IBD Updates: Dual Advanced Therapies in Pediatrics, IL23 agents/Psoriasis

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A Yerushalmy-Feler et al. Inflammatory Bowel Diseases, Volume 30, Issue 2, February 2024, Pages 159–166. Open Access! Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN

In this retrospective study with 62 children (35 Crohn’s disease, 27 ulcerative colitis) with extensive and severe IBD that was refractory to various therapies, the authors examined the outcomes of combination therapies: the dual therapy included an anti-tumor necrosis factor agent and vedolizumab in 30 children (48%), anti-tumor necrosis factor and ustekinumab in 21 (34%) children, vedolizumab and ustekinumab in 8 (13%) children, and tofacitinib with a biologic in 3 (5%) children.

Key findings:

  • Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively.
  • Normalization of C-reactive protein and decrease in fecal calprotectin to <250 µg/g were achieved in 75% and 64%, respectively, at 12 months 
  • Twenty-nine (47%) children sustained adverse events, 8 of which were regarded as serious and led to discontinuation of therapy in 6.
  • Among the 43% that were receiving steroids at the start of dual therapy, twenty (74%) of them could be successfully weaned within 3 months after the initiation of dual therapy.
  • Only 2 of 23 (8.7%) had endoscopic healing

My take (borrowed partly from authors):

  1. “Dual biologic therapy may be effective in children with refractory IBD. The potential efficacy should be weighed against the risk of serious adverse events” and affordability.
  2. “There are currently no data for identifying the patients that are more likely to benefit from dual therapy….The ideal selection of dual biologic regimens remains to be determined.”

A Al-Janabi et al. JAMA Dermatol. 2024;160(1):71-79. doi:10.1001/jamadermatol.2023.4846 Open Access! Risk of Paradoxical Eczema in Patients Receiving Biologics for Psoriasis

This study examined more than 13,000 patients enrolled in a prospective cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register for adults treated with biologics for plaque psoriasis.

Key findings:

  •  A total of 273 exposures (1%) were associated with paradoxical eczema.
  • The adjusted incidence rates were 0.94 per 100 000 person-years for TNF inhibitors, 0.80 per 100 000 person-years for IL-12/23 inhibitors, and 0.56 per 100 000 person-years for IL-23 inhibitors.  IL-23 inhibitors were associated with a lower risk of paradoxical eczema (hazard ratio [HR], 0.39)

My take (from authors): The overall incidence of paradoxical eczema was low in biologic-treated patients with psoriasis. The risk was lowest in patients receiving IL-23 inhibitors. Increasing age, female sex, and history of AD or hay fever were associated with higher risk of paradoxical eczema.

Chattahoochee River in Sandy Springs, GA

IBD Updates: Preventing Inflammatory Bowel Disease with a Healthy Diet and Medication Safety Pyramid

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Guo A, Ludvigsson J, Brantsæter AL, et al. Gut Published Online First: 30 January 2024. doi: 10.1136/gutjnl-2023-330971 Open Access! Early-life diet and risk of inflammatory bowel disease: a pooled study in two Scandinavian birth cohorts Thanks to Mike Hart for this reference.

Methods: This study used prospectively collected data in children borne in Sweden from 1997-1999 as part of the ABIS (All Babies in Southeast Sweden, n=16,419) and in a similar study from Norway 1999-2008 as part of the MoBa (Norwegian Mother, Father and Child Cohort, n=113,106) study. Food data was recorded at 1 and 3 years. At the 1 year timepoint, there were 81,280 participants and 307 with IBD. At the 3 year timepoint, there were 65,692 participants and 266 with IBD.

Diet quality was examined using a modified Health Eating Index (HEI) (measure 1). ”The modified HEI reflects the child’s overall dietary quality, rather than food quantity and energy intake. This index included the intake of seven food groups: ‘fruits and vegetables’, ‘dairy foods’, ‘meat’, ‘fish and eggs’, ‘soft drinks’, ‘salty snacks’ and ‘sweet snacks’ (online supplemental tables 2 and 3). The intake of each food group was categorized by ranking weekly intake frequency by quartiles with a score of 1–4. Based on WHO dietary recommendations for children, being in the lowest intake category for ‘healthy food groups’ (eg, fruits and vegetables and fish and eggs) was assigned 1 point, the highest intake category was assigned 4 points, and vice versa for unhealthy foods, such as salty snacks and sweet snacks. Finally, the total HEI score, ranging from 7 to 28, with a higher score indicating a higher dietary quality, was divided into thirds representing low, medium and high diet quality.”

Key findings:

  • Compared with low diet quality, medium and high diet quality at 1 year of age were associated with a reduced risk of IBD (pooled aHR 0.75 and and 0.75 respectively)
  • Pooled aHR for children 1 year old with high versus low fish intake was 0.70  for IBD , and showed association with reduced risk of UC (pooled aHR=0.46)

In their discussion, the authors note several other studies (references 28,38, and 39) have shown an association with diet and development of IBD. A higher adherence to a Mediterranean diet was associated with a lower risk of developing IBD. The authors speculate that the reduction in IBD may be mediated by changes in the microbiome and and “early-life diet has a significant impact on gut microbiota composition.”

