Is There Renal Toxicity with Mesalamine Therapy for IBD?

A recent study (V Jairath et al. AP&T 2019; https://doi.org/10.1111/apt.15408) provides evidence that 5-aminosalicylic acid therapy for IBD does NOT increase the risk of nephrotoxicity.  This paper’s findings run counter to more than thirty years of teaching on this medication.

Full Free Link: No increased risk of nephrotoxicity associated with 5‐aminosalicylic acid in IBD: a population‐based cohort and nested case‐control study

Abstract (bold highlighted by blog author):

Background

There is conflicting evidence about nephrotoxicity risk associated with 5‐aminosalicylates for treatment of IBD.

Methods

Retrospective cohort and nested case‐control study, using the Health Improvement Network primary care database linked to hospital discharge coding for patients in England, 1996‐2017. Nephrotoxicity risk analysis was a first recorded renal impairment diagnosis adjusted for key variables and was assessed between 2008 and 2017.

Results

A total of 35 601 patients with prevalent UC or CD were included. The proportion of patients prescribed 5‐aminosalicylates fell from 83% in 1996‐1999 to 71% in 2012‐2015 for UC patients and 64% to 45% for CD patients. Thirty per cent of patients had prolonged 5‐aminosalicylate use. Between 2008 and 2017, the incident rate of nephrotoxicity was similar and stable for UC (12.6/1000 person‐years) and CD (10.9/1000 person‐years) patients. Multivariate analysis showed no evidence for association between current prescription of 5‐aminosalicylate and nephrotoxicity in UC or CD patients, comparing ≤ 30 days prescription prior to index vs 31‐≤180 days. However, active disease, disease duration, concomitant cardiovascular disease or diabetes and nephrotoxic drug use were independently associated with development of nephrotoxicity in UC and CD.

Conclusions

Despite the paucity of evidence for their benefit, 5‐aminosalicylates were prescribed to approximately half of CD patients (30% prolonged therapy). Nephrotoxicity was rare in this patient cohort, and was not associated with 5‐aminosalicylate use, but rather with disease status, comorbidity and use of nephrotoxic drugs.

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Park Guell, Barcelona

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

 

Reform Needed of Orphan Drug Act

A recent commentary (A Sarpatwari et al NEJM 2019; 381: 106-8) details the need for reforming the Orphan Drug Act (passed in 1983).  To promote drugs for rare diseases, this act offered incentives including exclusive marketing rights for 7 years, a 50% tax credit for costs with clinical testing (reduced to 25% in 2017) and grants for clinical trials.

The problems that need to be addressed related to this act:

  • Soaring drug prices
  • “Slicing indications”

Key points:

  • “In 2017, the 100 best-selling rare-disease drugs had an estimated mean annual cost of more than $147,000 per patient, about $116,000 higher than that of the 100 best-selling drugs for other diseases.”  One of the most recent drugs for spinal muscular atrophy is priced at $2.1 million per patient.
  • 22% of these rare disease drugs have a non-rare disease indication (including Humira (adalimumab)).  This has led to concerns that manufacturers are slicing indications to secure the statutory benefits.
  • The authors argue that several of these favorable provisions need to be scaled back for blockbuster medications.

My take (borrowed from the authors): “The status quo increasingly threatens public health, as rising drug prices present growing access challenges for patients and indication slicing hampers collection of critical preapproval information on safety and efficacy when used in ways that will reflect their most common use in the market.”

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Park Guell, Barcelona

Park Guell, Barcelona

Informed Consent: Sedation Risks in Children Younger Than 3 Years

A recent review (DS Fishman, DB Andropoulos, JR Lightdale. JPGN 2019; 69: 3-5) discusses the topic of sedation and an FDA warning from 2016 that should be familiar to pediatric GI physicians. Related blog post (2017): FDA Warning Anesthesia and Developing Brains

The medications which induce an ‘anesthetic state’ may cause cell death and may be “causing some degree of irreversible cellular injury –at least in developing brains, which are particularly vulnerable to apoptosis… [which leads to the] sobering thought that …sedatives could be associated with long-term neurological effects.”  At the same time, the authors caution of the potential for the warnings to cause “a delay in the care of the patient.”  The authors advocate the following talking points:

  • “A single short exposure (~60 minutes) does not appear to cause adverse neurodevelopmental outcomes”
  • “There is some evidence that longer (>3 hours) or repeated exposure could have negative effects on behavior or learning.”

