Tag Archives: VEO-IBD

Selected Slides from NASPGHAN 2022 Postgraduate Course (Part 2)

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See previous post for lecturers

Oral small molecultes in IBD. Anne Griffiths, MD
Judith Kelsen, Very early onset IBD
VEO Evaluation
VEO Treatments
Jeremy Adler and Treat to Target for IBD
Jeremy Adler and Treat to Target for IBD
Jeremy Adler and Treat to Target for IBD
Jeremy Adler and Treat to Target for IBD
Jeremy Adler and Treat to Target for IBD
Timothy Sentongo and Growth and Nutrition Issues in the NICU
Maureen Leonard and Gluten-Related Disorders Update
Maureen Leonard and Gluten-Related Disorders Update
Maureen Leonard and Gluten-Related Disorders Update
Maureen Leonard and Gluten-Related Disorders Update
Rachel Rosen and Esophageal Motor Disorders
Katja Kovacic and Functional Nausea
This study was 20 yrs ago -we can do better today

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Biologics in Children with Very Early Onset Inflammatory Bowel Disease

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B Kerur et al. JPGN 2022; 75: 64-69. Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America

In this retrospective study, 120 of 294 children with VEO-IBD (diagnosed 2008 and 2013, PRO-KIDS network) received anti-TNF therapy (96% infliximab). 101 of these 120 had adequate data recorded. It is noted that additional data on this cohort has been previously published (IBD Updates: Outcomes of VEO-IBD, PIANO Study Update, and Insurance-Disparity Relationship). Key findings:

  • Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years
  • Patients with Crohn’s disease had better durability than those with UC/IBD-U (Hazard ratio 0.17)
  • The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children
  • 67 (66%) received combined therapy with an immunomodulator and this was associated with improved anti-TNF durability (Hazard ratio 0.30). However, authors note this was in era preceding widespread therapeutic drug monitoring.
  • The majority of children in the current study did not undergo testing for monogenic mutations

My take: Data for use of anti-TNF agents in this age group (< 6 yrs) has been limited. This study suggests similar effectiveness of anti-TNF agents in VEO-IBD compared to older groups. Given this groups increased risk for monogenic mutations, it is still a good idea, if feasible, to test for these disorders.

Related blog posts:

Targeted Therapy for Autoinflammatory Very Early Onset Inflammatory Bowel Disease

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S Rudra et al. Clin Gastroenterol Hepatol 2022; 20: 1408-1410. Ruxolitinib: Targeted Approach for Treatment of Autoinflammatory Very Early Onset Inflammatory Bowel Disease

As we start to understand the genetic basis for some of the cases of very early onset inflammatory bowel disease (VEO-IBD), identifying effective targeted treatment is needed. For example, abatacept has been shown to be helpful for CTLA4 deficiency. The report cited above reports the experience of ruxolitinib for autoinflammatory phenotype (AIP) of VEO-IBD.

AIP was defined by persistent fevers, leukocytosis, elevation of at least 2 cytokines: sIL2R, IL8, IL6, CXCL9 or IFN-gamma.

Ruxolitinib is a selective JAK1/2 inhibitor which is approved for treatment of polycythemia vera, myelofibrosis, and graft-versus-host disease. As an aside, its retail cost (with 10 mg, #60) is ~$15,000 per month.

In this case report, 6 children with severe VEO-IBD were treated with average starting dose of 5.6 mg/m2/dose twice daily. Most were receiving dual therapy –3 patients were treated with IL1 blockade and 2 patinents with anti-TNF therapy.

Key findings:

  • Over 6-months, all patients had clinical response, especially with regard to fever and stool frequency
  • All patients had improvement in lab studies
  • Among the 3 with endoscopic followup, 1 had deep mucosal healing and 2 had endoscopic improvement
  • Three mild infections occurred while on treatment, but no bone marrow suppression was noted

My take: Patients with VEO-IBD represent a huge challenge. Trying to target specific therapies is difficult given that there are more than 70 monogenic defects that have been identified and many of the therapies are quite expensive (and difficult to get).

Related blog posts:

Near Santa Fe, NM

IBD Updates: Outcomes of VEO-IBD, PIANO Study Update, and Insurance-Disparity Relationship

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Outcomes of VEO-IBD. B Kerur et al. Inflamm Bowel Dis 2021; 27: 295-302. Bowel Disease in North America: A Retrospective Cohort Study The study population included 269 children (105 [39%] Crohn’s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). Key findings:

  • By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children.
  • Median age at diagnosis was 4.2 years. 71 (26%) were ❤ yrs.
  • Only 5 (1.7%) had a coexisting immunological disorder.
  • Over 5 years, cumulative use of an immunomodulator and biologic was 61% and 41% respectively. Exclusive enteral nutrition was used in 10 children (4%).
  • 11.5% (n=19) had a change in diagnosis from UC/IBD-U to Crohn’s disease
  • The risk of any bowel surgery in Crohn’s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis.
  • The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis.

