduled is grounds for discontinuation of home- or office-based biologic therapy.

Recommendation 8: A proper appeals process should be in place to prevent cost transference from payer to patient in payer-mandated decisions for home- or office-based infusions.

Our office practice:

  • Emergencies: In our office, there is always one physician dedicated to being available to assess patients who are receiving infusions.  This helps insure safety and in addition, helps to make sure that minor medical problems do not needlessly postpone important treatment.
  • Documentation: With our office-based infusions, each infusion is documented by the administering nurse.  This documentation along with labs are embedded in the medical record (EPIC) to help modify treatment.
  • Communication: In our office, prior to each infusion, each patient’s chart is reviewed and specific orders are given.  This assures that needed blood tests/imaging, additional treatments (eg. iron infusion), insurance authorizations, necessary followup, and personalized adjustments are made.  This type of communication needs to be replicated for home-based infusions; hence, the use of home-based infusions could result in a huge increase in uncompensated work for the treating physician.

My take: In my experience, office-based infusions can be provided safely and in a cost-effective manner.  While the convenience of home-based infusion is desirable, before implementing broadly, issues regarding communication, safety protocols, and documentation to allow modifications in therapy need to be proactively addressed. Families may not realize some of the complexities involved in managing infusions and how these issues could affect their child’s long-term response to biologic therapy.

Related blog posts:

The following image relates to another convenience-related health trend:

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.

Screening for Colorectal Cancer in Cystic Fibrosis

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Briefly noted:

A Gini, et al. “Cost Effectiveness of Screening Individuals with Cystic Fibrosis for Colorectal Cancer” Gastroenterol 2018; 154: 556-67.

  • Key point: “Colonoscopy every 5 years, starting at age of 40 years was the optimal colonoscopy strategy for patients with cystic fibrosis” without prior organ transplantation.

D Hadjuliais, et al. “Cystic Fibrosis Colorectal Cancer Screening Consensus Recommendations: Gastroenterol 2018; 154: 736-45.

  • There are 10 Task Force recommendations. These include “initiation of screening at 40 years” in those without organ transplantation. Among those who have had organ transplantation, CRC screening is recommended at age 30 years and/or within 2 years of transplantation. Link: Abstract

My take: Fortunately, more individuals with cystic fibrosis are living long enough to benefit from CRC screening.  Due to increased risk, these guidelines recommend screening at a younger age than the general population.

More pics from Hoover Dam. The figure in this picture is a art piece honoring those who died while working on the construction

 

Position Paper: Nutrition in Pediatric Inflammatory Bowel Disease

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E Miele et al. JPGN 2018; 66: 687-708.

Full text link: Nutrition in Pediatric Inflammatory Bowel Disease: A Position Paper on Behalf of the Porto Inflammatory Bowel Disease Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition

This position paper from ESPGHAN makes a total of 53  recommendations and 47 practice points.  There are too many to summarize in this blog post, but I will highlight a few.

Vitamins/Minerals:

  • Due to insufficient data, we do not recommend routine measurement or supplementation of zinc and selenium in children with IBD (EL 2).
  • We recommend monitoring vitamin D levels in all children with IBD (EL 2).
  • We recommend monitoring folic acid annually (EL 2).
  • We do not recommend routine measurement or supplementation of vitamin B1, B2, B3, B6, B7 and vitamin C in children with IBD (EL 2).
  • We recommend folic acid supplementation (either 1 mg daily or 5 mg weekly) in children with IBD receiving MTX therapy (EL 2).
  • We recommend that either serum cobalamin levels or methylmalonic acid level in blood or urine should be measured in children with active ileal CD, children with ileal resection of >20 cm and UC children ileal pouch surgery at least annually (EL 4)

Enteral Nutrition:

  • EEN has the same efficacy as oral steroids in the induction of remission of children with active luminal CD (EL 1). EEN is recommended for a period of at least 8 weeks (EL 1).
  • The use of standard polymeric formula, with a moderate fat content, is recommended unless other conditions are present (eg, cow’s milk protein allergy) (EL 1).
  • Due to the highly demanding adherence, EEN should not be considered as an option for long-term maintenance therapy.
  • EEN is not efficacious in the induction and maintenance of remission of pediatric UC (EL 4).
  • PEN is a treatment option to maintain remission in selected patients with mild disease and low risk of relapse (EL 4).
  • A specific carbohydrate diet (SCD) for induction or maintenance of remission in pediatric IBD patients should not be recommended (EL 4). More evidence on the benefit of SCD from RCTs is needed before such a dietary restriction can be recommended to pediatric IBD patients

My take: This position paper provides a lot of useful information and makes some recommendations that are practical.  The use of diets for maintenance therapy does not receive a favorable view.

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.

Liver Disease in Joubert Syndrome

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A recent NIH study (A Strongin et al. JPGN 2018; 66: 428-35) provides prospectively-collected data from 100 individuals (mean age 9.1 years) with Joubert syndrome (JS). ( of the patients were >20 years old.

