Budesonide FDA-Approved for Eosinophilic Esophagitis

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AAP News 2/13/24: FDA approves first oral therapy for EoE

Eohilia is given in doses of 2 milligrams twice a day for 12 weeks. The label notes it has not been shown to be safe and effective for longer.

The FDA accepted Takeda’s new drug application in December 2020. A year later, the FDA determined more study was needed. Takeda revised its application and resubmitted it in September 2023.

Takeda conducted two multicenter, randomized, placebo-controlled trials in patients 11 to 56 years and 11 to 42 years, respectively. The first found 53% of the treatment group achieved histologic remission compared to 1% receiving a placebo. The second found 38% of the treatment group achieved remission vs. 2% of the placebo group, according to Takeda…

Patients [need] to refrain from eating or drinking for at least 30 minutes after taking Eohilia. After 30 minutes, patients should rinse their mouth and spit to reduce the risk of developing thrush.

My take: Budesonide has been used effectively for EoE for a long time; it is good news that it is recognized by FDA with a specific EoE indication. However, it is a little concerning that the label indication is for 12 weeks when we know that this is chronic disease. Also, I am eager to see how much this formulation costs in comparison to the budesonide ampules.

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How Not to Console an Irritable Infant

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A Berkwitt et al. NEJM 2024; 390: 358-366.Case 3-2024: An 8-Week-Old Male Infant with Inconsolable Crying and Weakness

This case report describes an 8 week old who been well until 7 days before the current presentation, when irritability, less frequent stooling and frequent crying developed. He was seen by his primary care clinic and symptoms were attributed to gas. Several days later, he presented to the emergency department with persistent crying but he had developed lethargy and weakness.

This case report details potential reasons for irritability in infants:

  • Infections
  • Neurologic causes including hydrocephalus
  • Ocular/skin such as a corneal abrasion and hair tourniquet
  • Cardiopulmonary causes such as heart failure and myocarditis
  • Gastrointestinal causes like colic, constipation gas, and reflux
  • Genitourinary like hernia and torsion
  • Musculoskeletal like fractures
  • Cancer including neuroblastoma and leukemia
  • Metabolic causes
  • Ingestions/Toxins

Then, the authors turn their attention to potential reasons for hypotonia:

  • CNS disease -accounts for 60 to 80% of cases of hypotonia, specifically hypoxic–ischemic encephalopathy and cerebral palsy
  • PNS disease -need to be considered in those with normal neuroimaging. To have an acquired PNS disease, the authors considered mainly botulism and Guillain-Barre syndrome.

Ultimately, the authors concluded that the infant likely had botulism which was in fact the correct diagnosis, confirmed by a stool test for Clostridium botulinum toxin type A (generally available only through local public health departments). Also, “On further interviewing, the patient’s family members reported that he typically had hard stools every 2 to 3 days. Two days before admission, the infant appeared to have abdominal discomfort, which his family members presumed was from constipation or gas. Honey was given to try to soothe him.”

Teaching points:

  1. Don’t give honey or corn syrup to a baby, though “clearly defined food exposures, such as exposures to honey or corn syrup, account for only a minority of cases.8..Often, there is a history involving rural living, dust production, or nearby soil perturbation.9“
  2. Give Baby BIG (infant botulism immune globulin) while waiting for results.
  3. Try to ascertain dietary exposures when obtaining a history.

Fortunately, this infant fully recovered.

Related blog post: Why call it botulinum?

View from The Windmill Bar in St John  

IBD Updates: Extending Mirkizumab Induction, Best Biologic, Fatigue in Pediatric IBD, Adalimumab Success in Patients with Abdominal Abscess

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  1. G D’Haens et al. Inflamm Bowel Dis 2024; https://doi.org/10.1093/ibd/izae004. Extended Induction and Prognostic Indicators of Response in Patients Treated with Mirikizumab with Moderately to Severely Active Ulcerative Colitis in the LUCENT Trials

Key findings:

  • Of patients not achieving clinical response during 12-week induction, 53.7% achieved response following extended induction (additional 3 doses of IV infusion every 4 weeks)
  • With “extended induction,” total of 80.3% mirikizumab-treated patients achieved clinical response by W24