My take:

  1. This study shows an association between better early-life diet quality, particularly more veggies and fish and less sugar-sweetened beverages, and a lower risk of developing IBD.
  2. Diet studies are very difficult to perform due to wide variations and lack of control. This type of prospective data with a large cohort is likely to be one of the most valuable in improving our understanding.

Related blog posts:

From Miguel Regureiro and Marcus Banks. Gastroenterology & Endoscopy News. Nov 20, 2023. Moving From IV to Subcutaneous Infliximab, and an Updated Look at Advanced Therapy Safety

Is Medicine a “Calling?”

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A recent thought-provoking commentary on medical training delved into the issue of “workism” and sacrifice in medicine. 

L Rosenbaum. NEJM 2024; 390: 471-475.On Calling — From Privileged Professionals to Cogs of Capitalism?

Dr. Rosenbaum notes that some believe using the concept of medicine as a “calling” is “weaponized against trainees as a means of subjugation — a way to force them to accept poor working conditions.”

Some excerpts:

  • The sacrifices that once brought physicians spiritual fulfillment have increasingly been replaced by a sense that we’re simply cogs in a wheel.
  • Historically the missions of trainees and hospitals were better aligned…there was a shared commitment to serve vulnerable people. Today,… most hospital boards and leaders — even at so-called not-for-profit hospitals — increasingly prioritize financial success. Some hospitals view trainees more as an inexpensive labor force… As educational missions are increasingly subordinated to corporate priorities (such as early discharges and billing documentation), sacrifice becomes far less appealing.
  • [Some younger doctors are] disheartened by what she saw as medicine’s dismissal of people’s pain, poor treatment of marginalized populations, and tendency to assume the worst about patients.
  • My interviews with trainees, educational leaders, and clinicians suggested that efforts to keep work from consuming life have unintentionally increased resistance to medical education’s demands… Some trainees insist that expectations to read up on patients or prepare for conferences violate duty hours.
  • Educators recognize changing norms… And many worried that they were guilty of the generational fallacy — a tendency sociologists call “kids these days” — of thinking their own training was superior to the next generation’s.2 

My take: Whether medicine is a job or a “calling,” like the author, I view doctoring as sacred work. There are many parts of this work that cannot conform to a 9-to-5 schedule. Some work cannot be delayed to the next day and some work can be difficult to delegate. Yet, I definitely understand how a focus on documentation/billing rather than patient care could result in physicians (young and old) not wanting to ‘go the extra mile.’

Related blog posts:

Donkeys at Honeymoon Beach

A “Swell Diagnosis” (part 2)

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Recently, this blog post reviewed a case presentation of hereditary angioedema which often presents with bouts of severe abdominal pain: “A Swell Diagnosis”

Now, a study has shown how this can be effectively treated with CRISPR gene editing:

  • HJ Longhurst et al. N Engl J Med 2024; 390:432-441. CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

My take: Gene therapies have been very expensive. If this therapy is approved for hereditary angioedema it will be too. However, some of the current treatments for preventing hereditary angioedema are also quite costly.

Related blog posts:

Early Treatment Can Prevent Fistulas in Pediatric Crohn’s Disease

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J Adler et al. Inflamm Bowel Dis 2024; https://doi.org/10.1093/ibd/izae020.056. EARLY TUMOR NECROSIS FACTOR ANTAGONIST TREATMENT PREVENTS PERIANAL FISTULA IN PEDIATRIC CROHN’S DISEASE

The authors utilized the prospectively-enrolled RISK cohort to assess the effect of early ANTI-TNF therapy and the development of perianal fistulizing complications (PFCs); this included 621 propensity-matched pediatric patients without PFCs at enrollment. ”The study included a moderately ill population, including 21% with growth delay, 43% with deep ulcers, and 70% with weighted pediatric Crohn’s disease activity index (wPCDAI) >30.”

Key findings:

  • Anti-TNF therapy was associated with 79% reduced odds of developing PFCs
  • The presence of perianal lesions increased the risk of PFCs more than 3-fold

My take: This study, in agreement with others (see below), shows that early treatment with effective therapy reduces the risk of disease complications like perianal fistulas.

Related blog posts:

Irritable Bowel Syndrome Associated with Improved Survival

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F Li et al. AJG 2024; DOI: 10.14309/ajg.0000000000002675. The Time-Dependent Association between Irritable Bowel Syndrome and All-cause and Cause-specific Mortality: A Prospective Cohort Study within the UK Biobank

Key findings:

  • Having an IBS diagnosis was strongly associated with lower risks of all-cause (HR=0.70) and all cancer (HR=0.69) mortality in the first 5-years of follow-up. These associations were attenuated over follow-up, but even after 10 years of follow-up, associations remained inverse (all-cause: HR=0.89; all cancer: HR=0.87) after full adjustment.
  • Individuals with IBS had decreased risk of mortality from breast, prostate, and colorectal cancer in some of the follow-up time categories.

My take: Having IBS may cause suffering but appears to lower risk of death. The reason for this is not clear.

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.

Related blog posts:

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.”