Background: JS is classified as a ciliopathy as mutations in JS genes result in nonmotile cilia.  Clinical features in this autosomal recessive condition include the following:

  • MRI finding of a “molar tooth sign” caused by cerebellar vermis hypoplasia, horizontally-oriented cerbellar peducles, and a deep interpeduncular fossa
  • Ocular features: retinal dystrophy, colobomas
  • Renal: nephronophthisis, polycystic kidneys
  • Skeletal abnormalities including polydactaly
  • Hepatic: congenital hepatic fibrosis (CHF).  CHF typically causes noncirrhotic portal hypertension and generally maintain synthetic function and do not progress to cirrhosis

Study Key Findings:

  • 43 (43%) had liver involvement indicated by elevated liver enzymes, and/or liver hyperechogenicity and/or splenomegaly
  • 13 (13%) developed probable portal hypertension; this group had more significant elevations in alkaline phosphatase (269 vs 169), ALT (92 vs 42), AST (77 vs 40) and GGT (226 vs 51)
  • The portal hypertension group were much more likely to have TMEM67 gene mutation
  • Probable portal hypertension was associated with renal involvement (P=0.001)
  • None of the patients with JS had macrocystic liver disease (which likely indicates a low risk of cholangitis)

The authors note that previous estimates of liver disease with JS of 10-15% are likely an underestimate and that “hepatic disease becomes more noticeable later in life.” In their discussion, they describe the limitations of their study which includes ascertainment bias as their cohort may differ significantly from those who have not bee brought to the attention of the NIH.

My take: JS patients are at increased risk for hepatic disease/portal hypertension, particularly at older ages.  The optimal surveillance strategy remains undefined.

Related blog posts:

Tanyard Creek Park

 

Do Acid Blockers Given to Infants Increase the Risk of Allergic Disease?

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A recent retrospective study (Mitre E, et al. JAMA Pediatr. 2018;doi:10.1001/jamapediatrics.2018.0315) suggests that acid blockers, both histamine receptor antagonists and proton pump inhibitors increase the risk of developing allergic disease.  Since this is a retrospective study, this association with allergic diseases has NOT been proven to have a causal relationship; thus, an alternative explanation would be that infants who are likely to develop allergic diseases could be prescribed these agents more frequently due to symptoms attributed to reflux.

Here is an excerpt from a summary of this study (from Healio):  Acid-suppressor, antibiotic use in infancy tied to later allergic disease

Of the 792,130 children included in the study (49.9% female), 7.6% were prescribed a histamine-2 receptor antagonist (H2RA) and 1.7% were prescribed a proton pump inhibitor (PPI) within the first 6 months of life. Antibiotics also were prescribed for 16.6% of infants included in the study during this time. Mitre and colleagues noted that data continued to be collected on these infants for a median of 4.6 years…

When children were prescribed an H2RA, the researchers noted adjusted HRs of 2.18 (95% CI, 2.04-2.33) for food allergy, 1.70 (95% CI, 1.60-1.80) for medication allergy, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) for allergic rhinitis and 1.25 (95% CI, 1.21-1.29) for asthma.

Infants who were prescribed PPIs had comparable aHRs, which the researchers observed at 2.59 (95% CI, 2.25-3.00) for food allergy, 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.45 (95% CI, 1.22-1.73) for anaphylaxis and 1.44 (95% CI, 1.36-1.52) for asthma.

Mitre and colleagues also calculated the aHRs related to later allergic disease in children who were prescribed antibiotics within the first 6 months of life. They observed these rates at 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis.

My take: This study is another reminder that these agents may be more detrimental than beneficial in the vast majority of infants.

Related blog post:

Physician Burnout -“Hidden Health Care Crisis”

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A really good review on the topic of physician burnout: BE Lacy, JL Chan. Clin Gastroenterol Hepatol 2018; 16: 311-17.

This topic has been discussed on this blog and multiple other sites.  This reference covers a lot of ground and provides a lot of useful information.  Also, some esoteric piece of information: “The term burnout first was used in the psychology literature in 1974 by Herbert Freudenberg during his work with drug addicts. He observed that many of his patients would stare blankly at their cigarettes until they burned out.”

Three key components to burnout: emotional exhaustion, depersonalization, and decrease sense of personal accomplishment

Physicians at greatest risk: perfectionists, personal qualities of idealism, and “intense sense of responsibility”

Root causes -work stress (in all its forms)

Prevention of burnout: take care of yourself, exercise, good sleep habits, “learn to say no,” use your vacation time/disconnect

Keys to treating physician burnout:

  • “learn to balance personal and professional goals”
  • “shape your career and identify stressors”
  • “nuture wellness strategies”
  • Try to become engaged in your job
  • Work on resilence

Related blog posts:

Liver Articles -Spring 2018

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C Sikavi et al. Hepatology 2018; 67: 847-57.  This systematic review highlights that the combination of hepatitis C virus (HCV) infection and HIV infection is no longer a difficult-to-treat population with the implementation of direct-acting antivirals (DAAs). There are similar sustained virologic responses (SVRs) among those with and those without HIV.  In clinical trials, patients with combined HCV-HIV had SVRs of 93.5-98% with DAA treatment; “real-world cohorts” had SVRs of 90.9%-98%.