Related blog posts:

IBD Therapies and Newborn Outcomes (also covered in a prior blog post: Disease Activity, Not Medications, Linked to Neonatal Outcomes in Women with IBD). U Mahadevan et al. Gastroenterol 2021; 160: 1131-1139. Pregnancy and Neonatal Outcomes After Fetal Exposure to Biologics and Thiopurines Among Women With Inflammatory Bowel Disease

In this PIANO study (2007-2019), pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. PIANO is an acronym for Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes.

Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). 

Disparity Not Apparent Among Insured Population. EL Barnes et al. Inflamm Bowel Dis 2021; 27: 364-370. Black and White Patients With Inflammatory Bowel Disease Show Similar Biologic Use Patterns With Medicaid Insurance

In this study, which analyzed Medicaid Analytic eXtract data from 4 states (California, Georgia, North Carolina, and Texas) between 2006 and 2011, the authors identified 14,735 patients with IBD (4672 black [32%]). Key finding: “In patients with Medicaid insurance, where access to IBD-specific therapy should be similar for all individuals, there was no significant disparity by race in the utilization of IBD-specific therapies.”

When To Perform Genetic Testing In The Setting Of Inflammatory Bowel Disease

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HH Uhilg et al. JPGN 2021; 72: 45-473. Free Full Text: Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition

  • This is a very useful article. Table 3 lists many of the features of some monogenic inflammatory bowel disease (IBD). Table 4 details potential immune workup tests. Table 5 lists 75 genes that should be included when testing for monogenic IBD.
  • Box 2 (see below) provides a list of conditions that should prompt consideration of genetic testing. Figure 1 provides an algorithm for testing.
  • Table 6 provides a summary of statements
    • #3:”Genetic screening for monogenic IBD is recommended in all patients with infantile-onset IBD (<2 years) and should be considered in patients with very early-onset IBD (<6 years), in particular, in those patients with relevant comorbidity, extraintestinal manifestations, and/or family history”
    • #5: “Routine genetic screening for all IBD patients is not recommended since a monogenic cause of IBD in patients with IBD onset over 6 year of age, especially those with adolescent or adult age onset of IBD is exceptional in the absence of relevant comorbidity”
  • There is also some advice on variants of unknown significance: “Databases, such as Clinvar, ClinGen, or The Human Gene Mutation Database can help to assess variant phenotype relations”

Related blog posts:

From The Onion:

From The Onion

In Case You Missed It: IBD Year in Review (Eric Benchimol)

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I did not have the opportunity to hear this #NASPGHAN20 lecture but Dr. Benchimol has shared his slides. Link to Dropbox Slides: IBD Clinical Science: Year in Review

Some of the key points on slides (links to articles below):

Some screenshots:

Links to many of the referenced papers:


Related links:

How Very Early Onset-Inflammatory Bowel Disease is Different, Plus One

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A recent retrospective study (JR Kelsen et al. Inflamm Bowel Dis 2020; 26: 909-18) compares children diagnosed with inflammatory bowel disease at different age points and their outcomes.  During a 9 year study span (2008-16), there were 229 subjects diagnosed as very-early onset (<6 years, VEO), 221 diagnosed as intermediate onset (6-10 years), and 521 diagnosed as older onset (> 10 years)

Key findings:

  • VEO-IBD patients were significantly more likely to have had a diverting ileostomy and colectomy than the older patients.  Diverting ileostomy rates: 12.2%, 4.1%, and 1.2% respectively.  Colectomy rates: 7.4%, 4.1%, and 1.7% respectively.
  • Ileocecal resections were significantly higher in the older-onset IBD population. In the older group, these resections were noted in 64/521 (12.2%) compared to 1/229 (0.4%) in the VEO group and 10/221 (4.5%) in the intermediate group.
  • VEO-IBD patients had higher medication failure rates at 1 year into treatment and were more frequently readmitted to the hospital. For infliximab (IFX), failure rates were 62.4% for VEO subjects compared to 14.6% for older-onset subjects.  For adalimumab, the respective rates were 53.2% vs. 7.2%.
  • Targeted therapy was successfully used almost exclusively in the VEO-IBD population

My take: Children with VEO-IBD have a more severe disease course than older children.  Since monogenetic disorders occur in ~8% of the VEO population, targeted therapies are more likely; however; ~2% of older children also have a monogenetic disorder and as such, targeted therapy could be important in this group as well.

Related review article: J Ouahed et al. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis 2020; 26: 820-842.  This is a useful review.  A couple of key points:

  • “There are no quality studies assessing the use of nutritional approaches in VEO-IBD”
  • Stem Cell Transplantation NOT efficacious in these disorders (per Table 3): TTC7A, STXBP2, IKBKG (NEMO)

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VEO-IBD -Useful “Position” Paper is Really a Review

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A recent publication (Full text: NASPGHAN Position Paper on the Evaluation and Management for Patients with Very Early-onset Inflammatory Bowel Disease. JR Kelsen et al. JPGN 2020; 70: 389-403) is more of a review than a true position paper. A related upcoming study (highlighted tomorrow) indicates that ~8% of VEO-IBD patients have underlying monogenetic forms of IBD.