Websites for physicians and families:

My take: These FDA warnings need to be taken seriously and low yield/low value endoscopy needs to be avoided.

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Park Guell, Barcelona

“Mistrust in Science –A Threat to the Patient-Physician Relationship”

A recent commentary, “Mistrust in Science –A Threat to the Patient-Physician Relationship” (RJ Baron, AJ Berinsky. NEJM 2019; 381: 182-5), addresses the deterioration of trust in the patient-physician relationship and potential ways to improve this.

Shortly before reading this, I read a newspaper article titled “Newtown Parents Fight Back” in Sunday’s AJC (related article online: Newton Parents Score a Win…). In this article, some of the parents of the 20 children who were killed in Newton, Connecticut have brought successful lawsuits against ‘hoaxers’ who claimed that the “rampage had been staged, with crisis actors.” Some of the parents have received death threats subsequently.

In this ‘misinformation’ age, it would be naive to expect that medicine and science would be spared. The alluded commentary makes the following points:

  • “Clinicians enter patient encounters with the reasonable presumption that they will be trusted. After all, they have powerful knowledge and good intentions…But, medicine is changing.”
  • “The legitimacy of the medical community rests on the the credibility of medical science…Physicians rely on that foundation in every interaction they have with their patients.” And on “the intimate and personal nature of each individual doctor-patient relationship”
  • “Medical practice is becoming increasingly corporate…In 2016, for the first time, less than half of practicing physicians owned their own practice…Less attention has been paid to how corporatization changes patients’ experience and …trust.”
  • “Gallup polling has revealed that confidence in almost all institutions in the United States…has deteriorated greatly…confidence in the medical system fell from 80% in 1975 to 37% in 2015.”
  • “Alternative sources of ‘authority’ have emerged to fill gap” including social media platforms, friends and relatives.

“Given the decline in trust in the institution of medicine, simply asserting medical authority or citing evidence is unlikely to win adherents…Skepticism…is a widespread phenomenon…appealing to a neutral or independent ‘referee’ of the truth…on a given subject–does not actually change minds…attempts by experts to correct misinformation may further entrench erroneous beliefs.”

Pathways to Trust

  • “Feeling recognized is a precondition for trust.”  Having to repeat stories over and over again can be ‘trust-destroying’ as the individual feels as a stranger in the health care system
  • “Explicitly acknowledging the role…of other members of the health care team may be another way…Speak positively about the staff [and colleagues]…This practice …increased patients’ trust and satisfaction.”

My take: The authors note that in this age, science s devalued and relationships are more influential.  Thus, creating trust goes back to Peabody’s 1927 admonition: “The secret of the care of the patient is in caring for the patient.”

In the newspaper article, a book publisher involved in the promoting the Sandy Hook conspiracy had to meet one of the parents as part of a lawsuit.  “At the end of the day, Gahary shook Pozner’s hand and apologized. He offered condolences for Noah’s death.”  As in medicine, getting to know each other is the surest way to garner trust.

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Briefly Noted: Microscopic Duodenitis and Autism

A recent study (C Alessandria et al JPGN 2019; 69: 39-44) enrolled 151 patients to examine for correlation between mucosal disease and autistic children with gastrointestinal symptoms. Patients were prescribed a gluten-casein free diet (GCFD)

Key findings:

  • 134 (89%) had negative celiac disease serology
  • 56 (*37%) showed microscopic inflammation of duodenum
  • Response to GCFD diet was much higher in those with duodenitis (OR 11.3). It was unrelated to HLA-DQ2/DQ8 positivity (which was present in 48%)
  • Response to GCFD occureed with both rigourous and partial adherence without statistical difference

My view: The authors suggest that an EGD may help predict who would respond to GCFD. An alternative approach would be to offer a GCFD in those with significant GI symptoms given the unclear clinical relevance of microscopic duodenitis.  This view is supported by previous studies which have indicated that the GI findings are similar among children with and without autism.

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Park Guell, Barccelona

 

Orodispensable Budesonide Tablets for Eosinophilic Esophagitis

Full Text Link (courtesy of AGA twitter feed):Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial  AJ Lucendo et al. Gastroenterol 2019; 157: 74-86. https://doi.org/10.1053/j.gastro.2019.03.025

Abstract:

Background & Aims

Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE.

Methods

We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0–10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily).

Results

At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P< .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent.