“For Hospitalized Patients With ASUC, 5-ASA Adds No Value to Steroids”

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From Gastroenterology and Endoscopy News (4/25/22): Open Access: For Hospitalized Patients With ASUC, 5-ASA Adds No Value to Steroids

In the first prospective randomized study, presented at the 2022 Crohn’s & Colitis Congress and published in Inflammatory Bowel Dis (S Ben-Horin et al 2022;28 [suppl 1]:S14 CORTICOSTEROIDS AND 5ASA VERSUS CORTICOSTEROIDS ALONE FOR ACUTE SEVERE ULCERATIVE COLITIS: A RANDOMIZED CONTROLLED TRIAL), investigators at 10 centers in six countries randomly assigned 149 patients hospitalized for ASUC to receive daily doses of 300 mg of hydrocortisone (or equivalent methylprednisolone) alone or in combination with 4 g of mesalamine.

Key findings:

  • 72.6% of patients receiving combination corticosteroids with 5-ASA responded to treatment at one week compared with 76.3% of responders in the group receiving corticosteroids alone
  • “There were no differences in hospital length of stay between groups (median, 10 vs. nine days for the combination and monotherapy groups, respectively), the proportion of patients whose C-reactive protein level normalized (34.2% vs. 34.3%, respectively), or the proportion requiring colectomy within 90 days (4.9% vs. 4.5%, respectively).”
  • While 5-ASAs did not alter the trajectory of acute colitis, one other finding was a lower rate of biologic use (27% vs 47%, P=.07) at 90 days in those who continued to receive 5-ASA therapy at 90 days.

My take: 5-ASAs do not appear to be helpful during hospitalization for ASUC but may be beneficial as a maintenance therapy in some patients.

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How Industry Manipulates Physicians For Product Promotion

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As an homage to May 4th, I wanted to highlight an AAP report that reminded me of Yoda telling Luke Skywalker: “If once you start down the dark path, forever will it dominate your destiny, consume you it will, as it did Obi-Wan’s apprentice.”

DS Diekema. AAP Committee on Bioethics. Pediatrics 2022; 149: e2022056549. Open Access. Health Care Clinicians and Product Promotion by Industry.

Background:

  • “In 2016, pharmaceutical companies spent $29.9 billion on marketing, of which $20.3 billion (68%) was directed toward health care clinicians in the form of prescriber detailing ($5.6 billion), free samples ($13.5 billion), direct physician payments related to specific drugs ($979 million), and disease education ($59 million)”
  • “In 2019, 615 000 physicians received payments or investment interests worth $3.6 billion (an average of $5854 per physician recipient), and 1194 teaching hospitals accepted payments totaling $2.63 billion”
  • “Despite their own sense of invulnerability to persuasive techniques, physicians do consider other physicians to be vulnerable.125  This phenomenon is what social scientists refer to as the “bias blind spot.”147  As a general rule, individuals underestimate the degree to which they are influenced by cognitive and motivational bias and overestimate the degree to which others are influenced by the same things.147 “

Key points:

“In his book, Influence: The Psychology of Persuasion, Cialdini summarizes this literature and describes 6 basic categories of effective persuasive techniques.57“

  • “Commitment and Consistency…Industry representatives are trained to get health care clinicians to make a verbal commitment to use their products…once the health care clinician has tried the drug on 5 patients, he or she is more likely to continue to use the drug.7 “
  • “Social Proof…When told that almost all of the physicians in the region are now using drug A to treat disease B, a health care clinician will be hard-pressed not to join the group”
  • “Liking… Humans tend to be more responsive and receptive to individuals who are friendly, likeable, and attractive”
  • “Appeals to Authority…The use of opinion leaders and experts to give lectures supporting the use of a product”
  • “Scarcity…Opportunities to engage in consulting and speaking opportunities fall into this category”
  • “Reciprocation…A sense of obligation to reciprocate accompanies the receipt of any favor, gift, or kindness. Gifts can take many forms and need not be valuable.”