2. S Schreiber et al. Inflamm Bowel Dis 2024; 30: S7. NETWORK META-ANALYSIS TO EVALUATE THE COMPARATIVE EFFICACY OF BIOLOGICS FOR MAINTENANCE TREATMENT OF ADULT PATIENTS WITH CROHN’S DISEASE

Methods: A network meta-analysis (NMA) was conducted to evaluate comparative efficacy of licensed biologics. Phase 3 randomized controlled-trials (RCTs) evaluating biologics approved by the European Medicines Agency or United States Food and Drug Administration as of 31 March 2023 for maintenance treatment of adult patients with moderate-to-severe CD were included, i.e. infliximab (IFX) intravenous (IV) and SC, adalimumab (ADL) SC, vedolizumab (VDZ) IV and SC, ustekinumab (UST) SC, and risankizumab (RZB) SC.

Key findings:

  • Among 8 comparator arms, IFX SC 120 mg every 2 weeks (Q2W) showed the highest odds ratio (95% credible interval) vs. PBO for clinical remission during the maintenance phase (3.52 [2.18–5.65]).

My take: This meta-analysis shows a favorable response for IFX SC; however, head-to-head trials are needed to really determine which biologic has the highest efficacy.

3. N Bevers et al. JPGN 2024; 2023; 77: 628-633. Fatigue and Physical Activity Patterns in Children With Inflammatory Bowel Disease

In this cross-sectional study with 104 children (24 with fatigue), biological parameters (CRP, fecal calprotectin) did not discriminate fatigued from non-fatigued patient

4. Y Bouhnik et al. Clin Gastroenterol Hepatol 2023; 21: 3365-3378. Adalimumab in Biologic-naïve Patients With Crohn’s Disease After Resolution of an Intra-abdominal Abscess: A Prospective Study From the GETAID

In this multicenter prospective study with 117 patients, the authors examined the success rate of adalimumab (ADA) in patients with CD with an intra-abdominal abscess resolved without surgery.

Key findings:

  • At W24, the survival rate without abscess recurrence or surgery was 74% (n=87)
  • Abscess drainage was significantly associated with ADA failure at W24 (odds ratio, 4.18)

My take (borrowed from authors): Provided that the abscess was carefully managed before initiating medical treatment, this study showed the high efficacy of ADA in the short and long term in biologic-naïve patients with CD complicated by an intra-abdominal abscess

Adjacent to Honeymoon Beach, St John

Predicting the Burden of IBD Until 2040

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R Patel et al. Inflamm Bowel Dis 2024; https://doi.org/10.1093/ibd/izae020.067. DECIPHERING THE BURDEN OF INFLAMMATORY BOWEL DISEASE LANDSCAPE (1990-2019) IN HIGH INCOME NORTH AMERICA: PROJECTIONS, TEMPORAL SHIFTS, AND A GLIMPSE BEYOND TO 2040 

Methods: “Utilizing Global Burden of DIsease tool, we estimated IBD prevalence, incidence, mortality, and Disability Adjusted Life Years (DALYs) of IBD in High-Income North America. Standardized statistical techniques facilitated comparisons by age, sex, year within this specific region. The DisMod-MR 2.1 tool was employed to estimate incidence and prevalence, while mortality rates were discerned using the Cause of Death Ensemble Model (CODEm). Additionally, we projected the deaths and Years of Life Lost (YLLs) up to 2040 using regression analysis.”

What to Do with Refractory Autoimmune Hepatitis: Case Report

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N Hadzic et al. NEJM 2024; 390: 284-286.JAK Inhibition in STAT1 Gain-of-Function–Mediated Treatment-Resistant Autoimmune Hepatitis

In this case report, the authors describe a 21 month old who presented with jaundice and abnormal liver tests. Diagnostic evaluation identified high titers of LKM antibodies (1:10,520) along with liver biopsy findings consistent with type 2 autoimmune hepatitis (AIH). After 6 months of treatment with steroids and subsequently azathioprine, the patient continued with severe biochemical relapses and a liver biopsy showed only a partial response.

