Tag Archives: FLIP

How HLA DQA1*05 and Combination Therapy Modulate Treatment Outcomes in Children with Crohn’s Disease

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J Adler et al. Am J Gastroenterol 2025; 120: 1076-1086. HLA DQA1*05 and Risk of Antitumor Necrosis Factor Treatment Failure and Anti-Drug Antibody Development in Children’s with Crohn’s Disease.

This was a prospective, double-blind, placebo-controlled trial with 204 patients examining the clinical outcomes of anti-TNF with or without methotrexate (COMBINE).

Key findings:

  • Treatment failure in HLA DQA1*O5: A trend toward increased treatment failure among HLA DQA1*05-positive participants was not statistically-significant (hazard ratio 1.58; P = 0.08).
  • HLA DQA1*05 and Treatment Failure Rate: During the followup period, HLA DQA1*05-positive patients had a 35% failure rate compared to 26% for those who were HLA DQA1*05-negative (P=0.098). The overall failure rate was 30%
  • Methotrexate Combined with HLA DQA1*05 Effect: Patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13-0.70; P = 0.005).
  • Anti-TNF Medication Comparison: Treatment failure was similar between infliximab and adalimumab, 29% and 33% respectively
  • Antidrug antibodies (ADA): A trend toward increased ADA development among HLA DQA1*05-positive participants was not significant (odds ratio 1.96, P = 0.09). The addition of methotrexate to the treatment regimen mitigated the risk of treatment failure among individuals positive for HLA DQA1*05 and reduced the odds of developing ADA by 90%.
  • Rate of ADA: “After further stratification, HLA DQA1*05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05-positive patients on placebo (odds ratio 0.12; P = 0.008).”

Discussion Points:

  • “A retrospective by Fuentes-Valenzuela et al …found that if patients underwent proactive TDM, there was no increase in the rate of treatment discontinuation among those who were HLA DQ-A105 positive compared with HLA DQ-A105 negative”
  • “The totality of evidence suggests that HLA DQ-A1*05 seems to confer a risk of both immunogenicity and treatment failure, particularly among infliximab-treated patients. Furthermore, this risk may be mitigated by the use of proactive TDM and/or concomitant immunomodulators.”

My take (borrowed in part from authors):  “40% of patients were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate.” The use of combination therapy (methotrexate with anti-TNF) was associated with the lowest failure rates.

Also, unrelated article: DA Carlson et al. Gastroenterology 2025; 168: 1114-1127. A Standardized Approach to Performing and Interpreting Functional Lumen Imaging Probe Panometry for Esophageal Motility Disorders: The Dallas Consensus. Congratulations to Dr. Garza from our group who was one of the authors

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Jose Garza: What’s New in Motility (Part 1)

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Dr. Jose Garza joined our group in 2013 and has been providing excellent care for children throughout the South with suspected motility disorders. Recently, he gave our group a fabulous update on what’s new in motility.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included some of his slides. His talk had 123 slides; true motilists would be appalled that I haven’t included more of the high resolution tracing slides (though there are a few tomorrow).

Reflux:

Colic:

BRUE:

Laryngomalacia/Thickening:

Impedance

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How Reliable is a Motilist in Interpreting Manometry and FLIP Studies?

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Correction: Yesterday’s post was updated after an astute observation from one of my colleagues (Jordan) to note that the pictured instrument was in fact a harpsichord rather than a piano. A harpsichord’s sound is derived from plucking a string whereas a piano’s sound comes after a hammer strikes a chord.

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JW Chen et al. AJG 2023; 118: 1334-1343. Interrater Reliability of Functional Lumen Imaging Probe Panometry and High-Resolution Manometry for the Assessment of Esophageal Motility Disorders

Thanks to Ben Gold for this reference. Also, congratulations to Jose Garza -our motility specialist and a coauthor of this study.