Reciprocation Elaborated:

  • “Much cognitive activity occurs without conscious awareness, and the most effective marketing and persuasion strategies are designed to engage the subconscious aspects of decision making…Decision making appears to rely on dual systems within the brain, a socioemotional system” and the cognitive control system.
  • “The socioemotional system tends to involve rapid, automatic processing that is often reactive, intuitive, unconscious, and sensitive to social norms…Effective marketing strategies, including the use of incentives and gifts and the nurturing of relationships, are designed to engage the socioemotional decision-making areas of the brain”
  • “The cognitive control system, on the other hand, tends to be consciously controlled, reasoned, and analytic and requires more time and conscious effort”
  • “Most health care clinicians believe they cannot be bribed and that they would never trade a small gift for changing their prescribing behavior…Gifts may subtly and subconsciously affect the way the receiver of the gift evaluates the information provided by the gift giver, and these feelings of indebtedness may ultimately lead to changes in prescribing behavior”

“With regard to the receipt of gifts from the industry, the American Academy of Pediatrics (AAP) has endorsed the AMA guidelines, which do not prohibit gifts outright but offer the following basic principles for managing them:198 

  • Physicians should decline cash gifts in any amount from an entity that has a direct interest in physicians’ treatment recommendations.
  • Physicians should decline any gifts for which reciprocity is expected or implied.
  • Physicians should accept an in-kind gift for the physician’s practice only when the gift is of minimal value and will directly benefit patients, including patient education.
  • Academic institutions and residency and fellowship programs may accept special funding on behalf of trainees to support their participation in professional meetings, including educational meetings, provided the program identifies recipients based on independent institutional criteria and funds are distributed to recipients without specific attribution to sponsors”

As a final incentive,  “in late 2020, the Department of Health and Human Services Office of the Inspector General issued a special fraud alert highlighting concerns … in connection with speaker programs.” The Office of the Inspector General warned both companies and health care professionals that such arrangements may, under certain circumstances, violate antikickback statutes.”

My take (from the report): “At a minimum, health care clinicians should be cognizant of the techniques used to attempt to alter their behavior and guard against them.”

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“How Can You Tell If You Have Good-Quality Health Care?”

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The blog title is a quote from Avedis Donabedian, a pioneer in the study of health care quality.

L Rosenbaum. NEJM 2022; 386: 1663-1667. Reassessing Quality Assessment — The Flawed System for Fixing a Flawed System

Background -Cost: “The Centers for Medicare and Medicaid Services (CMS) spent about $1.3 billion on measure development and maintenance between 2008 and 2018.3 Hospitals’ QI investments vary with their size, but data from the National Academy of Medicine suggest that health systems each employ 50 to 100 people for $3.5 million to $12 million per year to support measurement efforts…[and] if good care is the goal, the greatest cost of all this activity may be wasted time.”

Key points:

  • It is hard to know if health care quality is improving after early successes in “reducing nosocomial infections,8,9 improving surgical outcomes,10 and improving processes of care for patients with pneumonia, heart failure, or myocardial infarction.”
  • One study found only 37% of CMS’s Merit-Based Incentive Payment System for internal medicine were valid.
  • “Once a measure is implemented and tied to a financial incentive, an entire industry arises to boost organizations’ scores on that measure… a tremendous amount of resources are directed toward the appearance of quality rather than its substance… QI has become more a box-checking exercise for billing purposes than a meaningful act to improve care.”
  • Even if QI measures are important, there has not been adequate “consideration of whether the movement’s costs are justified by its benefits.”
  • Lost in the grumbling: “doctors want the best care for their patients.” However, there are considerable documentation burdens tied to demonstrating quality.
  • “Using internal performance standards to motivate better care — which many physicians embrace — differs starkly from using external financial incentives to improve quality.”
  • Quality metrics remain hampered by faulty risk adjustment.

Paradoxical Effects of Quality Improvement Efforts

  • Since ” better-resourced hospitals can afford administrative support to optimize billing, value-based payment initiatives can also worsen inequities…after implementation of CMS’s value-based purchasing programs, safety-net hospitals disproportionately bore the brunt of financial penalties…Billions of dollars are thus being transferred from poorly resourced hospitals or those serving the sickest patients to well-resourced hospitals, worsening the disparities we claim to be trying to fix.”
  • Also, there is “the broader irony of attempting to reduce spending with programs that create untold administrative costs and possibly greater net costs to the system long term. For instance, smaller practices that are unable to afford these administrative costs are increasingly being bought by larger health systems that sometimes charge higher prices.”

My take: It is worthwhile to try to improve quality and value in healthcare, but, not surprisingly, quite difficult to achieve. Unintended associated consequences of current efforts include an epidemic of burnout and workforce demoralization.

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White Sands National Park, New Mexico


“Crossing Lines” and Why Firearm Deaths are The Leading Cause of Death in Children

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LK Lee et al. N Engl J Med 2022; 386:1485-1487. Open Access: Crossing Lines — A Change in the Leading Cause of Death among U.S. Children

This short commentary explains how the childhood deaths due to motor vehicle accidents have improved. “The crossing of these trend lines demonstrates how a concerted approach to injury prevention can reduce injuries and deaths — and, conversely, how a public health problem can be exacerbated in the absence of such attention.”