Subsequently, “genetic testing found the patient had a heterozygous c.821G→A p.(Arg274Gln) pathogenic variant in the gene encoding signal transducer and activator of transcription 1 (STAT1)… Functional assays in the patient repeatedly showed abnormally high STAT1 phosphorylation as compared with healthy controls; this confirmed an autosomal dominant STAT1 gain-of-function defect.”

Treatment with “baricitinib, an inhibitor of Janus kinase 1 (JAK1) and 2 (JAK2), was started. Within weeks, the patient’s aminotransferase levels normalized. ..A liver-biopsy sample that was obtained 4 months after the initiation of baricitinib therapy showed an absence of appreciable inflammation with residual mild fibrosis…She was weaned off mycophenolate and is continuing to receive daily baricitinib (8 mg) and prednisolone (2.5 mg) along with fluconazole and azithromycin for infection prophylaxis.”

My take: In children with refractory autoimmune hepatitis, genetic testing is worthwhile and may allow targeted therapy.

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Tyre Palm on St. John

Severe Cognitive Slowing Identified in Long COVID

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S Zhao et al. eClinical Medicine 2024; DOI:https://doi.org/10.1016/j.eclinm.2024.102434. Open Access! Long COVID is associated with severe cognitive slowing: a multicentre cross-sectional study

Methods: To examine cognitive slowing, patients with post-COVID-19 conditions (PCC) completed two short web-based cognitive tasks, Simple Reaction Time (SRT) and Number Vigilance Test (NVT). 270 patients diagnosed with PCC at two different clinics in UK and Germany were compared to two control groups: individuals who contracted COVID-19 before but did not experience PCC after recovery. For the SRT, participants were required to press the spacebar when a large red circle appeared in the center of the screen.

.**The simple reaction time task and the number vigilance task can be tried online at [https://octalportal.com/pcc]..

Key finding:

  • There was pronounced cognitive slowing in patients with PCC, which distinguished them from age-matched healthy individuals who previously had symptomatic COVID-19 but did not manifest PCC. Cognitive slowing was evident even on a 30-s task measuring simple reaction time (SRT), with patients with PCC responding to stimuli ∼3 standard deviations slower than healthy controls. 53.5% of patients with PCC’s response speed was slower than 2 standard deviations from the control mean, indicating a high prevalence of cognitive slowing in PCC.
  • Comorbidities such as fatigue, depression, anxiety, sleep disturbance, and post-traumatic stress disorder did not account for the extent of cognitive slowing in patients with PCC.
  • Cognitive slowing on the SRT was highly correlated with the poor performance of patients with PCC on the NVT measure of sustained attention.
Results of simple reaction time       

My take (borrowed from authors): Using a 30-s web-based, self-administered psychomotor task, cognitive slowing in PCC can be reliably and easily measured as part of diagnostic work-up, and has potential to be a biomarker to track the progress of rehabilitation of PCC.

**The simple reaction time task and the number vigilance task can be tried online at [https://octalportal.com/pcc].

AGA Guideline on Pouchitis Management

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Key recommendations

  • AGA recommends metronidazole and/or ciprofloxacin as preferred treatment of pouchitis with duration of treatment 2-4 weeks.
  • For Crohn’s-like disease of the pouch, AGA guideline recommends using either ileal-release budesonide or advanced immunosuppressive agents (eg. Biological therapies and small molecule therapies)
  • “In patients with cuffitis, topical therapies should be the first-line therapy, such as mesalamine suppositories, corticosteroid suppositories, or corticosteroid ointment applied directly to the cuff. Biological therapies and small molecule therapies are recommended in refractory cases

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Cannabis Toxic Effects

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Two recent articles review cannabis-related disorders:

DA Gorelik. NEJM 2023; 389: 2267-2275. Cannabis-Related Disorders and Toxic Effects

Background: “In the United States, an estimated 52.4 million persons 12 years of age or older used cannabis in 2021, representing 18.7% of the community-dwelling population in that age group,5 and 16.2 million persons met the diagnostic criteria for cannabis use disorder, which has as its core feature the use of cannabis despite adverse consequences…Cannabis use poses a global disease burden, albeit substantially less than that posed by other psychoactive substances such as alcohol, tobacco (nicotine), opioids, and stimulants.10 The Global Burden of Disease project calculated that cannabis use in 2016 was responsible for an estimated 646,000 years of healthy life lost to disability.”