MS Middleton et al. Hepatology 2018; 67: 858-72.  Using data from the prospective CyNCh trial (cysteamine for NAFLD), the authors examined MRIs for diagnostic accuracy among 169 enrolled children.  In this group, 110 (65%) and 83 (49%) had MRI and liver biopsy at baseline. MRI-PDFF (proton density fat fraction) was able to classify grade 1 steatosis from grade 2-3 steatosis with area under receiving operator characteristic curve of 0.87.  Thus, this study shows MRI-estimated PDFF has high diagnostic accuracy.

G Mieli-Vergani et al. JPGN 2018; 66: 345-60.  Position paper for Pediatric Autoimmune Liver Disease (AIH, ASC, de novo AIH after liver transplantation). This is a very useful review.  A couple of pointers from the authors:

  • “Present experience with budesonide as the first-line treatment is limited and does not appear to offer clear clinical advantage over the standard treatment”[prednisone]
  • Fecal calprotectin should be obtained to evaluate for IBD in patients with autoimmune liver disease, “even in asymptomatic children.”

JM Cotter et al. JPGN 2018; 66: 227-33. This retrospective study with 39 patients with primary sclerosing cholangitis (PSC) showed a lack of correlation between liver tests and fibrosis at presentation.  Average age of PSC diagnosis was 11.2 years, 74% had inflammatory bowel disease and 51% had autoimmune hepatitis. Related blog post: Big Pediatric PSC Study (with 781 children)

Interchangeability, Immunogenecity and Infliximab Biosimilars

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A recent study (G Fiorino et al. IBD 2018; 24: 601-6, editorial by KH Katsanos et al 465-6) provides more data on “full interchangeability” in regards to infliximab (IFX) and biosimilars CT-P13 and SB2. Full abstract below.

Key finding in study:

  • Antibodies to infliximab (ATI) cross-reacted with any type of IFX or IFX-biosimilar

Points from the editorial:

  • “The landmark NOR-SWITCH randomized controlled trial showed that 1-time switching from RMC [Remicade] to CT-P13 is not inferior to continued treatment with the infliximab originator…there are no data regarding multiple switches…Consequently, cross-switching (switching between 2 biosimilars), reverse switching (switching from biosimilar to its originator) or multiple/repeated switching is not currently recommended.”
  • This study, however, shows that “if you have already developed antibodies to 1 infliximab product, there is no point in switching to another infliximab product.”

Abstract:

Background: Infliximab (IFX) biosimilars CT-P13 and SB2 have comparable efficacy, safety, and immunogenicity to the originator Remicade (RMC). However, concerns about cross-switching patients between the 3 brands were raised in the absence of cross reactivity data between them. We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2.

Methods: Based on previous ATI status, samples from 34 patients participating in the BIOSIM01 study (13 RMC, 9 CT-P13, and 12 switchers) were selected. Patients were treated with either RMC only, or CT-P13 only, or with RMC switched to CT-P13. Additionally, 28 IFX-naïve patients were assayed as controls. In total, 180 samples were analyzed. ATI trough levels were measured in parallel with 3 different bridging Enzyme Linked Immunosorbent Assays constructed using the 3 drugs. Spearman’s coefficient and percentages of agreement were used to study the correlation between each assay.

Results: In total, 76 samples out of 152 IFX-treated patient samples were ATI-positive (30 RMC, 14 CT-P13, and 32 switchers). All resulted ATI-positive when either CT-P13 or SB2 bridging assays were used. The overall percentage of agreement was 100% when compared either with CT-P13 or SB2 assays. No significant differences were found among ATI levels and coefficients (Spearman’s 0.98 to 1.0, P < 0.0001).

Conclusions: ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.

My take: In patients doing well with IFX, switching to a biosimilar is not currently recommended.  In patients naive to IFX, use of IFX or biosimilar is expected to have similar efficacy.

Related study: B Kang et al. IBD 2018; 24: 607-16.  This prospective study of 36 pediatric patients did not identify any significant differences in efficacy…or immunogenicity after switching from IFX to CT-P13.

Related blog posts:

Breathing (Diaphragmatic) Helps Belching and Reflux Symptoms

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A recent prospective study (A M-L Ong et al. Clin Gastroenterol Hepatol 2018; 16: 407-16) of 36 patients (median age 45) showed that diaphragmatic breathing was helpful for PPI-refractory GERD symptoms/belching.  Patients enrolled all had “troublesome belching” for 6 months and GERD. Patients underwent high resolution manometry and pH-impedance study.

Key findings:

  • 9 of 15 (60%) in the diaphragmatic treatment group reduced their belching visual analog score by ≥50%, whereas none of the control group achieved the primary outcome
  • Treatment also resulted in lower GERD symptoms based on reflux disease questionnaire score -decrease of 12.2 vs 3.1 in the control group (P=.01)
  • Treatment improved QOL scores, based on Reflux-Qual Short form (15.7 increase for treatment group compared to 2.4 decrease in control group)
  • Treatment effects were sustained at 4 months after treatment

My take: Diaphragmatic breathing can be a useful adjunct in GERD, particularly in patients with belching.

Related blog post: Treatment for rumination and belching

 

Foggy Morning in Sandy Springs