Esophageal Squamous Papilloma in the Pediatric Population

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N Malhotra et al JPGN Reports 2022; doi: 10.1097/PG9.0000000000000178. Open Access: Esophageal Squamous Papilloma in the Pediatric Population

  • This is a case report of 4 cases of esophageal squamous papilloma (ESP); Three out of the 4 cases of ESP identified at our institution were positive for HPV in situ hybridization.
  • “Chronic mucosal irritation due to GERD or HPV is thought to be the most common cause of ESP…a recent study failed to identify a relationship between the prevalence of HPV and the occurrence of ESP in pediatric patients”
  • “Small esophageal lesions can be managed by excisional biopsy; however, conservative management is advised when the disease is extensive to avoid mucosal scarring and stenosis…Acid suppression may decrease ongoing inflammation.”
  • “Vaccinating children with active HPV infection could theoretically increase the immune response and potentially aid in clearance of lesions caused by the disease.”

Related blog post: Esophageal Squamous Papilloma in Children Are Rare

Interesting Case of Superior Mesenteric Artery Syndrome

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D Hsu et al. JPGN Reports; 2022; doi: 10.1097/PG9.0000000000000194. Open Access: Superior Mesenteric Artery Syndrome in an Adolescent With Anorexia and Suspected Pancreatitis

“A 17-year-old … presented with cachexia, nonbilious, nonbloody emesis, lower abdominal discomfort, and decreased oral intake for four days and 40 lb weight loss for 1 year”…Lipase was 4544 U/L, and abdominal ultrasound was reported as normal. Due to “persistent emesis, despite being on bowel rest… CT abdomen and pelvis was performed, which showed a massively dilated stomach and duodenum with cutoff at the third portion of the duodenum..due to the severity of the obstruction, duodenojejunal anastomosis, and gastrostomy tube placement were performed.”

SERENE Study: Does a Higher Induction Dose of Adalimumab Help for Crohn’s Disease?

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GR D’Haens et al. Gastroenterol 2022; DOI:https://doi.org/10.1053/j.gastro.2022.01.044. Open Access: Higher vs Standard Adalimumab Induction Dosing Regimens and Two Maintenance Strategies: Randomized SERENE CD Trial Results

Methods: In this phase 3, randomized, double-blind, multicenter trial, eligible adults were randomized to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3; n = 308) or standard induction regimen (adalimumab 160 mg at week 0 and 80 mg at week 2; n = 206) followed by 40 mg every other week from week 4 onward. Endoscopic results were interpreted by a central reviewer.

Key Findings:

  • Similar proportions of patients receiving higher induction regimen and standard induction regimen achieved clinical remission at week 4 (44% in both; P = .939) and endoscopic response at week 12 (43% vs 39%, respectively, P = .462).
  • There was a high proportion of patients (>70%) who achieved corticosteroid-free clinical remission after an early corticosteroid taper beginning at week 4
  • Week 56 efficacy was similar between clinically-adjusted (CA) and therapeutic drug monitoring (TDM).  28% of patients in the CA group and 39% of TDM had their dose escalated.
  • Safety profiles were comparable between dosing regimens.

In the discussion, the authors wade into the topic of TDM for adalimumab:

“Results from the exploratory SERENE CD study suggesting there is no clinical benefit of a proactive TDM strategy over a CA strategy for optimizing adalimumab maintenance dosing align with the results from previous studies evaluating TDM of anti–tumor necrosis factor therapies in adult patients with inflammatory bowel disease. In the TAXIT study, proactive TDM was not superior to CA dose optimization for achieving remission at 1 year in patients with CD or ulcerative colitis.24 Similarly, in the TAILORIX study of patients with CD, proactive TDM failed to improve clinical and endoscopic remission rates over a CA approach.25 In contrast, proactive TDM led to a higher clinical remission rate than did reactive TDM among pediatric patients with CD in the PAILOT trial, but this trial was nonblinded and lacked endoscopic assessments.26“

My take: This study shows that standard induction performed as well as higher dose induction in adults with Crohn’s disease. Also, this study found that TDM did not improve response at 56 weeks in adults. Due to differences in body size and metabolism, the exact role for TDM in pediatric patients needs further study.