15 motility specialists completed their interpretation of 40 consecutive HRM (high resolution manometry) and 40 FLIP (functional lumen imaging probe panometry) studies. All were part of a FLIP study group. Key findings:

  • Overall, there were high levels of interrater agreement and accuracy in the interpretation of HRM and FLIP metrics and moderate-to-high levels for motility classification in FLIP
  • There were no FLIP diagnoses of normal EGJ opening in patients with established achalasia and no FLIP diagnoses of achalasia in patients with normal EGJ opening and contractility. This was true with HRM as well.
  • In non-obstructive motor disorders, raters frequently indicated that they would request alternate confirmatory testing before invasive management

My take: This is a reassuring study indicating that with the most consequential esophageal findings, there is excellent agreement among motilist interpretation. Previous studies of colonic manometry, in contrast, have found much lower levels of agreement.

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FLIP Patterns for Adults with Eosinophilic Esophagitis

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DA Carlson et al. Gastroenterol 2023; 165: 552-563. Open Access! A PhysioMechanical Model of Esophageal Function in Eosinophilic Esophagitis

215 adults with EoE who completed FLIP during endoscopy were included in a cross-sectional study. FLIP helped separate the physiomechanical properties of esophageal function in this cohort. The criteria used to define the PhysioMechanical classification in EoE with a representative FLIP panometry image for each classification. Normal compliance was defined as a DP >17 mm and body compliance >450 mm3/mm Hg; reduced compliance (fibrostenosis) was defined by DP ≤17 mm or compliance ≤450 mm3/mm Hg. Normal EGJ opening was defined as a maximum EGJ diameter ≥16 mm; reduced as maximum EGJ diameter <16 mm. ∗Spastic-reactive contractile response (SRCR) with normal body distensibility and normal EGJ opening was assigned as “achalasia pattern” (n = 1 in this cohort).

Key findings:

  • FLIP was normal in 50 (23%), weak pattern in 7 (3%), IsoEGJOO stricture pattern in 27 (13%), IsoEGJOO achalasia pattern in 26 (12%), Fibrostenosis with normal reactivity in 61 (28%), spastic reactive fibrostenosis with normal reactivity in 30 (14%), and noreactive fibrostenosis in 14 (7%)

My take: FLIP testing helps define the mechanism of esophageal dysfunction in patients with EoE. Longer duration of symptoms was associated with more severe esophageal dysfunction.

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Newsflash Articles: Untreated Eosinophilic Esophagitis Worsens and the Severely-Damaged Esophagus Does Not Work Well

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NC Chang et al. Clin Gastroentol Hepatol 2022; 20: 1701-1708. Open Access! A Gap in Care Leads to Progression of Fibrosis in Eosinophilic Esophagitis Patients

In this retrospective review with 701 patients, 95 (14%) had a gap in care (mean time without care, 4.8 ± 2.3 years). Key findings:

  • Patients post-gap had higher endoscopic severity (2.4 vs 1.5; P < .001) and smaller esophageal diameters (11.0 vs 12.7 mm; P = .04).
  • Strictures were more prevalent with longer gap time (P < .05 for trend). Each additional year of gap time increased odds of stricture by 26%, even after accounting for pre-gap dilation. Additionally, of 67 patients without pre-gap fibrosis, 25 (37%) had at least one fibrotic feature (stricture, narrowing, or requiring dilation) post-gap.

DA Carlson et al. Clin Gastroenterol Hepatol 2022; 20: 1719-1728. Esophageal Dysmotility Is Associated With Disease Severity in Eosinophilic Esophagitis

Consecutive adult patients with EoE (n=199) completed a 16-cm functional luminal imaging probe (FLIP) during endoscopy were evaluated in a cross-sectional study. Key findings:

  • Mucosal eosinophil density was similar between abnormal contractile responses (CRs) and normal CRs (median 34 vs 25)
  • Abnormal CRs more frequently had reduced esophageal distensibility (distensibility plateau <17 mm in 56% vs 32%), with more severe ring scores, and a greater duration of symptoms (median, 10 y vs 7 y)

Thus, abnormal esophageal CRs were related to EoE disease severity, especially features of fibrostenosis. This study suggests that esophageal wall remodeling, rather than eosinophilic inflammatory intensity, was associated with esophageal dysmotility in EoE.

My take: Despite my satirical title, I think these articles are helpful by documenting that ongoing EoE results in worsening esophageal dysfunction/dysmotility (especially if not treated). In addition, they provide insight into the natural history/pathophysiology of EoE.

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