While the article makes numerous useful points, explicit recommendations are not clearly stated.

Key Points:

  • Epidemiology: 6-15% of pediatric IBD population presents at <6 years of age
  • Children with VEO-IBD need careful immunologic evaluation.  Some of the specific disorders that need to be considered include Chronic Granulomatous Disease (can check DHR) and XIAP (can check a flow cytometry-based assay).
  • Besides panendoscopy, the article recommends close collaboration with the pathologist to identify specific features of the numerous VEO-IBD disorders (most listed/described in Table 1)
  • Identification of VEO-IBD disorders with genetic testing (either whole exome or targeted gene panel) helps determine specific medical therapies and/or stem cell transplantation for disorders like CTLA4B deficiency, LRBA defects, IL-10 deficiency, XIAP, STXBP2, and FOXP3 deficiency.
  • Infliximab does not work as well in VEO-IBD patients.  A recent study found only 12% remained on infliximab 3 years after initiation.
  • VEO-IBD were much more likely to need surgery with rates of 50% for those with onset before 1 year and ~30% for those after 1 year of age.  Colectomy should be considered with caution due to the overlapping presentation of Crohn’s disease and ulcerative colitis in this age group.

One topic that was not discussed was the potential role for dietary therapy in this age group.

Related blog posts:

The following related images are from Eric Topol’s twitter feed and share figures from a Nature review.

Seen on Eric Benchimol’s twitter feed

IBD Shorts: September 2019

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S Olivia et al (including Stanley Cohen from GI Care for Kids) Clin Gastroenterol Hepatol 2019; 17: 2060-7. “A Treat to Target Strategy Using Panenteric Capsule Endoscopy in Pediatric Patients with Crohn’s Disease”  In this prospective study with 48 children with Crohn’s disease, pan-enteric capsule endoscopy (PCE) detected inflammation in 34 (71%) at baseline, 22 (46%) at week 24, and 18 (39%) at week 52.  PCE results were used to manage treatment and resulted in change in therapy in 71% at baseline and 23% at week 24.  Furthermore, PCE increased the proportions of patients in deep remission, up to 58% at week 52.

M Wright, et al. J Pediatr 2019; 210: 220-5. This case report of a 4 year-old boy with a perianal abscess and granulomatous colitis identified a NCF4 mutation causing severe neutrophil dysfunction.  He developed osteomyelitis with anti-TNF therapy and did not respond to vedolizumab. He had an excellent outcome following a hematopoietic stem cell transplantation. This study reinforces the potential benefit of investigating VEO-IBD which could allow more targeted therapy. Related blog post:

P Zapater et al. Inflamm Bowel Dis 2019; 25: 1357-66. This study with 112 patients with Crohn’s disease showed that serum interleukin-10 levels were directly related to infliximab and adalimumab levels.  This suggests that serum anti-TNF levels are significantly influenced by immunological activation.

JE Axelrad et al. Clin Gastroenterol Hepatol 2019; 17: 1311-22.  This study, using the Swedish National Patient Register, showed that gastrointestinal infection increased the odds of developing IBD in a nationwide case-control study.  “Of the patients with IBD, 3105 (7%) had a record of previous gastroenteritis compared with 17,685 control subjects (4.1%). IBD cases had higher odds for an antecedent episode of gastrointestinal infection (aOR 1.64), bacterial gastrointestinal infection (aOR 2.02) and viral gastrointestinal infection (aOR 1.55)…a previous episode of gastroenteriitis remained associated with odds for IBD more than 10 years later (aOR 1.26).”  The authors note that they cannot formally exclude misclassification bias, but it appears that enteric infections contribute to the development of IBD in susceptible individuals.

Exome Sequencing in VEO-IBD: More Data

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With more widespread use of whole-exome sequencing (WES), the ability to study the genetic basis for rare disorders like very early onset inflammatory bowel disease (VEO-IBD) has improved considerably. A recent study (JR Kelsen et al. Gastroenterol 2015; 149: 1415-24) analyzed 125 patients (3 weeks to 4 years of age) and compared with pediatric IBD patients (n=45), adult-onset Crohn’s (n=20), and healthy controls (n=145). Link to abstract and online material. (Link includes full-text as well).

The authors focused their study on 400 genes/regions associated with primary immunodeficiency.

Key finding:

  • “Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19.”

In their discussion, the authors elaborate on these findings. In addition, in Table 3, the authors elaborate on potential immunologic studies for these children.

Take home message: The authors recommend “a more complete immunologic evaluation be performed in patients with VEO-IBD.”  Ultimately, understanding the complex genetics will lead to more individualized and successful treatments.

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Lights at Life University

Lights at Life University