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HIR =high dose induction regimen, SIR =standard induction regimen

FLUTE Study: Fluticasone ODT for EoE -Phase 2b Study Shows Efficacy

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ES Dellon et al. Clin Gastroenterol Hepatol 2022; https://doi.org/10.1016/j.cgh.2022.02.013 (Ahead of print) Open Access: Fluticasone Propionate Orally Disintegrating Tablet (APT-1011) for Eosinophilic Esophagitis: Randomized Controlled Trial

Methods: In this randomized, double-blind, placebo-controlled, dose-finding, phase 2b trial, 106 adults with EoE received 1 of 4 APT-1011  (fluticasone propionate oral disintegrating tablet) doses or placebo for a 12-week induction period and 40 weeks of maintenance. 

Key findings:

  • Histologic response (≤6 eosinophils per high-power field at Week 12) rates were 0% for placebo, 80% for APT-1011 3 mg twice daily (BID), 67% for 3 mg at bedtime (HS), 86% for 1.5 mg BID, 48% for 1.5 mg HS (P < .001 for all groups vs placebo). 
  • There was also improvement in treatment group in dysphagia and EoE Endoscopic Reference Score (EREFS); the EREFS improved from 4.5 to 2.3 for 3 mg BID, 5.3 to 2.1 for 3 mg HS, 4.6 to 1.7 for 1.5 mg BID, 5.3 to 2.9 for 1.5 mg HS vs 5.2 to 4.5 for placebo. See Figure 2 for 52 week trend in EREFS.
  • Candidiasis: For the 3-mg BID group, oral and esophageal candidiasis was 40% in Part 1 and 32% in Part 2, 18% and 16% for 1.5 mg BID, and 5% and 7% for 3 mg HS (same subject)
  • Low morning cortisol noted 3 times in part 1 and 5 times in part 2. “All cortisol test abnormalities resolved upon retesting, with no dose adjustment or interruption of treatment.” Adrenal suppression is expected to be low because “FP undergoes extensive first-pass metabolism to inactive metabolites, with bioavailability demonstrated as <1%”

My take: A fluticasone ODT would represent a big improvement compared to current situation of asking families to either spray a pulmonary inhaler down their throat or to create a budesonide slurry using either honey or splenda. How much would this cost?

Histologic responders at Weeks 12. Interestingly, the 1.5 mg BID had a modestly higher response rate at 12 weeks, 26 weeks, and 52 weeks than the the 3 mg BID and the 3 mg qhs dosing groups.

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Sugary Beverage and Liver Stiffness in Healthy Adults

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CW Leung, EB Tapper. Clin Gastroenterol Hepatol 2022; 20; 959-961. Sugar-sweetened Beverages Are Associated With Increased Liver Stiffness and Steatosis Among Apparently Healthy Adults in the United States

In this representative sample (2706 adults, median 37.9 years) from 2017-2018 NHANES, subjects without any known chronic disease had tow 24-hr dietary recalls collected and had liver stiffness measurements (LSM) and controlled attenuation parameters (CAP); LSM <7 kPa (using vibration-controlled transient elastography) was considered low risk for advanced fibrosis and CAP >248 dB/m were at risk for heaptosteatosis. Key findings:

  • 11% (n=305) had LSM >7.0 kPa and 46% (n=1254) had CAP >248 dB/m
  • Sugar-sweetened beverage (SSB) >2/day was associated with greater LSM (OR 2.30)
  • In mutlivariate analysis, consuming >1-2 sugar-sweetened servings per day was associated with elevated CAP (OR 1.51 compared to adults with SSB consumption
  • Limitations: this cross-sectional study cannot prove causality

My take: Even in healthy adults, SSB consumption is associated with detrimental changes in the liver.

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How Esophageal Dilatation Affects Symptoms and Inflammation in Eosinophilic Esophagitis

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E Safroneeva et al. Clin Gastroenterol Hepatol 2022; 20: 766-775. Long-Lasting Dissociation of Esophageal Eosinophilia and Symptoms After Dilation in Adults With Eosinophilic Esophagitis

100 adults enrolled in a multisite prospective observational study in which 55 underwent dilatation. Key findings:

  • In nondilated patients, the association between eos/hpf and symptoms was moderate (ρ = 0.49; P < .001) based on the symptom-based EoE activity index (EEsAI); for a 10-eos/hpf increase, the predicted EEsAI increased by 2.69 (P = .002)
  • In patients dilated 1 or less and more than 1 year before index endoscopy, this association was abolished (ρ = -0.38; P = .157 for ≤1 y and ρ = 0.02; P = .883 >1 y)

Limitations: sample size (only 25% subset of total cohort due to missing data), cross-sectional study design

My take: This finding is a double-edge sword. The good part is that dilatation improves dysphagia despite ongoing inflammation which may be refractory to current medical treatments. The bad part is this dissociation in symptoms makes it less likely for patients to be adherent to therapy.

Pic from relative -Artic Circle