Key points:

  • “Cross-sectional surveys suggest that recent cannabis use increases the risk of motor vehicle crashes by 30 to 40%.26 By comparison, a blood alcohol concentration of 0.08% increases the risk of crashes by 250 to 300%.26“
  • “Cannabis use disorder, like other substance use disorders, is a chronic, relapsing condition.”
  • “A substantial reduction or a cessation of cannabis use after heavy or long-term use results in a withdrawal syndrome that is usually mild and self-limiting.39…Common psychological symptoms of cannabis withdrawal include depressed mood, anxiety, restlessness, irritability, decreased appetite, and sleep disturbance. Physical signs and symptoms are less common and include abdominal cramps, muscle aches, tremor, headache, sweating, chills, and weight loss. These signs and symptoms typically begin within 1 to 2 days, peak within 2 to 6 days, and last for several weeks…The prevalence of any withdrawal symptoms is almost 50% in persons who were using cannabis daily.”
  • Neonatal cannabis exposure: “Pregnant persons who use cannabis expose their neonates to cannabis. Such in utero exposure is associated with increased risk among newborns of having low birth weight, being small for gestational age, and being admitted to the neonatal intensive care unit.”
  • “Cannabinoid hyperemesis syndrome, a form of cyclic vomiting syndrome that is often accompanied by abdominal pain, occurs during or within 48 hours after frequent and heavy cannabis use.75 Cannabinoid hyperemesis syndrome is a major reason for cannabis-related visits to emergency departments, and it accounts for about 10% of patients with cyclic vomiting syndrome.76 Cannabinoid hyperemesis syndrome is distinguished from cyclic vomiting syndrome by its temporal association with cannabis use, relief with hot baths or showers, and resolution with extended abstinence from cannabis…The symptoms of cannabinoid hyperemesis syndrome are treated with benzodiazepines, haloperidol, and topical capsaicin. “
                 

M Camilleri, T Zheng. Clin Gastroenterol Hepatol 2023; 21: 3217-3229. Cannabinoids and the Gastrointestinal Tract This article focuses more on the GI tract effects of cannabinoids.

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Increased Risk of Suicide in Patients with IBD

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At a lot of IBD conferences, there is often a lot of focus on health maintenance including discussions on optimizing immunization levels and nutrition. It is often striking how, in comparison, so little attention is focused on emotional health which seems to cause a much greater health burden.

CS Tse et al. Inflamm Bowel Dis 2024; 30: 150-153. Increased Risks for Suicide, Self-Harm, Substance Use, and Psychiatric Disorders in Adults With Inflammatory Bowel Disease: A Nationwide Study in the United States From 2007 to 2017

Background: Patients with IBD are also at an increased risk for chronic opioid use, depression, anxiety, sleep disturbance, and disease-related disability (eg, unemployment), all known risk factors for suicide

Methods: This cross-sectional study uses the Nationwide Emergency Department Sample of the Healthcare Cost and Utilization Project (HCUP) as a public domain representing 80% of the U.S. population. This analysis included more than 260 million emergency department visits across the United States from 2007 to 2017.

Key findings:

  • Inflammatory bowel disease conferred >10-fold risk for suicide deaths, self-harm, substance use, and psychiatric disorders.
  • The absolute numbers of self-harm rates were low (<1% of all-cause inflammatory bowel disease emergency department visits; total 56 suicide deaths). This amounts to about 5 suicide deaths per year (compared to 0.5 per year for patients with celiac disease.
  • The risk of self-harm was higher in patients with Crohn’s disease than ulcerative colitis (RR, 3.3; 95% CI, 1.2-5.4), though the suicide risk was not statistically different (RR, 2.3; 95% CI, 0.8-4.5).
From Table 2: RR of self-harm, suicide, psychiatric disorders, and substance use of adults with inflammatory bowel disease compared with celiac disease in the United States from 2007 to 2017. 
The authors found that rates of self-harm and suicide were the same for patients with celiac disease as the general population (RR 1.0).

My take: Attention to mental health is important component of good care for patients with inflammatory bowel disease.

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